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Cho CJ, Nguyen T, Rougeau AK, Huang YZ, To S, Lin X, Thalalla Gamage S, Meier JL, Mills JC. Inhibition of Ribosome Biogenesis In Vivo Causes p53-Dependent Death and p53-Independent Dysfunction. Cell Mol Gastroenterol Hepatol 2025; 19:101496. [PMID: 40081569 DOI: 10.1016/j.jcmgh.2025.101496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 02/25/2025] [Accepted: 02/28/2025] [Indexed: 03/16/2025]
Abstract
BACKGROUND & AIMS Although it is well-known that ribosomes are critical for cell function, and their synthesis (known as ribosome biogenesis [RiBi]) is energy-intensive, surprisingly little is known about RiBi in vivo in adult tissue. METHODS Using a mouse model with conditional deletion of Nat10, an essential gene for RiBi and subsequent translation of mRNA, we investigated the effects of RiBi blockade in vivo, with a focus on pancreatic acinar cells during homeostasis and tumorigenesis. RESULTS We observed an unexpected latency of several weeks between Nat10 deletion and onset of structural and functional abnormalities and p53-dependent acinar cell death. Although deletion of Trp53 rescued acinar cells from apoptotic cell death, Nat10Δ/Δ; Trp53Δ/Δ acinar cells remained morphologically and functionally abnormal. Deletion of Nat10 in acinar cells blocked Kras-oncogene-driven pancreatic ductal adenocarcinoma, regardless of Trp53 mutation status. CONCLUSIONS Together, our results provide initial insights into how differentiated cells respond to defects in RiBi and translation in vivo in various physiological contexts.
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Affiliation(s)
- Charles J Cho
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas.
| | - Thanh Nguyen
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Amala K Rougeau
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Yang-Zhe Huang
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Sarah To
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Xiaobo Lin
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Supuni Thalalla Gamage
- Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, Maryland
| | - Jordan L Meier
- Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, Maryland
| | - Jason C Mills
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
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Brown JW, Lin X, Nicolazzi GA, Liu X, Nguyen T, Radyk MD, Burclaff J, Mills JC. Cathartocytosis: Jettisoning of Unwanted Material during Cellular Reprogramming. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.06.11.598489. [PMID: 38915707 PMCID: PMC11195262 DOI: 10.1101/2024.06.11.598489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Injury can cause differentiated cells to undergo massive reprogramming to become proliferative to repair tissue via a cellular program called paligenosis. Gastric digestive-enzyme-secreting chief cells use paligenosis to reprogram into progenitor-like Spasmolytic-Polypeptide Expressing Metaplasia (SPEM) cells. Stage 1 of paligenosis is the downscaling of mature cell architecture via a process involving lysosomes. Here, we noticed that sulfated glycoproteins were not only digested during paligenosis but also excreted into the gland lumen. Various genetic and pharmacological approaches showed that endoplasmic reticulum membranes and secretory granule cargo were also excreted and that the process proceeded in parallel with, but was mechanistically independent of autophagy. 3-dimensional light and electron-microscopy demonstrated that excretion occurred via unique, complex, multi-chambered invaginations of the apical plasma membrane. As this lysosome-independent cell cleansing process does not seem to have been priorly described, we termed it "cathartocytosis". Cathartocytosis allows a cell to rapidly eject excess material without waiting for autophagic and lysosomal digestion. We speculate the ejection of sulfated glycoproteins would aid in downscaling and might also help bind and flush pathogens away from tissue.
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Cho CJ, Nguyen T, Rougeau AK, Huang YZ, To S, Lin X, Gamage ST, Meier JL, Mills JC. Inhibition of Ribosome Biogenesis in vivo Causes p53-Dependent Death and p53-Independent Dysfunction. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.25.614959. [PMID: 39386693 PMCID: PMC11463434 DOI: 10.1101/2024.09.25.614959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
Ribosomes are critical for cell function; their synthesis (known as ribosome biogenesis; "RiBi") is complex and energy-intensive. Surprisingly little is known about RiBi in differentiated cells in vivo in adult tissue. Here, we generated mice with conditional deletion of Nat10 , an essential gene for RiBi and translation, to investigate effects of RiBi blockade in vivo. We focused on RiBi in a long-lived, ribosome-rich cell population, pancreatic acinar cells, during homeostasis and tumorigenesis. We observed a surprising latency of several weeks between Nat10 deletion and onset of structural and functional abnormalities and p53-dependent acinar cell death, which was associated with translocation of ribosomal proteins RPL5 and RPL11 into acinar cell nucleoplasm. Indeed, deletion of Trp53 could rescue acinar cells from apoptotic cell death; however, Nat10 Δ / Δ ; Trp53 Δ / Δ acinar cells remained morphologically and functionally abnormal. Moreover, the deletion of Trp53 did not rescue the lethality of inducible, globally deleted Nat10 in adult mice nor did it rescue embryonic lethality of global Nat10 deletion, emphasizing p53-independent consequences of RiBi inhibition. Deletion of Nat10 in acinar cells blocked Kras -oncogene-driven pancreatic intraepithelial neoplasia and subsequent pancreatic ductal adenocarcinoma, regardless of Trp53 mutation status. Together, our results provide initial insights into how cells respond to defects in RiBi and translation in vivo .
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Vanhecke D, Bugada V, Steiner R, Polić B, Buch T. Refined tamoxifen administration in mice by encouraging voluntary consumption of palatable formulations. Lab Anim (NY) 2024; 53:205-214. [PMID: 39080504 PMCID: PMC11291282 DOI: 10.1038/s41684-024-01409-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 06/24/2024] [Indexed: 08/02/2024]
Abstract
Drug administration in preclinical rodent models is essential for research and the development of novel therapies. Compassionate administration methods have been developed, but these are mostly incompatible with water-insoluble drugs such as tamoxifen or do not allow for precise timing or dosing of the drugs. For more than two decades, tamoxifen has been administered by oral gavage or injection to CreERT2-loxP gene-modified mouse models to spatiotemporally control gene expression, with the numbers of such inducible models steadily increasing in recent years. Animal-friendly procedures for accurately administering tamoxifen or other water-insoluble drugs would, therefore, have an important impact on animal welfare. On the basis of a previously published micropipette feeding protocol, we developed palatable formulations to encourage voluntary consumption of tamoxifen. We evaluated the acceptance of the new formulations by mice during training and treatment and assessed the efficacy of tamoxifen-mediated induction of CreERT2-loxP-dependent reporter genes. Both sweetened milk and syrup-based formulations encouraged mice to consume tamoxifen voluntarily, but only sweetened milk formulations were statistically noninferior to oral gavage or intraperitoneal injections in inducing CreERT2-mediated gene expression. Serum concentrations of tamoxifen metabolites, quantified using an in-house-developed cell assay, confirmed the lower efficacy of syrup- as compared to sweetened milk-based formulations. We found dosing with a micropipette to be more accurate than oral gavage or injection, with the added advantage that the method requires little training for the experimenter. The new palatable solutions encourage voluntary consumption of tamoxifen without loss of efficacy compared to oral gavage or injections and thus represent a refined administration method.
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Affiliation(s)
- Dominique Vanhecke
- Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland
| | - Viola Bugada
- Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland
| | - Regula Steiner
- Institute of Clinical Chemistry, University and University Hospital of Zurich, Zurich, Switzerland
| | - Bojan Polić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Thorsten Buch
- Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland.
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5
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Adkins-Threats M, Arimura S, Huang YZ, Divenko M, To S, Mao H, Zeng Y, Hwang JY, Burclaff JR, Jain S, Mills JC. Metabolic regulator ERRγ governs gastric stem cell differentiation into acid-secreting parietal cells. Cell Stem Cell 2024; 31:886-903.e8. [PMID: 38733994 PMCID: PMC11162331 DOI: 10.1016/j.stem.2024.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 02/26/2024] [Accepted: 04/19/2024] [Indexed: 05/13/2024]
Abstract
Parietal cells (PCs) produce gastric acid to kill pathogens and aid digestion. Dysregulated PC census is common in disease, yet how PCs differentiate is unclear. Here, we identify the PC progenitors arising from isthmal stem cells, using mouse models and human gastric cells, and show that they preferentially express cell-metabolism regulator and orphan nuclear receptor Estrogen-related receptor gamma (Esrrg, encoding ERRγ). Esrrg expression facilitated the tracking of stepwise molecular, cellular, and ultrastructural stages of PC differentiation. EsrrgP2ACreERT2 lineage tracing revealed that Esrrg expression commits progenitors to differentiate into mature PCs. scRNA-seq indicated the earliest Esrrg+ PC progenitors preferentially express SMAD4 and SP1 transcriptional targets and the GTPases regulating acid-secretion signal transduction. As progenitors matured, ERRγ-dependent metabolic transcripts predominated. Organoid and mouse studies validated the requirement of ERRγ for PC differentiation. Our work chronicles stem cell differentiation along a single lineage in vivo and suggests ERRγ as a therapeutic target for PC-related disorders.
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Affiliation(s)
- Mahliyah Adkins-Threats
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Division of Biomedical and Biological Sciences, Washington University, St. Louis, MO 63130, USA; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Sumimasa Arimura
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yang-Zhe Huang
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Margarita Divenko
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sarah To
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Heather Mao
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yongji Zeng
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jenie Y Hwang
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Laboratory Medicine, University of Texas Health San Antonio, San Antonio, TX 78249, USA
| | - Joseph R Burclaff
- Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Chapel Hill, NC 27599, USA
| | - Shilpa Jain
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jason C Mills
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
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Miao ZF, Sun JX, Huang XZ, Bai S, Pang MJ, Li JY, Chen HY, Tong QY, Ye SY, Wang XY, Hu XH, Li JY, Zou JW, Xu W, Yang JH, Lu X, Mills JC, Wang ZN. Metaplastic regeneration in the mouse stomach requires a reactive oxygen species pathway. Dev Cell 2024; 59:1175-1191.e7. [PMID: 38521055 DOI: 10.1016/j.devcel.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 10/07/2023] [Accepted: 03/04/2024] [Indexed: 03/25/2024]
Abstract
In pyloric metaplasia, mature gastric chief cells reprogram via an evolutionarily conserved process termed paligenosis to re-enter the cell cycle and become spasmolytic polypeptide-expressing metaplasia (SPEM) cells. Here, we use single-cell RNA sequencing (scRNA-seq) following injury to the murine stomach to analyze mechanisms governing paligenosis at high resolution. Injury causes induced reactive oxygen species (ROS) with coordinated changes in mitochondrial activity and cellular metabolism, requiring the transcriptional mitochondrial regulator Ppargc1a (Pgc1α) and ROS regulator Nf2el2 (Nrf2). Loss of the ROS and mitochondrial control in Ppargc1a-/- mice causes the death of paligenotic cells through ferroptosis. Blocking the cystine transporter SLC7A11(xCT), which is critical in lipid radical detoxification through glutathione peroxidase 4 (GPX4), also increases ferroptosis. Finally, we show that PGC1α-mediated ROS and mitochondrial changes also underlie the paligenosis of pancreatic acinar cells. Altogether, the results detail how metabolic and mitochondrial changes are necessary for injury response, regeneration, and metaplasia in the stomach.
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Affiliation(s)
- Zhi-Feng Miao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China.
| | - Jing-Xu Sun
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Xuan-Zhang Huang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Shi Bai
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Min-Jiao Pang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Jia-Yi Li
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Han-Yu Chen
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Qi-Yue Tong
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Shi-Yu Ye
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Xin-Yu Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Xiao-Hai Hu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Jing-Ying Li
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Jin-Wei Zou
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Wen Xu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Jun-Hao Yang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Xi Lu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Jason C Mills
- Section of Gastroenterology & Hepatology, Department of Medicine, Departments of Pathology & Immunology, Molecular and Cellular Biology, Baylor College of Medicine, 535E Anderson-Jones Building, One Baylor Plaza, Houston, TX, USA.
| | - Zhen-Ning Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China.
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Liu L, Fan XH, Tang XD. Revolutionizing Gastric Cancer Prevention: Novel Insights on Gastric Mucosal Inflammation-Cancer Transformation and Chinese Medicine. Chin J Integr Med 2024:10.1007/s11655-024-3806-5. [PMID: 38676828 DOI: 10.1007/s11655-024-3806-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2024] [Indexed: 04/29/2024]
Abstract
The progression from gastric mucosal inflammation to cancer signifies a pivotal event in the trajectory of gastric cancer (GC) development. Chinese medicine (CM) exhibits unique advantages and holds significant promise in inhibiting carcinogenesis of the gastric mucosa. This review intricately examines the critical pathological events during the transition from gastric mucosal inflammation-cancer transformation (GMICT), with a particular focus on pathological evolution mechanisms of spasmolytic polypeptide-expressing metaplasia (SPEM). Moreover, it investigates the pioneering applications and advancements of CM in intervening within the medical research domain of precancerous transformations leading to GC. Furthermore, the analysis extends to major shortcomings and challenges confronted by current research in gastric precancerous lesions, and innovative studies related to CM are presented. We offer a highly succinct yet optimistic outlook on future developmental trends. This paper endeavors to foster a profound understanding of forefront dynamics in GMICT research and scientific implications of modernizing CM. It also introduces a novel perspective for establishing a collaborative secondary prevention system for GC that integrates both Western and Chinese medicines.
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Affiliation(s)
- Lin Liu
- Institute of Digestive Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Xiao-Hui Fan
- School of Pharmacy, Zhejiang University, Hangzhou, 310058, China
- Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, Zhejiang Province, 314100, China
| | - Xu-Dong Tang
- Institute of Digestive Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China.
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Klochkova A, Karami AL, Fuller AD, Parham LR, Panchani SR, Natarajan S, Jackson JL, Mu A, Tan Y, Cai KQ, Klein-Szanto AJ, Muir AB, Tétreault MP, Graña X, Hamilton KE, Whelan KA. Autophagy Contributes to Homeostasis in Esophageal Epithelium Where High Autophagic Vesicle Level Marks Basal Cells With Limited Proliferation and Enhanced Self-Renewal Potential. Cell Mol Gastroenterol Hepatol 2024; 18:15-40. [PMID: 38452871 PMCID: PMC11126828 DOI: 10.1016/j.jcmgh.2024.02.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 02/27/2024] [Accepted: 02/28/2024] [Indexed: 03/09/2024]
Abstract
BACKGROUND & AIMS Autophagy plays roles in esophageal pathologies both benign and malignant. Here, we aim to define the role of autophagy in esophageal epithelial homeostasis. METHODS We generated tamoxifen-inducible, squamous epithelial-specific Atg7 (autophagy related 7) conditional knockout mice to evaluate effects on esophageal homeostasis and response to the carcinogen 4-nitroquinoline 1-oxide (4NQO) using histologic and biochemical analyses. We fluorescence-activated cell sorted esophageal basal cells based on fluorescence of the autophagic vesicle (AV)-identifying dye Cyto-ID and then subjected these cells to transmission electron microscopy, image flow cytometry, three-dimensional organoid assays, RNA sequencing, and cell cycle analysis. Three-dimensional organoids were subjected to passaging, single-cell RNA sequencing, cell cycle analysis, and immunostaining. RESULTS Genetic autophagy inhibition in squamous epithelium resulted in increased proliferation of esophageal basal cells under homeostatic conditions and also was associated with significant weight loss in mice treated with 4NQO that further displayed perturbed epithelial tissue architecture. Esophageal basal cells with high AV level (Cyto-IDHigh) displayed limited organoid formation capability on initial plating but passaged more efficiently than their counterparts with low AV level (Cyto-IDLow). RNA sequencing suggested increased autophagy in Cyto-IDHigh esophageal basal cells along with decreased cell cycle progression, the latter of which was confirmed by cell cycle analysis. Single-cell RNA sequencing of three-dimensional organoids generated by Cyto-IDLow and Cyto-IDHigh cells identified expansion of 3 cell populations and enrichment of G2/M-associated genes in the Cyto-IDHigh group. Ki67 expression was also increased in organoids generated by Cyto-IDHigh cells, including in basal cells localized beyond the outermost cell layer. CONCLUSIONS Autophagy contributes to maintenance of the esophageal proliferation-differentiation gradient. Esophageal basal cells with high AV level exhibit limited proliferation and generate three-dimensional organoids with enhanced self-renewal capacity.
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Affiliation(s)
- Alena Klochkova
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Adam L Karami
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Annie D Fuller
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Louis R Parham
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Surali R Panchani
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Shruthi Natarajan
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Jazmyne L Jackson
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Anbin Mu
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Yinfei Tan
- Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Kathy Q Cai
- Histopathology Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | | | - Amanda B Muir
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Marie-Pier Tétreault
- Department of Medicine, Gastroenterology and Hepatology Division, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Xavier Graña
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania; Department of Cancer & Cellular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Kathryn E Hamilton
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Kelly A Whelan
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania; Department of Cancer & Cellular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania.
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9
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Wu Y, Adeniyi-Ipadeola G, Adkins-Threats M, Seasock M, Suarez-Reyes C, Fujiwara R, Bottazzi ME, Song L, Mills JC, Weatherhead JE. Host gastric corpus microenvironment facilitates Ascaris suum larval hatching and infection in a murine model. PLoS Negl Trop Dis 2024; 18:e0011930. [PMID: 38324590 PMCID: PMC10878500 DOI: 10.1371/journal.pntd.0011930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 02/20/2024] [Accepted: 01/21/2024] [Indexed: 02/09/2024] Open
Abstract
Ascariasis (roundworm) is the most common parasitic helminth infection globally and can lead to significant morbidity in children including chronic lung disease. Children become infected with Ascaris spp. via oral ingestion of eggs. It has long been assumed that Ascaris egg hatching and larval translocation across the gastrointestinal mucosa to initiate infection occurs in the small intestine. Here, we show that A. suum larvae hatched in the host stomach in a murine model. Larvae utilize acidic mammalian chitinase (AMCase; acid chitinase; Chia) from chief cells and acid pumped by parietal cells to emerge from eggs on the surface of gastric epithelium. Furthermore, antagonizing AMCase and gastric acid in the stomach decreases parasitic burden in the liver and lungs and attenuates lung disease. Given Ascaris eggs are chitin-coated, the gastric corpus would logically be the most likely organ for egg hatching, though this is the first study directly evincing the essential role of the host gastric corpus microenvironment. These findings point towards potential novel mechanisms for therapeutic targets to prevent ascariasis and identify a new biomedical significance of AMCase in mammals.
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Affiliation(s)
- Yifan Wu
- Department of Pediatrics, Division of Pediatric Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Grace Adeniyi-Ipadeola
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Mahliyah Adkins-Threats
- Department of Medicine, Section of Gastroenterology, Baylor College of Medicine, Houston, Texas, United States of America
- Departments of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Matthew Seasock
- Department of Medicine, Immunology, Pathology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Charlie Suarez-Reyes
- Department of Pediatrics, Division of Pediatric Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Ricardo Fujiwara
- Departamento de Parasitologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Maria Elena Bottazzi
- Department of Pediatrics, Division of Pediatric Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America
- National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Lizhen Song
- Department of Medicine, Immunology, Pathology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Jason C. Mills
- Department of Medicine, Section of Gastroenterology, Baylor College of Medicine, Houston, Texas, United States of America
- Departments of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Jill E. Weatherhead
- Department of Pediatrics, Division of Pediatric Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, Texas, United States of America
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10
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Leibold J, Tsanov KM, Amor C, Ho YJ, Sánchez-Rivera FJ, Feucht J, Baslan T, Chen HA, Tian S, Simon J, Wuest A, Wilkinson JE, Lowe SW. Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease. NATURE CANCER 2024; 5:315-329. [PMID: 38177458 PMCID: PMC10899107 DOI: 10.1038/s43018-023-00686-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 11/10/2023] [Indexed: 01/06/2024]
Abstract
Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models. Here we developed methods to somatically introduce different oncogenic lesions directly into the murine gastric epithelium. Genotypic configurations observed in patients produced metastatic gastric cancers that recapitulated the histological, molecular and clinical features of all nonviral molecular subtypes of the human disease. Applying this platform to both wild-type and immunodeficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells, which produced distinct patterns of metastasis that were mirrored in patients. Our results establish a highly portable platform for generating autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts.
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Affiliation(s)
- Josef Leibold
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Department of Medical Oncology and Pneumology, University Hospital Tuebingen, Tuebingen, Germany.
- iFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tuebingen, Tuebingen, Germany.
| | - Kaloyan M Tsanov
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Corina Amor
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA
| | - Yu-Jui Ho
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Francisco J Sánchez-Rivera
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Judith Feucht
- iFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tuebingen, Tuebingen, Germany
- Department I-General Paediatrics, Haematology/Oncology, University Children's Hospital Tuebingen, Tuebingen, Germany
| | - Timour Baslan
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Biomedical Sciences, School of Veterinary Medicine, The University of Pennsylvania, Philadelphia, PA, USA
| | - Hsuan-An Chen
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sha Tian
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Janelle Simon
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alexandra Wuest
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - John E Wilkinson
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Scott W Lowe
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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11
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Hong X, Li H, Lin Y, Luo L, Xu W, Kang J, Li J, Huang B, Xu Y, Pan H, Guo S. Efficacy and potential therapeutic mechanism of Weiwei decoction on Spasmolytic polypeptide-expressing metaplasia in Helicobacter pylori-infected and Atp4a-knockout mice. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117062. [PMID: 37598768 DOI: 10.1016/j.jep.2023.117062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 08/16/2023] [Accepted: 08/17/2023] [Indexed: 08/22/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Spasmolytic polypeptide-expressing metaplasia (SPEM) is characterized by mucus cell morphologies at the base of gastric glands, which is considered advanced SPEM when accompanied with an increase in transcripts associated with intestinal-type gastric cancer. Weiwei decoction (WWD) was modified from "Si-Jun-Zi Tang," which has been used for thousands of years in China against gastric atrophy and metaplasia. AIM OF THE STUDY To investigate the effects and potential mechanisms of WWD against advanced SPEM. MATERIALS AND METHODS Liquid chromatography-mass spectrometry was employed to analyze the constituents of WWD. Five-month-infected Helicobacter pylori (H. pylori) Sydney strain 1 C57BL/6J mice and 6-week-old ATPase H+/K+ transporting subunit alpha-knockout mice (Atp4a-/-) were given folic acid (1.95 mg/kg) or WWD (13.65 g/kg, 27.30 g/kg, 54.60 g/kg) by gavage for one month. RESULTS WWD demonstrated beneficial effects on gastric mucosal pathology and mucus secretion. In H. pylori-infected mice, WWD effectively reduced the expression of GSII and inhibited the mRNA levels of key markers associated with advanced SPEM, including Clu, Cftr, Wfdc2, Dmbt1, and Gpx2. Similarly, in Atp4a-/- mice, WWD significantly decreased the expressions of GSII and Clusterin, and inhibited the mRNA levels of Wfdc2, Cftr, Dmbt1, and Gpx2. Notably, WWD restored the expression of markers for chief cells (PGC, GIF) and parietal cells (ATP4A), particularly in the medium- and high-dose groups, indicating its potential anti-atrophy effect on H. pylori-infected and Atp4a-/- mice. WWD administration resulted in a decline in TFF2 expression to baseline levels, suggesting that the mucous protection mediated by TFF2 was unaffected. Furthermore, the infiltration of CD163+F4/80+ M2 macrophages in the gastric mucosa of H. pylori-infected mice was reduced after WWD treatment, indicating a potential modulatory role of WWD on M2 macrophages. CONCLUSION WWD exerted protective effects against SPEM in H. pylori-infected and Atp4a-/- mice. The optimal doses of WWD were found to be medium doses in H. pylori-infected mice and high doses in Atp4a-/- mice. These effects include inhibition of transcripts associated with intestinal-type gastric adenocarcinoma, restoration of ATP4A and PGC expression, and reduction of M2 macrophage infiltration. These findings provide valuable insights into the therapeutic effects of WWD on advanced SPEM and highlight its potential as a treatment option.
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Affiliation(s)
- Xinxin Hong
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
| | - Haiwen Li
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
| | - Yandan Lin
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Liuru Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Weijun Xu
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
| | - Jianyuan Kang
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
| | - Jingwei Li
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
| | - Bin Huang
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
| | - Yifei Xu
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
| | - Huafeng Pan
- Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
| | - Shaoju Guo
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China.
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12
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O'Keefe RN, Carli ALE, Baloyan D, Chisanga D, Shi W, Afshar-Sterle S, Eissmann MF, Poh AR, Pal B, Seillet C, Locksley RM, Ernst M, Buchert M. A tuft cell - ILC2 signaling circuit provides therapeutic targets to inhibit gastric metaplasia and tumor development. Nat Commun 2023; 14:6872. [PMID: 37898600 PMCID: PMC10613282 DOI: 10.1038/s41467-023-42215-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 10/04/2023] [Indexed: 10/30/2023] Open
Abstract
Although gastric cancer is a leading cause of cancer-related deaths, systemic treatment strategies remain scarce. Here, we report the pro-tumorigenic properties of the crosstalk between intestinal tuft cells and type 2 innate lymphoid cells (ILC2) that is evolutionarily optimized for epithelial remodeling in response to helminth infection. We demonstrate that tuft cell-derived interleukin 25 (IL25) drives ILC2 activation, inducing the release of IL13 and promoting epithelial tuft cell hyperplasia. While the resulting tuft cell - ILC2 feed-forward circuit promotes gastric metaplasia and tumor formation, genetic depletion of tuft cells or ILC2s, or therapeutic targeting of IL13 or IL25 alleviates these pathologies in mice. In gastric cancer patients, tuft cell and ILC2 gene signatures predict worsening survival in intestinal-type gastric cancer where ~40% of the corresponding cancers show enriched co-existence of tuft cells and ILC2s. Our findings suggest a role for ILC2 and tuft cells, along with their associated cytokine IL13 and IL25 as gatekeepers and enablers of metaplastic transformation and gastric tumorigenesis, thereby providing an opportunity to therapeutically inhibit early-stage gastric cancer through repurposing antibody-mediated therapies.
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Affiliation(s)
- Ryan N O'Keefe
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - Annalisa L E Carli
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - David Baloyan
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - David Chisanga
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - Wei Shi
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - Shoukat Afshar-Sterle
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - Moritz F Eissmann
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - Ashleigh R Poh
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - Bhupinder Pal
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - Cyril Seillet
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, Australia
| | - Richard M Locksley
- Department of Medicine, University of California San Francisco, San Francisco, USA
- Howard Hughes Medical Institute, University of California San Francisco, San Francisco, USA
| | - Matthias Ernst
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - Michael Buchert
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia.
- School of Cancer Medicine, La Trobe University, Bundoora, Australia.
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13
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Willet SG, Thanintorn N, McNeill H, Huh SH, Ornitz DM, Huh WJ, Hoft SG, DiPaolo RJ, Mills JC. SOX9 Governs Gastric Mucous Neck Cell Identity and Is Required for Injury-Induced Metaplasia. Cell Mol Gastroenterol Hepatol 2023; 16:325-339. [PMID: 37270061 PMCID: PMC10444955 DOI: 10.1016/j.jcmgh.2023.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 05/26/2023] [Accepted: 05/26/2023] [Indexed: 06/05/2023]
Abstract
BACKGROUND & AIMS Acute and chronic gastric injury induces alterations in differentiation within the corpus of the stomach called pyloric metaplasia. Pyloric metaplasia is characterized by the death of parietal cells and reprogramming of mitotically quiescent zymogenic chief cells into proliferative, mucin-rich spasmolytic polypeptide-expressing metaplasia (SPEM) cells. Overall, pyloric metaplastic units show increased proliferation and specific expansion of mucous lineages, both by proliferation of normal mucous neck cells and recruitment of SPEM cells. Here, we identify Sox9 as a potential gene of interest in the regulation of mucous neck and SPEM cell identity in the stomach. METHODS We used immunostaining and electron microscopy to characterize the expression pattern of SRY-box transcription factor 9 (SOX9) during murine gastric development, homeostasis, and injury in homeostasis, after genetic deletion of Sox9 and after targeted genetic misexpression of Sox9 in the gastric epithelium and chief cells. RESULTS SOX9 is expressed in all early gastric progenitors and strongly expressed in mature mucous neck cells with minor expression in the other principal gastric lineages during adult homeostasis. After injury, strong SOX9 expression was induced in the neck and base of corpus units in SPEM cells. Adult corpus units derived from Sox9-deficient gastric progenitors lacked normal mucous neck cells. Misexpression of Sox9 during postnatal development and adult homeostasis expanded mucous gene expression throughout corpus units including within the chief cell zone in the base. Sox9 deletion specifically in chief cells blunts their reprogramming into SPEM. CONCLUSIONS Sox9 is a master regulator of mucous neck cell differentiation during gastric development. Sox9 also is required for chief cells to fully reprogram into SPEM after injury.
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Affiliation(s)
- Spencer G Willet
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri.
| | - Nattapon Thanintorn
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri
| | - Helen McNeill
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri
| | - Sung-Ho Huh
- Department of Otolaryngology-Head and Neck Surgery, University of Mississippi Medical Center, Jackson, Mississippi
| | - David M Ornitz
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri
| | - Won Jae Huh
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut
| | - Stella G Hoft
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Richard J DiPaolo
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Jason C Mills
- Section of Gastroenterology, Department of Medicine, Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
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14
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Chen Q, Weng K, Lin M, Jiang M, Fang Y, Chung SSW, Huang X, Zhong Q, Liu Z, Huang Z, Lin J, Li P, El-Rifai W, Zaika A, Li H, Rustgi AK, Nakagawa H, Abrams JA, Wang TC, Lu C, Huang C, Que J. SOX9 Modulates the Transformation of Gastric Stem Cells Through Biased Symmetric Cell Division. Gastroenterology 2023; 164:1119-1136.e12. [PMID: 36740200 PMCID: PMC10200757 DOI: 10.1053/j.gastro.2023.01.037] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 01/24/2023] [Accepted: 01/31/2023] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Transformation of stem/progenitor cells has been associated with tumorigenesis in multiple tissues, but stem cells in the stomach have been hard to localize. We therefore aimed to use a combination of several markers to better target oncogenes to gastric stem cells and understand their behavior in the initial stages of gastric tumorigenesis. METHODS Mouse models of gastric metaplasia and cancer by targeting stem/progenitor cells were generated and analyzed with techniques including reanalysis of single-cell RNA sequencing and immunostaining. Gastric cancer cell organoids were genetically manipulated with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) for functional studies. Cell division was determined by bromodeoxyuridine-chasing assay and the assessment of the orientation of the mitotic spindles. Gastric tissues from patients were examined by histopathology and immunostaining. RESULTS Oncogenic insults lead to expansion of SOX9+ progenitor cells in the mouse stomach. Genetic lineage tracing and organoid culture studies show that SOX9+ gastric epithelial cells overlap with SOX2+ progenitors and include stem cells that can self-renew and differentiate to generate all gastric epithelial cells. Moreover, oncogenic targeting of SOX9+SOX2+ cells leads to invasive gastric cancer in our novel mouse model (Sox2-CreERT;Sox9-loxp(66)-rtTA-T2A-Flpo-IRES-loxp(71);Kras(Frt-STOP-Frt-G12D);P53R172H), which combines Cre-loxp and Flippase-Frt genetic recombination systems. Sox9 deletion impedes the expansion of gastric progenitor cells and blocks neoplasia after Kras activation. Although Sox9 is not required for maintaining tissue homeostasis where asymmetric division predominates, loss of Sox9 in the setting of Kras activation leads to reduced symmetric cell division and effectively attenuates the Kras-dependent expansion of stem/progenitor cells. Similarly, Sox9 deletion in gastric cancer organoids reduces symmetric cell division, organoid number, and organoid size. In patients with gastric cancer, high levels of SOX9 are associated with recurrence and poor prognosis. CONCLUSION SOX9 marks gastric stem cells and modulates biased symmetric cell division, which appears to be required for the malignant transformation of gastric stem cells.
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Affiliation(s)
- Qiyue Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China; Columbia Center for Human Development, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, People's Republic of China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, People's Republic of China; Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York
| | - Kai Weng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, People's Republic of China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Mi Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China; Columbia Center for Human Development, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, People's Republic of China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, People's Republic of China; Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York
| | - Ming Jiang
- National Clinical Research Center for Child Health of the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China
| | - Yinshan Fang
- Columbia Center for Human Development, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York
| | - Sanny S W Chung
- Columbia Center for Human Development, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York
| | - Xiaobo Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, People's Republic of China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Qing Zhong
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, People's Republic of China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Zhiyu Liu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, People's Republic of China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Zening Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, People's Republic of China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Jianxian Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, People's Republic of China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, People's Republic of China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Wael El-Rifai
- Department of Surgery, University of Miami, Miami, Florida; Department of Veterans Affairs, Miami Healthcare System, Miami, Florida
| | - Alexander Zaika
- Department of Surgery, University of Miami, Miami, Florida; Department of Veterans Affairs, Miami Healthcare System, Miami, Florida
| | - Haiyan Li
- Department of Pathology & Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Anil K Rustgi
- Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York
| | - Hiroshi Nakagawa
- Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York
| | - Julian A Abrams
- Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York
| | - Timothy C Wang
- Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York
| | - Chao Lu
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York
| | - Changming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China; Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, People's Republic of China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian, People's Republic of China.
| | - Jianwen Que
- Columbia Center for Human Development, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.
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15
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Liu L, Wang Y, Zhao Y, Zhang W, Liu J, Wang F, Wang P, Tang X. Global knowledge mapping and emerging trends in research between spasmolytic polypeptide-expressing metaplasia and gastric carcinogenesis: A bibliometric analysis from 2002 to 2022. Front Cell Infect Microbiol 2023; 12:1108378. [PMID: 36776551 PMCID: PMC9912936 DOI: 10.3389/fcimb.2022.1108378] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 12/28/2022] [Indexed: 01/30/2023] Open
Abstract
Background Spasmolytic polypeptide expression metaplasia (SPEM) occurs in the corpus of the stomach and is closely related to inflammations caused by H. pylori infection. Recently, SPEM was suggested as one of the dubious precancerous lesions of gastric cancer (GC). Thus, further research on SPEM cell transdifferentiation and its underlying mechanisms could facilitate the development of new molecular targets improving the therapeutics of GC. Using bibliometrics, we analyzed publications, summarized the research hotspots and provided references for scientific researchers engaged in related research fields. Methods We searched the Web of Science Core Collection (WoSCC) for publications related to SPEM-GC from 2002 to 2022. The VOSviewer, SCImago, CiteSpace and R software were used to visualize and analyze the data. Gene targets identified in the keyword list were analyzed for functional enrichment using the KEGG and GO databases. Results Of the 292 articles identified in the initial search, we observed a stable trend in SPEM-GC research but rapid growth in the number of citations. The United States was the leader in terms of quality publications and international cooperation among them. The total number of articles published by Chinese scholars was second to the United States. Additionally, despite its low centrality and average citation frequency, China has become one of the world's most dynamic countries in academics. In terms of productivity, Vanderbilt University was identified as the most productive institution. Further, we also observed that Gastroenterology was the highest co-cited journal, and Goldenring Jr. was the most prolific author with the largest centrality. Conclusion SPEM could serve as an initial step in diagnosing gastric precancerous lesions. Current hotspots and frontiers of research include SPEM cell lineage differentiation, interaction with H. pylori, disturbances of the mucosal microenvironment, biomarkers, clinical diagnosis and outcomes of SPEM, as well as the development of proliferative SPEM animal models. However, further research and collaboration are still required. The findings presented in this study can be used as reference for the research status of SPEM-GC and determine new directions for future studies.
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Affiliation(s)
- Lin Liu
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Yang Wang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Yukun Zhao
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wei Zhang
- Department of Pathology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiong Liu
- Department of Pathology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengyun Wang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Ping Wang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Xudong Tang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China,*Correspondence: Xudong Tang,
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16
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Snyder BL, Blackshear PJ. Clinical implications of tristetraprolin (TTP) modulation in the treatment of inflammatory diseases. Pharmacol Ther 2022; 239:108198. [PMID: 35525391 PMCID: PMC9636069 DOI: 10.1016/j.pharmthera.2022.108198] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/19/2022] [Accepted: 04/25/2022] [Indexed: 11/24/2022]
Abstract
Abnormal regulation of pro-inflammatory cytokine and chemokine mediators can contribute to the excess inflammation characteristic of many autoimmune diseases, such as rheumatoid arthritis, psoriasis, Crohn's disease, type 1 diabetes, and many others. The tristetraprolin (TTP) family consists of a small group of related RNA-binding proteins that bind to preferred AU-rich binding sites within the 3'-untranslated regions of specific mRNAs to promote mRNA deadenylation and decay. TTP deficient mice develop a severe systemic inflammatory syndrome consisting of arthritis, myeloid hyperplasia, dermatitis, autoimmunity and cachexia, due at least in part to the excess accumulation of proinflammatory chemokine and cytokine mRNAs and their encoded proteins. To investigate the possibility that increased TTP expression or activity might have a beneficial effect on inflammatory diseases, at least two mouse models have been developed that provide proof of principle that increasing TTP activity can promote the decay of pro-inflammatory and other relevant transcripts, and decrease the severity of mouse models of inflammatory disease. Animal studies of this type are summarized here, and we briefly review the prospects for harnessing these insights for the development of TTP-based anti-inflammatory treatments in humans.
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Affiliation(s)
- Brittany L Snyder
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States of America; Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, United States of America
| | - Perry J Blackshear
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States of America; Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States of America; Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, United States of America.
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17
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Cifarelli V, Peche VS, Abumrad NA. Vascular and lymphatic regulation of gastrointestinal function and disease risk. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159207. [PMID: 35882297 PMCID: PMC9642046 DOI: 10.1016/j.bbalip.2022.159207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 06/17/2022] [Accepted: 07/07/2022] [Indexed: 11/29/2022]
Abstract
The vascular and lymphatic systems in the gut regulate lipid transport while restricting transfer of commensal gut microbiota and directing immune cell trafficking. Increased permeability of the endothelial systems in the intestine associates with passage of antigens and microbiota from the gut into the bloodstream leading to tissue inflammation, the release of pro-inflammatory mediators and ultimately to abnormalities of systemic metabolism. Recent studies show that lipid metabolism maintains homeostasis and function of intestinal blood and lymphatic endothelial cells, BECs and LECs, respectively. This review highlights recent progress in this area, and information related to the contribution of the lipid transporter CD36, abundant in BECs and LECs, to gastrointestinal barrier integrity, inflammation, and to gut regulation of whole body metabolism. The potential role of endothelial lipid delivery in epithelial tissue renewal after injury and consequently in the risk of gastric and intestinal diseases is also discussed.
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Affiliation(s)
- Vincenza Cifarelli
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, USA.
| | - Vivek S Peche
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Nada A Abumrad
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
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18
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Abstract
Like most solid tumours, the microenvironment of epithelial-derived gastric adenocarcinoma (GAC) consists of a variety of stromal cell types, including fibroblasts, and neuronal, endothelial and immune cells. In this article, we review the role of the immune microenvironment in the progression of chronic inflammation to GAC, primarily the immune microenvironment driven by the gram-negative bacterial species Helicobacter pylori. The infection-driven nature of most GACs has renewed awareness of the immune microenvironment and its effect on tumour development and progression. About 75-90% of GACs are associated with prior H. pylori infection and 5-10% with Epstein-Barr virus infection. Although 50% of the world's population is infected with H. pylori, only 1-3% will progress to GAC, with progression the result of a combination of the H. pylori strain, host susceptibility and composition of the chronic inflammatory response. Other environmental risk factors include exposure to a high-salt diet and nitrates. Genetically, chromosome instability occurs in ~50% of GACs and 21% of GACs are microsatellite instability-high tumours. Here, we review the timeline and pathogenesis of the events triggered by H. pylori that can create an immunosuppressive microenvironment by modulating the host's innate and adaptive immune responses, and subsequently favour GAC development.
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19
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Kwon SK, Park JC, Kim KH, Yoon J, Cho Y, Lee B, Lee JJ, Jeong H, Oh Y, Kim SH, Lee SD, Hwang BR, Chung Y, Kim JF, Nam KT, Lee YC. Human gastric microbiota transplantation recapitulates premalignant lesions in germ-free mice. Gut 2022; 71:1266-1276. [PMID: 34389621 DOI: 10.1136/gutjnl-2021-324489] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 07/28/2021] [Indexed: 12/26/2022]
Abstract
OBJECTIVE Gastric cancer (GC) is a leading cause of cancer-related mortality. Although microbes besides Helicobacter pylori may also contribute to gastric carcinogenesis, wild-type germ-free (GF) mouse models investigating the role of human gastric microbiota in the process are not yet available. We aimed to evaluate the histopathological features of GF mouse stomachs transplanted with gastric microbiota from patients with different gastric disease states and their relationships with the microbiota. DESIGN Microbiota profiles in corpus and antrum tissues and gastric fluid from 12 patients with gastric dysplasia or GC were analysed. Thereafter, biopsied corpus and antrum tissues and gastric fluid from patients (n=15 and n=12, respectively) with chronic superficial gastritis, intestinal metaplasia or GC were inoculated into 42 GF C57BL/6 mice. The gastric microbiota was analysed by amplicon sequencing. Histopathological features of mouse stomachs were analysed immunohistochemically at 1 month after inoculation. An independent set of an additional 15 GF mice was also analysed at 1 year. RESULTS The microbial community structures of patients with dysplasia or GC in the corpus and antrum were similar. The gastric microbiota from patients with intestinal metaplasia or GC selectively colonised the mouse stomachs and induced premalignant lesions: loss of parietal cells and increases in inflammation foci, in F4/80 and Ki-67 expression, and in CD44v9/GSII lectin expression. Marked dysplastic changes were noted at 1 year post inoculation. CONCLUSION Major histopathological features of premalignant changes are reproducible in GF mice transplanted with gastric microbiota from patients with intestinal metaplasia or GC. Our results suggest that GF mice are useful for analysing the causality of associations reported in human gastric microbiome studies.
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Affiliation(s)
- Soon-Kyeong Kwon
- Department of Systems Biology, Division of Life Sciences, and Institute for Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.,Division of Applied Life Science (Brain Korea 21), Gyeongsang National University, Jinju, Republic of Korea
| | - Jun Chul Park
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kwang H Kim
- Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jaekyung Yoon
- Department of Systems Biology, Division of Life Sciences, and Institute for Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Yejin Cho
- Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Buhyun Lee
- Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jin-Jae Lee
- Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.,Department of Life Science, Hallym University, Chuncheon, Republic of Korea
| | - Haengdueng Jeong
- Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yeseul Oh
- Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung-Hee Kim
- Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - So Dam Lee
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Bo Ram Hwang
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yusook Chung
- Department of Systems Biology, Division of Life Sciences, and Institute for Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Jihyun F Kim
- Department of Systems Biology, Division of Life Sciences, and Institute for Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea .,Strategic Initiative for Microbiomes in Agriculture and Food, Yonsei University, Seoul, Republic of Korea
| | - Ki Taek Nam
- Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong Chan Lee
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
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20
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Yang H, Yang WJ, Hu B. Gastric epithelial histology and precancerous conditions. World J Gastrointest Oncol 2022; 14:396-412. [PMID: 35317321 PMCID: PMC8919001 DOI: 10.4251/wjgo.v14.i2.396] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 11/08/2021] [Accepted: 01/05/2022] [Indexed: 02/06/2023] Open
Abstract
The most common histological type of gastric cancer (GC) is gastric adenocarcinoma arising from the gastric epithelium. Less common variants include mesenchymal, lymphoproliferative and neuroendocrine neoplasms. The Lauren scheme classifies GC into intestinal type, diffuse type and mixed type. The WHO classification includes papillary, tubular, mucinous, poorly cohesive and mixed GC. Chronic atrophic gastritis (CAG) and intestinal metaplasia are recommended as common precancerous conditions. No definite precancerous condition of diffuse/poorly/undifferentiated type is recommended. Chronic superficial inflammation and hyperplasia of foveolar cells may be the focus. Presently, the management of early GC and precancerous conditions mainly relies on endoscopy including diagnosis, treatment and surveillance. Management of precancerous conditions promotes the early detection and treatment of early GC, and even prevent the occurrence of GC. In the review, precancerous conditions including CAG, metaplasia, foveolar hyperplasia and gastric hyperplastic polyps derived from the gastric epithelium have been concluded, based on the overview of gastric epithelial histological organization and its renewal.
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Affiliation(s)
- Hang Yang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wen-Juan Yang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Bing Hu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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21
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Sáenz JB, Vargas N, Cho CJ, Mills JC. Regulation of the double-stranded RNA response through ADAR1 licenses metaplastic reprogramming in gastric epithelium. JCI Insight 2022; 7:153511. [PMID: 35132959 PMCID: PMC8855806 DOI: 10.1172/jci.insight.153511] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 12/15/2021] [Indexed: 01/17/2023] Open
Abstract
Cells recognize both foreign and host-derived double-stranded RNA (dsRNA) via a signaling pathway that is usually studied in the context of viral infection. It has become increasingly clear that the sensing and handling of endogenous dsRNA is also critical for cellular differentiation and development. The adenosine RNA deaminase, ADAR1, has been implicated as a central regulator of the dsRNA response, but how regulation of the dsRNA response might mediate cell fate during injury and whether such signaling is cell intrinsic remain unclear. Here, we show that the ADAR1-mediated response to dsRNA was dramatically induced in 2 distinct injury models of gastric metaplasia. Mouse organoid and in vivo genetic models showed that ADAR1 coordinated a cell-intrinsic, epithelium-autonomous, and interferon signaling–independent dsRNA response. In addition, dsRNA accumulated within a differentiated epithelial population (chief cells) in mouse and human stomachs as these cells reprogrammed to a proliferative, reparative (metaplastic) state. Finally, chief cells required ADAR1 to reenter the cell cycle during metaplasia. Thus, cell-intrinsic ADAR1 signaling is critical for the induction of metaplasia. Because metaplasia increases cancer risk, these findings support roles for ADAR1 and the response to dsRNA in oncogenesis.
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Affiliation(s)
- José B Sáenz
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
| | - Nancy Vargas
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
| | - Charles J Cho
- Section of Gastroenterology and Hepatology, Department of Medicine
| | - Jason C Mills
- Section of Gastroenterology and Hepatology, Department of Medicine.,Department of Pathology and Immunology; and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
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22
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Goldenring JR, Mills JC. Cellular Plasticity, Reprogramming, and Regeneration: Metaplasia in the Stomach and Beyond. Gastroenterology 2022; 162:415-430. [PMID: 34728185 PMCID: PMC8792220 DOI: 10.1053/j.gastro.2021.10.036] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 10/21/2021] [Accepted: 10/24/2021] [Indexed: 02/03/2023]
Abstract
The mucosa of the body of the stomach (ie, the gastric corpus) uses 2 overlapping, depth-dependent mechanisms to respond to injury. Superficial injury heals via surface cells with histopathologic changes like foveolar hyperplasia. Deeper, usually chronic, injury/inflammation, most frequently induced by the carcinogenic bacteria Helicobacter pylori, elicits glandular histopathologic alterations, initially manifesting as pyloric (also known as pseudopyloric) metaplasia. In this pyloric metaplasia, corpus glands become antrum (pylorus)-like with loss of acid-secreting parietal cells (atrophic gastritis), expansion of foveolar cells, and reprogramming of digestive enzyme-secreting chief cells into deep antral gland-like mucous cells. After acute parietal cell loss, chief cells can reprogram through an orderly stepwise progression (paligenosis) initiated by interleukin-13-secreting innate lymphoid cells (ILC2s). First, massive lysosomal activation helps mitigate reactive oxygen species and remove damaged organelles. Second, mucus and wound-healing proteins (eg, TFF2) and other transcriptional alterations are induced, at which point the reprogrammed chief cells are recognized as mucus-secreting spasmolytic polypeptide-expressing metaplasia cells. In chronic severe injury, glands with pyloric metaplasia can harbor both actively proliferating spasmolytic polypeptide-expressing metaplasia cells and eventually intestine-like cells. Gastric glands with such lineage confusion (mixed incomplete intestinal metaplasia and proliferative spasmolytic polypeptide-expressing metaplasia) may be at particular risk for progression to dysplasia and cancer. A pyloric-like pattern of metaplasia after injury also occurs in other gastrointestinal organs including esophagus, pancreas, and intestines, and the paligenosis program itself seems broadly conserved across tissues and species. Here we discuss aspects of metaplasia in stomach, incorporating data derived from animal models and work on human cells and tissues in correlation with diagnostic and clinical implications.
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Affiliation(s)
- James R Goldenring
- Nashville Veterans Affairs Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
| | - Jason C Mills
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas; Department of Medicine, Baylor College of Medicine, Houston, Texas; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
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23
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Ma Z, Lytle NK, Chen B, Jyotsana N, Novak SW, Cho CJ, Caplan L, Ben-Levy O, Neininger AC, Burnette DT, Trinh VQ, Tan MCB, Patterson EA, Arrojo E Drigo R, Giraddi RR, Ramos C, Means AL, Matsumoto I, Manor U, Mills JC, Goldenring JR, Lau KS, Wahl GM, DelGiorno KE. Single-Cell Transcriptomics Reveals a Conserved Metaplasia Program in Pancreatic Injury. Gastroenterology 2022; 162:604-620.e20. [PMID: 34695382 PMCID: PMC8792222 DOI: 10.1053/j.gastro.2021.10.027] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/15/2021] [Accepted: 10/09/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Acinar to ductal metaplasia (ADM) occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma. The goal of these studies was to define the populations arising from ADM, the associated transcriptional changes, and markers of disease progression. METHODS Acinar cells were lineage-traced with enhanced yellow fluorescent protein (EYFP) to follow their fate post-injury. Transcripts of more than 13,000 EYFP+ cells were determined using single-cell RNA sequencing (scRNA-seq). Developmental trajectories were generated. Data were compared with gastric metaplasia, KrasG12D-induced neoplasia, and human pancreatitis. Results were confirmed by immunostaining and electron microscopy. KrasG12D was expressed in injury-induced ADM using several inducible Cre drivers. Surgical specimens of chronic pancreatitis from 15 patients were evaluated by immunostaining. RESULTS scRNA-seq of ADM revealed emergence of a mucin/ductal population resembling gastric pyloric metaplasia. Lineage trajectories suggest that some pyloric metaplasia cells can generate tuft and enteroendocrine cells (EECs). Comparison with KrasG12D-induced ADM identifies populations associated with disease progression. Activation of KrasG12D expression in HNF1B+ or POU2F3+ ADM populations leads to neoplastic transformation and formation of MUC5AC+ gastric-pit-like cells. Human pancreatitis samples also harbor pyloric metaplasia with a similar transcriptional phenotype. CONCLUSIONS Under conditions of chronic injury, acinar cells undergo a pyloric-type metaplasia to mucinous progenitor-like populations, which seed disparate tuft cell and EEC lineages. ADM-derived EEC subtypes are diverse. KrasG12D expression is sufficient to drive neoplasia when targeted to injury-induced ADM populations and offers an alternative origin for tumorigenesis. This program is conserved in human pancreatitis, providing insight into early events in pancreas diseases.
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Affiliation(s)
- Zhibo Ma
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California
| | - Nikki K Lytle
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California
| | - Bob Chen
- Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Nidhi Jyotsana
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee
| | - Sammy Weiser Novak
- Waitt Advanced Biophotonics Center, Salk Insitute for Biological Studies, La Jolla, California
| | - Charles J Cho
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas
| | - Leah Caplan
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee
| | - Olivia Ben-Levy
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee
| | - Abigail C Neininger
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee
| | - Dylan T Burnette
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Nashville, Tennessee
| | - Vincent Q Trinh
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Marcus C B Tan
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Emilee A Patterson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Rafael Arrojo E Drigo
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Rajshekhar R Giraddi
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California
| | - Cynthia Ramos
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California
| | - Anna L Means
- Vanderbilt Ingram Cancer Center, Nashville, Tennessee; Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | - Uri Manor
- Waitt Advanced Biophotonics Center, Salk Insitute for Biological Studies, La Jolla, California
| | - Jason C Mills
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas
| | - James R Goldenring
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Nashville, Tennessee; Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee; Nashville VA Medical Center, Nashville, Tennessee
| | - Ken S Lau
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Nashville, Tennessee; Vanderbilt Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Geoffrey M Wahl
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California
| | - Kathleen E DelGiorno
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Nashville, Tennessee; Vanderbilt Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee.
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24
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Cho CJ, Park D, Mills JC. ELAPOR1 is a secretory granule maturation-promoting factor that is lost during paligenosis. Am J Physiol Gastrointest Liver Physiol 2022; 322:G49-G65. [PMID: 34816763 PMCID: PMC8698547 DOI: 10.1152/ajpgi.00246.2021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
A single transcription factor, MIST1 (BHLHA15), maximizes secretory function in diverse secretory cells (like pancreatic acinar cells) by transcriptionally upregulating genes that elaborate secretory architecture. Here, we show that the scantly studied MIST1 target, ELAPOR1 (endosome/lysosome-associated apoptosis and autophagy regulator 1), is an evolutionarily conserved, novel mannose-6-phosphate receptor (M6PR) domain-containing protein. ELAPOR1 expression was specific to zymogenic cells (ZCs, the MIST1-expressing population in the stomach). ELAPOR1 expression was lost as tissue injury caused ZCs to undergo paligenosis (i.e., to become metaplastic and reenter the cell cycle). In cultured cells, ELAPOR1 trafficked with cis-Golgi resident proteins and with the trans-Golgi and late endosome protein: cation-independent M6PR. Secretory vesicle trafficking was disrupted by expression of ELAPOR1 truncation mutants. Mass spectrometric analysis of co-immunoprecipitated proteins showed ELAPOR1 and CI-M6PR shared many binding partners. However, CI-M6PR and ELAPOR1 must function differently, as CI-M6PR co-immunoprecipitated more lysosomal proteins and was not decreased during paligenosis in vivo. We generated Elapor1-/- mice to determine ELAPOR1 function in vivo. Consistent with in vitro findings, secretory granule maturation was defective in Elapor1-/- ZCs. Our results identify a role for ELAPOR1 in secretory granule maturation and help clarify how a single transcription factor maintains mature exocrine cell architecture in homeostasis and helps dismantle it during paligenosis.NEW & NOTEWORTHY Here, we find the MIST1 (BHLHA15) transcriptional target ELAPOR1 is an evolutionarily conserved, trans-Golgi/late endosome M6PR domain-containing protein that is specific to gastric zymogenic cells and required for normal secretory granule maturation in human cell lines and in mouse stomach.
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Affiliation(s)
- Charles J. Cho
- 1Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Dongkook Park
- 2Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Jason C. Mills
- 1Department of Medicine, Baylor College of Medicine, Houston, Texas,3Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas,4Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
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Chen WQ, Tian FL, Zhang JW, Yang XJ, Li YP. Preventive and inhibitive effects of Yiwei Xiaoyu granules on the development and progression of spasmolytic polypeptide-expressing metaplasia lesions. World J Gastrointest Oncol 2021; 13:1741-1754. [PMID: 34853647 PMCID: PMC8603444 DOI: 10.4251/wjgo.v13.i11.1741] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/10/2021] [Accepted: 08/24/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Spasmolytic polypeptide-expressing metaplasia (SPEM) is a potential preneoplastic lesion.
AIM To elucidate the microRNA (miR)-7-mediated preventive and inhibitive effects of Yiwei Xiaoyu granules (YWXY) in SPEM lesions.
METHODS Gastric mucosa biopsies were collected from chronic atrophic gastritis patients and healthy people with signed informed consent. YWXY was administered to the mice with induced SPEM by tamoxifen, and the gastric mucosa was harvested on the tenth day of the experiment. Then immunohistochemistry and immunofluorescence were performed to validate the SPEM, lesions and the potential mechanism was investigated. RNA transcripts were detected with reverse transcription-quantitative polymerase chain reaction.
RESULTS The expression of miR-7 was downregulated in the SPEM lesions, and expression of trefoil factor 2 (TFF2) and clusterin was high in the human gastric mucosa. In vivo experiments showed that YWXY could inhibit the cell proliferation in the tamoxifen-induced SPEM lesions by regulating Ki67. Simultaneously, YWXY could restore the expression of miR-7 by regulating TFF2 by detection with immunofluorescence but not with reverse transcription-quantitative polymerase chain reaction, indicating its potential mechanism of targeting miR-7 by mediating TFF2. The expression of vascular endothelial growth factor-β and gastric intrinsic factor was restored within 3 d of YWXY administration for the SPEM lesions, speculating that the possible mechanism of YWXY is to inhibit the development and progression of SPEM by regulating vascular endothelial growth factor-β and gastric intrinsic factor.
CONCLUSION miR-7 downregulation is an early event in SPEM through regulation of TFF2 in human gastric mucosa. YWXY is able to inhibit the cell proliferation and restore the expression of miR-7 by mediating TFF2 in the SPEM mouse model.
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Affiliation(s)
- Wan-Qun Chen
- Department of Gastroenterology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400000, China
| | - Feng-Liang Tian
- Department of Gastroenterology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400000, China
| | - Jin-Wei Zhang
- Department of Dermatology and Cosmetology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400000, China
| | - Xiao-Jun Yang
- Department of Gastroenterology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400000, China
| | - Yan-Ping Li
- Department of Gastroenterology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400000, China
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26
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Jacome-Sosa M, Miao ZF, Peche VS, Morris EF, Narendran R, Pietka KM, Samovski D, Lo HYG, Pietka T, Varro A, Love-Gregory L, Goldenring JR, Kuda O, Gamazon ER, Mills JC, Abumrad NA. CD36 maintains the gastric mucosa and associates with gastric disease. Commun Biol 2021; 4:1247. [PMID: 34728772 PMCID: PMC8563937 DOI: 10.1038/s42003-021-02765-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 10/06/2021] [Indexed: 12/19/2022] Open
Abstract
The gastric epithelium is often exposed to injurious elements and failure of appropriate healing predisposes to ulcers, hemorrhage, and ultimately cancer. We examined the gastric function of CD36, a protein linked to disease and homeostasis. We used the tamoxifen model of gastric injury in mice null for Cd36 (Cd36-/-), with Cd36 deletion in parietal cells (PC-Cd36-/-) or in endothelial cells (EC-Cd36-/-). CD36 expresses on corpus ECs, on PC basolateral membranes, and in gastrin and ghrelin cells. Stomachs of Cd36-/- mice have altered gland organization and secretion, more fibronectin, and inflammation. Tissue respiration and mitochondrial efficiency are reduced. Phospholipids increased and triglycerides decreased. Mucosal repair after injury is impaired in Cd36-/- and EC-Cd36-/-, not in PC-Cd36-/- mice, and is due to defect of progenitor differentiation to PCs, not of progenitor proliferation or mature PC dysfunction. Relevance to humans is explored in the Vanderbilt BioVu using PrediXcan that links genetically-determined gene expression to clinical phenotypes, which associates low CD36 mRNA with gastritis, gastric ulcer, and gastro-intestinal hemorrhage. A CD36 variant predicted to disrupt an enhancer site associates (p < 10-17) to death from gastro-intestinal hemorrhage in the UK Biobank. The findings support role of CD36 in gastric tissue repair, and its deletion associated with chronic diseases that can predispose to malignancy.
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Affiliation(s)
- Miriam Jacome-Sosa
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
| | - Zhi-Feng Miao
- Department of Surgical Oncology, Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, First Hospital of China Medical University, Shenyang, China
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Vivek S Peche
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Edward F Morris
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Ramkumar Narendran
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Kathryn M Pietka
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Dmitri Samovski
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Hei-Yong G Lo
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Terri Pietka
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Andrea Varro
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Latisha Love-Gregory
- Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO, USA
| | - James R Goldenring
- Departments of Surgery and Cell and Developmental Biology, Vanderbilt University Medical Center and VA Medical Center, Nashville, TN, USA
| | - Ondrej Kuda
- Institute of Physiology, Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic
| | - Eric R Gamazon
- Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Jason C Mills
- Gastroenterology & Hepatology Section, Departments of Medicine and of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
| | - Nada A Abumrad
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
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27
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Radyk MD, Spatz LB, Peña BL, Brown JW, Burclaff J, Cho CJ, Kefalov Y, Shih C, Fitzpatrick JAJ, Mills JC. ATF3 induces RAB7 to govern autodegradation in paligenosis, a conserved cell plasticity program. EMBO Rep 2021; 22:e51806. [PMID: 34309175 PMCID: PMC8419698 DOI: 10.15252/embr.202051806] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 06/04/2021] [Accepted: 06/18/2021] [Indexed: 12/20/2022] Open
Abstract
Differentiated cells across multiple species and organs can re-enter the cell cycle to aid in injury-induced tissue regeneration by a cellular program called paligenosis. Here, we show that activating transcription factor 3 (ATF3) is induced early during paligenosis in multiple cellular contexts, transcriptionally activating the lysosomal trafficking gene Rab7b. ATF3 and RAB7B are upregulated in gastric and pancreatic digestive-enzyme-secreting cells at the onset of paligenosis Stage 1, when cells massively induce autophagic and lysosomal machinery to dismantle differentiated cell morphological features. Their expression later ebbs before cells enter mitosis during Stage 3. Atf3-/- mice fail to induce RAB7-positive autophagic and lysosomal vesicles, eventually causing increased death of cells en route to Stage 3. Finally, we observe that ATF3 is expressed in human gastric metaplasia and during paligenotic injury across multiple other organs and species. Thus, our findings indicate ATF3 is an evolutionarily conserved gene orchestrating the early paligenotic autodegradative events that must occur before cells are poised to proliferate and contribute to tissue repair.
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Affiliation(s)
- Megan D Radyk
- Division of GastroenterologyDepartment of MedicineWashington University School of MedicineSt. LouisMOUSA
| | - Lillian B Spatz
- Division of GastroenterologyDepartment of MedicineWashington University School of MedicineSt. LouisMOUSA
| | - Bianca L Peña
- Division of GastroenterologyDepartment of MedicineWashington University School of MedicineSt. LouisMOUSA
| | - Jeffrey W Brown
- Division of GastroenterologyDepartment of MedicineWashington University School of MedicineSt. LouisMOUSA
| | - Joseph Burclaff
- Division of GastroenterologyDepartment of MedicineWashington University School of MedicineSt. LouisMOUSA
| | - Charles J Cho
- Division of GastroenterologyDepartment of MedicineWashington University School of MedicineSt. LouisMOUSA
| | - Yan Kefalov
- Division of GastroenterologyDepartment of MedicineWashington University School of MedicineSt. LouisMOUSA
| | - Chien‐Cheng Shih
- Washington University Center for Cellular ImagingWashington University School of MedicineSt. LouisMOUSA
| | - James AJ Fitzpatrick
- Washington University Center for Cellular ImagingWashington University School of MedicineSt. LouisMOUSA
- Departments of Neuroscience and Cell Biology & PhysiologyWashington University School of MedicineSt. LouisMOUSA
- Department of Biomedical EngineeringWashington University in St. LouisSt. LouisMOUSA
| | - Jason C Mills
- Division of GastroenterologyDepartment of MedicineWashington University School of MedicineSt. LouisMOUSA
- Department of Developmental BiologyWashington University School of MedicineSt. LouisMOUSA
- Department of Pathology and ImmunologyWashington University School of MedicineSt. LouisMOUSA
- Present address:
Section of Gastroenterology and HepatologyDepartments of Medicine and PathologyBaylor College of MedicineHoustonTXUSA
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28
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Busada JT, Khadka S, Peterson KN, Druffner SR, Stumpo DJ, Zhou L, Oakley RH, Cidlowski JA, Blackshear PJ. Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic Inflammation. Cell Mol Gastroenterol Hepatol 2021; 12:1831-1845. [PMID: 34358715 PMCID: PMC8554534 DOI: 10.1016/j.jcmgh.2021.07.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 07/27/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Aberrant immune activation is associated with numerous inflammatory and autoimmune diseases and contributes to cancer development and progression. Within the stomach, inflammation drives a well-established sequence from gastritis to metaplasia, eventually resulting in adenocarcinoma. Unfortunately, the processes that regulate gastric inflammation and prevent carcinogenesis remain unknown. Tristetraprolin (TTP) is an RNA-binding protein that promotes the turnover of numerous proinflammatory and oncogenic messenger RNAs. Here, we assess the role of TTP in regulating gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM) development. METHODS We used a TTP-overexpressing model, the TTPΔadenylate-uridylate rich element mouse, to examine whether TTP can protect the stomach from adrenalectomy (ADX)-induced gastric inflammation and SPEM. RESULTS We found that TTPΔadenylate-uridylate rich element mice were completely protected from ADX-induced gastric inflammation and SPEM. RNA sequencing 5 days after ADX showed that TTP overexpression suppressed the expression of genes associated with the innate immune response. Importantly, TTP overexpression did not protect from high-dose-tamoxifen-induced SPEM development, suggesting that protection in the ADX model is achieved primarily by suppressing inflammation. Finally, we show that protection from gastric inflammation was only partially due to the suppression of Tnf, a well-known TTP target. CONCLUSIONS Our results show that TTP exerts broad anti-inflammatory effects in the stomach and suggest that therapies that increase TTP expression may be effective treatments of proneoplastic gastric inflammation. Transcript profiling: GSE164349.
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Affiliation(s)
- Jonathan T. Busada
- Molecular Endocrinology Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina,Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia,Correspondence Address correspondence to: Jonathan T. Busada, PhD, Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, 64 Medical Center Drive, PO Box 9177, Morgantown, West Virginia 26506.
| | - Stuti Khadka
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia
| | - Kylie N. Peterson
- Molecular Endocrinology Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
| | - Sara R. Druffner
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia
| | - Deborah J. Stumpo
- Post-Transcriptional Gene Expression Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
| | - Lecong Zhou
- Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
| | - Robert H. Oakley
- Molecular Endocrinology Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
| | - John A. Cidlowski
- Molecular Endocrinology Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
| | - Perry J. Blackshear
- Post-Transcriptional Gene Expression Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
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29
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Zhang Y, Zeng F, Han X, Weng J, Gao Y. Lineage tracing: technology tool for exploring the development, regeneration, and disease of the digestive system. Stem Cell Res Ther 2020; 11:438. [PMID: 33059752 PMCID: PMC7559019 DOI: 10.1186/s13287-020-01941-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 09/17/2020] [Indexed: 12/15/2022] Open
Abstract
Lineage tracing is the most widely used technique to track the migration, proliferation, and differentiation of specific cells in vivo. The currently available gene-targeting technologies have been developing for decades to study organogenesis, tissue injury repairing, and tumor progression by tracing the fates of individual cells. Recently, lineage tracing has expanded the platforms available for disease model establishment, drug screening, cell plasticity research, and personalized medicine development in a molecular and cellular biology perspective. Lineage tracing provides new views for exploring digestive organ development and regeneration and techniques for digestive disease causes and progression. This review focuses on the lineage tracing technology and its application in digestive diseases.
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Affiliation(s)
- Yue Zhang
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Fanhong Zeng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Xu Han
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Jun Weng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China. .,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China.
| | - Yi Gao
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China. .,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China.
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30
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Kunze B, Wein F, Fang HY, Anand A, Baumeister T, Strangmann J, Gerland S, Ingermann J, Münch NS, Wiethaler M, Sahm V, Hidalgo-Sastre A, Lange S, Lightdale CJ, Bokhari A, Falk GW, Friedman RA, Ginsberg GG, Iyer PG, Jin Z, Nakagawa H, Shawber CJ, Nguyen T, Raab WJ, Dalerba P, Rustgi AK, Sepulveda AR, Wang KK, Schmid RM, Wang TC, Abrams JA, Quante M. Notch Signaling Mediates Differentiation in Barrett's Esophagus and Promotes Progression to Adenocarcinoma. Gastroenterology 2020; 159:575-590. [PMID: 32325086 PMCID: PMC7484392 DOI: 10.1053/j.gastro.2020.04.033] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 03/19/2020] [Accepted: 04/13/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Studies are needed to determine the mechanism by which Barrett's esophagus (BE) progresses to esophageal adenocarcinoma (EAC). Notch signaling maintains stem cells in the gastrointestinal tract and is dysregulated during carcinogenesis. We explored the relationship between Notch signaling and goblet cell maturation, a feature of BE, during EAC pathogenesis. METHODS We measured goblet cell density and levels of Notch messenger RNAs in BE tissues from 164 patients, with and without dysplasia or EAC, enrolled in a multicenter study. We analyzed the effects of conditional expression of an activated form of NOTCH2 (pL2.Lgr5.N2IC), conditional deletion of NOTCH2 (pL2.Lgr5.N2fl/fl), or loss of nuclear factor κB (NF-κB) (pL2.Lgr5.p65fl/fl), in Lgr5+ (progenitor) cells in L2-IL1B mice (which overexpress interleukin 1 beta in esophagus and squamous forestomach and are used as a model of BE). We collected esophageal and stomach tissues and performed histology, immunohistochemistry, flow cytometry, transcriptome, and real-time polymerase chain reaction analyses. Cardia and forestomach tissues from mice were cultured as organoids and incubated with inhibitors of Notch or NF-kB. RESULTS Progression of BE to EAC was associated with a significant reduction in goblet cell density comparing nondysplastic regions of tissues from patients; there was an inverse correlation between goblet cell density and levels of NOTCH3 and JAG2 messenger RNA. In mice, expression of the activated intracellular form of NOTCH2 in Lgr5+ cells reduced goblet-like cell maturation, increased crypt fission, and accelerated the development of tumors in the squamocolumnar junction. Mice with deletion of NOTCH2 from Lgr5+ cells had increased maturation of goblet-like cells, reduced crypt fission, and developed fewer tumors. Esophageal tissues from in pL2.Lgr5.N2IC mice had increased levels of RelA (which encodes the p65 unit of NF-κB) compared to tissues from L2-IL1B mice, and we found evidence of increased NF-κB activity in Lgr5+ cells. Esophageal tissues from pL2.Lgr5.p65fl/fl mice had lower inflammation and metaplasia scores than pL2.Lgr5.N2IC mice. In organoids derived from pL2-IL1B mice, the NF-κB inhibitor JSH-23 reduced cell survival and proliferation. CONCLUSIONS Notch signaling contributes to activation of NF-κB and regulates differentiation of gastric cardia progenitor cells in a mouse model of BE. In human esophageal tissues, progression of BE to EAC was associated with reduced goblet cell density and increased levels of Notch expression. Strategies to block this pathway might be developed to prevent EAC in patients with BE.
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Affiliation(s)
- Bettina Kunze
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Frederik Wein
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Hsin-Yu Fang
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Akanksha Anand
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Theresa Baumeister
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Julia Strangmann
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Sophie Gerland
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Jonas Ingermann
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | | | - Maria Wiethaler
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Vincenz Sahm
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Ana Hidalgo-Sastre
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Sebastian Lange
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Charles J Lightdale
- Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Aqiba Bokhari
- Yosemite Pathology Medical Group, Modesto, California
| | - Gary W Falk
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Richard A Friedman
- Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
| | - Gregory G Ginsberg
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Prasad G Iyer
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Zhezhen Jin
- Department of Biostatistics, Columbia University Mailman School of Public Health, New York, New York
| | - Hiroshi Nakagawa
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
| | - Carrie J Shawber
- Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York
| | - TheAnh Nguyen
- Oregon Health and Science University, Portland, Oregon
| | - William J Raab
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Piero Dalerba
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York; Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, New York
| | - Anil K Rustgi
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
| | - Antonia R Sepulveda
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Kenneth K Wang
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Roland M Schmid
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Timothy C Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
| | - Julian A Abrams
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
| | - Michael Quante
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany.
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31
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Bockerstett KA, Lewis SA, Wolf KJ, Noto CN, Jackson NM, Ford EL, Ahn TH, DiPaolo RJ. Single-cell transcriptional analyses of spasmolytic polypeptide-expressing metaplasia arising from acute drug injury and chronic inflammation in the stomach. Gut 2020; 69:1027-1038. [PMID: 31481545 PMCID: PMC7282188 DOI: 10.1136/gutjnl-2019-318930] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 08/21/2019] [Accepted: 08/25/2019] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Spasmolytic polypeptide-expressing metaplasia (SPEM) is a regenerative lesion in the gastric mucosa and is a potential precursor to intestinal metaplasia/gastric adenocarcinoma in a chronic inflammatory setting. The goal of these studies was to define the transcriptional changes associated with SPEM at the individual cell level in response to acute drug injury and chronic inflammatory damage in the gastric mucosa. DESIGN Epithelial cells were isolated from the gastric corpus of healthy stomachs and stomachs with drug-induced and inflammation-induced SPEM lesions. Single cell RNA sequencing (scRNA-seq) was performed on tissue samples from each of these settings. The transcriptomes of individual epithelial cells from healthy, acutely damaged and chronically inflamed stomachs were analysed and compared. RESULTS scRNA-seq revealed a population Mucin 6 (Muc6)+gastric intrinsic factor (Gif)+ cells in healthy tissue, but these cells did not express transcripts associated with SPEM. Furthermore, analyses of SPEM cells from drug injured and chronically inflamed corpus yielded two major findings: (1) SPEM and neck cell hyperplasia/hypertrophy are nearly identical in the expression of SPEM-associated transcripts and (2) SPEM programmes induced by drug-mediated parietal cell ablation and chronic inflammation are nearly identical, although the induction of transcripts involved in immunomodulation was unique to SPEM cells in the chronic inflammatory setting. CONCLUSIONS These data necessitate an expansion of the definition of SPEM to include Tff2+Muc6+ cells that do not express mature chief cell transcripts such as Gif. Our data demonstrate that SPEM arises by a highly conserved cellular programme independent of aetiology and develops immunoregulatory capabilities in a setting of chronic inflammation.
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Affiliation(s)
- Kevin A Bockerstett
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
| | - Scott A Lewis
- Department of Computer Science, Saint Louis University, Saint Louis, Missouri, USA
| | - Kyle J Wolf
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
| | - Christine N Noto
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
| | - Nicholas M Jackson
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
| | - Eric L Ford
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
| | - Tae-Hyuk Ahn
- Department of Computer Science, Saint Louis University, Saint Louis, Missouri, USA
| | - Richard J DiPaolo
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
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32
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Bockerstett KA, Petersen CP, Noto CN, Kuehm LM, Wong CF, Ford EL, Teague RM, Mills JC, Goldenring JR, DiPaolo RJ. Interleukin 27 Protects From Gastric Atrophy and Metaplasia During Chronic Autoimmune Gastritis. Cell Mol Gastroenterol Hepatol 2020; 10:561-579. [PMID: 32376420 PMCID: PMC7399182 DOI: 10.1016/j.jcmgh.2020.04.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS The association between chronic inflammation and gastric carcinogenesis is well established, but it is not clear how immune cells and cytokines regulate this process. We investigated the role of interleukin 27 (IL27) in the development of gastric atrophy, hyperplasia, and metaplasia (preneoplastic lesions associated with inflammation-induced gastric cancer) in mice with autoimmune gastritis. METHODS We performed studies with TxA23 mice (control mice), which express a T-cell receptor against the H+/K+ adenosine triphosphatase α chain and develop autoimmune gastritis, and TxA23xEbi3-/- mice, which develop gastritis but do not express IL27. In some experiments, mice were given high-dose tamoxifen to induce parietal cell atrophy and spasmolytic polypeptide-expressing metaplasia (SPEM). Recombinant IL27 was administered to mice with mini osmotic pumps. Stomachs were collected and analyzed by histopathology and immunofluorescence; we used flow cytometry to measure IL27 and identify immune cells that secrete IL27 in the gastric mucosa. Single-cell RNA sequencing was performed on immune cells that infiltrated stomach tissues. RESULTS We identified IL27-secreting macrophages and dendritic cell in the corpus of mice with chronic gastritis (TxA23 mice). Mice deficient in IL27 developed more severe gastritis, atrophy, and SPEM than control mice. Administration of recombinant IL27 significantly reduced the severity of inflammation, atrophy, and SPEM in mice with gastritis. Single-cell RNA sequencing showed that IL27 acted almost exclusively on stomach-infiltrating CD4+ T cells to suppress expression of inflammatory genes. CONCLUSIONS In studies of mice with autoimmune gastritis, we found that IL27 is an inhibitor of gastritis and SPEM, suppressing CD4+ T-cell-mediated inflammation in the gastric mucosa.
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Affiliation(s)
- Kevin A Bockerstett
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri
| | - Christine P Petersen
- Nashville Veterans Affairs Medical Center, Department of Surgery, Department of Cell and Developmental Biology, Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Christine N Noto
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri
| | - Lindsey M Kuehm
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri
| | - Chun Fung Wong
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri
| | - Eric L Ford
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri
| | - Ryan M Teague
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri
| | - Jason C Mills
- Division of Gastroenterology, Department of Medicine, Pathology and Immunology, Department of Developmental Biology, Washington University School of Medicine, Saint Louis, Missouri
| | - James R Goldenring
- Nashville Veterans Affairs Medical Center, Department of Surgery, Department of Cell and Developmental Biology, Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Richard J DiPaolo
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri.
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Chen WQ, Yang XJ, Zhang JW. Progress in research of gastric spasmolytic polypeptide expressing metaplasia. Shijie Huaren Xiaohua Zazhi 2020; 28:254-259. [DOI: 10.11569/wcjd.v28.i7.254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Spasmolytic polypeptide expressing metaplasia (SPEM) is a critical precursor of gastric precancerous lesions and can lead to dysplasia or neoplasia in the presence of continuous chronic inflammation. Current research on SPEM using mouse models implies that the immune dysfunction of the gastric mucosa triggered by Helicobacter pylori infection might result in the progression of SPEM to intestinal metaplasia and even gastric cancer. Therefore, elucidating the origin and mechanism of progression of SPEM can help avoid the occurrence of SPEM, prevent SPEM progressing to intestinal metaplasia, and reduce the incidence of gastric cancer. In this paper, we will review the progress in the research of SPEM over the recent 10 years.
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Affiliation(s)
- Wan-Qun Chen
- Department of Gastroenterology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400037, China
| | - Xiao-Jun Yang
- Department of Gastroenterology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400037, China
| | - Jin-Wei Zhang
- Department of Dermatology and Cosmetology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400037, China
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Miao ZF, Adkins-Threats M, Burclaff JR, Osaki LH, Sun JX, Kefalov Y, He Z, Wang ZN, Mills JC. A Metformin-Responsive Metabolic Pathway Controls Distinct Steps in Gastric Progenitor Fate Decisions and Maturation. Cell Stem Cell 2020; 26:910-925.e6. [PMID: 32243780 DOI: 10.1016/j.stem.2020.03.006] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 12/06/2019] [Accepted: 03/10/2020] [Indexed: 02/06/2023]
Abstract
Cellular metabolism plays important functions in dictating stem cell behaviors, although its role in stomach epithelial homeostasis has not been evaluated in depth. Here, we show that the energy sensor AMP kinase (AMPK) governs gastric epithelial progenitor differentiation. Administering the AMPK activator metformin decreases epithelial progenitor proliferation and increases acid-secreting parietal cells (PCs) in mice and organoids. AMPK activation targets Krüppel-like factor 4 (KLF4), known to govern progenitor proliferation and PC fate choice, and PGC1α, which we show controls PC maturation after their specification. PC-specific deletion of AMPKα or PGC1α causes defective PC maturation, which could not be rescued by metformin. However, metformin treatment still increases KLF4 levels and suppresses progenitor proliferation. Thus, AMPK activates KLF4 in progenitors to reduce self-renewal and promote PC fate, whereas AMPK-PGC1α activation within the PC lineage promotes maturation, providing a potential suggestion for why metformin increases acid secretion and reduces gastric cancer risk in humans.
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Affiliation(s)
- Zhi-Feng Miao
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, First Hospital of China Medical University, Shenyang, China
| | - Mahliyah Adkins-Threats
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Joseph R Burclaff
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Luciana H Osaki
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Jing-Xu Sun
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, First Hospital of China Medical University, Shenyang, China
| | - Yan Kefalov
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Zheng He
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Radiation Oncology, First Hospital of China Medical University, Shenyang, China
| | - Zhen-Ning Wang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, First Hospital of China Medical University, Shenyang, China
| | - Jason C Mills
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.
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Burclaff J, Willet SG, Sáenz JB, Mills JC. Proliferation and Differentiation of Gastric Mucous Neck and Chief Cells During Homeostasis and Injury-induced Metaplasia. Gastroenterology 2020; 158:598-609.e5. [PMID: 31589873 PMCID: PMC7010566 DOI: 10.1053/j.gastro.2019.09.037] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 09/24/2019] [Accepted: 09/30/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Adult zymogen-producing (zymogenic) chief cells (ZCs) in the mammalian gastric gland base are believed to arise from descending mucous neck cells, which arise from stem cells. Gastric injury, such as from Helicobacter pylori infection in patients with chronic atrophic gastritis, can cause metaplasia, characterized by gastric cell expression of markers of wound-healing; these cells are called spasmolytic polypeptide-expressing metaplasia (SPEM) cells. We investigated differentiation and proliferation patterns of neck cells, ZCs, and SPEM cells in mice. METHODS C57BL/6 mice were given intraperitoneal injections of high-dose tamoxifen to induce SPEM or gavaged with H pylori (PMSS1) to induce chronic gastric injury. Mice were then given pulses of 5-bromo-2'-deoxyuridine (BrdU) in their drinking water, followed by chase periods without BrdU, or combined with intraperitoneal injections of 5-ethynyl-2'-deoxyuridine. We collected gastric tissues and performed immunofluorescence and immunohistochemical analyses to study gastric cell proliferation, differentiation, and turnover. RESULTS After 8 weeks of continuous BrdU administration, fewer than 10% of homeostatic ZCs incorporated BrdU, whereas 88% of neck cells were labeled. In pulse-chase experiments, various chase periods decreased neck cell label but did not increase labeling of ZCs. When mice were given BrdU at the same time as tamoxifen, more than 90% of cells were labeled in all gastric lineages. After 3 months' recovery (no tamoxifen), ZCs became the predominant BrdU-labeled population, whereas other cells, including neck cells, were mostly negative. When we tracked the labeled cells in such mice over time, we observed that the proportion of BrdU-positive ZCs remained greater than 60% up to 11 months. In mice whose ZCs were the principal BrdU-positive population, acute injury by tamoxifen or chronic injury by H pylori infection resulted in SPEM cells becoming the principal BrdU-positive population. After withdrawal of tamoxifen, BrdU-positive ZCs reappeared. CONCLUSIONS We studied mice in homeostasis or with tamoxifen- or H pylori-induced SPEM. Our findings indicated that mucous neck cells do not contribute substantially to generation of ZCs during homeostasis and that ZCs maintain their own census, likely through infrequent self-replication. After metaplasia-inducing injury, ZCs can become SPEM cells, and then redifferentiate into ZCs on injury resolution.
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Affiliation(s)
- Joseph Burclaff
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri
| | - Spencer G Willet
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri
| | - José B Sáenz
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri
| | - Jason C Mills
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri; Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri; Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.
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Seidlitz T, Chen YT, Uhlemann H, Schölch S, Kochall S, Merker SR, Klimova A, Hennig A, Schweitzer C, Pape K, Baretton GB, Welsch T, Aust DE, Weitz J, Koo BK, Stange DE. Mouse Models of Human Gastric Cancer Subtypes With Stomach-Specific CreERT2-Mediated Pathway Alterations. Gastroenterology 2019; 157:1599-1614.e2. [PMID: 31585123 PMCID: PMC6902245 DOI: 10.1053/j.gastro.2019.09.026] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 09/02/2019] [Accepted: 09/09/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patterns of genetic alterations characterize different molecular subtypes of human gastric cancer. We aimed to establish mouse models of these subtypes. METHODS We searched databases to identify genes with unique expression in the stomach epithelium, resulting in the identification of Anxa10. We generated mice with tamoxifen-inducible Cre recombinase (CreERT2) in the Anxa10 gene locus. We created 3 mouse models with alterations in pathways that characterize the chromosomal instability (CIN) and the genomically stable (GS) subtypes of human gastric cancer: Anxa10-CreERT2;KrasG12D/+;Tp53R172H/+;Smad4fl/f (CIN mice), Anxa10-CreERT2;Cdh1fl/fl;KrasG12D/+;Smad4fl/fl (GS-TGBF mice), and Anxa10-CreERT2;Cdh1fl/fl;KrasG12D/+;Apcfl/fl (GS-Wnt mice). We analyzed tumors that developed in these mice by histology for cell types and metastatic potential. We derived organoids from the tumors and tested their response to chemotherapeutic agents and the epithelial growth factor receptor signaling pathway inhibitor trametinib. RESULTS The gastric tumors from the CIN mice had an invasive phenotype and formed liver and lung metastases. The tumor cells had a glandular morphology, similar to human intestinal-type gastric cancer. The gastric tumors from the GS-TGFB mice were poorly differentiated with diffuse morphology and signet ring cells, resembling human diffuse-type gastric cancer. Cells from these tumors were invasive, and mice developed peritoneal carcinomatosis and lung metastases. GS-Wnt mice developed adenomatous tooth-like gastric cancer. Organoids derived from tumors of GS-TGBF and GS-Wnt mice were more resistant to docetaxel, whereas organoids from the CIN tumors were more resistant to trametinib. CONCLUSIONS Using a stomach-specific CreERT2 system, we created mice that develop tumors with morphologic similarities to subtypes of human gastric cancer. These tumors have different patterns of local growth, metastasis, and response to therapeutic agents. They can be used to study different subtypes of human gastric cancer.
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Affiliation(s)
- Therese Seidlitz
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Yi-Ting Chen
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan,Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Heike Uhlemann
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Sebastian Schölch
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany,Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany,German Cancer Consortium (DKTK), Dresden, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Susan Kochall
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Sebastian R. Merker
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Anna Klimova
- Institute for Medical Informatics and Biometry, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany,Core Unit for Data Management and Analytics (CDMA), National Center for Tumor Diseases (NCT), Dresden, Germany
| | - Alexander Hennig
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany,National Center for Tumor Diseases, Dresden, Germany
| | - Christine Schweitzer
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Kristin Pape
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Gustavo B. Baretton
- German Cancer Consortium (DKTK), Dresden, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany,Core Unit for Molecular Tumour Diagnostics, National Center for Tumor Diseases (NCT), Dresden, Germany,Institute of Pathology and Tumour and Normal Tissue Bank of the University Cancer Center, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany,National Center for Tumor Diseases, Dresden, Germany
| | - Thilo Welsch
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Daniela E. Aust
- German Cancer Consortium (DKTK), Dresden, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany,Core Unit for Molecular Tumour Diagnostics, National Center for Tumor Diseases (NCT), Dresden, Germany,Institute of Pathology and Tumour and Normal Tissue Bank of the University Cancer Center, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany,National Center for Tumor Diseases, Dresden, Germany
| | - Jürgen Weitz
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany,German Cancer Consortium (DKTK), Dresden, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany,National Center for Tumor Diseases, Dresden, Germany
| | - Bon-Kyoung Koo
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna Biocenter, Vienna, Austria
| | - Daniel E. Stange
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany,German Cancer Consortium (DKTK), Dresden, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany,National Center for Tumor Diseases, Dresden, Germany,Reprint requests Address requests for reprints to: Daniel E. Strange, MD, PhD, Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
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Key PN, Germino J, Yang L, Piersma SJ, Tripathy SK. Chronic Ly49H Receptor Engagement in vivo Decreases NK Cell Response to Stimulation Through ITAM-Dependent and Independent Pathways Both in vitro and in vivo. Front Immunol 2019; 10:1692. [PMID: 31396217 PMCID: PMC6664057 DOI: 10.3389/fimmu.2019.01692] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 07/08/2019] [Indexed: 01/15/2023] Open
Abstract
Natural killer (NK) cells play an important role in the innate immune response. The summation of activation and inhibitory signals delivered through cell surface membrane receptors determines NK cell function. However, the continuous engagement of an activating receptor on NK cells appears to render the cells hyporesponsive to stimulation through other unrelated activating receptors. The mechanism by which this takes place remains unclear. Herein we demonstrate that continuous in vivo engagement of the Ly49H receptor with its ligand, m157, results in Ly49H+ NK cells that are hyporesponsive to further stimulation by other ITAM-dependent and independent receptors, while Ly49H− NK cells remain unaffected. The hyporesponsiveness of the NK cell correlates with the degree of Ly49H receptor downmodulation on its cell surface. We observe defects in calcium flux in the hyporesponsive NK cells following stimulation through the NK1.1 receptor. In addition, we observe differences in signaling molecules that play a role in calcium flux, including spleen tyrosine kinase (Syk) at baseline and phosphorylated phospholipase C gamma 2 (p-PLCγ2) at both baseline and following stimulation through NK1.1. We also demonstrate that various ITAM associated activation receptors, including Ly49H, remain associated with their respective adaptor molecules. With regard to in vivo NK cell function, we did not find differences in the formation of metastatic lung lesions following IV injection of B16 melanoma cells. However, we did observe defects in rejection of missing-self targets in vivo. The data suggest that continuous engagement of the Ly49H activating receptor on NK cells results in hyporesponsiveness of the NK cells to all of the ITAM-dependent and independent receptors we analyzed due to altered signaling pathways downstream of the receptor and adaptor molecule.
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Affiliation(s)
- Phillip N Key
- Gastroenterology Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
| | - Joe Germino
- Gastroenterology Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
| | - Liping Yang
- Rheumatology Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
| | - Sytse J Piersma
- Rheumatology Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
| | - Sandeep K Tripathy
- Gastroenterology Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
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Keeley TM, Horita N, Samuelson LC. Tamoxifen-Induced Gastric Injury: Effects of Dose and Method of Administration. Cell Mol Gastroenterol Hepatol 2019; 8:365-367. [PMID: 31233898 PMCID: PMC6713893 DOI: 10.1016/j.jcmgh.2019.06.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 05/23/2019] [Accepted: 06/03/2019] [Indexed: 12/12/2022]
Affiliation(s)
- Theresa M Keeley
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Nobukatsu Horita
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Linda C Samuelson
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
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Distinct Localization of Mature HGF from its Precursor Form in Developing and Repairing the Stomach. Int J Mol Sci 2019; 20:ijms20122955. [PMID: 31212972 PMCID: PMC6628191 DOI: 10.3390/ijms20122955] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 06/06/2019] [Accepted: 06/13/2019] [Indexed: 01/23/2023] Open
Abstract
Hepatocyte growth factor (HGF) is secreted as an inactive single-chain HGF (scHGF); however, only proteolytically processed two-chain HGF (tcHGF) can activate the MET receptor. We investigated the localization of tcHGF and activated/phosphorylated MET (pMET) using a tcHGF-specific antibody. In day 16.5 mouse embryos, total HGF (scHGF + tcHGF) was mainly localized in smooth muscle cells close to, but separate from, MET-positive epithelial cells in endodermal organs, including the stomach. In the adult stomach, total HGF was localized in smooth muscle cells, and tcHGF was mainly localized in the glandular base region. Immunostaining for pMET and Lgr5-driven green fluorescent protein (GFP) indicated that pMET localization overlapped with Lgr5+ gastric stem cells. HGF promoted organoid formation similar to EGF, indicating the potential for HGF to promote the survival and growth of gastric stem cells. pMET and tcHGF localizations changed during regeneration following gastric injury. These results indicate that MET is constantly activated in gastric stem cells and that the localization of pMET differs from the primary localization of precursor HGF but has a close relationship to tcHGF. Our results suggest the importance of the microenvironmental generation of tcHGF in the regulation of development, regeneration, and stem cell behavior.
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Sáenz JB, Vargas N, Mills JC. Tropism for Spasmolytic Polypeptide-Expressing Metaplasia Allows Helicobacter pylori to Expand Its Intragastric Niche. Gastroenterology 2019; 156:160-174.e7. [PMID: 30287170 PMCID: PMC6309511 DOI: 10.1053/j.gastro.2018.09.050] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 09/10/2018] [Accepted: 09/25/2018] [Indexed: 01/18/2023]
Abstract
BACKGROUND & AIMS In patients with chronic Helicobacter pylori (H pylori) infection, parietal and chief cell atrophy in the gastric corpus, a process known as spasmolytic polypeptide-expressing metaplasia (SPEM), increases the risk for progression to cancer. The relation between H pylori and these metaplastic changes is unclear. We investigated whether H pylori localizes to regions of SPEM. METHODS We developed an in situ adherence assay in which we incubated H pylori with free-floating tissue sections from the gastric corpora of mice; we assessed H pylori distribution along the gastric unit by immunofluorescence. We analyzed the interactions of H pylori with tissue collected from mice with acute SPEM, induced by high-dose tamoxifen. We also evaluated how adhesin-deficient H pylori strains, chemical competition assays, and epithelial glycosylation affected H pylori adhesion to SPEM glands. Mice colonized with the mouse-adapted PMSS1 strain were analyzed for H pylori colonization in vivo during tamoxifen-induced SPEM or after decrease of stomach acid with omeprazole. RESULTS Compared with uninjured glands, H pylori penetrated deep within SPEM glands, in situ, through interaction of its adhesin, SabA, with sialyl-Lewis X, which expanded in SPEM. H pylori markedly increased gastric corpus colonization when SPEM was induced, but this proximal spread reversed in mice allowed to recover from SPEM. Decreasing corpus acidity also promoted proximal spread. However, H pylori penetrated deep within corpus glands in vivo only when sialyl-Lewis X expanded during SPEM. CONCLUSIONS Helicobacter pylori differentially binds SPEM glands in situ and in mice, in large part by interacting with sialyl-Lewis X. Our findings indicate that H pylori expands its niche into the gastric corpus by promoting and exploiting epithelial metaplastic changes that can lead to tumorigenesis.
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Affiliation(s)
- José B Sáenz
- Division of Gastroenterology, Department of Internal Medicine, Washington University in St Louis School of Medicine, St Louis, Missouri
| | - Nancy Vargas
- Division of Gastroenterology, Department of Internal Medicine, Washington University in St Louis School of Medicine, St Louis, Missouri
| | - Jason C Mills
- Division of Gastroenterology, Department of Internal Medicine, Washington University in St Louis School of Medicine, St Louis, Missouri; Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, Missouri; Department of Developmental Biology, Washington University in St Louis School of Medicine, St Louis, Missouri.
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Lrig1 marks a population of gastric epithelial cells capable of long-term tissue maintenance and growth in vitro. Sci Rep 2018; 8:15255. [PMID: 30323305 PMCID: PMC6189208 DOI: 10.1038/s41598-018-33578-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 10/02/2018] [Indexed: 12/16/2022] Open
Abstract
The processes involved in renewal of the epithelium that lines the mouse stomach remain unclear. Apart from the cells in the isthmus, several other populations located deeper in the gastric glands have been suggested to contribute to the maintenance of the gastric epithelium. Here, we reveal that Lrig1 is expressed in the basal layer of the forestomach and the lower part of glands in the corpus and pylorus. In the glandular epithelium of the stomach, Lrig1 marks a heterogeneous population comprising mainly non-proliferative cells. Yet, fate-mapping experiments using a knock-in mouse line expressing Cre specifically in Lrig1+ cells demonstrate that these cells are able to contribute to the long-term maintenance of the gastric epithelium. Moreover, when cultured in vitro, cells expressing high level of Lrig1 have much higher organoid forming potential than the corresponding cellular populations expressing lower levels of Lrig1. Taken together, these observations show that Lrig1 is expressed primarily by differentiated cells, but that these cells can be recruited to contribute to the maintenance of the gastric epithelium. This confirms previous observations that cells located in the lower segments of gastric glands can participate in tissue replenishment.
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Abstract
Chronic injury and inflammation in the esophagus can cause a change in cellular differentiation known as metaplasia. Most commonly, the differentiation changes manifest as Barrett's esophagus (BE), characterized by the normal stratified squamous epithelium converting into a cuboidal-columnar, glandular morphology. BE cells can phenotypically resemble specific normal cell types of the stomach or intestine, or they can have overlapping phenotypes in disorganized admixtures. The stomach can also undergo metaplasia characterized by aberrant gastric or intestinal differentiation patterns. In both organs, it has been argued that metaplasia may represent a recapitulation of the embryonic or juvenile gastrointestinal tract, as cells access a developmental progenitor genetic program that can help repair damaged tissue. Here, we review the normal development of esophagus and stomach, and describe how BE represents an intermixing of cells resembling gastric pseudopyloric (SPEM) and intestinal metaplasia. We discuss a cellular process recently termed "paligenosis" that governs how mature, differentiated cells can revert to a proliferating progenitor state in metaplasia. We discuss the "Cyclical Hit" theory in which paligenosis might be involved in the increased risk of metaplasia for progression to cancer. However, somatic mutations might occur in proliferative phases and then be warehoused upon redifferentiation. Through years of chronic injury and many rounds of paligenosis and dedifferentiation, eventually a cell with a mutation that prevents dedifferentiation may arise and clonally expand fueling stable metaplasia and potentially thereafter acquiring additional mutations and progressing to dysplasia and cancer.
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Affiliation(s)
- Ramon U Jin
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Jason C Mills
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
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Burclaff J, Mills JC. Plasticity of differentiated cells in wound repair and tumorigenesis, part I: stomach and pancreas. Dis Model Mech 2018; 11:dmm033373. [PMID: 30037967 PMCID: PMC6078397 DOI: 10.1242/dmm.033373] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
For the last century or so, the mature, differentiated cells throughout the body have been regarded as largely inert with respect to their regenerative potential, yet recent research shows that they can become progenitor-like and re-enter the cell cycle. Indeed, we recently proposed that mature cells can become regenerative via a conserved set of molecular mechanisms ('paligenosis'), suggesting that a program for regeneration exists alongside programs for death (apoptosis) and division (mitosis). In two Reviews describing how emerging concepts of cellular plasticity are changing how the field views regeneration and tumorigenesis, we present the commonalities in the molecular and cellular features of plasticity at homeostasis and in response to injury in multiple organs. Here, in part 1, we discuss these advances in the stomach and pancreas. Understanding the extent of cell plasticity and uncovering its underlying mechanisms may help us refine important theories about the origin and progression of cancer, such as the cancer stem cell model, as well as the multi-hit model of tumorigenesis. Ultimately, we hope that the new concepts and perspectives on inherent cellular programs for regeneration and plasticity may open novel avenues for treating or preventing cancers.
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Affiliation(s)
- Joseph Burclaff
- Division of Gastroenterology, Departments of Medicine, Pathology and Immunology, and Developmental Biology, Washington University, St Louis, MO 63110, USA
| | - Jason C Mills
- Division of Gastroenterology, Departments of Medicine, Pathology and Immunology, and Developmental Biology, Washington University, St Louis, MO 63110, USA
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Sáenz JB, Mills JC. Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer. Nat Rev Gastroenterol Hepatol 2018; 15:257-273. [PMID: 29463907 PMCID: PMC6016373 DOI: 10.1038/nrgastro.2018.5] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Subjected to countless daily injuries, the stomach still functions as a remarkably efficient digestive organ and microbial filter. In this Review, we follow the lead of the earliest gastroenterologists who were fascinated by the antiseptic and digestive powers of gastric secretions. We propose that it is easiest to understand how the stomach responds to injury by stressing the central role of the most important gastric secretion, acid. The stomach follows two basic patterns of adaptation. The superficial response is a pattern whereby the surface epithelial cells migrate and rapidly proliferate to repair erosions induced by acid or other irritants. The stomach can also adapt through a glandular response when the source of acid is lost or compromised (that is, the process of oxyntic atrophy). We primarily review the mechanisms governing the glandular response, which is characterized by a metaplastic change in cellular differentiation known as spasmolytic polypeptide-expressing metaplasia (SPEM). We propose that the stomach, like other organs, exhibits marked cellular plasticity: the glandular response involves reprogramming mature cells to serve as auxiliary stem cells that replace lost cells. Unfortunately, such plasticity might mean that the gastric epithelium undergoes cycles of differentiation and de-differentiation that increase the risk of accumulating cancer-predisposing mutations.
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Affiliation(s)
- José B. Sáenz
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine
| | - Jason C. Mills
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine
- Department of Developmental Biology, Washington University School of Medicine
- Department of Pathology and Immunology, Washington University School of Medicine
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Willet SG, Lewis MA, Miao ZF, Liu D, Radyk MD, Cunningham RL, Burclaff J, Sibbel G, Lo HYG, Blanc V, Davidson NO, Wang ZN, Mills JC. Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis. EMBO J 2018; 37:e98311. [PMID: 29467218 PMCID: PMC5881627 DOI: 10.15252/embj.201798311] [Citation(s) in RCA: 129] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 01/18/2018] [Accepted: 01/19/2018] [Indexed: 12/18/2022] Open
Abstract
In 1900, Adami speculated that a sequence of context-independent energetic and structural changes governed the reversion of differentiated cells to a proliferative, regenerative state. Accordingly, we show here that differentiated cells in diverse organs become proliferative via a shared program. Metaplasia-inducing injury caused both gastric chief and pancreatic acinar cells to decrease mTORC1 activity and massively upregulate lysosomes/autophagosomes; then increase damage associated metaplastic genes such as Sox9; and finally reactivate mTORC1 and re-enter the cell cycle. Blocking mTORC1 permitted autophagy and metaplastic gene induction but blocked cell cycle re-entry at S-phase. In kidney and liver regeneration and in human gastric metaplasia, mTORC1 also correlated with proliferation. In lysosome-defective Gnptab-/- mice, both metaplasia-associated gene expression changes and mTORC1-mediated proliferation were deficient in pancreas and stomach. Our findings indicate differentiated cells become proliferative using a sequential program with intervening checkpoints: (i) differentiated cell structure degradation; (ii) metaplasia- or progenitor-associated gene induction; (iii) cell cycle re-entry. We propose this program, which we term "paligenosis", is a fundamental process, like apoptosis, available to differentiated cells to fuel regeneration following injury.
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Affiliation(s)
- Spencer G Willet
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Mark A Lewis
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Zhi-Feng Miao
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Dengqun Liu
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Megan D Radyk
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Rebecca L Cunningham
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA
| | - Joseph Burclaff
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Greg Sibbel
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Hei-Yong G Lo
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Valerie Blanc
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Nicholas O Davidson
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Zhen-Ning Wang
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jason C Mills
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
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Radyk MD, Burclaff J, Willet SG, Mills JC. Metaplastic Cells in the Stomach Arise, Independently of Stem Cells, via Dedifferentiation or Transdifferentiation of Chief Cells. Gastroenterology 2018; 154:839-843.e2. [PMID: 29248442 PMCID: PMC5847468 DOI: 10.1053/j.gastro.2017.11.278] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 11/27/2017] [Accepted: 11/27/2017] [Indexed: 02/08/2023]
Abstract
Spasmolytic polypeptide-expressing metaplasia (SPEM) develops in patients with chronic atrophic gastritis due to infection with Helicobacter pylori; it might be a precursor to intestinal metaplasia and gastric adenocarcinoma. Lineage tracing experiments of the gastric corpus in mice have not established whether SPEM derives from proliferating stem cells or differentiated, post-mitotic zymogenic chief cells in the gland base. We investigated whether differentiated cells can give rise to SPEM using a nongenetic approach in mice. Mice were given intraperitoneal injections of 5-fluorouracil, which blocked gastric cell proliferation, plus tamoxifen to induce SPEM. Based on analyses of molecular and histologic markers, we found SPEM developed even in the absence of cell proliferation. SPEM therefore did not arise from stem cells. In histologic analyses of gastric resection specimens from 10 patients with adenocarcinoma, we found normal zymogenic chief cells that were transitioning into SPEM cells only in gland bases, rather than the proliferative stem cell zone. Our findings indicate that SPEM can arise by direct reprogramming of existing cells-mainly of chief cells.
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Affiliation(s)
- Megan D Radyk
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri
| | - Joseph Burclaff
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri
| | - Spencer G Willet
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri
| | - Jason C Mills
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri; Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
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Burkitt MD, Williams JM, Townsend T, Hough R, Duckworth CA, Pritchard DM. Mice lacking NF-κB1 exhibit marked DNA damage responses and more severe gastric pathology in response to intraperitoneal tamoxifen administration. Cell Death Dis 2017; 8:e2939. [PMID: 28726772 PMCID: PMC5584614 DOI: 10.1038/cddis.2017.332] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 06/14/2017] [Accepted: 06/15/2017] [Indexed: 01/15/2023]
Abstract
Tamoxifen (TAM) has recently been shown to cause acute gastric atrophy and metaplasia in mice. We have previously demonstrated that the outcome of Helicobacter felis infection, which induces similar gastric lesions in mice, is altered by deletion of specific NF-κB subunits. Nfkb1-/- mice developed more severe gastric atrophy than wild-type (WT) mice 6 weeks after H. felis infection. In contrast, Nfkb2-/- mice were protected from this pathology. We therefore hypothesized that gastric lesions induced by TAM may be similarly regulated by signaling via NF-κB subunits. Groups of five female C57BL/6 (WT), Nfkb1-/-, Nfkb2-/- and c-Rel-/- mice were administered 150 mg/kg TAM by IP injection. Seventy-two hours later, gastric corpus tissues were taken for quantitative histological assessment. In addition, groups of six female WT and Nfkb1-/- mice were exposed to 12 Gy γ-irradiation. Gastric epithelial apoptosis was quantified 6 and 48 h after irradiation. TAM induced gastric epithelial lesions in all strains of mice, but this was more severe in Nfkb1-/- mice than in WT mice. Nfkb1-/- mice exhibited more severe parietal cell loss than WT mice, had increased gastric epithelial expression of Ki67 and had an exaggerated gastric epithelial DNA damage response as quantified by γH2AX. To investigate whether the difference in gastric epithelial DNA damage response of Nfkb1-/- mice was unique to TAM-induced DNA damage or a generic consequence of DNA damage, we also assessed gastric epithelial apoptosis following γ-irradiation. Six hours after γ-irradiation, gastric epithelial apoptosis was increased in the gastric corpus and antrum of Nfkb1-/- mice. NF-κB1-mediated signaling regulates the development of gastric mucosal pathology following TAM administration. This is associated with an exaggerated gastric epithelial DNA damage response. This aberrant response appears to reflect a more generic sensitization of the gastric mucosa of Nfkb1-/- mice to DNA damage.
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Affiliation(s)
- Michael D Burkitt
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, The Henry Wellcome Laboratory, Liverpool, UK
| | | | - Tristan Townsend
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, The Henry Wellcome Laboratory, Liverpool, UK
| | - Rachael Hough
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, The Henry Wellcome Laboratory, Liverpool, UK
| | | | - D Mark Pritchard
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, The Henry Wellcome Laboratory, Liverpool, UK
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Burclaff J, Osaki LH, Liu D, Goldenring JR, Mills JC. Targeted Apoptosis of Parietal Cells Is Insufficient to Induce Metaplasia in Stomach. Gastroenterology 2017; 152:762-766.e7. [PMID: 27932312 PMCID: PMC5391042 DOI: 10.1053/j.gastro.2016.12.001] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Revised: 11/10/2016] [Accepted: 12/01/2016] [Indexed: 12/14/2022]
Abstract
Parietal cell atrophy is considered to cause metaplasia in the stomach. We developed mice that express the diphtheria toxin receptor specifically in parietal cells to induce their death, and found this to increase proliferation in the normal stem cell zone and neck but not to cause metaplastic reprogramming of chief cells. Furthermore, the metaplasia-inducing agents tamoxifen or DMP-777 still induced metaplasia even after previous destruction of parietal cells by diphtheria toxin. Atrophy of parietal cells alone therefore is not sufficient to induce metaplasia: completion of metaplastic reprogramming of chief cells requires mechanisms beyond parietal cell injury or death.
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Affiliation(s)
- Joseph Burclaff
- Division of Gastroenterology, Department of Medicine, Department of Pathology and Immunology, Department of Developmental Biology, Washington University, St. Louis, Missouri
| | - Luciana H Osaki
- Division of Gastroenterology, Department of Medicine, Department of Pathology and Immunology, Department of Developmental Biology, Washington University, St. Louis, Missouri
| | - Dengqun Liu
- Institute of Combined Injury, College of Preventive Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
| | - James R Goldenring
- Nashville Veterans Affairs Medical Center, Epithelial Biology Center, Department of Surgery, and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Jason C Mills
- Division of Gastroenterology, Department of Medicine, Department of Pathology and Immunology, Department of Developmental Biology, Washington University, St. Louis, Missouri.
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A single transcription factor is sufficient to induce and maintain secretory cell architecture. Genes Dev 2017; 31:154-171. [PMID: 28174210 PMCID: PMC5322730 DOI: 10.1101/gad.285684.116] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 01/13/2017] [Indexed: 01/02/2023]
Abstract
Here, Lo et al. demonstrate that cell architecture can be controlled by a developmentally regulated transcriptional program independent of the program that specifies cell identity. They show that MIST1 (BHLHA15) is a “scaling factor” that universally establishes secretory morphology in cells that perform regulated secretion, and targeted deletion of MIST1 causes dismantling of the secretory apparatus of diverse exocrine cells. We hypothesized that basic helix–loop–helix (bHLH) MIST1 (BHLHA15) is a “scaling factor” that universally establishes secretory morphology in cells that perform regulated secretion. Here, we show that targeted deletion of MIST1 caused dismantling of the secretory apparatus of diverse exocrine cells. Parietal cells (PCs), whose function is to pump acid into the stomach, normally lack MIST1 and do not perform regulated secretion. Forced expression of MIST1 in PCs caused them to expand their apical cytoplasm, rearrange mitochondrial/lysosome trafficking, and generate large secretory granules. Mist1 induced a cohort of genes regulated by MIST1 in multiple organs but did not affect PC function. MIST1 bound CATATG/CAGCTG E boxes in the first intron of genes that regulate autophagosome/lysosomal degradation, mitochondrial trafficking, and amino acid metabolism. Similar alterations in cell architecture and gene expression were also caused by ectopically inducing MIST1 in vivo in hepatocytes. Thus, MIST1 is a scaling factor necessary and sufficient by itself to induce and maintain secretory cell architecture. Our results indicate that, whereas mature cell types in each organ may have unique developmental origins, cells performing similar physiological functions throughout the body share similar transcription factor-mediated architectural “blueprints.”
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Abstract
Intestinal-type gastric adenocarcinoma evolves in a field of pre-existing metaplasia. Over the past 20 years, a number of murine models have been developed to address aspects of the physiology and pathophysiology of metaplasia induction. Although none of these models has achieved true recapitulation of the induction of adenocarcinoma, they have led to important insights into the factors that influence the induction and progression of metaplasia. Here, we review the pathologic definitions relevant to alterations in gastric corpus lineages and classification of metaplasia by specific lineage markers. In addition, we review present murine models of the induction and progression of spasmolytic polypeptide (TFF2)-expressing metaplasia, the predominant metaplastic lineage observed in murine models. These models provide a basis for the development of a broader understanding of the physiological and pathophysiological roles of metaplasia in the stomach.
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Key Words
- ATPase, adenosine triphosphatase
- BMP, bone morphogenic protein
- Chief Cell
- EGF, epidermal growth factor
- EGFR, epidermal growth factor receptor
- Gastric Cancer
- Hip1r, Huntington interacting protein 1 related
- Hyperplasia
- IFN, interferon
- Intestinal Metaplasia
- MUC, mucin
- SDF1, stromal-derived factor 1
- SPEM
- SPEM, spasmolytic polypeptide–expressing metaplasia
- TFF, trefoil factor
- TFF2
- TGF, transforming growth factor
- Tg, transgene
- Th, T-helper
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