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Morris MT, Duncan BC, Piazuelo MB, Olfert IM, Xu X, Hussain S, Peek RM, Busada JT. Chronic Cigarette Smoke Exposure Masks Pathological Features of Helicobacter pylori Infection While Promoting Tumor Initiation. Cancer Prev Res (Phila) 2025; 18:271-281. [PMID: 39789851 PMCID: PMC12045739 DOI: 10.1158/1940-6207.capr-24-0378] [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: 08/18/2024] [Revised: 11/26/2024] [Accepted: 01/08/2025] [Indexed: 01/12/2025]
Abstract
Gastric cancer is the fifth most common cancer and the fifth leading cause of cancer deaths worldwide. Chronic infection by the bacterium Helicobacter pylori is the most prominent gastric cancer risk factor, but only 1% to 3% of infected individuals will develop gastric cancer. Cigarette smoking is another independent gastric cancer risk factor, and H. pylori-infected smokers are at a 2- to 11-fold increased risk of gastric cancer development, but the direct impacts of cigarette smoke (CS) on H. pylori pathogenesis remain unknown. In this study, male C57BL/6 mice were infected with H. pylori and began smoking within 1 week of infection. The mice were exposed to CS 5 days/week for 8 weeks. CS exposure had no notable impact on gross gastric morphology or inflammatory status compared with filtered-air (FA) exposed controls in mock-infected mice. However, CS exposure significantly blunted H. pylori-induced gastric inflammatory responses, reducing gastric atrophy and pyloric metaplasia development. Despite blunting these classic pathological features of H. pylori infection, CS exposures increased DNA damage within the gastric epithelial cells and accelerated H. pylori-induced dysplasia onset in the INS-GAS gastric cancer model. These data suggest that cigarette smoking may clinically silence classic clinical symptoms of H. pylori infection but enhance the accumulation of mutations and accelerate gastric cancer initiation. Prevention Relevance: These findings suggest that cigarette smoking suppresses pathophysiological hallmarks of H. pylori infection while accelerating gastric carcinogenesis. Therefore, smokers should receive screening for H. pylori infection to reduce gastric cancer risk. See related Spotlight, p. 257.
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Affiliation(s)
- Maeve T. Morris
- Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV, 26505, USA
| | - Benjamin C. Duncan
- Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV, 26505, USA
| | - M Blanca Piazuelo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - I. Mark Olfert
- Division of Exercise Physiology West Virginia University West Virginia University, Morgantown, WV, 26505, USA
- Department of Physiology, Pharmacology and Toxicology, West Virginia University, Morgantown, WV, 26505, USA
| | - Xiaojiang Xu
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, United States
| | - Salik Hussain
- Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV, 26505, USA
- Department of Physiology, Pharmacology and Toxicology, West Virginia University, Morgantown, WV, 26505, USA
| | - Richard M. Peek
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jonathan T. Busada
- Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV, 26505, USA
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Yoshihiro T, Yamaguchi K, Ariyama H, Koreishi S, Uehara K, Ohmura H, Ito M, Tsuchihashi K, Isobe T, Shindo K, Ohuchida K, Nakamura M, Nagao Y, Oda Y, Akashi K, Baba E. Elucidation of the mechanism of carcinogenic transformation of human gastric epithelial cells in atrophic gastritis. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167843. [PMID: 40220876 DOI: 10.1016/j.bbadis.2025.167843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 04/07/2025] [Accepted: 04/08/2025] [Indexed: 04/14/2025]
Abstract
BACKGROUND Helicobacter pylori infection and subsequent atrophic gastritis (AG) and intestinal metaplasia (IM) are regarded as precursor conditions for gastric cancer (GC). Though diverse mechanisms of carcinogenesis from AG and IM have been clarified using mouse models, few studies using human models have been reported. Here, we describe in vitro modeling of IM, as well as in vivo modeling of the oncogenic transformation from AG using human gastric organoids. METHODS Organoids derived from patients with AG were established and characterized by immunohistochemistry and in situ hybridization. Niche factor withdrawal and genetic engineering using CRISPR/Cas9 were conducted for modeling IM, and manipulated organoids were xenografted subcutaneously in mice to establish a GC model. RESULTS AG organoids (AGOs) were maintained by Wnt niche factors; withdrawal of these factors led to differentiation toward foveolar cells. Knockout of Runt-related transcription factor 3 (RUNX3), or activation of bone morphogenetic protein (BMP) signaling, resulted in accumulation of the key IM markers caudal-type homeobox 2 (CDX2) and mucin 2 (MUC2) in AGOs; disruption of SMAD4 counteracted the induction of these markers. Organoids doubly deficient for TP53 and SMAD4 formed larger and more proliferative p21 -negative subcutaneous tumors than did RUNX3-deficient organoids, suggesting that induction of a senescent state is a key barrier in stepwise carcinogenesis from AG. CONCLUSIONS Wnt signaling is essential for homeostasis of AG, and SMAD4-dependent activation of BMP signaling promotes intestinal differentiation. Combined disruption of TP53 and SMAD4 confers tumorigenic potential to AGOs by inhibiting p21 induction.
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Affiliation(s)
- Tomoyasu Yoshihiro
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Kyoko Yamaguchi
- Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Hiroshi Ariyama
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Sakuya Koreishi
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Koki Uehara
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Hirofumi Ohmura
- Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Mamoru Ito
- Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Kenji Tsuchihashi
- Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Taichi Isobe
- Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Koji Shindo
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Kenoki Ohuchida
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Yoshihiro Nagao
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Eishi Baba
- Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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Tu R, Zheng H, Zheng B, Zhong Q, Qian J, Wu F, Shiokawa T, Ochiai Y, Kobayashi H, Waterbury QT, Zamechek LB, Takahashi S, Mizuno S, Huang C, Li P, Hayakawa Y, Wang TC. Tff2 marks gastric corpus progenitors that give rise to pyloric metaplasia/SPEM following injury. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.09.647847. [PMID: 40291734 PMCID: PMC12027342 DOI: 10.1101/2025.04.09.647847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
In Brief Tu et al. show that Tff2 + corpus isthmus cells are TA progenitors, and they, not chief cells, are the primary source of SPEM following injury. Upon Kras mutation, these progenitors directly progress to dysplasia, bypassing metaplasia, highlighting them as a potential origin of gastric cancer. Highlights Tff2 + corpus cells are TA progenitors that give rise to secretory cells. Tff2 + progenitors, not chief cells, are the primary source of SPEM after injury. Kras-mutant Tff2 + progenitors progress directly to dysplasia, bypassing metaplasia. Multi-omics analysis reveals distinct trajectories for SPEM and gastric cancer. Abstract Figure Pyloric metaplasia, also known as spasmolytic polypeptide-expressing metaplasia (SPEM), arises in the corpus in response to oxyntic atrophy, but its origin and role in gastric cancer remain poorly understood. Using Tff2-CreERT knockin mice, we identified highly proliferative Tff2 + progenitors in the corpus isthmus that give rise to multiple secretory lineages, including chief cells. While lacking long-term self-renewal ability, Tff2 + corpus progenitors rapidly expand to form short-term SPEM following acute injury or loss of chief cells. Genetic ablation of Tff2 + progenitors abrogated SPEM formation, while genetic ablation of GIF + chief cells enhanced SPEM formation from Tff2 + progenitors. In response to H. pylori infection, Tff2 + progenitors progressed first to metaplasia and then later to dysplasia. Interestingly, induction of Kras G12D mutations in Tff2 + progenitors facilitated direct progression to dysplasia in part through the acquisition of stem cell-like properties. In contrast, Kras-mutated SPEM and chief cells were not able to progress to dysplasia. Tff2 mRNA was downregulated in isthmus cells during progression to dysplasia. Single-cell RNA sequencing and spatial transcriptomics of human tissues revealed distinct differentiation trajectories for SPEM and gastric cancer. These findings challenge the conventional interpretation of the stepwise progression through metaplasia and instead identify Tff2 + progenitor cells as potential cells of origin for SPEM and possibly for gastric cancer.
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Trinh VQH, Ankenbauer KE, Torbit SM, Liu J, Batardiere M, Kumar B, Maurer HC, Revetta F, Chen Z, Kruse A, Judd A, Copeland C, Wong J, Ben-Levy O, Jarvis B, Brown M, Brown JW, Das K, Makino Y, Spraggins JM, Lau K, Azadi P, Maitra A, Tan MCB, DelGiorno KE. Mutant GNAS drives a pyloric metaplasia with tumor suppressive glycans in intraductal papillary mucinous neoplasia. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.02.25.581948. [PMID: 38464029 PMCID: PMC10925208 DOI: 10.1101/2024.02.25.581948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
BACKGROUND & AIMS Intraductal Papillary Mucinous Neoplasms (IPMNs) are cystic lesions and bona fide precursors for pancreatic ductal adenocarcinoma (PDAC). Recent studies have shown that pancreatic precancer is characterized by a transcriptomic program similar to gastric metaplasia. The aims of this study were to assay IPMN for pyloric markers, to identify molecular drivers, and to determine a functional role for this program in the pancreas. METHODS Pyloric marker expression was evaluated by RNA-seq and multiplex immunostaining in patient samples. Cell lines and organoids expressing KrasG12D +/- GNASR201C underwent RNA sequencing. A PyScenic-based regulon analysis was performed to identify molecular drivers, and candidates were evaluated by RNA-seq, immunostaining, and small interfering RNA knockdown. Glycosylation profiling was performed to identify GNASR201C-driven changes. Glycan abundance was evaluated in patient samples. RESULTS Pyloric markers were identified in human IPMN. GNASR201C drove expression of this program as well as an indolent phenotype characterized by distinct glycosyltransferase changes. Glycan profiling identified an increase in LacdiNAcs and loss of pro-tumorigenic Lewis antigens. Knockdown of transcription factors Spdef or Creb3l1 or chitinase treatment reduced LacdiNAc deposition and reversed the indolent phenotype. LacdiNAc and 3-sulfoLeA/C abundance discriminated low from high grade patient IPMN. CONCLUSION GNASR201C drives an indolent phenotype in IPMN by amplifying a differentiated, pyloric phenotype through SPDEF/CREB3L1 which is characterized by distinct glycans. Acting as a glycan rheostat, mutant GNAS elevates LacdiNAcs at the expense of pro-tumorigenic acidic Lewis epitopes, inhibiting cancer cell invasion and disease progression. LacdiNAc and 3-Sulfo-LeA/C are mutually exclusive and may serve as markers of disease progression.
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He L, Zhang X, Zhang S, Wang Y, Hu W, Li J, Liu Y, Liao Y, Peng X, Li J, Zhao H, Wang L, Lv Y, Hu C, Yang S. H. Pylori-Facilitated TERT/Wnt/β-Catenin Triggers Spasmolytic Polypeptide-Expressing Metaplasia and Oxyntic Atrophy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2401227. [PMID: 39587848 PMCID: PMC11744579 DOI: 10.1002/advs.202401227] [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: 02/02/2024] [Revised: 10/23/2024] [Indexed: 11/27/2024]
Abstract
Persistent H. pylori infection triggers the repair program of the mucosa, such as spasmolytic polypeptide-expressing metaplasia (SPEM). However, the mechanism underlying the initiation of SPEM in gastric tissues by H. pylori remains unclear. Here, an increase in telomerase reverse transcriptase (TERT) protein expression is observed in chief cells upon infection with cagA-positive H. pylori. Tert knockout significantly ameliorated H. pylori-induced SPEM and single-cell RNA sequencing demonstrated that the Wnt/β-Catenin pathway is suppressed in gastric cells with Tert knockout. Mechanism study revealed that CagA elevated TERT abundance by disrupting the interaction between TERT and its novel E3 ligase, SYVN1. Interestingly, Nitazoxanide effectively relieved SPEM via inhibition of the Wnt/β-Catenin signaling in vivo. This results clarified the mechanism underlying which CagA activated the TERT/Wnt/β-Catenin pathway, thus promoting the dedifferentiation of chief cells and the occurrence of SPEM in gastric mucosa. This highlights a molecular basis for targeting CagA-activated Wnt signaling in chief cells for the treatment of gastric precancerous lesions.
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Affiliation(s)
- Lijiao He
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Xiao Zhang
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
- Cancer Center of Daping HospitalArmy Medical UniversityChongqing400000China
| | - Shengwei Zhang
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
- Department of GastroenterologyThe 987th Hospital of the Joint Logistics Support Force of the People's Liberation Army of China, BaojiShaanxi721000China
| | - Yi Wang
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
- Biological Science Research CenterSouthwest UniversityChongqing400715China
| | - Weichao Hu
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Jie Li
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Yunyi Liu
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Yu Liao
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Xue Peng
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Jianjun Li
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Haiyan Zhao
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Liting Wang
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
- Central LaboratoryArmy Medical UniversityChongqing400038China
| | - Yang‐Fan Lv
- Department of PathologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Chang‐Jiang Hu
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
| | - Shi‐Ming Yang
- Department of GastroenterologyThe Second Affiliated Hospital of Army Medical UniversityChongqing400037China
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Hoft SG, Brennan M, Carrero JA, Jackson NM, Pretorius CA, Bigley TM, Sáenz JB, DiPaolo RJ. Unveiling Cancer-Related Metaplastic Cells in Both Helicobacter pylori Infection and Autoimmune Gastritis. Gastroenterology 2025; 168:53-67. [PMID: 39236896 PMCID: PMC11663102 DOI: 10.1053/j.gastro.2024.08.032] [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: 04/23/2024] [Revised: 08/21/2024] [Accepted: 08/28/2024] [Indexed: 09/07/2024]
Abstract
BACKGROUND & AIMS Gastric metaplasia may arise as a consequence of chronic inflammation and is associated with an increased risk of gastric cancer development. Although Helicobacter pylori (Hp) infection and autoimmune gastritis (AIG) both induce gastric metaplasia, possible distinctions in resulting metaplastic cells and their respective cancer risks requires further investigation. METHODS Using both mouse models and human participants, we scrutinized the metaplasia originating from Hp infection and AIG. Gastric pathology and metaplasia were examined through histopathologic assessment. Molecular features of metaplastic cells were defined using single-cell transcriptomics in murine models of Hp infection and AIG, as well as in human biopsy specimens from patients with Hp infection and AIG. Expression of a newly defined cancer-related metaplastic biomarker was confirmed through immunofluorescence. RESULTS Metaplasia in Hp infection and AIG displayed comparable histopathologic and transcriptional features. Diverse metaplastic subtypes were identified across both disease settings, with subtle differences in the prevalence of certain subtypes between inflammatory contexts. Notably, Hp infection did not drive a unique metaplastic cell phenotype. One metaplastic subtype, which resembled incomplete intestinal metaplasia and shared transcriptional features with gastric cancer, was identified in both diseases. This cancer-like metaplastic subtype was characterized by expression of the cancer-associated biomarker ANPEP/CD13. CONCLUSION Both Hp infection and AIG trigger a diverse array of metaplastic cell types. Identification of a cancer-related metaplastic cell uniquely expressing ANPEP/CD13, present in both Hp- and AIG-induced gastritis, indicates the carcinogenic capacity of both diseases. This discovery can guide early detection and risk stratification for patients with chronic gastritis.
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Affiliation(s)
- Stella G Hoft
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Michelle Brennan
- Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Javier A Carrero
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Nicholas M Jackson
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Challen A Pretorius
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Tarin M Bigley
- Department of Pediatrics, Division of Rheumatology/Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri
| | - José B Sáenz
- Division of Gastroenterology, Departments of Medicine and Molecular Cell Biology, Washington University in St. Louis School of Medicine, St. Louis, Missouri
| | - Richard J DiPaolo
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
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Ye Q, Zhu Y, Ma Y, Wang Z, Xu G. Emerging role of spasmolytic polypeptide-expressing metaplasia in gastric cancer. J Gastrointest Oncol 2024; 15:2673-2683. [PMID: 39816029 PMCID: PMC11732338 DOI: 10.21037/jgo-24-508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 11/04/2024] [Indexed: 01/18/2025] Open
Abstract
Gastric cancer (GC) ranks among the top five most diagnosed cancers globally, with particularly high incidence and mortality rates observed in Asian regions. Despite certain advancements achieved through early screening and treatment strategies in many countries, GC continues to pose a significant public health challenge. Approximately 20% of patients infected with Helicobacter pylori develop precancerous lesions, among which metaplasia is the most critical. Except for intestinal metaplasia (IM), which is characterized by goblet cells appearing in the stomach glands, one type of mucous cell metaplasia, spasmolytic polypeptide-expressing metaplasia (SPEM), has attracted much attention. SPEM represents a specific epithelial cell alteration within the gastric mucosa, characterized by the expressing trefoil factor 2 (TFF2) in basal glands, resembling the basal metaplasia of deep antral gland cells. It primarily arises from the transdifferentiation of mature chief cells, mucous neck cells (MNCs), or isthmus stem cells. SPEM is commonly regarded as a precursor lesion in the development of gastric inflammation and subsequent carcinogenesis. The formation of SPEM is intricately associated with chronic gastric inflammation, Helicobacter pylori infection, and various other environmental and genetic factors. Recently, with the profound exploration of the biological and molecular mechanisms underlying SPEM, a deeper understanding of its role in GC initiation and progression has emerged. This review summarizes the role, molecular mechanisms, and clinical significance of SPEM in the onset and progression of GC.
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Affiliation(s)
- Qiange Ye
- Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, China
- Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yanmei Zhu
- Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yichun Ma
- Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhangding Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Guifang Xu
- Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, China
- Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
- Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
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Jiang Y, Glandorff C, Sun M. GSH and Ferroptosis: Side-by-Side Partners in the Fight against Tumors. Antioxidants (Basel) 2024; 13:697. [PMID: 38929136 PMCID: PMC11201279 DOI: 10.3390/antiox13060697] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/26/2024] [Accepted: 06/01/2024] [Indexed: 06/28/2024] Open
Abstract
Glutathione (GSH), a prominent antioxidant in organisms, exhibits diverse biological functions and is crucial in safeguarding cells against oxidative harm and upholding a stable redox milieu. The metabolism of GSH is implicated in numerous diseases, particularly in the progression of malignant tumors. Consequently, therapeutic strategies targeting the regulation of GSH synthesis and metabolism to modulate GSH levels represent a promising avenue for future research. This study aimed to elucidate the intricate relationship between GSH metabolism and ferroptosis, highlighting how modulation of GSH metabolism can impact cellular susceptibility to ferroptosis and consequently influence the development of tumors and other diseases. The paper provides a comprehensive overview of the physiological functions of GSH, including its structural characteristics, physicochemical properties, sources, and metabolic pathways, as well as investigate the molecular mechanisms underlying GSH regulation of ferroptosis and potential therapeutic interventions. Unraveling the biological role of GSH holds promise for individuals afflicted with tumors.
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Affiliation(s)
- Yulang Jiang
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.J.); (C.G.)
- Internal Medicine in Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Christian Glandorff
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.J.); (C.G.)
- Internal Medicine in Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- University Clinic of Hamburg at the HanseMerkur Center of TCM, 20251 Hamburg, Germany
| | - Mingyu Sun
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.J.); (C.G.)
- Internal Medicine in Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Druffner SR, Venkateshwaraprabu S, Khadka S, Duncan BC, Morris MT, Sen-Kilic E, Damron FH, Liechti GW, Busada JT. Comparison of gastric inflammation and metaplasia induced by Helicobacter pylori or Helicobacter felis colonization in mice. Microbiol Spectr 2024; 12:e0001524. [PMID: 38682907 PMCID: PMC11237807 DOI: 10.1128/spectrum.00015-24] [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: 01/04/2024] [Accepted: 03/18/2024] [Indexed: 05/01/2024] Open
Abstract
Gastric cancer is the fifth most diagnosed cancer in the world. Infection by the bacteria Helicobacter pylori (HP) is associated with approximately 75% of gastric cancer cases. HP infection induces chronic gastric inflammation, damaging the stomach and fostering carcinogenesis. Most mechanistic studies on gastric cancer initiation are performed in mice and utilize either mouse-adapted strains of HP or the natural mouse pathogen Helicobacter felis (HF). Here, we identified the differences in gastric inflammation, atrophy, and metaplasia associated with HP and HF infection in mice. PMSS1 HP strain or the CS1 HF strain were co-cultured with mouse peritoneal macrophages to assess their immunostimulatory effects. HP and HF induced similar cytokine production from cultured mouse peritoneal macrophages revealing that both bacteria exhibit similar immunostimulatory effects in vitro. Next, C57BL/6J mice were infected with HP or HF and were assessed 2 months post-infection. HP-infected mice caused modest inflammation within both the gastric corpus and antrum, and did not induce significant atrophy within the gastric corpus. In contrast, HF induced significant inflammation throughout the gastric corpus and antrum. Moreover, HF infection was associated with significant atrophy of the chief and parietal cell compartments and induced the expression of pyloric metaplasia (PM) markers. HP is poorly immunogenic compared to HF. HF induces dramatic CD4+ T cell activation, which is associated with increased gastric cancer risk in humans. Thus, HP studies in mice are better suited for studies on colonization, while HF is more strongly suited for studies on the effects of gastric inflammation on tumorigenesis. . IMPORTANCE Mouse infection models with Helicobacter species are widely used to study Helicobacter pathogenesis and gastric cancer initiation. However, Helicobacter pylori is not a natural mouse pathogen, and mouse-adapted H. pylori strains are poorly immunogenic. In contrast, Helicobacter felis is a natural mouse pathogen that induces robust gastric inflammation and is often used in mice to investigate gastric cancer initiation. Although both bacterial strains are widely used, their disease pathogenesis in mice differs dramatically. However, few studies have directly compared the pathogenesis of these bacterial species in mice, and the contrasting features of these two models are not clearly defined. This study directly compares the gastric inflammation, atrophy, and metaplasia development triggered by the widely used PMSS1 H. pylori and CS1 H. felis strains in mice. It serves as a useful resource for researchers to select the experimental model best suited for their studies.
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Affiliation(s)
- Sara R. Druffner
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Shrinidhi Venkateshwaraprabu
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Stuti Khadka
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Benjamin C. Duncan
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Maeve T. Morris
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Emel Sen-Kilic
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Fredrick H. Damron
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - George W. Liechti
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
| | - Jonathan T. Busada
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
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10
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Chong Y, Yu D, Lu Z, Nie F. Role and research progress of spasmolytic polypeptide‑expressing metaplasia in gastric cancer (Review). Int J Oncol 2024; 64:33. [PMID: 38299264 PMCID: PMC10836494 DOI: 10.3892/ijo.2024.5621] [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: 10/10/2023] [Accepted: 12/20/2023] [Indexed: 02/02/2024] Open
Abstract
Gastric cancer ranks as one of the most prevalent cancers worldwide. While the incidence of gastric cancer in Western countries has notably diminished over the past century, it continues to be a leading cause of cancer‑related mortality on a global scale. The majority of gastric cancers in humans are attributed to chronic Helicobacter pylori infection and the progression of gastric cancer is often preceded by gastritis, atrophy, metaplasia and dysplasia. However, the precise mechanisms underlying the development of gastric cancer remain ambiguous, including the formation of gastric polyps and precancerous lesions. In humans, two types of precancerous metaplasia have been identified in relation to gastric malignancies: Intestinal metaplasia and spasmolytic polypeptide‑expressing metaplasia (SPEM). The role of SPEM in the induction of gastric cancer has gained recent attention and its link with early‑stage human gastric cancer is increasingly evident. To gain insight into SPEM, the present study reviewed the role and research progress of SPEM in gastric cancer.
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Affiliation(s)
- Yang Chong
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
- Department of General Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
| | - Dong Yu
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
- Department of General Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
| | - Zhaoyu Lu
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
- Department of General Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
| | - Fengsong Nie
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
- Department of General Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
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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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Xiong M, Chen X, Wang H, Tang X, Wang Q, Li X, Ma H, Ye X. Combining transcriptomics and network pharmacology to reveal the mechanism of Zuojin capsule improving spasmolytic polypeptide-expressing metaplasia. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:117075. [PMID: 37625606 DOI: 10.1016/j.jep.2023.117075] [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: 07/06/2023] [Revised: 08/12/2023] [Accepted: 08/21/2023] [Indexed: 08/27/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Spasmolytic polypeptide-expressing metaplasia (SPEM) is a gastric precancerous lesion (GPL). Zuojin capsule (ZJC), consisting of Coptis chinensis Franch. (Ranunculaceae, recorded in the Chinese Pharmacopoeia as Rhizoma Coptidis) and Tetradium ruticarpum (A.Juss.) T.G.Hartley (Rutaceae, recorded in the Chinese Pharmacopoeia as Fructus Evodiae), has long been used for various gastrointestinal diseases. However, the effect and mechanism of ZJC on SPEM remain unclear. AIM OF THE STUDY To clarify the role of ZJC in improving SPEM and study its mechanism. MATERIALS AND METHODS The study utilized SPEM mice induced by 250 mg/kg body weight of tamoxifen (TAM) to assess the effects of ZJC and investigate its possible mechanisms. A strategy of transcriptomics combined with network pharmacology was conducted to explore the targets and mechanisms of ZJC in improving SPEM. The "ingredients-target-pathway" network was constructed, and the possible connections were verified by RT-qPCR and Western blot assays. RESULTS ZJC significantly attenuated the abnormal serological indices, destruction of the gastric mucosal structure, hyperplasia of gastric pits, increased gastric mucus, massive secretion of CD44 and TFF2, oxyntic atrophy and massive proliferation of stem/progenitor cells in TAM-induced SPEM mice. Combined transcriptomics and network pharmacology analysis, 50 core targets of ZJC related to SPEM improvement were obtained. KEGG results showed that the core targets were significantly enriched in the cell cycle, and PI3K-AKT signaling pathway. The top-ranked targets according to PPI network analysis were CDK1, CCNB1, and CCNA2, which are also associated with cell cycle. Combined experiments demonstrated that ZJC can induce G2/M phase cycle arrest and inhibit TAM-induced malignant proliferation by regulating abnormal activation of cell cycle-related proteins such as CDK1, CCNB1, CCNA2 and PI3K-AKT signaling pathways. CONCLUSIONS ZJC may improve TAM-induced SPEM by inhibiting abnormal activation of cell cycle-related proteins (CDK1, CCNB1, CCNA2) and PI3K-AKT signaling pathway. This finding supports the use of ZJC, a famous traditional Chinese medicine compound, as a potential treatment for gastric precancerous lesions.
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Affiliation(s)
- Mengyuan Xiong
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing, 400715, China.
| | - Xiantao Chen
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing, 400715, China.
| | - Hongmei Wang
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing, 400715, China.
| | - Xiang Tang
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing, 400715, China.
| | - Qiaojiao Wang
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing, 400715, China.
| | - Xuegang Li
- College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.
| | - Hang Ma
- College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.
| | - Xiaoli Ye
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing, 400715, China.
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13
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Druffner SR, Venkateshwaraprabu S, Khadka S, Duncan BC, Morris MT, Sen-Kilic E, Damron FH, Liechti GW, Busada JT. Comparison of gastric inflammation and metaplasia induced by Helicobacter pylori or Helicobacter felis colonization in mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.22.573128. [PMID: 38187587 PMCID: PMC10769338 DOI: 10.1101/2023.12.22.573128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Background Gastric cancer is the fifth most diagnosed cancer in the world. Infection by the bacteria Helicobacter pylori (HP) is associated with approximately 75% of gastric cancer cases. HP infection induces chronic gastric inflammation, damaging the stomach and fostering carcinogenesis. Most mechanistic studies on Helicobacter- induced gastric cancer initiation are performed in mice and utilize either mouse-adapted strains of HP or the natural mouse pathogen Helicobacter felis (HF). Each of these infection models is associated with strengths and weaknesses. Here, we identified the differences in immunogenicity and gastric pathological changes associated with HP and HF infection in mice. Material and Methods PMSS1 HP strain or with the CS1 HF strain were co-cultured with mouse peritoneal macrophages to assess their immunostimulatory effects. C57BL/6J mice were infected with HP or HF, and gastric inflammation, atrophy, and metaplasia development were assessed 2 months post-infection. Results HP and HF induced similar cytokine production from cultured mouse peritoneal macrophages. HP-infected mice caused modest inflammation within both the gastric corpus and antrum and did not induce significant atrophy within the gastric corpus. In contrast, HF induced significant inflammation throughout the gastric corpus and antrum. Moreover, HF infection was associated with significant atrophy of the chief and parietal cell compartments and induced expression of pyloric metaplasia markers. Conclusions HP is poorly immunogenic compared to HF. HF induces dramatic CD4+ T cell activation, which is associated with increased gastric cancer risk in humans. Thus, HP studies in mice are better suited for studies on colonization, while HF is more strongly suited for pathogenesis and cancer initiation studies.
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14
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Li ML, Hong XX, Zhang WJ, Liang YZ, Cai TT, Xu YF, Pan HF, Kang JY, Guo SJ, Li HW. Helicobacter pylori plays a key role in gastric adenocarcinoma induced by spasmolytic polypeptide-expressing metaplasia. World J Clin Cases 2023; 11:3714-3724. [PMID: 37383139 PMCID: PMC10294147 DOI: 10.12998/wjcc.v11.i16.3714] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 03/01/2023] [Accepted: 04/23/2023] [Indexed: 06/02/2023] Open
Abstract
Heliobacter pylori (H. pylori), a group 1 human gastric carcinogen, is significantly associated with chronic gastritis, gastric mucosal atrophy, and gastric cancer. Approximately 20% of patients infected with H. pylori develop precancerous lesions, among which metaplasia is the most critical. Except for intestinal metaplasia (IM), which is characterized by goblet cells appearing in the stomach glands, one type of mucous cell metaplasia, spasmolytic polypeptide-expressing metaplasia (SPEM), has attracted much attention. Epidemiological and clinicopathological studies suggest that SPEM may be more strongly linked to gastric adenocarcinoma than IM. SPEM, characterized by abnormal expression of trefoil factor 2, mucin 6, and Griffonia simplicifolia lectin II in the deep glands of the stomach, is caused by acute injury or inflammation. Although it is generally believed that the loss of parietal cells alone is a sufficient and direct cause of SPEM, further in-depth studies have revealed the critical role of immunosignals. There is controversy regarding whether SPEM cells originate from the transdifferentiation of mature chief cells or professional progenitors. SPEM plays a functional role in the repair of gastric epithelial injury. However, chronic inflammation and immune responses caused by H. pylori infection can induce further progression of SPEM to IM, dysplasia, and adenocarcinoma. SPEM cells upregulate the expression of whey acidic protein 4-disulfide core domain protein 2 and CD44 variant 9, which recruit M2 macrophages to the wound. Studies have revealed that interleukin-33, the most significantly upregulated cytokine in macrophages, promotes SPEM toward more advanced metaplasia. Overall, more effort is needed to reveal the specific mechanism of SPEM malignant progression driven by H. pylori infection.
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Affiliation(s)
- Mian-Li Li
- Department of Gastroenterology, Shenzhen Hospital of Integrated, Traditional Chinese and Western Medicine, Shenzhen 518033, Guangdong Province, China
| | - Xin-Xin Hong
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Wei-Jian Zhang
- Science and Technology Innovation Center, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Yi-Zhong Liang
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Tian-Tian Cai
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Yi-Fei Xu
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Hua-Feng Pan
- Science and Technology Innovation Center, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Jian-Yuan Kang
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Shao-Ju Guo
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Hai-Wen Li
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
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15
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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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16
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Liu X, Ma Z, Deng Z, Yi Z, Tuo B, Li T, Liu X. Role of spasmolytic polypeptide-expressing metaplasia in gastric mucosal diseases. Am J Cancer Res 2023; 13:1667-1681. [PMID: 37293144 PMCID: PMC10244109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 04/07/2023] [Indexed: 06/10/2023] Open
Abstract
Spasmolytic polypeptide-expressing metaplasia (SPEM) is a trefoil factor 2-expressing metaplasia in the fundic glands that resembles the fundic metaplasia of deep antral glandular cells and arises mainly from transdifferentiation of mature chief cells as well as mucous neck cells or isthmic stem cells. SPEM participates in the regulation of gastric mucosal injury, including focal and diffuse injury. This review focuses on the origin, models, and regulatory mechanisms of SPEM and on its role in the development of gastric mucosal injury. We hope to provide new prospects for the prevention and treatment of gastric mucosal diseases from the perspective of cell differentiation and transformation.
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Affiliation(s)
- Xi Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical UniversityZunyi, Guizhou, China
| | - Zhiyuan Ma
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical UniversityZunyi, Guizhou, China
| | - Zilin Deng
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical UniversityZunyi, Guizhou, China
| | - Zhiqiang Yi
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical UniversityZunyi, Guizhou, China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical UniversityZunyi, Guizhou, China
| | - Taolang Li
- Department of General Surgery, Affiliated Hospital of Zunyi Medical UniversityZunyi, Guizhou, China
| | - Xuemei Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical UniversityZunyi, Guizhou, China
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17
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Pan L, Han J, Lin M. Targeting breast cancer stem cells directly to treat refractory breast cancer. Front Oncol 2023; 13:981247. [PMID: 37251931 PMCID: PMC10213424 DOI: 10.3389/fonc.2023.981247] [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: 06/29/2022] [Accepted: 01/02/2023] [Indexed: 05/31/2023] Open
Abstract
For patients with refractory breast cancer (BC), integrative immunotherapies are emerging as a critical component of treatment. However, many patients remain unresponsive to treatment or relapse after a period. Different cells and mediators in the tumor microenvironment (TME) play important roles in the progression of BC, and cancer stem cells (CSCs) are deemed the main cause of relapse. Their characteristics depend on their interactions with their microenvironment as well as on the inducing factors and elements in this environment. Strategies to modulate the immune system in the TME of BC that are aimed at reversing the suppressive networks within it and eradicating residual CSCs are, thus, essential for improving the current therapeutic efficacy of BC. This review focuses on the development of immunoresistance in BCs and discusses the strategies that can modulate the immune system and target breast CSCs directly to treat BC including immunotherapy with immune checkpoint blockades.
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Affiliation(s)
- Liping Pan
- Wuhan Center for Clinical Laboratory, Wuhan, China
| | - Juan Han
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ming Lin
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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18
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Min J, Zhang C, Bliton RJ, Caldwell B, Caplan L, Presentation KS, Park DJ, Kong SH, Lee HS, Washington MK, Kim WH, Lau KS, Magness ST, Lee HJ, Yang HK, Goldenring JR, Choi E. Dysplastic Stem Cell Plasticity Functions as a Driving Force for Neoplastic Transformation of Precancerous Gastric Mucosa. Gastroenterology 2022; 163:875-890. [PMID: 35700772 PMCID: PMC9509466 DOI: 10.1053/j.gastro.2022.06.021] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 05/31/2022] [Accepted: 06/02/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Dysplasia carries a high risk of cancer development; however, the cellular mechanisms for dysplasia evolution to cancer are obscure. We have previously identified 2 putative dysplastic stem cell (DSC) populations, CD44v6neg/CD133+/CD166+ (double positive [DP]) and CD44v6+/CD133+/CD166+ (triple positive [TP]), which may contribute to cellular heterogeneity of gastric dysplasia. Here, we investigated functional roles and cell plasticity of noncancerous Trop2+/CD133+/CD166+ DSCs initially developed in the transition from precancerous metaplasia to dysplasia in the stomach. METHODS Dysplastic organoids established from active Kras-induced mouse stomachs were used for transcriptome analysis, in vitro differentiation, and in vivo tumorigenicity assessments of DSCs. Cell heterogeneity and genetic alterations during clonal evolution of DSCs were examined by next-generation sequencing. Tissue microarrays were used to identify DSCs in human dysplasia. We additionally evaluated the effect of casein kinase 1 alpha (CK1α) regulation on the DSC activities using both mouse and human dysplastic organoids. RESULTS We identified a high similarity of molecular profiles between DP- and TP-DSCs, but more dynamic activities of DP-DSCs in differentiation and survival for maintaining dysplastic cell lineages through Wnt ligand-independent CK1α/β-catenin signaling. Xenograft studies demonstrated that the DP-DSCs clonally evolve toward multiple types of gastric adenocarcinomas and promote cancer cell heterogeneity by acquiring additional genetic mutations and recruiting the tumor microenvironment. Last, growth and survival of both mouse and human dysplastic organoids were controlled by targeting CK1α. CONCLUSIONS These findings indicate that the DSCs are de novo gastric cancer-initiating cells responsible for neoplastic transformation and a promising target for intervention in early induction of gastric cancer.
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Affiliation(s)
- Jimin Min
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Changqing Zhang
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - R Jarrett Bliton
- Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina at Chapel Hill, Raleigh, North Carolina; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Brianna Caldwell
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Leah Caplan
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Kimberly S Presentation
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Do-Joong Park
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Seong-Ho Kong
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Seung Lee
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - M Kay Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Woo-Ho Kim
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Ken S Lau
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Scott T Magness
- Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina at Chapel Hill, Raleigh, North Carolina; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Hyuk-Joon Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Han-Kwang Yang
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - James R Goldenring
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Nashville VA Medical Center, Nashville, Tennessee
| | - Eunyoung Choi
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
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19
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He J, Hu W, Ouyang Q, Zhang S, He L, Chen W, Li X, Hu C. Helicobacter pylori infection induces stem cell-like properties in Correa cascade of gastric cancer. Cancer Lett 2022; 542:215764. [PMID: 35654291 DOI: 10.1016/j.canlet.2022.215764] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 05/16/2022] [Accepted: 05/26/2022] [Indexed: 02/09/2023]
Abstract
Gastric cancer (GC) is the fourth leading cause of cancer-related death. Its poor prognosis is attributed to unclear pathogenesis. Currently, the most widely accepted model for elucidating the mechanism of GC is the Correa cascade, which covers several histological lesions of the gastric mucosa. GC stem cells (CSCs) are crucial for oncogenesis in the Correa cascade and GC progression. As Helicobacter pylori (H. pylori) is the etiological factor in the Correa cascade, growing evidence suggests that enhancement of gastric stem cell-like properties and increase in CSCs correlate with H. pylori infection. In this paper, we review recent studies that present pathogenic mechanisms by which H. pylori induces gastric stem cell-like properties and CSCs, which may supplement the existing Correa model of GC. First, the dysfunction of developmental signaling pathways associated with H. pylori infection leads to the enhancement of gastric stemness. Second, H. pylori infection promotes alteration of the gastric mucosal microenvironment. In addition, epithelial-mesenchymal transition (EMT) may contribute to H. pylori-induced gastric stemness. Taken together, understanding these pathogeneses will provide potential therapeutic targets for the treatment of CSCs and malignant GC in H. pylori induced-Correa cascade of GC.
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Affiliation(s)
- JunJian He
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - WeiChao Hu
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Qin Ouyang
- Department of Medicinal Chemistry, College of Pharmacy, Army Medical University, Chongqing, 400038, China
| | - ShengWei Zhang
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - LiJiao He
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - WeiYan Chen
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - XinZhe Li
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
| | - ChangJiang Hu
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
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20
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Hsieh CH, Huang YW, Tsai TF. Oral Conventional Synthetic Disease-Modifying Antirheumatic Drugs with Antineoplastic Potential: a Review. Dermatol Ther (Heidelb) 2022; 12:835-860. [PMID: 35381976 PMCID: PMC9021342 DOI: 10.1007/s13555-022-00713-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Indexed: 01/17/2023] Open
Abstract
There is an increasing trend of malignancy worldwide. Disease-modifying antirheumatic drugs (DMARDs) are the cornerstones for the treatment of immune-mediated inflammatory diseases (IMIDs), but risk of malignancy is a major concern for patients receiving DMARDs. In addition, many IMIDs already carry higher background risks of neoplasms. Recently, the black box warning of malignancies has been added for Janus kinase inhibitors. Also, the use of biologic DMARDs in patients with established malignancies is usually discouraged owing to exclusion of such patients in pivotal studies and, hence, lack of evidence. In contrast, some conventional synthetic DMARDs (csDMARDs) have been reported to show antineoplastic properties and can be beneficial for patients with cancer. Among the csDMARDs, chloroquine and hydroxychloroquine have been the most extensively studied, and methotrexate is an established chemotherapeutic agent. Even cyclosporine A, a well-known drug associated with cancer risk, can potentiate the effect of some chemotherapeutic agents. We review the possible mechanisms behind and clinical evidence of the antineoplastic activities of csDMARDs, including chloroquine and hydroxychloroquine, cyclosporine, leflunomide, mycophenolate mofetil, mycophenolic acid, methotrexate, sulfasalazine, and thiopurines. This knowledge may guide physicians in the choice of csDMARDs for patients with concurrent IMIDs and malignancies.
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Affiliation(s)
- Cho-Hsun Hsieh
- Department of Medical Education, National Taiwan University Hospital, Taipei, Taiwan
| | - Yi-Wei Huang
- Department of Dermatology, National Taiwan University Hospital, 7 Chung Shan S Rd, Taipei, 10048, Taiwan
| | - Tsen-Fang Tsai
- Department of Dermatology, National Taiwan University Hospital, 7 Chung Shan S Rd, Taipei, 10048, Taiwan. .,Department of Dermatology, National Taiwan University Hospital & National Taiwan University College of Medicine, Taipei, Taiwan.
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21
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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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22
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Jeong H, Lee B, Kim KH, Cho SY, Cho Y, Park J, Lee Y, Oh Y, Hwang BR, Jang AR, Park JH, Park JH, Jeong SH, Lee D, Lee YC, Lim KM, Goldenring JR, Nam KT. WFDC2 Promotes Spasmolytic Polypeptide-Expressing Metaplasia Through the Up-Regulation of IL33 in Response to Injury. Gastroenterology 2021; 161:953-967.e15. [PMID: 34116028 PMCID: PMC8380710 DOI: 10.1053/j.gastro.2021.05.058] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 05/27/2021] [Accepted: 05/29/2021] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS WAP 4-disulfide core domain protein 2 (WFDC2), also known as human epididymis protein 4, is a small secretory protein that is highly expressed in fibrosis and human cancers, particularly in the ovaries, lungs, and stomach. However, the role of WFDC2 in carcinogenesis is not fully understood. The present study aimed to investigate the role of WFDC2 in gastric carcinogenesis with the use of preneoplastic metaplasia models. METHODS Three spasmolytic polypeptide-expressing metaplasia (SPEM) models were established in both wild-type and Wfdc2-knockout mice with DMP-777, L635, and high-dose tamoxifen, respectively. To reveal the functional role of WFDC2, we performed transcriptomic analysis with DMP-777-treated gastric corpus specimens. RESULTS Wfdc2-knockout mice exhibited remarkable resistance against oxyntic atrophy, SPEM emergence, and accumulation of M2-type macrophages in all 3 SPEM models. Transcriptomic analysis revealed that Wfdc2-knockout prevented the up-regulation of interleukin-33 (IL33) expression in the injured mucosal region of SPEM models. Notably, supplementation of recombinant WFDC2 induced IL33 production and M2 macrophage polarization, and ultimately promoted SPEM development. Moreover, long-term treatment with recombinant WFDC2 was able to induce SPEM development. CONCLUSIONS WFDC2 expressed in response to gastric injury promotes SPEM through the up-regulation of IL33 expression. These findings provide novel insights into the role of WFDC2 in gastric carcinogenesis.
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Affiliation(s)
- Haengdueng Jeong
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Buhyun Lee
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang H Kim
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | | | - Yejin Cho
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Jeongeun Park
- Department of Life Science, Ewha Womans University, Seoul, Korea
| | - Yura Lee
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Yeseul Oh
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Bo Ram Hwang
- Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul, Korea
| | - Ah-Ra Jang
- Laboratory of Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea
| | - Jong-Hwan Park
- Laboratory of Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea
| | - Ji-Ho Park
- Department of Surgery, Gyeongsang National University Hospital, Jinju, Korea
| | - Sang-Ho Jeong
- Department of Surgery, Gyeongsang National University Hospital, Jinju, Korea
| | - Daekee Lee
- Department of Life Science, Ewha Womans University, Seoul, Korea
| | - Yong Chan Lee
- Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung-Min Lim
- College of Pharmacy, Ewha Womans University, Seoul, Korea.
| | - James R Goldenring
- Epithelial Biology Center and Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee; Nashville VA Medical Center, Nashville, Tennessee.
| | - Ki Taek Nam
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
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23
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Hayashi N, Yamasaki A, Ueda S, Okazaki S, Ohno Y, Tanaka T, Endo Y, Tomioka Y, Masuko K, Masuko T, Sugiura R. Oncogenic transformation of NIH/3T3 cells by the overexpression of L-type amino acid transporter 1, a promising anti-cancer target. Oncotarget 2021; 12:1256-1270. [PMID: 34194623 PMCID: PMC8238248 DOI: 10.18632/oncotarget.27981] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 05/26/2021] [Indexed: 01/10/2023] Open
Abstract
L-type amino acid transporter 1 (LAT1)/SLC7A5 is the first identified CD98 light chain disulfide linked to the CD98 heavy chain (CD98hc/SLC3A2). LAT1 transports large neutral amino acids, including leucine, which activates mTOR, and is highly expressed in human cancers. We investigated the oncogenicity of human LAT1 introduced to NIH/3T3 cells by retrovirus infection. NIH/3T3 cell lines stably expressing human native (164C) or mutant (164S) LAT1 (naLAT1/3T3 or muLAT1/3T3, respectively) were established. We confirmed that endogenous mouse CD98hc forms a disulfide bond with exogenous human LAT1 in naLAT1/3T3, but not in muLAT1/3T3. Endogenous mouse CD98hc mRNA increased in both naNIH/3T3 and muLAT1/3T3, and a similar amount of exogenous human LAT1 protein was detected in both cell lines. Furthermore, naLAT1/3T3 and muLAT1/3T3 cell lines were evaluated for cell growth-related phenotypes (phosphorylation of ERK, cell-cycle progression) and cell malignancy-related phenotypes (anchorage-independent cell growth, tumor formation in nude mice). naLAT1/3T3 had stronger growth- and malignancy- related phenotypes than NIH/3T3 and muLAT1/3T3, suggesting the oncogenicity of native LAT1 through its interaction with CD98hc. Anti-LAT1 monoclonal antibodies significantly inhibited in vitro cell proliferation and in vivo tumor growth of naLAT1/3T3 cells in nude mice, demonstrating LAT1 to be a promising anti-cancer target.
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Affiliation(s)
- Natsumi Hayashi
- Laboratory of Molecular Pharmacogenomics, Faculty of Pharmacy, Kindai University, Higashiosaka-Shi, Osaka, Japan.,Cell Biology Laboratory, School of Pharmacy, Kindai University, Osaka, Japan.,Co-first authors.,This laboratory (April, 2000~) was closed at the end of March, 2020, after the mandatory retirement of Takashi Masuko
| | - Akitaka Yamasaki
- Cell Biology Laboratory, School of Pharmacy, Kindai University, Osaka, Japan.,Laboratory of Oncology Pharmacy Practice and Science, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai-Shi, Miyagi, Japan.,Co-first authors.,This laboratory (April, 2000~) was closed at the end of March, 2020, after the mandatory retirement of Takashi Masuko
| | - Shiho Ueda
- Cell Biology Laboratory, School of Pharmacy, Kindai University, Osaka, Japan
| | - Shogo Okazaki
- Division of Cell Fate Regulation, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda-shi, Chiba, Japan
| | - Yoshiya Ohno
- Laboratory of Immunobiology, Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe-Shi, Hyogo, Japan
| | - Toshiyuki Tanaka
- Laboratory of Immunobiology, Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe-Shi, Hyogo, Japan
| | - Yuichi Endo
- Natural Drug Resources, Faculty of Pharmacy, Kindai University, Osaka, Japan
| | - Yoshihisa Tomioka
- Laboratory of Oncology Pharmacy Practice and Science, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai-Shi, Miyagi, Japan
| | - Kazue Masuko
- Cell Biology Laboratory, School of Pharmacy, Kindai University, Osaka, Japan
| | - Takashi Masuko
- Cell Biology Laboratory, School of Pharmacy, Kindai University, Osaka, Japan.,Natural Drug Resources, Faculty of Pharmacy, Kindai University, Osaka, Japan
| | - Reiko Sugiura
- Laboratory of Molecular Pharmacogenomics, Faculty of Pharmacy, Kindai University, Higashiosaka-Shi, Osaka, Japan
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24
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Matsuzaki J, Tsugawa H, Suzuki H. Precision Medicine Approaches to Prevent Gastric Cancer. Gut Liver 2021; 15:3-12. [PMID: 31893631 PMCID: PMC7817924 DOI: 10.5009/gnl19257] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 10/18/2019] [Accepted: 11/15/2019] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer remains one of the most common causes of cancer-related death worldwide, although the incidence is declining gradually. The primary risk factor for gastric cancer is Helicobacter pylori infection. The Kyoto global consensus report recommends eradication of H. pylori in all infected patients. However, because it is difficult to stratify the risk of carcinogenesis among patients with a history of H. pylori infection, annual endoscopic surveillance is performed for everyone after eradication. This review summarizes the current approaches used to screen for novel molecules that could assist in the diagnosis of gastric cancer and reduce mortality. Most well-studied molecules are tissue protein biomarkers expressed by the gastric epithelium and associated with metaplasia-dysplasia-carcinoma sequences. Other strategies focus on the origin of cancer stem cell-related markers, such as CD44, and immune reaction-related markers, such as matrix metallopeptidases. Noninvasive methods such as blood-based approaches are more attractive. Serum pepsinogen levels predict the severity of gastric mucosal atrophy before H. pylori eradication, whereas plasma ghrelin levels are associated with atrophy even after eradication. Cell-free DNAs and RNAs are attractive tools for the early detection of cancer. These ideas could lead to the development of more personalized strategies for cancer prevention based on cutting-edge technologies.
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Affiliation(s)
- Juntaro Matsuzaki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hitoshi Tsugawa
- Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan
| | - Hidekazu Suzuki
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
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25
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De Salvo C, Pastorelli L, Petersen CP, Buttò LF, Buela KA, Omenetti S, Locovei SA, Ray S, Friedman HR, Duijser J, Xin W, Osme A, Cominelli F, Mahabeleshwar GH, Mills JC, Goldenring JR, Pizarro TT. Interleukin 33 Triggers Early Eosinophil-Dependent Events Leading to Metaplasia in a Chronic Model of Gastritis-Prone Mice. Gastroenterology 2021; 160:302-316.e7. [PMID: 33010253 PMCID: PMC7755675 DOI: 10.1053/j.gastro.2020.09.040] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Interleukin (IL)33/IL1F11 is an important mediator for the development of type 2 T-helper cell (Th2)-driven inflammatory disorders and has also been implicated in the pathogenesis of gastrointestinal (GI)-related cancers, including gastric carcinoma. We therefore sought to mechanistically determine IL33's potential role as a critical factor linking chronic inflammation and gastric carcinogenesis using gastritis-prone SAMP1/YitFc (SAMP) mice. METHODS SAMP and (parental control) AKR mice were assessed for baseline gastritis and progression to metaplasia. Expression/localization of IL33 and its receptor, ST2/IL1R4, were characterized in corpus tissues, and activation and neutralization studies were both performed targeting the IL33/ST2 axis. Dissection of immune pathways leading to metaplasia was evaluated, including eosinophil depletion studies using anti-IL5/anti-CCR3 treatment. RESULTS Progressive gastritis and, ultimately, intestinalized spasmolytic polypeptide-expressing metaplasia (SPEM) was detected in SAMP stomachs, which was absent in AKR but could be moderately induced with exogenous, recombinant IL33. Robust peripheral (bone marrow) expansion of eosinophils and local recruitment of both eosinophils and IL33-expressing M2 macrophages into corpus tissues were evident in SAMP. Interestingly, IL33 blockade did not affect bone marrow-derived expansion and local infiltration of eosinophils, but markedly decreased M2 macrophages and SPEM features, while eosinophil depletion caused a significant reduction in both local IL33-producing M2 macrophages and SPEM in SAMP. CONCLUSIONS IL33 promotes metaplasia and the sequelae of eosinophil-dependent downstream infiltration of IL33-producing M2 macrophages leading to intestinalized SPEM in SAMP, suggesting that IL33 represents a critical link between chronic gastritis and intestinalizing metaplasia that may serve as a potential therapeutic target for preneoplastic conditions of the GI tract.
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Affiliation(s)
| | - Luca Pastorelli
- Department of Pathology; Department of IRCCS Policlinico San Donato, Gastroenterology & Gastrointestinal Endoscopy Unit, San Donato Milanese, 20097 and Department of Biomedical Sciences, University of Milan, Milan, 20122, Italy
| | - Christine P. Petersen
- Department of Department of Surgery and the Epithelial Biology Center, Vanderbilt University, Nashville, TN, 37235, USA
| | - Ludovica F. Buttò
- Department of Medicine/Division of Gastroenterology & Liver Disease, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | | | | | - Silviu A. Locovei
- Department of Pathology; Department of Medicine/Division of Gastroenterology & Liver Disease, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | | | | | | | | | | | - Fabio Cominelli
- Department of Medicine/Division of Gastroenterology & Liver Disease, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | | | - Jason C. Mills
- Department of Medicine, Gastroenterology Division, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - James R. Goldenring
- Department of Department of Surgery and the Epithelial Biology Center, Vanderbilt University, Nashville, TN, 37235, USA
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26
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Zhang T, Li M, Lu H, Peng T. Up-Regulation of circEIF6 Contributes to Pancreatic Cancer Development Through Targeting miR-557/ SLC7A11/PI3K/AKT Signaling. Cancer Manag Res 2021; 13:247-258. [PMID: 33469368 PMCID: PMC7811442 DOI: 10.2147/cmar.s280307] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 11/30/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Accruing evidences have pointed out that abnormal expression of circular RNAs (circRNAs) was closely related to the development of many malignancies. The present study intended to disclose the role of circRNA eukaryotic translation initiation factor 6 (circEIF6; hsa_circ_0060055) in pancreatic cancer progression. METHODS Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to determine the expression of circEIF6, EIF6 messenger RNA (mRNA), microRNA-557 (miR-557) and solute carrier family 7 member 11 (SLC7A11) mRNA. Cell proliferation ability, migration and invasion abilities and apoptosis were evaluated by Cell Counting Kit 8 (CCK8) assay, transwell migration and invasion assays and flow cytometry. Western blot assay was performed for the expression determination of all proteins. The predicted interaction between miR-557 and circEIF6 or SLC7A11 was confirmed by dual-luciferase reporter assay. Xenograft tumor model was used for exploring the biological function of circEIF6 in vivo. RESULTS CircEIF6 abundance was aberrantly up-regulated in pancreatic tumor tissues and cell lines. Cell proliferation, migration and invasion were significantly restrained while cell apoptosis was induced with the silencing of circEIF6 in pancreatic cancer cells. CircEIF6 silencing also hampered the activation of phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) pathway. CircEIF6 bound to miR-557, and circEIF6 silencing elevated the expression of miR-557 in pancreatic cancer cells. MiR-557 knockdown partly overturned circEIF6 silencing-induced effects in pancreatic cancer cells. SLC7A11 was a target of miR-557, and miR-557 overexpression suppressed malignant potential of pancreatic cancer cells partly through reducing the expression of SLC7A11. CircEIF6 knockdown blocked xenograft tumor growth in vivo. CONCLUSION CircEIF6 aggravated pancreatic cancer development through promoting cell proliferation, migration and invasion and suppressing cell apoptosis through targeting miR-557/SLC7A11/PI3K/AKT signaling.
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Affiliation(s)
- Tiequan Zhang
- Department of Hepatobiliary Surgery, The First People’s Hospital of Jingzhou, Jingzhou434000, People’s Republic of China
- Correspondence: Tiequan Zhang Department of Hepatobiliary Surgery, The First People’s Hospital of Jingzhou, No. 8 Hangkong Road, Shashi District, Jingzhou, Hubei434000, People’s Republic of ChinaTel +86-716-8115036 Email
| | - Mi Li
- Department of Hepatobiliary Surgery, The First People’s Hospital of Jingzhou, Jingzhou434000, People’s Republic of China
| | - Haofeng Lu
- Department of Hepatobiliary Surgery, The First People’s Hospital of Jingzhou, Jingzhou434000, People’s Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First People’s Hospital of Jingzhou, Jingzhou434000, People’s Republic of China
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27
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Teal E, Dua-Awereh M, Hirshorn ST, Zavros Y. Role of metaplasia during gastric regeneration. Am J Physiol Cell Physiol 2020; 319:C947-C954. [PMID: 32755448 DOI: 10.1152/ajpcell.00415.2019] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Spasmolytic polypeptide/trefoil factor 2 (TFF2)-expressing metaplasia (SPEM) is a mucous-secreting reparative lineage that emerges at the ulcer margin in response to gastric injury. Under conditions of chronic inflammation with parietal cell loss, SPEM has been found to emerge and evolve into neoplasia. Cluster-of-differentiation gene 44 (CD44) is known to coordinate normal and metaplastic epithelial cell proliferation. In particular, CD44 variant isoform 9 (CD44v9) associates with the cystine-glutamate transporter xCT, stabilizes the protein, and provides defense against reactive oxygen species (ROS). xCT stabilization by CD44v9 leads to defense against ROS by cystine uptake, glutathione (GSH) synthesis, and maintenance of the redox balance within the intracellular environment. Furthermore, p38 signaling is a known downstream ROS target, leading to diminished cell proliferation and migration, two vital processes of gastric epithelial repair. CD44v9 emerges during repair of the gastric epithelium after injury, where it is coexpressed with other markers of SPEM. The regulatory mechanisms for the emergence of CD44v9 and the role of CD44v9 during the process of gastric epithelial regeneration are largely unknown. Inflammation and M2 macrophage infiltration have recently been demonstrated to play key roles in the induction of SPEM after injury. The following review proposes new insights into the functional role of metaplasia in the process of gastric regeneration in response to ulceration. Our insights are extrapolated from documented studies reporting oxyntic atrophy and SPEM development and our current unpublished findings using the acetic acid-induced gastric injury model.
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Affiliation(s)
- Emma Teal
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Martha Dua-Awereh
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.,Department of Cellular and Molecular Medicine, University of Arizona College of Medicine, Tucson, Arizona
| | - Sabrina T Hirshorn
- Department of Cellular and Molecular Medicine, University of Arizona College of Medicine, Tucson, Arizona
| | - Yana Zavros
- Department of Cellular and Molecular Medicine, University of Arizona College of Medicine, Tucson, Arizona
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Suwannakul N, Ma N, Midorikawa K, Oikawa S, Kobayashi H, He F, Kawanishi S, Murata M. CD44v9 Induces Stem Cell-Like Phenotypes in Human Cholangiocarcinoma. Front Cell Dev Biol 2020; 8:417. [PMID: 32582701 PMCID: PMC7283556 DOI: 10.3389/fcell.2020.00417] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
Background: Our previous study demonstrated an overexpression of CD44 variant 9 (CD44v9) in human cholangiocarcinoma (CCA) tissues that was associated with inflammation-related tumor development. However, the participation of CD44v9 in cholangiocarcinogenesis remains poorly understood. Therefore, in this study, we examined the potential roles of CD44v9 in CCA cells to understand the carcinogenic mechanism. Methods: Using normal cholangiocytes (MMNK1) and CCA cells (KKU213), the expression levels of CD44v9 and its related molecules were quantified through RT-qPCR and immunofluorescence (IF) staining. To evaluate its biological functions, we performed CD44v9 (exon 13) silencing using siRNA transfection, and assessed cell proliferation through MTT assay, cell migration and invasion by transwell technique, and carried out cell cycle analysis by flow cytometry. In vivo tumor growth was assessed by nude mouse xenografts, and histological and molecular changes were determined. Results: KKU213 exhibited higher protein expression levels of CD44v9 than those of MMNK1 through IF staining. RT-qPCR analysis revealed that the mRNA expression level of CD44v9 was predominantly elevated in CCA cells along with its neighboring exons such as variant 8 and 10, minimally affecting the standard form of CD44. CD44v9 silencing could regulate redox system in CCA cells by reducing the expression levels of SOD3 and cysteine transporter xCT. CD44v9 silencing suppressed the CCA cell proliferation by induction of apoptosis and cell cycle arrest. Migration and invasion were decreased in CD44v9 siRNA-treated CCA cells. CD44v9 downregulation inhibited CCA tumor growth in mouse xenografts. IF analysis demonstrated the histological changes in xenograft tissues such as an increase in connective tissues through collagen deposition and reduction of hyaluronic acid synthesis through CD44v9 silencing. CD44v9 knockdown in vitro and in vivo increased E-cadherin and reduced vimentin expression levels, resulting in reduction of epithelial-mesenchymal transition (EMT) process. Moreover, CD44v9 modulated Wnt10a and β-catenin in tumorigenesis. Conclusion: Our results indicate that CD44v9 plays a potential role in CCA development by the regulation of cell proliferation and redox balancing. CD44v9 silencing may suppress tumor growth, migration and invasion through EMT: a finding that could potentially be applied in the development of targeted cancer therapy.
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Affiliation(s)
- Nattawan Suwannakul
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Japan
| | - Ning Ma
- Graduate School of Health Science, Suzuka University of Medical Science, Suzuka, Japan
| | - Kaoru Midorikawa
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Japan
| | - Shinji Oikawa
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Japan
| | - Hatasu Kobayashi
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Japan
| | - Feng He
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Japan
| | - Shosuke Kawanishi
- Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan
| | - Mariko Murata
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Japan
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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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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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31
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Gastric Corpus Mucosal Hyperplasia and Neuroendocrine Cell Hyperplasia, but not Spasmolytic Polypeptide-Expressing Metaplasia, Is Prevented by a Gastrin Receptor Antagonist in H +/K +ATPase Beta Subunit Knockout Mice. Int J Mol Sci 2020; 21:ijms21030927. [PMID: 32023822 PMCID: PMC7037105 DOI: 10.3390/ijms21030927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 01/28/2020] [Accepted: 01/29/2020] [Indexed: 11/23/2022] Open
Abstract
Proton pump inhibitor use is associated with an increased risk of gastric cancer, which may be mediated by hypergastrinemia. Spasmolytic polypeptide-expression metaplasia (SPEM) has been proposed as a precursor of gastric cancer. We have examined the effects of the gastrin receptor antagonist netazepide (NTZ) or vehicle on the gastric corpus mucosa of H+/K+ATPase beta subunit knockout (KO) and wild-type (WT) mice. The gastric corpus was evaluated by histopathology, immunohistochemistry (IHC), in situ hybridization (ISH) and whole-genome gene expression analysis, focusing on markers of SPEM and neuroendocrine (NE) cells. KO mice had pronounced hypertrophy, intra- and submucosal cysts and extensive expression of SPEM and NE cell markers in the gastric corpus, but not in the antrum. Numerous SPEM-related genes were upregulated in KO mice compared to WT mice. NTZ reduced hypertrophia, cysts, inflammation and NE hyperplasia. However, NTZ neither affected expression of SPEM markers nor of SPEM-related genes. In conclusion, NTZ prevented mucosal hypertrophy, cyst formation and NE cell hyperplasia but did not affect SPEM. The presence of SPEM seems unrelated to the changes caused by hypergastrinemia in this animal model.
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Shimizu T, Sohn Y, Choi E, Petersen CP, Prasad N, Goldenring JR. Decrease in MiR-148a Expression During Initiation of Chief Cell Transdifferentiation. Cell Mol Gastroenterol Hepatol 2019; 9:61-78. [PMID: 31473306 PMCID: PMC6881610 DOI: 10.1016/j.jcmgh.2019.08.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/19/2019] [Accepted: 08/22/2019] [Indexed: 02/07/2023]
Abstract
Gastric chief cells differentiate from mucous neck cells and develop their mature state at the base of oxyntic glands with expression of secretory zymogen granules. After parietal cell loss, chief cells transdifferentiate into mucous cell metaplasia, designated spasmolytic polypeptide-expressing metaplasia (SPEM), which is considered a candidate precursor of gastric cancer. We examined the range of microRNA (miRNA) expression in chief cells and identified miRNAs involved in chief cell transdifferentiation into SPEM. Among them, miR-148a was strongly and specifically expressed in chief cells and significantly decreased during the process of chief cell transdifferentiation. Interestingly, suppression of miR-148a in a conditionally immortalized chief cell line induced up-regulation of CD44 variant 9 (CD44v9), one of the transcripts expressed at an early stage of SPEM development, and DNA methyltransferase 1 (Dnmt1), an established target of miR-148a. Immunostaining analyses showed that Dnmt1 was up-regulated in SPEM cells as well as in chief cells before the emergence of SPEM in mouse models of acute oxyntic atrophy using either DMP-777 or L635. In the cascade of events that leads to transdifferentiation, miR-148a was down-regulated after acute oxyntic atrophy either in xCT knockout mice or after sulfasalazine inhibition of xCT. These findings suggest that the alteration of miR-148a expression is an early event in the process of chief cell transdifferentiation into SPEM.
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Affiliation(s)
- Takahiro Shimizu
- Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoojin Sohn
- Department of Cell and Developmental Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Eunyoung Choi
- Nashville VA Medical Center, Nashville, Tennessee; Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Christine P Petersen
- Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Nripesh Prasad
- HudsonAlpha Institute for Biotechnology, Huntsville, Alabama
| | - James R Goldenring
- Nashville VA Medical Center, Nashville, Tennessee; Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
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Meyer AR, Engevik AC, Willet SG, Williams JA, Zou Y, Massion PP, Mills JC, Choi E, Goldenring JR. Cystine/Glutamate Antiporter (xCT) Is Required for Chief Cell Plasticity After Gastric Injury. Cell Mol Gastroenterol Hepatol 2019; 8:379-405. [PMID: 31071489 PMCID: PMC6713894 DOI: 10.1016/j.jcmgh.2019.04.015] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 04/10/2019] [Accepted: 04/16/2019] [Indexed: 12/23/2022]
Abstract
BACKGROUND & AIMS Many differentiated epithelial cell types are able to reprogram in response to tissue damage. Although reprogramming represents an important physiological response to injury, the regulation of cellular plasticity is not well understood. Damage to the gastric epithelium initiates reprogramming of zymogenic chief cells into a metaplastic cell lineage known as spasmolytic polypeptide-expressing metaplasia (SPEM). The present study seeks to identify the role of xCT, a cystine/glutamate antiporter, in chief cell reprogramming after gastric injury. We hypothesize that xCT-dependent reactive oxygen species (ROS) detoxification is required for the reprogramming of chief cells into SPEM. METHODS Sulfasalazine (an xCT inhibitor) and small interfering RNA knockdown were used to target xCT on metaplastic cells in vitro. Sulfasalazine-treated wild-type mice and xCT knockout mice were analyzed. L635 or DMP-777 treatment was used to chemically induce acute gastric damage. The anti-inflammatory metabolites of sulfasalazine (sulfapyridine and mesalazine) were used as controls. Normal gastric lineages, metaplastic markers, autophagy, proliferation, xCT activity, ROS, and apoptosis were assessed. RESULTS xCT was up-regulated early as chief cells transitioned into SPEM. Inhibition of xCT or small interfering RNA knockdown blocked cystine uptake and decreased glutathione production by metaplastic cells and prevented ROS detoxification and proliferation. Moreover, xCT activity was required for chief cell reprogramming into SPEM after gastric injury in vivo. Chief cells from xCT-deficient mice showed decreased autophagy, mucus granule formation and proliferation, as well as increased levels of ROS and apoptosis compared with wild-type mice. On the other hand, the anti-inflammatory metabolites of sulfasalazine did not affect SPEM development. CONCLUSIONS The results presented here suggest that maintaining redox balance is crucial for progression through the reprogramming process and that xCT-mediated cystine uptake is required for chief cell plasticity and ROS detoxification.
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Affiliation(s)
- Anne R Meyer
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Amy C Engevik
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Spencer G Willet
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri; Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Janice A Williams
- Cell Imaging Shared Resources, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Yong Zou
- Cancer Early Detection and Prevention Initiative, Vanderbilt University School of Medicine, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Division of Allergy, Vanderbilt University School of Medicine, Nashville, Tennessee; Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; Tennessee Valley Healthcare Systems, Nashville, Tennessee
| | - Pierre P Massion
- Cancer Early Detection and Prevention Initiative, Vanderbilt University School of Medicine, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Division of Allergy, Vanderbilt University School of Medicine, Nashville, Tennessee; Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; Tennessee Valley Healthcare Systems, Nashville, Tennessee
| | - Jason C Mills
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri; Department of Internal 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
| | - Eunyoung Choi
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee; Nashville Veterans Affairs Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - James R Goldenring
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee; Nashville Veterans Affairs Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
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Suzuki K, Sentani K, Tanaka H, Yano T, Suzuki K, Oshima M, Yasui W, Tamura A, Tsukita S. Deficiency of Stomach-Type Claudin-18 in Mice Induces Gastric Tumor Formation Independent of H pylori Infection. Cell Mol Gastroenterol Hepatol 2019; 8:119-142. [PMID: 30910700 PMCID: PMC6554658 DOI: 10.1016/j.jcmgh.2019.03.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 03/06/2019] [Accepted: 03/14/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Epithelial cells are joined by tight junctions (TJs) to form a cell sheet. In the stomach, epithelial cell sheet forms an essential barrier against gastric material, including gastric acid. Although the decreased expression of stomach-type claudin-18 (stCldn18), a TJ protein, is generally observed in human gastritis and gastric cancer, its pathological roles are not fully understood. We previously reported that mice lacking stCldn18 (stCldn18-/-) exhibit gastric acid leakage through TJs, which induces active gastritis at a young age. Here, we examined the gastric pathologies in mice after long-term stCldn18 deficiency. METHODS The gastric pathologies in stCldn18-/- mice were sequentially analyzed from youth to old age, and compared to those in humans. To examine the relationship between stCldn18 deficiency-induced gastric pathologies and Wnt-dependent tumorigenesis, we generated Wnt1-overexpressing stCldn18-/- mice. RESULTS StCldn18-/- mice developed chronic active gastritis at middle age, with expression of the chemoattractant CCL28. At old age, 20-30% of these mice developed gastric tumors with CXCL5 expression, indicative of EMT. In this process, spasmolytic polypeptide-expressing metaplasia (SPEM) cells appeared. Increased expressions of CD44-variants, TLR2, and CXCL5 indicated age-dependent changes in cell characteristics. Some features of the stCldn18-/- mouse gastric tumorigenesis resembled H pylori-infection-related human carcinogenesis. The gastric tumorigenesis was accelerated in Wnt1-overexpressing stCldn18-/- mice, indicating that Wnt is involved in the stCldn18-/- mouse gastric tumorigenesis. CONCLUSIONS StCldn18 deficiency induced gastric tumorigenesis in mice without H pylori infection. Our findings revealed that several signaling networks, including the cytokine-, stemness-, and Wnt-signaling pathways, may be activated under the stCldn18-deficiency-induced chronic active gastritis to accelerate the gastric tumorigenesis.
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Affiliation(s)
- Koya Suzuki
- Laboratory of Biological Science, Graduate School of Frontier Biosciences, and Graduate School of Medicine, Osaka University, Osaka, Japan; Research Institute for Diseases of Old Age and Department of Clinical Laboratory Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
| | - Kazuhiro Sentani
- Department of Molecular Pathology, Hiroshima University, Institute of Biomedical and Health Sciences, Hiroshima, Japan
| | - Hiroo Tanaka
- Laboratory of Biological Science, Graduate School of Frontier Biosciences, and Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Tomoki Yano
- Laboratory of Biological Science, Graduate School of Frontier Biosciences, and Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Kazuo Suzuki
- Department of Health Protection, Graduate School of Medicine, Asia International Institute of Infectious Disease Control, Teikyo University, Tokyo, Japan
| | - Masanobu Oshima
- Division of Genetics, Cancer Research Institute, and Nano Life Science Institute, Kanazawa University, Kanazawa, Japan
| | - Wataru Yasui
- Department of Molecular Pathology, Hiroshima University, Institute of Biomedical and Health Sciences, Hiroshima, Japan
| | - Atsushi Tamura
- Laboratory of Biological Science, Graduate School of Frontier Biosciences, and Graduate School of Medicine, Osaka University, Osaka, Japan.
| | - Sachiko Tsukita
- Laboratory of Biological Science, Graduate School of Frontier Biosciences, and Graduate School of Medicine, Osaka University, Osaka, Japan.
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Busada JT, Ramamoorthy S, Cain DW, Xu X, Cook DN, Cidlowski JA. Endogenous glucocorticoids prevent gastric metaplasia by suppressing spontaneous inflammation. J Clin Invest 2019; 129:1345-1358. [PMID: 30652972 DOI: 10.1172/jci123233] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 01/10/2019] [Indexed: 02/06/2023] Open
Abstract
In the stomach, chronic inflammation causes metaplasia and creates a favorable environment for the evolution of gastric cancer. Glucocorticoids are steroid hormones that repress proinflammatory stimuli, but their role in the stomach is unknown. In this study, we show that endogenous glucocorticoids are required to maintain gastric homeostasis. Removal of circulating glucocorticoids in mice by adrenalectomy resulted in the rapid onset of spontaneous gastric inflammation, oxyntic atrophy, and spasmolytic polypeptide-expressing metaplasia (SPEM), a putative precursor of gastric cancer. SPEM and oxyntic atrophy occurred independently of lymphocytes. However, depletion of monocytes and macrophages by clodronate treatment or inhibition of gastric monocyte infiltration using the Cx3cr1 knockout mouse model prevented SPEM development. Our results highlight the requirement for endogenous glucocorticoid signaling within the stomach to prevent spontaneous gastric inflammation and metaplasia, and suggest that glucocorticoid deficiency may lead to gastric cancer development.
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Affiliation(s)
- Jonathan T Busada
- Molecular Endocrinology Group, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
| | - Sivapriya Ramamoorthy
- Molecular Endocrinology Group, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
| | - Derek W Cain
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA
| | | | - Donald N Cook
- Immunogenetics Group, Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
| | - John A Cidlowski
- Molecular Endocrinology Group, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
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Osaki LH, Bockerstett KA, Wong CF, Ford EL, Madison BB, DiPaolo RJ, Mills JC. Interferon-γ directly induces gastric epithelial cell death and is required for progression to metaplasia. J Pathol 2019; 247:513-523. [PMID: 30511397 DOI: 10.1002/path.5214] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 11/14/2018] [Accepted: 11/29/2018] [Indexed: 12/26/2022]
Abstract
Chronic inflammation of the gastric mucosa, often caused by autoimmune gastritis and/or infection with Helicobacter pylori, can lead to atrophy of acid-secreting parietal cells with metaplasia of remaining cells. The histological pattern marks a critical step in the progression from chronic gastritis to gastric cancer, yet underlying mechanism(s) of inflammation-induced cell death of gastric epithelial cells are poorly understood. We investigated direct effects of a type 1 cytokine associated with autoimmunity and infection, interferon-γ (IFN-γ), on gastric epithelial cells. IFN-γ was applied to three-dimensional organoid cultures of gastric epithelial cells derived from gastric corpus gland (gastroids) of control and IFN-γ receptor-deficient mice. Gastroids were also treated with supernatants from activated immune cells isolated from a mouse model of autoimmune-mediated atrophic gastritis (TxA23) with and without IFN-γ expression. Finally, histopathological analysis of atrophy and metaplasia severity was performed in TxA23 mice and compared to TxA23 × Ifng-/- mice. Gastric epithelial cells in gastroid cultures expressed IFN-γ receptor in the basolateral membrane, and gastroids died when treated with IFN-γ in an IFN-γ receptor-dependent manner. Supernatants from immune cells containing high levels of IFN-γ were highly toxic to gastroids, and toxicity was tempered when IFN-γ was either neutralized using a monoclonal antibody or when supernatants from Ifng-/- mouse immune cells were used. Finally, TxA23 × Ifng-/- mice showed near-complete abrogation of pre-cancerous histopathological atrophy and metaplasia versus IFN-γ-sufficient controls. We identify IFN-γ as a critical promoter of parietal cell atrophy with metaplasia during the progression of gastritis to gastric atrophy and metaplasia. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Luciana H Osaki
- Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Kevin A Bockerstett
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
| | - Chun F Wong
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
| | - Eric L Ford
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
| | - Blair B Madison
- Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Richard J DiPaolo
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
| | - Jason C Mills
- Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA.,Developmental Biology, Pathology & Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA
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Ueda S, Hayashi H, Miyamoto T, Abe S, Hirai K, Matsukura K, Yagi H, Hara Y, Yoshida K, Okazaki S, Tamura M, Abe Y, Agatsuma T, Niwa S, Masuko K, Masuko T. Anti-tumor effects of mAb against L-type amino acid transporter 1 (LAT1) bound to human and monkey LAT1 with dual avidity modes. Cancer Sci 2019; 110:674-685. [PMID: 30548114 PMCID: PMC6361610 DOI: 10.1111/cas.13908] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 11/30/2018] [Accepted: 12/05/2018] [Indexed: 02/06/2023] Open
Abstract
l‐Type amino acid transporter 1 (LAT1) disulfide linked to CD98 heavy chain (hc) is highly expressed in most cancer cells, but weakly expressed in normal cells. In the present study, we developed novel anti‐LAT1 mAbs and showed internalization activity, inhibitory effects of amino acid uptake and cell growth and antibody‐dependent cellular cytotoxicity, as well as in vivo antitumor effects in athymic mice. Furthermore, we examined the reactivity of mAbs with LAT1 of Macaca fascicularis to evaluate possible side‐effects of antihuman LAT1 mAbs in clinical trials. Antihuman LAT1 mAbs reacted with ACHN human and MK.P3 macaca kidney‐derived cells, and this reactivity was significantly decreased by siRNAs against LAT1. Macaca LAT1 cDNA was cloned from MK.P3, and only two amino acid differences between human and macaca LAT1 were seen. RH7777 rat hepatoma and HEK293 human embryonic kidney cells expressing macaca LAT1 were established as stable transfectants, and antihuman LAT1 mAbs were equivalently reactive against transfectants expressing human or macaca LAT1. Dual (high and low) avidity modes were detected in transfectants expressing macaca LAT1, MK.P3, ACHN and HCT116 human colon cancer cells, and KA values were increased by anti‐CD98hc mAb, suggesting anti‐LAT1 mAbs detect an epitope on LAT1‐CD98hc complexes on the cell surface. Based on these results, LAT1 may be a promising anticancer target and Macaca fascicularis can be used in preclinical studies with antihuman LAT1 mAbs.
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Affiliation(s)
- Shiho Ueda
- Cell Biology LaboratorySchool of PharmacyKindai UniversityOsakaJapan
| | | | - Takako Miyamoto
- Cell Biology LaboratorySchool of PharmacyKindai UniversityOsakaJapan
| | - Shinya Abe
- Laboratory of Biological ProtectionInstitute for Viral Research, Kyoto UniversityKyotoJapan
| | - Kana Hirai
- Cell Biology LaboratorySchool of PharmacyKindai UniversityOsakaJapan
| | - Kanji Matsukura
- Cell Biology LaboratorySchool of PharmacyKindai UniversityOsakaJapan
| | - Hideki Yagi
- School of PharmacyInternational University of Health and WelfareOtawaraJapan
| | - Yuta Hara
- Cell Biology LaboratorySchool of PharmacyKindai UniversityOsakaJapan
| | - Kinji Yoshida
- Cell Biology LaboratorySchool of PharmacyKindai UniversityOsakaJapan
| | - Shogo Okazaki
- Division of Development and Aging, Research Institute for Biomedical SciencesTokyo University of ScienceChibaJapan
| | - Masakazu Tamura
- Modality Research Laboratories, Biologics DivisionDaiichi Sankyo Co., LtdTokyoJapan
| | - Yuki Abe
- Biologics & Immuno‐Oncology Laboratories, R&D DivisionDaiichi Sankyo Co., LtdTokyoJapan
| | - Toshinori Agatsuma
- Biologics & Immuno‐Oncology Laboratories, R&D DivisionDaiichi Sankyo Co., LtdTokyoJapan
| | | | - Kazue Masuko
- Cell Biology LaboratorySchool of PharmacyKindai UniversityOsakaJapan
| | - Takashi Masuko
- Cell Biology LaboratorySchool of PharmacyKindai UniversityOsakaJapan
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Holokai L, Chakrabarti J, Broda T, Chang J, Hawkins JA, Sundaram N, Wroblewski LE, Peek RM, Wang J, Helmrath M, Wells JM, Zavros Y. Increased Programmed Death-Ligand 1 is an Early Epithelial Cell Response to Helicobacter pylori Infection. PLoS Pathog 2019; 15:e1007468. [PMID: 30703170 PMCID: PMC6380601 DOI: 10.1371/journal.ppat.1007468] [Citation(s) in RCA: 135] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 02/19/2019] [Accepted: 11/13/2018] [Indexed: 12/24/2022] Open
Abstract
Helicobacter pylori (H. pylori) is the major risk factor for the development of gastric cancer. Our laboratory has reported that the Sonic Hedgehog (Shh) signaling pathway is an early response to infection that is fundamental to the initiation of H. pylori-induced gastritis. H. pylori also induces programmed death ligand 1 (PD-L1) expression on gastric epithelial cells, yet the mechanism is unknown. We hypothesize that H. pylori-induced PD-L1 expression within the gastric epithelium is mediated by the Shh signaling pathway during infection. To identify the role of Shh signaling as a mediator of H. pylori-induced PD-L1 expression, human gastric organoids generated from either induced pluripotent stem cells (HGOs) or tissue (huFGOs) were microinjected with bacteria and treated with Hedgehog/Gli inhibitor GANT61. Gastric epithelial monolayers generated from the huFGOs were also infected with H. pylori and treated with GANT61 to study the role of Hedgehog signaling as a mediator of induced PD-1 expression. A patient-derived organoid/autologous immune cell co-culture system infected with H. pylori and treated with PD-1 inhibitor (PD-1Inh) was developed to study the protective mechanism of PD-L1 in response to bacterial infection. H. pylori significantly increased PD-L1 expression in organoid cultures 48 hours post-infection when compared to uninfected controls. The mechanism was cytotoxic associated gene A (CagA) dependent. This response was blocked by pretreatment with GANT61. Anti-PD-L1 treatment of H. pylori infected huFGOs, co-cultured with autologous patient cytotoxic T lymphocytes and dendritic cells, induced organoid death. H. pylori-induced PD-L1 expression is mediated by the Shh signaling pathway within the gastric epithelium. Cells infected with H. pylori that express PD-L1 may be protected from the immune response, creating premalignant lesions progressing to gastric cancer.
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Affiliation(s)
- Loryn Holokai
- Department of Molecular Genetics, Biochemistry, and Microbiology, Cincinnati OH, United States of America
| | - Jayati Chakrabarti
- Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati OH, United States of America
| | - Taylor Broda
- Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati OH, United States of America
- Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati OH, United States of America
| | - Julie Chang
- Department of Biomedical Engineering, University of Cincinnati, Cincinnati OH, United States of America
| | - Jennifer A. Hawkins
- Department of Pediatric Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati OH, United States of America
| | - Nambirajan Sundaram
- Department of Pediatric Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati OH, United States of America
| | - Lydia E. Wroblewski
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America
| | - Richard M. Peek
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America
| | - Jiang Wang
- Department of Pathology and Lab Medicine, University of Cincinnati College of Medicine, Cincinnati OH, United States of America
| | - Michael Helmrath
- Department of Pediatric Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati OH, United States of America
| | - James M. Wells
- Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati OH, United States of America
- Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati OH, United States of America
| | - Yana Zavros
- Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati OH, United States of America
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39
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Overexpression of CD44 Variant 9: A Novel Cancer Stem Cell Marker in Human Cholangiocarcinoma in Relation to Inflammation. Mediators Inflamm 2018; 2018:4867234. [PMID: 30402042 PMCID: PMC6198546 DOI: 10.1155/2018/4867234] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 08/29/2018] [Accepted: 09/09/2018] [Indexed: 12/15/2022] Open
Abstract
Various CD44 isoforms are expressed in several cancer stem cells during tumor progression and metastasis. In particular, CD44 variant 9 (CD44v9) is highly expressed in chronic inflammation-induced cancer. We investigated the expression of CD44v9 and assessed whether CD44v9 is a selective biomarker of human cholangiocarcinoma (CCA). The expression profile of CD44v9 was evaluated in human liver fluke Opisthorchis viverrini-related CCA (OV-CCA) tissues, human CCA (independent of OV infection, non-OV-CCA) tissues, and normal liver tissues. CD44v9 overexpression was detected by immunohistochemistry (IHC) in CCA tissues. There was a higher level of CD44v9 expression and IHC score in OV-CCA tissues than in non-OV-CCA tissues, and there was no CD44v9 staining in the bile duct cells of normal liver tissues. In addition, we observed significantly higher expression of inflammation-related markers, such as S100P and COX-2, in OV-CCA tissues compared to that in non-OV and normal liver tissues. Thus, these findings suggest that CD44v9 may be a novel candidate CCA stem cell marker and may be related to inflammation-associated cancer development.
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40
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Choi E, Lantz TL, Vlacich G, Keeley TM, Samuelson LC, Coffey RJ, Goldenring JR, Powell AE. Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach. Gut 2018; 67:1595-1605. [PMID: 28814482 PMCID: PMC5815959 DOI: 10.1136/gutjnl-2017-313874] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 06/26/2017] [Accepted: 06/29/2017] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Lrig1 is a marker of proliferative and quiescent stem cells in the skin and intestine. We examined whether Lrig1-expressing cells are long-lived gastric progenitors in gastric glands in the mouse stomach. We also investigated how the Lrig1-expressing progenitor cells contribute to the regeneration of normal gastric mucosa by lineage commitment to parietal cells after acute gastric injury in mice. DESIGN We performed lineage labelling using Lrig1-CreERT2/+;R26R-YFP/+ (Lrig1/YFP) or R26R-LacZ/+ (Lrig1/LacZ) mice to examine whether the Lrig1-YFP-marked cells are gastric progenitor cells. We studied whether Lrig1-YFP-marked cells give rise to normal gastric lineage cells in damaged mucosa using Lrig1/YFP mice after treatment with DMP-777 to induce acute injury. We also studied Lrig1-CreERT2/CreERT2 (Lrig1 knockout) mice to examine whether the Lrig1 protein is required for regeneration of gastric corpus mucosa after acute injury. RESULTS Lrig1-YFP-marked cells give rise to gastric lineage epithelial cells both in the gastric corpus and antrum, in contrast to published results that Lgr5 only marks progenitor cells within the gastric antrum. Lrig1-YFP-marked cells contribute to replacement of damaged gastric oxyntic glands during the recovery phase after acute oxyntic atrophy in the gastric corpus. Lrig1 null mice recovered normally from acute gastric mucosal injury indicating that Lrig1 protein is not required for lineage differentiation. Lrig1+ isthmal progenitor cells did not contribute to transdifferentiating chief cell lineages after acute oxyntic atrophy. CONCLUSIONS Lrig1 marks gastric corpus epithelial progenitor cells capable of repopulating the damaged oxyntic mucosa by differentiating into normal gastric lineage cells in mouse stomach.
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Affiliation(s)
- Eunyoung Choi
- Nashville VA Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Epithelial Biology Center, Nashville, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Tyler L Lantz
- Department of Biology, Institute of Molecular Biology, University of Oregon, Oregon, USA
| | - Gregory Vlacich
- Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Theresa M Keeley
- Department of Molecular & Integrative Physiology, The University of Michigan, Michigan, USA
| | - Linda C Samuelson
- Department of Molecular & Integrative Physiology, The University of Michigan, Michigan, USA
| | - Robert J Coffey
- Nashville VA Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Epithelial Biology Center, Nashville, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - James R Goldenring
- Nashville VA Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Epithelial Biology Center, Nashville, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Anne E Powell
- Department of Biology, Institute of Molecular Biology, University of Oregon, Oregon, USA
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41
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Baek SJ, Sato K, Nishida N, Koseki J, Hayashi K, Kawamoto K, Konno M, Doki Y, Mori M, Ogawa K, Ishii H. Carbon ion beam radioresistant rodent cells are sensitized to trifluorothymidine exposure. Oncol Lett 2018; 16:3389-3393. [PMID: 30127939 DOI: 10.3892/ol.2018.9004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 02/27/2018] [Indexed: 11/06/2022] Open
Abstract
Although charged particle therapy, including carbon ion beam radiation, is a cutting-edge technology in human cancer treatment, the molecular mechanisms underlying cellular resistance to this type of therapy remain unknown. Furthermore, the chemotherapeutic agents that are most effective at overcoming cellular resistance remain unknown. In the present study, carbon ion beam radioresistant rodent cells were developed and their sensitization to trifluorothymidine (FTD), a derivative of deoxythymidine, was studied. The results of the present study demonstrated that carbon ion beam radioresistant cells were more sensitive to FTD compared with X-ray radioresistant cells. The results of the present study suggested that FTD is involved in carbon ion beam radioresistance, encouraging further study of cellular resistance to charged particle therapy for refractory human cancer.
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Affiliation(s)
- Sung-Jae Baek
- Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.,Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Katsutoshi Sato
- National Institute for Radiological Science, Chiba 263-8555, Japan
| | - Naohiro Nishida
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.,Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Jun Koseki
- Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Kazuhiko Hayashi
- Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.,Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Koichi Kawamoto
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.,Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Masamitsu Konno
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Kazuhiko Ogawa
- Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Hideshi Ishii
- Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
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42
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Uchida D, Takaki A, Adachi T, Okada H. Beneficial and Paradoxical Roles of Anti-Oxidative Nutritional Support for Non-Alcoholic Fatty Liver Disease. Nutrients 2018; 10:E977. [PMID: 30060482 PMCID: PMC6116036 DOI: 10.3390/nu10080977] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 07/17/2018] [Accepted: 07/24/2018] [Indexed: 02/06/2023] Open
Abstract
Oxidative stress is being recognized as a key factor in the progression of chronic liver disease (CLD), especially non-alcoholic fatty liver disease (NAFLD). Many NAFLD treatment guidelines recommend the use of antioxidants, especially vitamin E. Many prospective studies have described the beneficial effects of such agents for the clinical course of NAFLD. However, as these studies are usually short-term evaluations, lasting only a few years, whether or not antioxidants continue to exert favorable long-term effects, including in cases of concomitant hepatocellular carcinoma, remains unclear. Antioxidants are generally believed to be beneficial for human health and are often commercially available as health-food products. Patients with lifestyle-related diseases often use such products to try to be healthier without practicing lifestyle intervention. However, under some experimental NAFLD conditions, antioxidants have been shown to encourage the progression of hepatocellular carcinoma, as oxidative stress is toxic for cancer cells, just as for normal cells. In this review, we will highlight the paradoxical effects of antioxidants against NAFLD and related hepatocellular carcinoma.
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Affiliation(s)
- Daisuke Uchida
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
| | - Takuya Adachi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
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43
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Pinzon-Guzman C, Meyer AR, Wise R, Choi E, Muthupalani S, Wang TC, Fox JG, Goldenring JR. Evaluation of Lineage Changes in the Gastric Mucosa Following Infection With Helicobacter pylori and Specified Intestinal Flora in INS-GAS Mice. J Histochem Cytochem 2018; 67:53-63. [PMID: 29969055 DOI: 10.1369/0022155418785621] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Gastric adenocarcinoma develops in metaplastic mucosa associated with Helicobacter pylori infection in the stomach. We have sought to evaluate the precise lineage changes in the stomachs of insulin-gastrin (INS-GAS) mice infected with H. pylori and/or intestinal flora (Altered Schaedler's Flora; ASF). Stomachs from groups infected with H. pylori contained progressive spasmolytic polypeptide-expressing metaplasia (SPEM) compared with germ-free and mice infected with ASF alone. The overall phenotype of the H. pylori-infected mice was dominated by Ulex europaeus lectin (UEAI)-positive foveolar hyperplasia that was distinct from GSII/CD44v9-positive SPEM. However, in the mice with H. pylori co-infected with ASF, we identified a subpopulation of UEAI-positive foveolar cells that co-expressed intestinal mucin 4 (MUC4). These regions of foveolar cells were variably positive for CD44v9 as well as TFF3. Interestingly, an intravascular lesion identified in a dual H. pylori/ASF-infected mouse expressed both UEAI and Muc4. Finally, we identified an increase in the number of tuft cells within the mucosa of H. pylori-infected groups. Our findings suggest that H. pylori infection promotes foveolar hyperplasia as well as metaplasia, while co-infection may promote progressive foveolar and metaplastic lesions as well as dysplasia. Grading of gastric lesions in mice as preneoplastic requires multiple immunostaining markers to assign lineage derivation and behavior.
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Affiliation(s)
- Carolina Pinzon-Guzman
- Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee.,Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Anne R Meyer
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.,Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Rachel Wise
- Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee.,Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Eunyoung Choi
- Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee.,Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Sureshkumar Muthupalani
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Timothy C Wang
- Department of Medicine, Columbia University Medical Center, New York, New York
| | - James G Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - James R Goldenring
- Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee.,Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.,Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.,Vanderbilt Ingram Cancer Center, Nashville, Tennessee.,Nashville Veterans Affairs (VA) Medical Center, Nashville, Tennessee
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44
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Petersen CP, Meyer AR, DeSalvo C, Choi E, Schlegel C, Petersen A, Engevik AC, Prasad N, Levy SE, Peebles RS, Pizarro TT, Goldenring JR. A signalling cascade of IL-33 to IL-13 regulates metaplasia in the mouse stomach. Gut 2018; 67:805-817. [PMID: 28196875 PMCID: PMC5681443 DOI: 10.1136/gutjnl-2016-312779] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 01/13/2017] [Accepted: 01/15/2017] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Alternatively activated macrophages (M2) are associated with the progression of spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach. However, the precise mechanism(s) and critical mediators that induce SPEM are unknown. DESIGN To determine candidate genes important in these processes, macrophages from the stomach corpus of mice with SPEM (DMP-777-treated) or advanced SPEM (L635-treated) were isolated and RNA sequenced. Effects on metaplasia development after acute parietal cell loss induced by L635 were evaluated in interleukin (IL)-33, IL-33 receptor (ST2) and IL-13 knockout (KO) mice. RESULTS Profiling of metaplasia-associated macrophages in the stomach identified an M2a-polarised macrophage population. Expression of IL-33 was significantly upregulated in macrophages associated with advanced SPEM. L635 induced metaplasia in the stomachs of wild-type mice, but not in the stomachs of IL-33 and ST2 KO mice. While IL-5 and IL-9 were not required for metaplasia induction, IL-13 KO mice did not develop metaplasia in response to L635. Administration of IL-13 to ST2 KO mice re-established the induction of metaplasia following acute parietal cell loss. CONCLUSIONS Metaplasia induction and macrophage polarisation after parietal cell loss is coordinated through a cytokine signalling network of IL-33 and IL-13, linking a combined response to injury by both intrinsic mucosal mechanisms and infiltrating M2 macrophages.
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Affiliation(s)
- Christine P. Petersen
- Departments of Cell and Developmental Biology, Vanderbilt University, Nashville, TN,Department of Epithelial Biology Center, Vanderbilt University, Nashville, TN
| | - Anne R. Meyer
- Departments of Cell and Developmental Biology, Vanderbilt University, Nashville, TN,Department of Epithelial Biology Center, Vanderbilt University, Nashville, TN
| | - Carlo DeSalvo
- Department of Pathology, Case Western Reserve School of Medicine, Cleveland, OH
| | - Eunyoung Choi
- Department of Nashville VA Medical Center, Vanderbilt University, Nashville, TN,Department of Surgery, Vanderbilt University, Nashville, TN,Department of Epithelial Biology Center, Vanderbilt University, Nashville, TN
| | - Cameron Schlegel
- Department of Surgery, Vanderbilt University, Nashville, TN,Department of Epithelial Biology Center, Vanderbilt University, Nashville, TN
| | - Alec Petersen
- Department of Epithelial Biology Center, Vanderbilt University, Nashville, TN
| | - Amy C. Engevik
- Department of Surgery, Vanderbilt University, Nashville, TN,Department of Epithelial Biology Center, Vanderbilt University, Nashville, TN
| | - Nripesh Prasad
- Department of HudsonAlpha Institute for Biotechnology, Huntsville, AL
| | - Shawn E. Levy
- Department of HudsonAlpha Institute for Biotechnology, Huntsville, AL
| | | | - Theresa T. Pizarro
- Department of Pathology, Case Western Reserve School of Medicine, Cleveland, OH
| | - James R. Goldenring
- Department of Nashville VA Medical Center, Vanderbilt University, Nashville, TN,Departments of Cell and Developmental Biology, Vanderbilt University, Nashville, TN,Department of Surgery, Vanderbilt University, Nashville, TN,Department of Epithelial Biology Center, Vanderbilt University, Nashville, TN
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45
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Goldenring JR. Pyloric metaplasia, pseudopyloric metaplasia, ulcer-associated cell lineage and spasmolytic polypeptide-expressing metaplasia: reparative lineages in the gastrointestinal mucosa. J Pathol 2018; 245:132-137. [PMID: 29508389 DOI: 10.1002/path.5066] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 02/27/2018] [Accepted: 02/28/2018] [Indexed: 12/16/2022]
Abstract
The gastrointestinal mucosae provide a critical barrier between the external and internal milieu. Thus, damage to the mucosa requires an immediate response to provide appropriate wound closure and healing. Metaplastic lineages with phenotypes similar to the mucous glands of the distal stomach or Brunner's glands have been associated with various injurious scenarios in the stomach, small bowel, and colon. These lineages have been assigned various names including pyloric metaplasia, pseudopyloric metaplasia, ulcer-associated cell lineage (UACL), and spasmolytic polypeptide-expressing metaplasia (SPEM). A re-examination of the literature on these various forms of mucous cell metaplasia suggests that pyloric-type mucosal gland lineages may provide a ubiquitous response to mucosal injury throughout the gastrointestinal tract as well as in the pancreas, esophagus, and other mucosal surfaces. While the cellular origin of these putative reparative lineages likely varies in different regions of the gut, their final phenotypes may converge on a pyloric-type gland dedicated to mucous secretion. In addition to their healing properties in the setting of acute injury, these pyloric-type lineages may also represent precursors to neoplastic transitions in the face of chronic inflammatory influences. Further investigations are needed to determine how discrete molecular profiles relate to the origin and function of pyloric-type metaplasias previously described by histological characteristics in multiple epithelial mucosal systems in the setting of acute and chronic damage. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- James R Goldenring
- Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.,Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.,Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.,Vanderbilt Ingram Cancer Center, Nashville, TN, USA.,Nashville VA Medical Center, Nashville, TN, USA
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46
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Sulfasalazine, an inhibitor of the cystine-glutamate antiporter, reduces DNA damage repair and enhances radiosensitivity in murine B16F10 melanoma. PLoS One 2018; 13:e0195151. [PMID: 29649284 PMCID: PMC5896924 DOI: 10.1371/journal.pone.0195151] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 03/16/2018] [Indexed: 12/31/2022] Open
Abstract
The sodium-independent cystine-glutamate antiporter plays an important role in extracellular cystine uptake. It comprises the transmembrane protein, xCT and its chaperone, CD98. Because glutathione is only weakly cell membrane permeable, cellular uptake of its precursor, cystine, is known to be a key step in glutathione synthesis. Moreover, it has been reported that xCT expression affects the progression of tumors and their resistance to therapy. Sulfasalazine is an inhibitor of xCT that is known to increase cellular oxidative stress, giving it anti-tumor potential. Here, we describe a radio-sensitizing effect of sulfasalazine using a B16F10 melanoma model. Sulfasalazine decreased glutathione concentrations and resistance to H2O2 in B16F10 melanoma cells, but not in mouse embryonic fibroblasts. It synergistically enhanced the cyto-killing effect of X-irradiation in B16F10 cells. It inhibited cellular DNA damage repair and prolonged cell cycle arrest after X-irradiation. Furthermore, in an in vivo transplanted melanoma model, sulfasalazine decreased intratumoral glutathione content, leading to enhanced susceptibility to radiation therapy. These results suggest the possibility of using SAS to augment the treatment of radio-resistant cancers.
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47
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Zhang L, Huang Y, Ling J, Zhuo W, Yu Z, Luo Y, Zhu Y. Overexpression of SLC7A11: a novel oncogene and an indicator of unfavorable prognosis for liver carcinoma. Future Oncol 2018. [PMID: 29528250 DOI: 10.2217/fon-2017-0540] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
AIM SLC7A11 is a gene that encodes a cystine-glutamate antiporter, which has been detected to be overexpressed in various cancers. Thus, we aimed to validate its expression and clinical significance in liver cancer. METHODS Bioinformatic analysis was conducted and a tissue microarray was utilized for detecting SLC7A11 expression in liver cancer tissues by immunohistochemistry assay. RESULTS High expressions of SLC7A11 have no association with clinical parameters such as age, sex and clinical stages, except for advanced pathological stages. Cox regression analysis revealed that SLC7A11 might be an independent prognostic factor for liver cancer patients. CONCLUSION SLC7A11 overexpression might be a novel biomarker and a potential unfavorable prognostic factor as well as a potential therapeutic target for liver carcinoma.
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Affiliation(s)
- Liang Zhang
- College of Food Science & Nutritional Engineering, China Agricultural University, Beijing, PR China.,Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
| | - Yi Huang
- Department of Internal Medicine, Affiliated Hospital of Guizhou Medical University, Guiyang, PR China
| | - Junjun Ling
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
| | - Wenlei Zhuo
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China
| | - Zhen Yu
- College of Food Science & Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Yunbo Luo
- College of Food Science & Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Yi Zhu
- College of Food Science & Nutritional Engineering, China Agricultural University, Beijing, PR China
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Hagiwara M, Kikuchi E, Tanaka N, Kosaka T, Mikami S, Saya H, Oya M. Variant isoforms of CD44 involves acquisition of chemoresistance to cisplatin and has potential as a novel indicator for identifying a cisplatin-resistant population in urothelial cancer. BMC Cancer 2018; 18:113. [PMID: 29385995 PMCID: PMC5793458 DOI: 10.1186/s12885-018-3988-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 01/14/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Cisplatin is the most commonly used chemotherapeutic agent in the treatment of patients with metastatic and/or recurrent urothelial cancer. However, the effectiveness of these treatments is severely limited due to the development of cisplatin resistance. Cancer stem cells have been documented as one of the key hypotheses involved in chemoresistance. CD44v8-10 has been identified as one of the new cancer stem cells markers and was recently shown to enhance the antioxidant system by interaction with xCT, a subunit of the cystine transporter modulating intracellular glutathione synthesis. The aim of the present study was to investigate the clinical role of CD44v8-10 and the molecular mechanism underlying the acquisition of cisplatin resistance through CD44v8-10 in urothelial cancer. METHODS We analyzed the clinical significance of the immunohistochemical CD44v9 expression, which detects the immunogen of human CD44v8-10, in 77 urothelial cancer patients treated with cisplatin-based systemic chemotherapy for recurrence and/or metastasis. We then evaluated the biological role of CD44v8-10 in the acquisition of cisplatin resistance using the urothelial cancer cell lines, T24 and T24PR, which were generated to acquire resistance to cisplatin. RESULTS The 5-year cancer-specific survival rate was significantly lower in the CD44v9-positive group than in the CD44v9-negative group (P = 0.008). Multivariate analyses revealed that CD44v9 positivity was an independent risk factor of cancer-specific survival (P = 0.024, hazard ratio = 5.16) in urothelial cancer patients who had recurrence and/or metastasis and received cisplatin-based chemotherapy. The expression of CD44v8-10 and xCT was stronger in T24PR cells than in T24 cells. The amount of intracellular glutathione was significantly higher in T24PR cells than in T24 cells (p < 0.001), and intracellular reactive oxygen species production by cisplatin was lower in T24PR cells than in T24 cells. Furthermore, the knockdown of CD44v8-10 by siRNA led to the recovery of cisplatin sensitivity in T24PR cells. CONCLUSIONS CD44v9 in tumor specimens has potential as a novel indicator for identifying a cisplatin-chemoresistant population among urothelial cancer patients. CD44v8-10 contributes to reactive oxygen species defenses, which are involved in chemoresistance, by promoting the function of xCT, which adjusts the synthesis of glutathione.
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Affiliation(s)
- Masayuki Hagiwara
- Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Eiji Kikuchi
- Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Nobuyuki Tanaka
- Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Takeo Kosaka
- Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Shuji Mikami
- Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Hideyuki Saya
- Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Mototsugu Oya
- Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
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Ye W, Takabayashi H, Yang Y, Mao M, Hibdon ES, Samuelson LC, Eaton KA, Todisco A. Regulation of Gastric Lgr5+ve Cell Homeostasis by Bone Morphogenetic Protein (BMP) Signaling and Inflammatory Stimuli. Cell Mol Gastroenterol Hepatol 2018; 5:523-538. [PMID: 29930977 PMCID: PMC6009760 DOI: 10.1016/j.jcmgh.2018.01.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Accepted: 01/09/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Gastric Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) cells exert important functions during injury and homeostasis. Bone morphogenetic protein (BMP) signaling regulates gastric inflammation and epithelial homeostasis. We investigated if BMP signaling controls the fate of Lgr5+ve cells during inflammation. METHODS The H+/K+-adenosine triphosphatase β-subunit promoter was used to express the BMP inhibitor noggin (Nog) in the stomach (H+/K+-Nog mice). Inhibition of BMP signaling in Lgr5 cells was achieved by crossing Lgr5-EGFP-ires-CreERT2 (Lgr5-Cre) mice to mice with floxed alleles of BMP receptor 1A (Lgr5-Cre;Bmpr1aflox/flox mice). Lgr5/GFP+ve cells were isolated using flow cytometry. Lineage tracing studies were conducted by crossing Lgr5-Cre mice to mice that express Nog and tdTomato (Lgr5-Cre;H+/K+-Nog;Rosa26-tdTom). Infection with Helicobacter felis was used to induce inflammation. Morphology of the mucosa was analyzed by H&E staining. Distribution of H+/K+-adenosine triphosphatase-, IF-, Ki67-, CD44-, CD44v9-, and bromodeoxyuridine-positive cells was analyzed by immunostaining. Expression of neck and pit cell mucins was determined by staining with the lectins Griffonia (Bandeiraea) simplicifolia lectin II and Ulex europaeus agglutinin 1, respectively. Id1, Bmpr1a, Lgr5, c-Myc, and Cd44 messenger RNAs were measured by quantitative reverse-transcription polymerase chain reaction. RESULTS Lgr5-Cre;Bmpr1aflox/flox mice showed diminished expression of Bmpr1a in Lgr5/GFP+ve cells. Infection of Lgr5-Cre;Bmpr1aflox/flox mice with H felis led to enhanced inflammation, increased cell proliferation, parietal cell loss, and to the development of metaplasia and dysplasia. Infected Lgr5-Cre;H+/K+-Nog;Rosa26-tdTom mice, but not control mice, showed the presence of tomato+ve glands lining the lesser curvature that stained positively with Griffonia (Bandeiraea) simplicifolia lectin II and Ulex europaeus agglutinin 1, and with anti-IF, -CD44, -CD44v9, and -bromodeoxyuridine antibodies. CONCLUSIONS Inflammation and inhibition of BMP signaling activate Lgr5+ve cells, which give rise to metaplastic, dysplastic, proliferating lineages that express markers of mucus neck and zymogenic cell differentiation.
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Key Words
- ATPase, adenosine triphosphatase
- BMP, bone morphogenetic protein
- BrdU, bromodeoxyuridine
- Chief Cells
- Differentiation
- Dysplasia
- EGFP, enhanced green fluorescent protein
- ERK, extracellular signal–regulated kinase
- GFP, green fluorescent protein
- GSII, Griffonia (Bandeiraea) simplicifolia lectin II
- H/K-nog, H/K-noggin
- HBSS, Hank's balanced salt solution
- IF, intrinsic factor
- Metaplasia
- QRT-PCR, quantitative reverse-transcription polymerase chain reaction
- SPEM, spasmolytic polypeptide expressing metaplasia
- TFF2, Trefoil factor 2
- mRNA, messenger RNA
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Affiliation(s)
- Wei Ye
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan,Department of Gastroenterology, Hangzhou Chinese Medicine Hospital, Hangzhou, Zhejiang, China
| | - Hidehiko Takabayashi
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan
| | - Yitian Yang
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan,Department of Gastroenterology, Hangzhou Chinese Medicine Hospital, Hangzhou, Zhejiang, China
| | - Maria Mao
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan
| | - Elise S. Hibdon
- Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, Michigan
| | - Linda C. Samuelson
- Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, Michigan
| | - Kathryn A. Eaton
- Department of Microbiology and Immunology, University of Michigan Medical Center, Ann Arbor, Michigan
| | - Andrea Todisco
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan,Correspondence Address correspondence to: Andrea Todisco, MD, 6520 Medical Science Research Building I, Ann Arbor, Michigan 48109-0682. fax: (734) 763-2535.
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Interleukin-17A Promotes Parietal Cell Atrophy by Inducing Apoptosis. Cell Mol Gastroenterol Hepatol 2018; 5:678-690.e1. [PMID: 29930985 PMCID: PMC6009015 DOI: 10.1016/j.jcmgh.2017.12.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 12/28/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Atrophic gastritis caused by chronic inflammation in the gastric mucosa leads to the loss of gastric glandular cells, including acid-secreting parietal cells. Parietal cell atrophy in a setting of chronic inflammation induces spasmolytic polypeptide expressing metaplasia, a critical step in gastric carcinogenesis. However, the mechanisms by which inflammation causes parietal cell atrophy and spasmolytic polypeptide expressing metaplasia are not well defined. We investigated the role of interleukin-17A (IL-17A) in causing parietal cell atrophy. METHODS A mouse model of autoimmune atrophic gastritis was used to examine IL-17A production during early and late stages of disease. Organoids derived from corpus glands were used to determine the direct effects of IL-17A on gastric epithelial cells. Immunofluorescent staining was used to examine IL-17A receptors and the direct effect of signaling on parietal cells. Mice were infected with an IL-17A-producing adenovirus to determine the effects of IL-17A on parietal cells in vivo. Finally, IL-17A neutralizing antibodies were administered to mice with active atrophic gastritis to evaluate the effects on parietal cell atrophy and metaplasia. RESULTS Increased IL-17A correlated with disease severity in mice with chronic atrophic gastritis. IL-17A caused caspase-dependent gastric organoid degeneration, which could not be rescued with a necroptosis inhibitor. Parietal cells expressed IL-17A receptors and IL-17A treatment induced apoptosis in parietal cells. Overexpressing IL-17A in vivo induced caspase-3 activation and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining in parietal cells. Finally, IL-17A neutralizing antibody decreased parietal cell atrophy and metaplasia in mice with chronic atrophic gastritis. CONCLUSIONS These data identify IL-17A as a cytokine that promotes parietal cell apoptosis during atrophic gastritis, a precursor lesion for gastric cancer.
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