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1
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He Y, Liu HH, Zhou XL, He TT, Zhang AZ, Wang X, Wei SZ, Li HT, Chen LS, Chang L, Zhao YL, Jing MY. Rutaecarpine Ameliorates Murine N-Methyl-N'-Nitro-N-Nitrosoguanidine-Induced Chronic Atrophic Gastritis by Sonic Hedgehog Pathway. Molecules 2023; 28:6294. [PMID: 37687125 PMCID: PMC10489734 DOI: 10.3390/molecules28176294] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 07/25/2023] [Accepted: 08/18/2023] [Indexed: 09/10/2023] Open
Abstract
CAG is a burdensome and progressive disease. Numerous studies have shown the effectiveness of RUT in digestive system diseases. The therapeutic effects of RUT on MNNG-induced CAG and the potential mechanisms were probed. MNNG administration was employed to establish a CAG model. The HE and ELISA methods were applied to detect the treatment effects. WB, qRT-PCR, immunohistochemistry, TUNEL, and GES-1 cell flow cytometry approaches were employed to probe the mechanisms. The CAG model was successfully established. The ELISA and HE staining data showed that the RUT treatment effects on CAG rats were reflected by the amelioration of histological damage. The qRT-PCR and WB analyses indicated that the protective effect of RUT is related to the upregulation of the SHH pathway and downregulation of the downstream of apoptosis to improve gastric cellular survival. Our data suggest that RUT induces a gastroprotective effect by upregulating the SHH signaling pathway and stimulating anti-apoptosis downstream.
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Affiliation(s)
- Yong He
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.H.); (X.W.)
| | - Hong-Hong Liu
- Department of Pharmacy, Chinese PLA General Hospital, Beijing 100039, China
| | - Xue-Lin Zhou
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100039, China
| | - Ting-Ting He
- Department of Pharmacy, Chinese PLA General Hospital, Beijing 100039, China
| | - Ao-Zhe Zhang
- Department of Pharmacy, Chinese PLA General Hospital, Beijing 100039, China
| | - Xin Wang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.H.); (X.W.)
| | - Shi-Zhang Wei
- Department of Pharmacy, Chinese PLA General Hospital, Beijing 100039, China
| | - Hao-Tian Li
- Department of Pharmacy, Chinese PLA General Hospital, Beijing 100039, China
| | - Li-Sheng Chen
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.H.); (X.W.)
| | - Lei Chang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Yan-Ling Zhao
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.H.); (X.W.)
- Department of Pharmacy, Chinese PLA General Hospital, Beijing 100039, China
| | - Man-Yi Jing
- Department of Pharmacy, Chinese PLA General Hospital, Beijing 100039, China
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2
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Bagheri V, Memar B, Behzadi R, Aliakbarian M, Jangjoo A, Bahar MM, Talebi S, Gholamin M, Abbaszadegan MR. Isolation and identification of chemotherapy-enriched sphere-forming cells from a patient with gastric cancer. J Cell Physiol 2018; 233:7036-7046. [PMID: 29744869 DOI: 10.1002/jcp.26627] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 03/28/2018] [Indexed: 01/13/2023]
Abstract
Gastric cancer (GC) is the third and fifth cause of cancer-associated mortality for men and women throughout the world, respectively. Despite the use of surgery and chemotherapy for GC therapy, there are no efficient therapeutic protocols for it to date. Cancer stem cells (CSCs) due to their pivotal role in tumor initiation, growth, progression, invasion, distant metastasis, recurrence and resistance to anticancer drugs are very appealing targets for cancer therapies. Here, we isolated and identified CSCs from a chemotherapy-treated patient. Small subpopulation of dissociated cells after tissue digestion formed spheroid colonies in serum-free media under the non-adherent condition. These spheroid colonies differentiated into epithelial like cells in serum-containing medium. Few sphere-forming cells carried CD44 and CD54 markers overexpressed DLL4 that is responsible for tumor growth and angiogenesis. Subcutaneous injections of sphere-forming cells in different passages conferred tumorigenicity in nude mice. Sphere-forming cells upregulated CD44 polymorphisms CD44v3, -v6, and -v8 -10, stemness factors OCT4, SOX2, SALL4 and Cripto-1, self-renewal molecules IHh, Wnt, β-catenin and BMI1, and epithelial mesenchymal transition (EMT) markers Twist1 and Snail1 in vitro and in vivo. Moreover, these cells similar to sphere-forming cells isolated from a chemotherapy-free patient expressed Oct-4 and β-catenin proteins. However, the Twist1 protein was only expressed by sphere-forming cells derived from the chemotherapy-treated patient. Thus, these cells have all the characteristics of stationary and migratory CSCs, including tumorigenicity, self-renewal, pluripotency, invasion and metastasis. Taken together, targeting chemotherapy-enriched CSCs as chemo-resistance cells observed in GC patients can provide more effective therapeutic strategies compared to untreated patients.
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Affiliation(s)
- Vahid Bagheri
- School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.,Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Council for Stem Cell Sciences and Technologies, Vice-presidency for Science and Technology, Presidency of the Islamic Republic of Iran, Tehran, Iran
| | - Bahram Memar
- Surgical Oncology Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ramezan Behzadi
- Msc North research Center-Pasture Institute of Iran, North Research Center-Pasture Institute of Iran, Amol, Iran
| | - Mohsen Aliakbarian
- Surgical Oncology Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Jangjoo
- Surgical Oncology Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mostafa Mehrabi Bahar
- Surgical Oncology Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Samaneh Talebi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehran Gholamin
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Council for Stem Cell Sciences and Technologies, Vice-presidency for Science and Technology, Presidency of the Islamic Republic of Iran, Tehran, Iran.,Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
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3
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Ballweg R, Schozer F, Elliott K, Kuhn A, Spotts L, Aihara E, Zhang T. Multiscale positive feedbacks contribute to unidirectional gastric disease progression induced by helicobacter pylori infection. BMC SYSTEMS BIOLOGY 2017; 11:111. [PMID: 29166909 PMCID: PMC5700561 DOI: 10.1186/s12918-017-0497-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Accepted: 11/13/2017] [Indexed: 12/27/2022]
Abstract
Background Helicobacter Pylori (HP) is the most common risk factor for gastric cancer. Nearly half the world’s population is infected with HP, but only a small percentage of those develop significant pathology. The bacteria itself does not directly cause cancer; rather it promotes an environment that is conducive to tumor formation. Upon infection, HP induces transcriptional changes in the host, leading to enhanced proliferation and host immune response. In addition, HP causes direct damage to gastric epithelial cells. Results We present a multiscale mechanistic model of HP induced changes. The model includes four modules representing the host transcriptional changes in response to infection, gastric atrophy, the Hedgehog pathway response, and the restriction point that controls cell cycle. This model was able to recapture a number of literature reported observations and was used as an “in silico” representation of the biological system for further analysis. Dynamical analysis of the model revealed that HP might induce the activation of multiple interplayed positive feedbacks, which in turn might result in a “ratchet ladder” system that promotes a unidirectional progression of gastric disease. Conclusions The current multiscale model is able to recapitulate the observed experimental features of HP host interactions and provides dynamic insights on the epidemiologically observed heterogeneity in disease progression. This model provides a solid framework that can be further expanded and validated to include additional experimental evidence, to understand the complex multi-pathway interactions characterizing HP infection, and to design novel treatment protocols for HP induced diseases. Electronic supplementary material The online version of this article (10.1186/s12918-017-0497-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Richard Ballweg
- Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Frederick Schozer
- Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Kelsey Elliott
- Division of Plastic Surgery, Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.,Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Alexander Kuhn
- Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Logan Spotts
- Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Eitaro Aihara
- Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Tongli Zhang
- Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
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4
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Ding S, Yang J, Huang X, Liu L, Hu J, Xu Z, Zhuge Q. Dopamine Burden Induced the Inactivation of Sonic Hedgehog Signaling to Cognitive Decline in Minimal Hepatic Encephalopathy. Aging Dis 2017; 8:442-457. [PMID: 28840059 PMCID: PMC5524807 DOI: 10.14336/ad.2016.1123] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Accepted: 11/23/2016] [Indexed: 12/20/2022] Open
Abstract
Minimal hepatic encephalopathy (MHE) is induced by elevated intracranial dopamine (DA). The relationship of the Shh pathway with memory loss in MHE, however, is elusive. In the current study, rats with MHE induced with DA displayed downregulation of the Shh pathway. Additionally, injection of Shh into MHE/DA-treated rats reversed downregulation of BDNF/NT3, whereas administration of cyclopamine (Cyc) enhanced the inhibition of expression of BDNF/NT3. Furthermore, naringin (Nrg) substantially prevented cognitive impairment in MHE/DA-treated rats and upregulated the Shh pathway, paralleling the elevated expression of BDNF/NT3. Overall, our results indicate that the Shh pathway can induce the expression of BDNF/NT3, and DA causes memory loss by inactivation of Shh pathway signaling to BDNF/NT3 in MHE rats, which is reversed by Nrg. Our study may provide new theory basis of pathogenesis and therapeutic target of MHE.
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Affiliation(s)
- Saidan Ding
- 1Zhejiang Provincial Key Laboratory of Aging and Neurological Disease Research, Department of Surgery Laboratory, the First Affiliated Hospital, Wenzhou Medical University, Zhejiang 325000, China
| | - Jianjing Yang
- 2Department of Neurosurgery, the First Affiliated Hospital, Wenzhou Medical University, Zhejiang 325000, China
| | - Xueli Huang
- 3School of Pharmaceutical Sciences, Wenzhou Medical University, Zhejiang 325000, China
| | - Leping Liu
- 1Zhejiang Provincial Key Laboratory of Aging and Neurological Disease Research, Department of Surgery Laboratory, the First Affiliated Hospital, Wenzhou Medical University, Zhejiang 325000, China
| | - Jiangnan Hu
- 4Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA
| | - Zhu Xu
- 2Department of Neurosurgery, the First Affiliated Hospital, Wenzhou Medical University, Zhejiang 325000, China
| | - Qichuan Zhuge
- 2Department of Neurosurgery, the First Affiliated Hospital, Wenzhou Medical University, Zhejiang 325000, China
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5
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Lee DH, Lee SY, Oh SC. Hedgehog signaling pathway as a potential target in the treatment of advanced gastric cancer. Tumour Biol 2017. [DOI: 10.1177/1010428317692266] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Affiliation(s)
- Dae-Hee Lee
- Division of Brain Korea 21 Program for Biomedicine Science, College of Medicine, Korea University, Seoul, Republic of Korea
- Division of Oncology and Hematology, Department of Internal Medicine, College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Suk-young Lee
- Division of Oncology and Hematology, Department of Internal Medicine, College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Sang Cheul Oh
- Division of Brain Korea 21 Program for Biomedicine Science, College of Medicine, Korea University, Seoul, Republic of Korea
- Division of Oncology and Hematology, Department of Internal Medicine, College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
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6
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Abbaszadegan MR, Bagheri V, Razavi MS, Momtazi AA, Sahebkar A, Gholamin M. Isolation, identification, and characterization of cancer stem cells: A review. J Cell Physiol 2017; 232:2008-2018. [PMID: 28019667 DOI: 10.1002/jcp.25759] [Citation(s) in RCA: 139] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 12/22/2016] [Indexed: 12/17/2022]
Abstract
Cancer stem cells (CSCs) or tumor-initiating cells (TICs) as a small subset of neoplastic cells are able to produce a tumor (tumorigenesis), maintain the population of tumorigenic cells (self-renewal), and generate the heterogeneous cells constructing the entire tumor (pluripotency). The research on stationary and circulating CSCs due to resistance to conventional therapies and inability in complete eradication of cancer is critical for developing novel therapeutic strategies for a more effective reduction in the risk of tumor metastasis and cancer recurrence. This review compiles information about different methods of detection and dissociation, side population, cellular markers, and establishment culture of CSCs, as well as characteristics of CSCs such as tumorigenicity, and signaling pathways associated with self-renewal and the capability of the same histological tumor regeneration in various cancers.
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Affiliation(s)
- Mohammad Reza Abbaszadegan
- Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Medical Genetics Research Center, Faculty of Medical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vahid Bagheri
- Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahya Shariat Razavi
- Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Biology, Faculty of Sciences, University of Sistan and Baluchestan, Zahedan, Iran
| | - Amir Abbas Momtazi
- Student Research Committee, Nanotechnology Research Center, Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehran Gholamin
- Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Laboratory Sciences, Faculty of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
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7
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Cetin B, Gumusay O, Cengiz M, Ozet A. Advances of Molecular Targeted Therapy in Gastric Cancer. J Gastrointest Cancer 2016; 47:125-134. [PMID: 26875080 DOI: 10.1007/s12029-016-9806-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancer is the second most common cause of cancer-related death in the world, and its prognosis remains poor with a median overall survival of 12 months for advanced disease. Advances in the understanding of molecular genetics have led to the development of directed molecular targeted therapy in gastric cancer, leading to improve patient outcomes and quality of life. DISCUSSION In the treatment of human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, the addition of trastuzumab significantly improves survival in the first-line setting of therapy. Ramucirumab, an antibody directed against vascular endothelial growth factor receptor 2, significantly improved progression-free and overall survival and has been approved for second-line treatment of gastric cancer. Anti-mesenchymal-epithelial transition (c-MET), mammalian target of rapamycin inhibitors, and polo-like kinase 1 inhibitors are under investigation as a novel therapeutic option for the treatment of gastric cancer. The novel therapies target the key immune checkpoint interaction between a T cell co-inhibitory receptor called programmed death 1 (PD-1) and one of its immunosuppressive ligands, PD-L1. This article reviews molecular targeted therapies in gastric cancer, in light of recent advances.
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Affiliation(s)
- Bulent Cetin
- Department of Internal Medicine, Division of Medical Oncology, Cumhuriyet University Faculty of Medicine, Sivas, 58140, Turkey.
| | - Ozge Gumusay
- Faculty of Medicine, Department of Internal Medicine, Division of Medical Oncology, Gaziosmanpasa University, Tokat, Turkey
| | - Mustafa Cengiz
- Department of Internal Medicine, Division of Gastroenterology, Dr. Abdurrahman Yurtaslan Training and Research Hospital, Ankara, Turkey
| | - Ahmet Ozet
- Department of Internal Medicine, Division of Medical Oncology, Gazi University Faculty of Medicine, Ankara, Turkey
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8
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Recapitulating Human Gastric Cancer Pathogenesis: Experimental Models of Gastric Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 908:441-78. [PMID: 27573785 DOI: 10.1007/978-3-319-41388-4_22] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
This review focuses on the various experimental models to study gastric cancer pathogenesis, with the role of genetically engineered mouse models (GEMMs) used as the major examples. We review differences in human stomach anatomy compared to the stomachs of the experimental models, including the mouse and invertebrate models such as Drosophila and C. elegans. The contribution of major signaling pathways, e.g., Notch, Hedgehog, AKT/PI3K is discussed in the context of their potential contribution to foregut tumorigenesis. We critically examine the rationale behind specific GEMMs, chemical carcinogens, dietary promoters, Helicobacter infection, and direct mutagenesis of relevant oncogenes and tumor suppressor that have been developed to study gastric cancer pathogenesis. Despite species differences, more efficient and effective models to test specific genes and pathways disrupted in human gastric carcinogenesis have yet to emerge. As we better understand these species differences, "humanized" versions of mouse models will more closely approximate human gastric cancer pathogenesis. Towards that end, epigenetic marks on chromatin, the gut microbiota, and ways of manipulating the immune system will likely move center stage, permitting greater overlap between rodent and human cancer phenotypes thus providing a unified progression model.
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9
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Marwaha S, Schumacher MA, Zavros Y, Eghbalnia HR. Crosstalks between cytokines and Sonic Hedgehog in Helicobacter pylori infection: a mathematical model. PLoS One 2014; 9:e111338. [PMID: 25364910 PMCID: PMC4218723 DOI: 10.1371/journal.pone.0111338] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Accepted: 09/23/2014] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori infection of gastric tissue results in an immune response dominated by Th1 cytokines and has also been linked with dysregulation of Sonic Hedgehog (SHH) signaling pathway in gastric tissue. However, since interactions between the cytokines and SHH during H. pylori infection are not well understood, any mechanistic understanding achieved through interpretation of the statistical analysis of experimental results in the context of currently known circuit must be carefully scrutinized. Here, we use mathematical modeling aided by restraints of experimental data to evaluate the consistency between experimental results and temporal behavior of H. pylori activated cytokine circuit model. Statistical analysis of qPCR data from uninfected and H. pylori infected wild-type and parietal cell-specific SHH knockout (PC-SHHKO) mice for day 7 and 180 indicate significant changes that suggest role of SHH in cytokine regulation. The experimentally observed changes are further investigated using a mathematical model that examines dynamic crosstalks among pro-inflammatory (IL1β, IL-12, IFNγ, MIP-2) cytokines, anti-inflammatory (IL-10) cytokines and SHH during H. pylori infection. Response analysis of the resulting model demonstrates that circuitry, as currently known, is inadequate for explaining of the experimental observations; suggesting the need for additional specific regulatory interactions. A key advantage of a computational model is the ability to propose putative circuit models for in-silico experimentation. We use this approach to propose a parsimonious model that incorporates crosstalks between NFĸB, SHH, IL-1β and IL-10, resulting in a feedback loop capable of exhibiting cyclic behavior. Separately, we show that analysis of an independent time-series GEO microarray data for IL-1β, IFNγ and IL-10 in mock and H. pylori infected mice further supports the proposed hypothesis that these cytokines may follow a cyclic trend. Predictions from the in-silico model provide useful insights for generating new hypothesis and design of subsequent experimental studies.
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Affiliation(s)
- Shruti Marwaha
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America
- * E-mail:
| | - Michael A. Schumacher
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America
| | - Yana Zavros
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America
| | - Hamid R. Eghbalnia
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America
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10
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Ishimoto T, Sawayama H, Sugihara H, Baba H. Interaction between gastric cancer stem cells and the tumor microenvironment. J Gastroenterol 2014; 49:1111-20. [PMID: 24652101 DOI: 10.1007/s00535-014-0952-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 03/05/2014] [Indexed: 02/04/2023]
Abstract
Gastric cancer (GC) remains a leading cause of cancer-related deaths worldwide. Cancer stem cells (CSCs) are selectively capable of tumor initiation and are implicated in tumor relapse and metastasis, thus, governing the prognosis of GC patients. Stromal cells and extracellular matrix adjacent to cancer cells are known to form a supportive environment for cancer progression. CSC properties are also regulated by their microenvironment through cell signaling and related factors. This review presents the current findings regarding the influence of the tumor microenvironment on GC stem cells, which will support the development of novel therapeutic strategies for patients with GC.
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Affiliation(s)
- Takatsugu Ishimoto
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
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11
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Song B, Kim B, Choi SH, Song KY, Chung YG, Lee YS, Park G. Mesenchymal stromal cells promote tumor progression in fibrosarcoma and gastric cancer cells. KOREAN JOURNAL OF PATHOLOGY 2014; 48:217-24. [PMID: 25013420 PMCID: PMC4087135 DOI: 10.4132/koreanjpathol.2014.48.3.217] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 05/29/2014] [Accepted: 05/30/2014] [Indexed: 01/10/2023]
Abstract
Background Extensive evidence has accumulated regarding the role of mesenchymal stromal cells (MSCs) in tumor progression, but the exact effects and mechanisms underlying this role remain unclear. We investigated the effects of MSC-associated tumor progression in MSC-sarcoma models and a gastric cancer metastatic model. Methods We conducted an in vitro growth kinetics assay and an in vivo tumor progression assay for sarcoma cells and gastric cancer cells in the presence or absence of MSCs. Results MSC-cocultured human fibrosarcoma cells (HT1080) showed accelerated growth compared with HT1080 alone (79- vs 37-fold change, p<.050). For HT1080, human MSC-coinjected tumors showed significantly greater and highly infiltrative growth compared to those of HT1080 alone (p=.035). For mouse fibrosarcoma cells (WEHI164), mouse MSC-coinjected tumors had greater volume than those of WEHI164 alone (p=.141). For rat sarcoma cells (RR1022), rat MSC-coinjected tumors exhibited greater volume and infiltrative growth than those of RR1022 alone (p=.050). For human gastric cancer cells (5FU), tumors of 5FU alone were compact, nodular in shape, and expansile with good demarcation and no definite lung metastatic nodules, whereas tumors grown in the presence of human MSCs showed highly desmoplastic and infiltrative growth and multiple lung metastasis. Conclusions We observed morphological evidence for MSC-associated tumor progression of fibrosarcomas and gastric cancer cells.
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Affiliation(s)
- Byunghoo Song
- Department of Pathology, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea. ; Cancer Research Institute, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Bokyung Kim
- Department of Pathology, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea. ; Cancer Research Institute, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Se-Ha Choi
- Cancer Research Institute, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Kyo Young Song
- Department of Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Yang-Guk Chung
- Department of Orthopedic Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Youn-Soo Lee
- Department of Pathology, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Gyeongsin Park
- Department of Pathology, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea. ; Cancer Research Institute, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
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12
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Wang LW, Lin H, Lu Y, Xia W, Gao J, Li ZS. Sonic hedgehog expression in a rat model of chronic pancreatitis. World J Gastroenterol 2014; 20:4712-4717. [PMID: 24782623 PMCID: PMC4000507 DOI: 10.3748/wjg.v20.i16.4712] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Accepted: 03/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the activation of sonic hedgehog (SHh) signaling pathways in a rat model of chronic pancreatitis.
METHODS: Forty Wistar rats were randomly divided into 2 groups: experimental group and control group (20 rats in each group). Dibutyltin dichloride was infused into the tail vein of the rats to induce chronic pancreatitis in the experimental group. The same volume of ethanol and glycerol mixture was infused in the control group. The expression of Ptch, Smo and Gli were analyzed using immunohistochemistry, and real-time reverse transcription polymerase chain reaction (RT-PCR).
RESULTS: Compared with the control group, significant histological changes in terms of the areas of abnormal architecture, glandular atrophy, fibrosis, pseudo tubular complexes, and edema were observed at week 4 in the experimental group. The expression of Ptch1, Smo and Gli1 in the pancreatic tissue increased significantly in the experimental group. Using RT-PCR, mRNA levels of Ptch, Smo and Gli in the experimental group increased significantly compared with the control group.
CONCLUSION: The SHh signaling pathway is aberrantly activated in rats with chronic pancreatitis. The SHh signaling pathway plays an important role in the development of chronic pancreatitis. These results may be helpful in studies focusing on the relationship between chronic pancreatitis and pancreatic cancer.
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MESH Headings
- Animals
- Atrophy
- Disease Models, Animal
- Fibrosis
- Hedgehog Proteins/metabolism
- Kruppel-Like Transcription Factors/genetics
- Kruppel-Like Transcription Factors/metabolism
- Male
- Organotin Compounds
- Pancreas/metabolism
- Pancreas/pathology
- Pancreatitis, Chronic/chemically induced
- Pancreatitis, Chronic/genetics
- Pancreatitis, Chronic/metabolism
- Pancreatitis, Chronic/pathology
- Patched Receptors
- Patched-1 Receptor
- RNA, Messenger/metabolism
- Rats, Wistar
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism
- Signal Transduction
- Smoothened Receptor
- Time Factors
- Zinc Finger Protein GLI1
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Loh M, Liem N, Vaithilingam A, Lim PL, Sapari NS, Elahi E, Mok ZY, Cheng CL, Yan B, Pang B, Salto-Tellez M, Yong WP, Iacopetta B, Soong R. DNA methylation subgroups and the CpG island methylator phenotype in gastric cancer: a comprehensive profiling approach. BMC Gastroenterol 2014; 14:55. [PMID: 24674026 PMCID: PMC3986689 DOI: 10.1186/1471-230x-14-55] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 03/25/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Methylation-induced silencing of promoter CpG islands in tumor suppressor genes plays an important role in human carcinogenesis. In colorectal cancer, the CpG island methylator phenotype (CIMP) is defined as widespread and elevated levels of DNA methylation and CIMP+ tumors have distinctive clinicopathological and molecular features. In contrast, the existence of a comparable CIMP subtype in gastric cancer (GC) has not been clearly established. To further investigate this issue, in the present study we performed comprehensive DNA methylation profiling of a well-characterised series of primary GC. METHODS The methylation status of 1,421 autosomal CpG sites located within 768 cancer-related genes was investigated using the Illumina GoldenGate Methylation Panel I assay on DNA extracted from 60 gastric tumors and matched tumor-adjacent gastric tissue pairs. Methylation data was analysed using a recursively partitioned mixture model and investigated for associations with clinicopathological and molecular features including age, Helicobacter pylori status, tumor site, patient survival, microsatellite instability and BRAF and KRAS mutations. RESULTS A total of 147 genes were differentially methylated between tumor and matched tumor-adjacent gastric tissue, with HOXA5 and hedgehog signalling being the top-ranked gene and signalling pathway, respectively. Unsupervised clustering of methylation data revealed the existence of 6 subgroups under two main clusters, referred to as L (low methylation; 28% of cases) and H (high methylation; 72%). Female patients were over-represented in the H tumor group compared to L group (36% vs 6%; P = 0.024), however no other significant differences in clinicopathological or molecular features were apparent. CpG sites that were hypermethylated in group H were more frequently located in CpG islands and marked for polycomb occupancy. CONCLUSIONS High-throughput methylation analysis implicates genes involved in embryonic development and hedgehog signaling in gastric tumorigenesis. GC is comprised of two major methylation subtypes, with the highly methylated group showing some features consistent with a CpG island methylator phenotype.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Richie Soong
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
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14
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Stojnev S, Krstic M, Ristic-Petrovic A, Stefanovic V, Hattori T. Gastric cancer stem cells: therapeutic targets. Gastric Cancer 2014; 17:13-25. [PMID: 23563919 DOI: 10.1007/s10120-013-0254-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Accepted: 03/15/2013] [Indexed: 02/07/2023]
Abstract
During the past decade, a growing body of evidence has implied that cancer stem cells (CSCs) play an important role in the development of gastric cancer (GC). The notion that CSCs give rise to GC and may be responsible for invasion, metastasis, and resistance to treatment has profound implications for anti-cancer therapy. Recent major advances in the rapidly evolving field of CSCs have opened novel exciting opportunities for developing CSC-targeted therapies. Discovery of specific markers and signaling pathways in gastric CSCs (GCSCs), with the perfecting of technologies for identification, isolation, and validation of CSCs, may provide the basis for a revolutionary cancer treatment approach based on the eradication of GCSCs. Emerging therapeutic tools based on specific properties and functions of CSCs, including activation of self-renewal signaling pathways, differences in gene expression profiles, and increased activity of telomerase or chemoresistance mechanisms, are developing in parallel with advances in nanotechnology and bioengineering. The addition of GCSC-targeted therapies to current oncological protocols and their complementary application may be the key to successfully fighting GC.
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Affiliation(s)
- Slavica Stojnev
- Faculty of Medicine, Institute of Pathology, University of Nis, Zorana Djindjica Blvd 81, 18000, Nis, Serbia,
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15
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Zhou W, Sun M, Wang DL, Wang Y, Jin F, Zhang YY, Yang L, Wu XL, Wu YZ. Silencing of RegIV by shRNA causes the loss of stemness properties of cancer stem cells in MKN45 gastric cancer cells. Oncol Rep 2013; 30:2685-90. [PMID: 24064664 DOI: 10.3892/or.2013.2745] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Accepted: 05/27/2013] [Indexed: 11/05/2022] Open
Abstract
Regenerating islet-derived family member 4 (RegIV) is overexpressed in several types of tumours, including pancreatic and gastric cancer (GC). However, the role it plays in gastric cancer stem cells (GCSCs) remains unknown. The present study tested the hypothesis that the silencing of RegIV by shRNA in GC cells may cause the loss of their stemness properties, indicating the inhibition of growth, proliferation and increased sensitivity to chemoradiation-induced cell death. MKN45 poorly differentiated human GC cells were propagated as mammospheres in stem cell culture conditions. Mammospheres were identified as CSCs using generally acknowledged CSC markers such as CD44. A panel of 21-nucleotide shRNAs were designed to target RegIV gene expression. Several shRNA constructs were identified that led to significant reduction in RegIV mRNA expression. Furthermore, the stemness properties of control mammospheres and RegIV knockdown mammospheres were compared by tumourigenicity assay in vivo and plate colony formation assay in vitro. Finally, we evaluated the treatment response in both mammospheres which underwent chemoradiation. The knockdown expression of RegIV by shRNA deprived CSCs of their stemness properties and increased the effectiveness of cell killing following chemoradiation. Inhibition of endogenous RegIV expression may be a new therapeutic strategy for human GC.
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Affiliation(s)
- Wei Zhou
- Department of Radiotherapy, Chongqing Cancer Institute, Chongqing 400011, P.R. China
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16
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Abstract
Gastric cancer (GC) remains one of the most common cancers worldwide. Its prevalence is still on the rise in the developing countries due to the ageing population. The cancer stem cell (CSC) theory provides a new insight into the interpretation of tumor initiation, aggressive growth, recurrence, and metastasis of cancer, as well as the development of new strategies for cancer treatment. This review will focus on the progress of biomarkers and signaling pathways of CSCs, the complex crosstalk networks between the microenvironment and CSCs, and the development of therapeutic approaches against CSCs, predominantly focusing on GC.
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17
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Strong MJ, Xu G, Coco J, Baribault C, Vinay DS, Lacey MR, Strong AL, Lehman TA, Seddon MB, Lin Z, Concha M, Baddoo M, Ferris M, Swan KF, Sullivan DE, Burow ME, Taylor CM, Flemington EK. Differences in gastric carcinoma microenvironment stratify according to EBV infection intensity: implications for possible immune adjuvant therapy. PLoS Pathog 2013; 9:e1003341. [PMID: 23671415 PMCID: PMC3649992 DOI: 10.1371/journal.ppat.1003341] [Citation(s) in RCA: 129] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2012] [Accepted: 03/20/2013] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV) is associated with roughly 10% of gastric carcinomas worldwide (EBVaGC). Although previous investigations provide a strong link between EBV and gastric carcinomas, these studies were performed using selected EBV gene probes. Using a cohort of gastric carcinoma RNA-seq data sets from The Cancer Genome Atlas (TCGA), we performed a quantitative and global assessment of EBV gene expression in gastric carcinomas and assessed EBV associated cellular pathway alterations. EBV transcripts were detected in 17% of samples but these samples varied significantly in EBV coverage depth. In four samples with the highest EBV coverage (hiEBVaGC – high EBV associated gastric carcinoma), transcripts from the BamHI A region comprised the majority of EBV reads. Expression of LMP2, and to a lesser extent, LMP1 were also observed as was evidence of abortive lytic replication. Analysis of cellular gene expression indicated significant immune cell infiltration and a predominant IFNG response in samples expressing high levels of EBV transcripts relative to samples expressing low or no EBV transcripts. Despite the apparent immune cell infiltration, high levels of the cytotoxic T-cell (CTL) and natural killer (NK) cell inhibitor, IDO1, was observed in the hiEBVaGCs samples suggesting an active tolerance inducing pathway in this subgroup. These results were confirmed in a separate cohort of 21 Vietnamese gastric carcinoma samples using qRT-PCR and on tissue samples using in situ hybridization and immunohistochemistry. Lastly, a panel of tumor suppressors and candidate oncogenes were expressed at lower levels in hiEBVaGC versus EBV-low and EBV-negative gastric cancers suggesting the direct regulation of tumor pathways by EBV. Epstein-Barr virus (EBV) is detected in roughly 10% of gastric carcinoma (GC) cases worldwide. Despite a strong link between EBV and gastric carcinoma, the contribution of EBV to the tumor environment in EBV associated gastric carcinoma is unclear. We performed a global assessment of EBV and host cell gene expression in gastric carcinoma tumors from 71 patients to link EBV genes (and expression intensities) to cell and microenvironmental changes. In addition to the finding that EBV is associated with down-regulated tumor regulatory genes, this study revealed that samples with high levels of EBV gene expression (hiEBVaGCs) displayed elevated immune cell infiltration with high interferon-gamma (IFNG) expression compared to samples with low or no EBV gene expression. Despite this evidence of increased immune posturing, hiEBVaGC samples also showed elevated expression of the potent immune cell inhibitor, IDO1. This finding may partly explain the persistence of these virus associated tumors in the face of local immune cell concentration. Importantly, the small molecule IDO inhibitor, 1MT (1-methyl Tryptophan), has been shown to reverse the tolerance inducing effects of IDO1 in other tumors. We propose that stratification of gastric carcinomas into EBV-negative, EBV-low and EBV-high may provide indicator value for the use of IDO1 inhibitors as adjuvant therapies against hiEBVaGCs.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Databases, Nucleic Acid
- Epstein-Barr Virus Infections/epidemiology
- Epstein-Barr Virus Infections/genetics
- Epstein-Barr Virus Infections/immunology
- Epstein-Barr Virus Infections/metabolism
- Epstein-Barr Virus Infections/pathology
- Epstein-Barr Virus Infections/therapy
- Female
- Gene Expression Regulation, Neoplastic/genetics
- Gene Expression Regulation, Neoplastic/immunology
- Gene Expression Regulation, Viral/genetics
- Gene Expression Regulation, Viral/immunology
- Herpesvirus 4, Human/genetics
- Herpesvirus 4, Human/immunology
- Herpesvirus 4, Human/metabolism
- Humans
- Immunotherapy
- Male
- Middle Aged
- Neoplasm Proteins/biosynthesis
- Neoplasm Proteins/genetics
- Neoplasm Proteins/immunology
- RNA, Neoplasm/biosynthesis
- RNA, Neoplasm/genetics
- RNA, Neoplasm/immunology
- RNA, Viral/biosynthesis
- RNA, Viral/genetics
- RNA, Viral/immunology
- Stomach Neoplasms/epidemiology
- Stomach Neoplasms/genetics
- Stomach Neoplasms/immunology
- Stomach Neoplasms/metabolism
- Stomach Neoplasms/pathology
- Stomach Neoplasms/therapy
- Tumor Microenvironment/genetics
- Tumor Microenvironment/immunology
- Viral Proteins/biosynthesis
- Viral Proteins/genetics
- Viral Proteins/immunology
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Affiliation(s)
- Michael J. Strong
- Department of Pathology, Tulane University, New Orleans, Louisiana, United States of America
- Tulane Cancer Center, New Orleans, Louisiana, United States of America
| | - Guorong Xu
- Department of Computer Science, University of New Orleans, New Orleans, Louisiana, United States of America
| | - Joseph Coco
- Department of Computer Science, University of New Orleans, New Orleans, Louisiana, United States of America
| | - Carl Baribault
- Tulane Cancer Center, New Orleans, Louisiana, United States of America
- Department of Mathematics, Tulane University, New Orleans, Louisiana, United States of America
| | - Dass S. Vinay
- Department of Medicine, Section of Clinical Immunology, Allergy, and Rheumatology, Tulane University, New Orleans, Louisiana, United States of America
| | - Michelle R. Lacey
- Tulane Cancer Center, New Orleans, Louisiana, United States of America
- Department of Mathematics, Tulane University, New Orleans, Louisiana, United States of America
| | - Amy L. Strong
- Tulane Center for Stem Cell Research and Regenerative Medicine, New Orleans, Louisiana, United States of America
| | - Teresa A. Lehman
- BioServe Biotechnologies, Ltd., Beltsville, Maryland, United States of America
| | - Michael B. Seddon
- BioServe Biotechnologies, Ltd., Beltsville, Maryland, United States of America
| | - Zhen Lin
- Department of Pathology, Tulane University, New Orleans, Louisiana, United States of America
- Tulane Cancer Center, New Orleans, Louisiana, United States of America
| | - Monica Concha
- Department of Pathology, Tulane University, New Orleans, Louisiana, United States of America
- Tulane Cancer Center, New Orleans, Louisiana, United States of America
| | - Melody Baddoo
- Department of Pathology, Tulane University, New Orleans, Louisiana, United States of America
- Tulane Cancer Center, New Orleans, Louisiana, United States of America
| | - MaryBeth Ferris
- Department of Microbiology & Immunology, Tulane University, New Orleans, Louisiana, United States of America
| | - Kenneth F. Swan
- Department of Obstetrics and Gynecology, Tulane University, New Orleans, Louisiana, United States of America
| | - Deborah E. Sullivan
- Department of Microbiology & Immunology, Tulane University, New Orleans, Louisiana, United States of America
| | - Matthew E. Burow
- Tulane Cancer Center, New Orleans, Louisiana, United States of America
- Department of Medicine, Section of Hematology and Medical Oncology, Tulane University, New Orleans, Louisiana, United States of America
| | - Christopher M. Taylor
- Department of Computer Science, University of New Orleans, New Orleans, Louisiana, United States of America
- Department of Microbiology, Immunology & Parasitology, Louisiana State University School of Medicine, New Orleans, Louisiana, United States of America
- Research Institute for Children, Children's Hospital, New Orleans, Louisiana, United States of America
- * E-mail: (CMT); (EKF)
| | - Erik K. Flemington
- Department of Pathology, Tulane University, New Orleans, Louisiana, United States of America
- Tulane Cancer Center, New Orleans, Louisiana, United States of America
- * E-mail: (CMT); (EKF)
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18
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Li H, Mo J, Jia G, Liu C, Luan Z, Guan Y. Activation of Wnt signaling inhibits the pro-apoptotic role of Notch in gastric cancer cells. Mol Med Rep 2013; 7:1751-6. [PMID: 23563575 DOI: 10.3892/mmr.2013.1412] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2012] [Accepted: 12/04/2012] [Indexed: 01/02/2023] Open
Abstract
Notch and Wnt signaling play critical roles in the regulation of development and diseases. Several studies have previously reported that Notch may be a therapeutic target in the treatment of various types of human cancer. In this study, we report that activation of Notch1 inhibits the proliferation of BGC-823 gastric cancer cells. However, the activation of the Wnt/β‑catenin signaling pathway promotes the growth of BGC-823 cells. Furthermore, the combinational activation of the two signaling pathways promotes the proliferation of BGC-823 cells. These data suggest that the activation of Wnt signaling overcomes the pro-apoptotic role of Notch in BGC-823 gastric cancer cells.
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Affiliation(s)
- Hong Li
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, Liaoning 110001, P.R. China
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19
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Han ME, Oh SO. Gastric stem cells and gastric cancer stem cells. Anat Cell Biol 2013; 46:8-18. [PMID: 23560232 PMCID: PMC3615616 DOI: 10.5115/acb.2013.46.1.8] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Revised: 01/14/2013] [Accepted: 01/23/2013] [Indexed: 12/16/2022] Open
Abstract
The gastric epithelium is continuously regenerated by gastric stem cells, which give rise to various kinds of daughter cells, including parietal cells, chief cells, surface mucous cells, mucous neck cells, and enteroendocrine cells. The self-renewal and differentiation of gastric stem cells need delicate regulation to maintain the normal physiology of the stomach. Recently, it was hypothesized that cancer stem cells drive the cancer growth and metastasis. In contrast to conventional clonal evolution hypothesis, only cancer stem cells can initiate tumor formation, self-renew, and differentiate into various kinds of daughter cells. Because gastric cancer can originate from gastric stem cells and their self-renewal mechanism can be used by gastric cancer stem cells, we review here how critical signaling pathways, including hedgehog, Wnt, Notch, epidermal growth factor, and bone morphogenetic protein signaling, may regulate the self-renewal and differentiation of gastric stem cells and gastric cancer stem cells. In addition, the precancerous change of the gastric epithelium and the status of isolating gastric cancer stem cells from patients are reviewed.
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Affiliation(s)
- Myoung-Eun Han
- Department of Anatomy, Pusan National University School of Medicine, Yangsan, Korea. ; Medical Research Center for Ischemic Tissue Regeneration, Pusan National University, Yangsan, Korea
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20
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Song Y, Tian Y, Zuo Y, Tu JC, Feng YF, Qu CJ. Altered expression of PTCH and HHIP in gastric cancer through their gene promoter methylation: novel targets for gastric cancer. Mol Med Rep 2013; 7:1159-68. [PMID: 23440386 DOI: 10.3892/mmr.2013.1333] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Accepted: 02/15/2013] [Indexed: 11/06/2022] Open
Abstract
Human hedgehog-interacting protein (HHIP) and protein patched homolog (PTCH) are two negative regulators of the hedgehog signal, however, the mechanism of action in gastric cancer is unknown. Methylation of TSG promoters has been considered as a causative mechanism of tumorigenesis. In the present study, we first determined the expression of PTCH and HHIP mRNA and protein in gastric cancer tissues and adjacent normal tissues, and then detected methylation of the two genes to associate their expression and gene promoter methylation in gastric cancer. Expression in gastric cancer tissues and the cancer cells (AGS) were evaluated by reverse transcription-PCR (RT-PCR), qRT-PCR and IHC, while the methylation expression was valued by methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP). Cell viability and apoptosis were analyzed by MTT assay and flow cytometry following treatment with 5-aza-dc. Results showed that PTCH and HHIP expression was reduced in gastric cancer tissues that were not associated with clinical features. Moreover, methylation of the promoters was reversely correlated with the expression. Following treatment with 5-aza-dc, AGS reduced cell viability and induced apoptosis, which is associated with upregulation of HHIP expression. The data demonstrated that loss of expression of HHIP and PTCH is associated with the methylation of gene promoters. In addition, 5-aza-dc-induced apoptosis correlated with the upregulation of HHIP expression in AGS. The findings demonstrated that the PTCH and HHIP genes may be novel targets for the control of gastric cancer.
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Affiliation(s)
- Yu Song
- Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P.R. China
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21
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Wilson-Robles HM, Daly M, Pfent C, Sheppard S. Identification and evaluation of putative tumour-initiating cells in canine malignant melanoma cell lines. Vet Comp Oncol 2013; 13:60-9. [DOI: 10.1111/vco.12019] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Revised: 01/02/2013] [Accepted: 01/03/2013] [Indexed: 12/24/2022]
Affiliation(s)
- H. M. Wilson-Robles
- Department of Small Animal Clinical Sciences; College of Veterinary Medicine, Texas A&M University; College Station TX USA
| | - M. Daly
- Department of Small Animal Clinical Sciences; College of Veterinary Medicine, Texas A&M University; College Station TX USA
| | - C. Pfent
- Department of Veterinary Pathobiology; College of Veterinary Medicine, Texas A&M University; College Station TX USA
| | - S. Sheppard
- Department of Small Animal Clinical Sciences; College of Veterinary Medicine, Texas A&M University; College Station TX USA
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22
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Zhang JH, Feng YG, Gao GP, Tao YY, Zhang XQ, Zhang HM, Jiao JX. Effects of CagA +Helicobacter pylori infection on expression of HIF-2α and ABCG2 in human gastric cancer cell line SGC7901 under normoxia and hypoxia conditions. Shijie Huaren Xiaohua Zazhi 2013; 21:293-299. [DOI: 10.11569/wcjd.v21.i4.293] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe the effect of CagA+Helicobacter pylori (H. pylori) on the expression of HIF-2α and ABCG2 in human gastric cancer cell line SGC7901 under normoxia and hypoxia conditions to investigate whether H. pylori infection and the tumor microenvironment have a synergistic effect in the initiation and development of gastric cancer.
METHODS: Gastric mucosal biopsy specimens collected by endoscopy were cultured under microaerophilic conditions and H. pylori isolates were identified. CagA+H. pylori strains were confirmed by PCR. Gastric cancer cell line SGC7901 was co-cultured with a CagA+H. pylori strain for 48 h under either normoxia or hypoxia condition (cells were divided into a normoxia control group, a hypoxia control group, a normoxia plus CagA+H. pylori group, and a hypoxia plus CagA+H. pylori group). Immunocytochemistry was used to detect the expression of HIF-2α and ABCG2 proteins, and RT-PCR was used to detect the expression of ABCG2 mRNA.
RESULTS: Immunocytochemistry results showed that HIF-2α and ABCG2 proteins were expressed at low levels under normoxia, while both hypoxia and CagA+H. pylori could significantly induce the expression of HIF-2α and ABCG2 proteins compared to the normoxia control group (all P < 0.01). Compared to the hypoxia control group and normoxia plus CagA+H. pylori group, the expression of HIF-2α and ABCG2 proteins was further elevated in the hypoxia plus CagA+H. pylori group (all P < 0.01). There was a positive correlation between the expression of HIF-2α and that of ABCG2 (r = 0.976, P < 0.05). Similar results were obtained for ABCG2 mRNA expression by RT-PCR.
CONCLUSION: CagA+H. pylori can stimulate the expression of HIF-2α and ABCG2 in gastric cancer cells under normoxia condition, and their expression can be further up-regulated under hypoxia condition. CagA+H. pylori and hypoxia have a synergistic effect on the expression of HIF-2α and ABCG2, suggesting that CagA+H. pylori and hypoxia may play an important role in inducing gastric cancer cell de-differentiation and chemotherapy resistance.
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23
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Syu LJ, El-Zaatari M, Eaton KA, Liu Z, Tetarbe M, Keeley TM, Pero J, Ferris J, Wilbert D, Kaatz A, Zheng X, Qiao X, Grachtchouk M, Gumucio DL, Merchant JL, Samuelson LC, Dlugosz AA. Transgenic expression of interferon-γ in mouse stomach leads to inflammation, metaplasia, and dysplasia. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 181:2114-25. [PMID: 23036899 DOI: 10.1016/j.ajpath.2012.08.017] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 03/24/2012] [Revised: 08/24/2012] [Accepted: 08/30/2012] [Indexed: 02/08/2023]
Abstract
Gastric adenocarcinoma is one of the leading causes of cancer mortality worldwide. It arises through a stepwise process that includes prominent inflammation with expression of interferon-γ (IFN-γ) and multiple other pro-inflammatory cytokines. We engineered mice expressing IFN-γ under the control of the stomach-specific H(+)/K(+) ATPase β promoter to test the potential role of this cytokine in gastric tumorigenesis. Stomachs of H/K-IFN-γ transgenic mice exhibited inflammation, expansion of myofibroblasts, loss of parietal and chief cells, spasmolytic polypeptide expressing metaplasia, and dysplasia. Proliferation was elevated in undifferentiated and metaplastic epithelial cells in H/K-IFN-γ transgenic mice, and there was increased apoptosis. H/K-IFN-γ mice had elevated levels of mRNA for IFN-γ target genes and the pro-inflammatory cytokines IL-6, IL-1β, and tumor necrosis factor-α. Intracellular mediators of IFN-γ and IL-6 signaling, pSTAT1 and pSTAT3, respectively, were detected in multiple cell types within stomach. H/K-IFN-γ mice developed dysplasia as early as 3 months of age, and 4 of 39 mice over 1 year of age developed antral polyps or tumors, including one adenoma and one adenocarcinoma, which expressed high levels of nuclear β-catenin. Our data identified IFN-γ as a pivotal secreted factor that orchestrates complex changes in inflammatory, epithelial, and mesenchymal cell populations to drive pre-neoplastic progression in stomach; however, additional alterations appear to be required for malignant conversion.
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Affiliation(s)
- Li-Jyun Syu
- Department of Dermatology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA
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24
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Ma HY, Zhang F, Li J, Mo ML, Chen Z, Liu L, Zhou HM, Sheng Q. HSulf-1 suppresses cell growth and down-regulates Hedgehog signaling in human gastric cancer cells. Oncol Lett 2011; 2:1291-1295. [PMID: 22848304 DOI: 10.3892/ol.2011.407] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2011] [Accepted: 08/12/2011] [Indexed: 01/03/2023] Open
Abstract
Gastric cancer is the second most lethal cancer worldwide. Despite the current surgical and adjuvant therapies, 5-year survival remains less than 20-25% in the US, Europe and China. Therefore, there is an urgent need to identify new therapeutic targets for treating this malignant disease. Accumulating evidence has supported that aberrant activation of the Hedgehog signaling pathway plays a crucial role in tumorigenesis and progression of gastric cancer. Human sulfatase-1 (HSulf-1) is a recently identified enzyme that desulfates cell surface heparan sulfate proteoglycans (HSPGs), which is critical for Hedgehog signal transduction under a highly sulfated state. HSulf-1 has recently emerged as a tumor suppressor gene in certain types of cancer, including ovarian, breast, myeloma and hepatocellular carcinoma; however, its role in gastric cancer remains to be elucidated. Therefore, we established HSulf-1-expressing monoclonal MKN28 gastric cancer cells to investigate its function in gastric cancer. Expression of HSulf-1 significantly suppressed cellular proliferation and growth in MKN28 gastric cancer cells. Notably, HSulf-1 inhibits Gli-mediated transcription and down-regulates the expression of Hedgehog target genes, including GLI1, PTCH1/2, HHIP, CCND1, C-MYC and BCL-2. Collectively, the study provides evidence that HSulf-1 may function as a tumor suppressor in gastric cancer. It suppresses gastric cancer cell proliferation, possibly through abrogating the Hedgehog signaling pathway. The study provides new mechanistic insight into HSulf-1- mediated tumor suppression, and supports the use of HSulf-1 as a potential new therapeutic target in treating gastric cancer.
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Affiliation(s)
- Hui-Yan Ma
- College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018
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25
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Harris LG, Samant RS, Shevde LA. Hedgehog signaling: networking to nurture a promalignant tumor microenvironment. Mol Cancer Res 2011; 9:1165-74. [PMID: 21775419 DOI: 10.1158/1541-7786.mcr-11-0175] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
In addition to its role in embryonic development, the Hedgehog pathway has been shown to be an active participant in cancer development, progression, and metastasis. Although this pathway is activated by autocrine signaling by Hedgehog ligands, it can also initiate paracrine signaling with cells in the microenvironment. This creates a network of Hedgehog signaling that determines the malignant behavior of the tumor cells. As a result of paracrine signal transmission, the effects of Hedgehog signaling most profoundly influence the stromal cells that constitute the tumor microenvironment. The stromal cells in turn produce factors that nurture the tumor. Thus, such a resonating cross-talk can amplify Hedgehog signaling, resulting in molecular chatter that overall promotes tumor progression. Inhibitors of Hedgehog signaling have been the subject of intense research. Several of these inhibitors are currently being evaluated in clinical trials. Here, we review the role of the Hedgehog pathway in the signature characteristics of cancer cells that determine tumor development, progression, and metastasis. This review condenses the latest findings on the signaling pathways that are activated and/or regulated by molecules generated from Hedgehog signaling in cancer and cites promising clinical interventions. Finally, we discuss future directions for identifying the appropriate patients for therapy, developing reliable markers of efficacy of treatment, and combating resistance to Hedgehog pathway inhibitors.
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Affiliation(s)
- Lillianne G Harris
- University of South Alabama Mitchell Cancer Institute, Mobile, Alabama 36604, USA
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Merchant JL, Saqui-Salces M, El-Zaatari M. Hedgehog signaling in gastric physiology and cancer. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2010; 96:133-56. [PMID: 21075343 DOI: 10.1016/b978-0-12-381280-3.00006-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The Hedgehog family of ligands was originally identified in mutagenesis screens of Drosophila embryos. Hedgehog signaling in multiple tissues is important during embryonic development. A common theme regarding Hedgehog expression in adult tissues is that tissue injury reactivates the developmental pattern of expression. In most instances, this appears to be important to initiate tissue repair. In the gastrointestinal (GI) tract, where epithelial cells are constantly replenished from progenitor populations, Hedgehog signaling also appears to be essential for regeneration. By contrast, reactivated Hedgehog signaling in adult tissues does not automatically predispose the tissue to transformation, but instead requires sustained tissue injury in the form of chronic inflammation. In this chapter, we review what is known about Hedgehog ligands and signaling during development of relevant organs, and discuss how the patterns of Hedgehog regulation are recapitulated in the GI tract during embryogenesis, adult homeostasis, and neoplastic transformation.
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Affiliation(s)
- Juanita L Merchant
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
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