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Teshima H, Takigawa H, Kotachi T, Tsuboi A, Tanaka H, Yamashita K, Kishida Y, Urabe Y, Kuwai T, Ishikawa A, Oka S. A Proton Pump Inhibitor Independently Elevates Gastrin Levels as a Marker for Metachronous Gastric Cancer After Endoscopic Submucosal Dissection. J Clin Med 2024; 13:6599. [PMID: 39518740 PMCID: PMC11546463 DOI: 10.3390/jcm13216599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 10/31/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024] Open
Abstract
Background and Objective: Serum markers such as gastrin and pepsinogen are useful for stratifying gastric cancer risk. However, their utility in predicting metachronous gastric cancer after endoscopic submucosal dissection (ESD) in patients with gastric cancer after Helicobacter pylori eradication (GCAE) is unclear. This study aimed to clarify predictive factors for metachronous gastric cancer after ESD with a focus on serum markers. Methods: A retrospective analysis was conducted on 197 patients with 224 GCAE lesions who underwent ESD at Hiroshima University Hospital between April 2010 and December 2019. In total, 63 patients with 74 differentiated-type lesions were classified into metachronous gastric cancer (MG) and non-metachronous gastric cancer (NMG) groups, excluding proton pump inhibitor (PPI) users, female patients, and undifferentiated-type cases. The predictive value of serum markers was assessed using ROC curve analysis, and their association with carcinogenesis was evaluated using multiple logistic regression. Furthermore, the incidence of MG was compared between long-term PPI users and non-users. Results: ROC analysis revealed that serum gastrin had the highest discriminative ability for MG (AUC 0.77, cut-off 99 pg/mL, sensitivity 61.6%, and specificity 80.0%). Severe mucosal atrophy and high gastrin levels were significantly more common in the MG group and were independent predictors (p < 0.01). Although serum gastrin levels were significantly elevated in PPI users, no increased risk of MG was observed. Conclusions: In addition to severe mucosal atrophy, PPI-independent elevated serum gastrin levels may be associated with an increased risk of MG after ESD. Serum gastrin may serve as a valuable marker for post-ESD cancer surveillance in GCAE patients.
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Affiliation(s)
- Hajime Teshima
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (T.K.); (A.T.); (H.T.); (K.Y.); (Y.K.); (Y.U.); (S.O.)
| | - Hidehiko Takigawa
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (T.K.); (A.T.); (H.T.); (K.Y.); (Y.K.); (Y.U.); (S.O.)
| | - Takahiro Kotachi
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (T.K.); (A.T.); (H.T.); (K.Y.); (Y.K.); (Y.U.); (S.O.)
| | - Akiyoshi Tsuboi
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (T.K.); (A.T.); (H.T.); (K.Y.); (Y.K.); (Y.U.); (S.O.)
| | - Hidenori Tanaka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (T.K.); (A.T.); (H.T.); (K.Y.); (Y.K.); (Y.U.); (S.O.)
| | - Ken Yamashita
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (T.K.); (A.T.); (H.T.); (K.Y.); (Y.K.); (Y.U.); (S.O.)
| | - Yoshihiro Kishida
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (T.K.); (A.T.); (H.T.); (K.Y.); (Y.K.); (Y.U.); (S.O.)
| | - Yuji Urabe
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (T.K.); (A.T.); (H.T.); (K.Y.); (Y.K.); (Y.U.); (S.O.)
| | - Toshio Kuwai
- Gastrointestinal Endoscopy and Medicine, Hiroshima University Hospital, Hiroshima 734-8551, Japan;
| | - Akira Ishikawa
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiorshima University Hospital, Hiroshima 734-8551, Japan;
| | - Shiro Oka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (T.K.); (A.T.); (H.T.); (K.Y.); (Y.K.); (Y.U.); (S.O.)
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Urabe Y, Ishikawa H, Ishikawa A, Ishiguro S, Ishibashi K, Arihiro K, Mutoh M, Oka S. Two Cases of Increased Gastrointestinal Polyps in Familial Adenomatous Polyposis following Antiacid Agent Intake. Case Rep Gastroenterol 2024; 18:293-298. [PMID: 39015522 PMCID: PMC11250236 DOI: 10.1159/000538833] [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: 11/21/2023] [Accepted: 04/08/2024] [Indexed: 07/18/2024] Open
Abstract
INTRODUCTION Familial adenomatous polyposis (FAP), a hereditary disorder of the gastrointestinal tract, is an autosomal dominant inherited condition caused by germline mutations in the adenomatous polyposis coli (APC) gene. It is characterized by the development of hundreds to thousands of colorectal adenomatous polyps, which, if left untreated, can eventually develop into colorectal carcinomas. Representative extracolonic tumors in FAP include multiple duodenal adenomas and desmoid tumors. Moreover, multiple fundic gland polyps are frequently identified in the stomachs of patients with FAP. CASE PRESENTATION Herein, we report the two cases. A 52-year-old woman who underwent total colectomy for FAP, and pancreatoduodenectomy was initiated on esomeprazole for the treatment of anastomotic erosion. Esophagogastroduodenoscopy performed 42 months later showed an increased number and size of gastric fundic gland polyps, which subsequently decreased after replacing esomeprazole with ranitidine. Similarly, a 39-year-old woman with FAP was initiated on vonoprazan for the treatment of reflux symptoms. Esophagogastroduodenoscopy and colonoscopy performed 14 months later indicated an increase in the number of gastric fundic gland polyps and colorectal polyps, which subsequently decreased after vonoprazan discontinuation. In these two cases, the increase and decrease in the number and size of fundic gland polyps and colon adenoma were associated with serum gastrin levels. CONCLUSION Gastric fundic gland polyps and colon polyps may rapidly increase in number and size due to increased gastrin levels induced by proton pump inhibitor/potassium-competitive acid blocker use. Hence, these drugs should be prescribed with caution.
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Affiliation(s)
- Yuji Urabe
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
- Department of Gastrointestinal Endoscopy and Medicine, Hiroshima University Hospital, Hiroshima, Japan
| | - Hideki Ishikawa
- Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Ishikawa Gastrointestinal Clinic, Osaka, Japan
| | - Akira Ishikawa
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | | | - Kazuki Ishibashi
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Koji Arihiro
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Michihiro Mutoh
- Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shiro Oka
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
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3
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Huber MA, Nadella S, Cao H, Kallakury B, Tucker RD, Gay MD, Shivapurkar N, Edmondson EF, Yue Y, Dou W, Fang HB, Smith JP. Does Chronic Use of High Dose Proton Pump Inhibitors Increase Risk for Pancreatic Cancer? Pancreas 2022; 51:1118-1127. [PMID: 37078934 PMCID: PMC10119745 DOI: 10.1097/mpa.0000000000002145] [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] [Indexed: 04/21/2023]
Abstract
OBJECTIVES To analyze whether use of proton pump inhibitors increase the risk for pancreatic cancer in a mouse model and human clinical cohorts. METHODS p48-Cre/LSL-KrasG12D mice that develop precancerous pancreatic intraepithelial neoplasia (PanINs) were treated with low- or high-dose proton pump inhibitors (PPIs) orally for 1 and 4 months. The mechanism for the cholecystokinin receptor 2 (CCK-2R) activation was investigated in vitro. Two resources were employed to analyze the risk of pancreatic cancer in human subjects with PPI use. RESULTS Serum gastrin levels were increased 8-fold (P < 0.0001) in mice treated with chronic high-dose PPIs, and this change correlated with an increase (P = 0.02) in PanIN grade and the development of microinvasive cancer. The CCK-2R expression was regulated by microRNA-148a in the p48-Cre/LSL-KrasG12D mice pancreas and in human pancreatic cancer cells in vitro. Proton pump inhibitor consumption in human subjects was correlated with pancreatic cancer risk (odds ratio, 1.54). A validation analysis conducted using the large-scale United Kingdom Biobank database confirmed the correlation (odds ratio, 1.9; P = 0.00761) of pancreatic cancer risk with PPI exposure. CONCLUSIONS This investigation revealed in both murine models and human subjects, PPI use is correlated with a risk for development of pancreatic cancer.
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Affiliation(s)
| | | | | | | | - Robin D Tucker
- Department of Pathology, Georgetown University, Washington, DC
| | | | | | | | - Yuanzhen Yue
- Biostatistics, Bioinformatics and Biomathematics, Georgetown University, Washington, DC
| | - Wenyu Dou
- Biostatistics, Bioinformatics and Biomathematics, Georgetown University, Washington, DC
| | - Hong-Bin Fang
- Biostatistics, Bioinformatics and Biomathematics, Georgetown University, Washington, DC
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4
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Duan S, Rico K, Merchant JL. Gastrin: From Physiology to Gastrointestinal Malignancies. FUNCTION (OXFORD, ENGLAND) 2021; 3:zqab062. [PMID: 35330921 PMCID: PMC8788842 DOI: 10.1093/function/zqab062] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/14/2021] [Accepted: 11/16/2021] [Indexed: 01/07/2023]
Abstract
Abetted by widespread usage of acid-suppressing proton pump inhibitors (PPIs), the mitogenic actions of the peptide hormone gastrin are being revisited as a recurring theme in various gastrointestinal (GI) malignancies. While pathological gastrin levels are intricately linked to hyperplasia of enterochromaffin-like cells leading to carcinoid development, the signaling effects exerted by gastrin on distinct cell types of the gastric mucosa are more nuanced. Indeed, mounting evidence suggests dichotomous roles for gastrin in both promoting and suppressing tumorigenesis. Here, we review the major upstream mediators of gastrin gene regulation, including inflammation secondary to Helicobacter pylori infection and the use of PPIs. We further explore the molecular biology of gastrin in GI malignancies, with particular emphasis on the regulation of gastrin in neuroendocrine neoplasms. Finally, we highlight tissue-specific transcriptional targets as an avenue for targetable therapeutics.
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Affiliation(s)
- Suzann Duan
- Department of Medicine, Division of Gastroenterology and Hepatology, Arizona Comprehensive Cancer Center, University of Arizona, Tucson, AZ 85724, USA
| | - Karen Rico
- Department of Medicine, Division of Gastroenterology and Hepatology, Arizona Comprehensive Cancer Center, University of Arizona, Tucson, AZ 85724, USA
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5
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Choi Y, Kim N, Yoon H, Shin CM, Park YS, Lee DH, Park YS, Ahn SH, Suh YS, Park DJ, Kim HH. The Incidence and Risk Factors for Metachronous Gastric Cancer in the Remnant Stomach after Gastric Cancer Surgery. Gut Liver 2021; 16:366-374. [PMID: 34462394 PMCID: PMC9099384 DOI: 10.5009/gnl210202] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/10/2021] [Accepted: 06/23/2021] [Indexed: 01/04/2023] Open
Abstract
Background/Aims Less invasive surgical treatment is performed in East Asia to preserve postoperative digestive function and reduce complications such as postgastrectomy syndromes, but there is an issue of metachronous gastric cancer (GC) in the remaining stomach. This study aimed to analyze the incidence of metachronous GC and its risk factors in patients who had undergone partial gastrectomy. Methods A total of 3,045 GC patients who had undergone curative gastric partial resection at Seoul National University Bundang Hospital were enrolled and analyzed retrospectively for risk factors, including age, sex, smoking, alcohol, Helicobacterpylori status, family history of GC, histological type, and surgical method. Results Metachronous GC in the remaining stomach occurred in 35 of the 3,045 patients (1.1%) 23 in the distal gastrectomy group (18 with Billroth-I anastomosis, five with Billroth-II anastomosis), seven in the proximal gastrectomy (PG) group, and five in the pylorus-preserving gastrectomy (PPG) group. Univariate and multivariate Cox regression analyses showed that age ≥60 years (p=0.005) and surgical method used (PG or PPG, p<0.001) were related risk factors for metachronous GC, while male sex and intestinal type histology were potential risk factors. Conclusions Metachronous GC was shown to be related to older age and the surgical method used (PG or PPG). Regular and careful follow-up with endoscopy should be performed in the case of gastric partial resection, especially in patients with male sex and intestinal type histology as well as those aged ≥60 years undergoing the PG or PPG surgical method.
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Affiliation(s)
- Yonghoon Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Young Soo Park
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Young Suk Park
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sang-Hoon Ahn
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yun-Suhk Suh
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Do Joong Park
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hyung Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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6
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Osborne N, Sundseth R, Gay MD, Cao H, Tucker RD, Nadella S, Wang S, Liu X, Kroemer A, Sutton L, Cato A, Smith JP. Vaccine against gastrin, a polyclonal antibody stimulator, decreases pancreatic cancer metastases. Am J Physiol Gastrointest Liver Physiol 2019; 317:G682-G693. [PMID: 31433212 PMCID: PMC6879893 DOI: 10.1152/ajpgi.00145.2019] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/31/2019] [Accepted: 08/05/2019] [Indexed: 02/07/2023]
Abstract
Growth of pancreatic cancer is stimulated by gastrin in both a paracrine and an autocrine fashion. Traditional therapies have not significantly improved survival, and recently pancreatic cancer has been deemed a "cold" tumor due to its poor response to immunotherapy. Strategies to improve survival of pancreatic cancer are desperately needed. In the current investigation, we studied the effects of an anti-gastrin cancer vaccine, polyclonal antibody stimulator (PAS; formerly called G17DT and Gastrimmune), used alone or in combination with a programmed cell death receptor (PD)-1 immune checkpoint antibody on pancreatic cancer growth, metastases, and the tumor microenvironment (TME). Immune-competent female C57BL/6 mice bearing syngeneic orthotopic murine pancreatic cancer treated with PAS had significantly smaller tumors and fewer metastases. Examination of the TME demonstrated decreased fibrosis with fewer M2 and more M1 tumor-associated macrophages. Expression of the E-cadherin gene was significantly increased and expression of the TGFβR2 gene was decreased compared with controls. Mice treated with PAS or the combination of PAS and PD-1 antibody exhibited significantly less tumor expression of phospho-paxillin, the focal adhesion protein β-catenin, and matrix metalloproteinase-7. This study suggests that inhibition of the cancer-promoting effects of gastrin in pancreatic cancer can decrease metastases by altering the TME and decreasing pathways that activate the epithelial mesenchymal transition. The PAS vaccine appears to change the TME, making it more susceptible to therapy with an immune checkpoint antibody. This novel combination of two immunotherapies may improve survival of pancreatic cancer by decreasing both tumor growth and metastasis formation.NEW & NOTEWORTHY Survival from advanced pancreatic cancer is poor, in part due to dense fibrosis of the tumor microenvironment, increased number of M2-polarized macrophages that promote angiogenesis and invasion, and lack of "target-specific" therapy. Herein, we report that a tumor vaccine that selectively targets gastrin decreases pancreatic cancer growth and metastases. Furthermore, the gastrin vaccine polyclonal antibody stimulator alters the tumor microenvironment rendering it more responsive to immunotherapy with a programmed cell death receptor-1 immune checkpoint antibody.
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Affiliation(s)
| | | | - Martha D Gay
- Department of Medicine, Georgetown University, Washington, District of Columbia
| | - Hong Cao
- Department of Medicine, Georgetown University, Washington, District of Columbia
| | - Robin D Tucker
- Department of Pathology, Georgetown University, Washington, District of Columbia
| | - Sandeep Nadella
- Department of Medicine, Georgetown University, Washington, District of Columbia
| | - Shangzi Wang
- Department of Oncology, Georgetown University, Washington, District of Columbia
| | - Xunxian Liu
- The MedStar Georgetown Transplant Institute, Georgetown University, Washington, District of Columbia
| | - Alexander Kroemer
- The MedStar Georgetown Transplant Institute, Georgetown University, Washington, District of Columbia
| | | | | | - Jill P Smith
- Department of Medicine, Georgetown University, Washington, District of Columbia
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Incidence and treatment of metachronous gastric cancer after proximal gastrectomy. Surg Today 2018; 48:552-557. [PMID: 29460126 DOI: 10.1007/s00595-018-1632-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 01/05/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND PURPOSE Proximal gastrectomy (PG) is a widely accepted function-preserving surgical procedure; however, the incidence and treatment of metachronous gastric cancer (MGC) after PG have been the subject of a number of reports. METHODS We collected data from 1576 consecutive patients who underwent gastrectomy for gastric cancer between January, 2003 and December, 2010, and analyzed the outcomes of 671 patients treated with PG or distal gastrectomy (DG) for cT1N0 disease. We also discuss the treatments for MGC. RESULTS MGC was diagnosed within a median follow-up of 52.8 months after PG and DG in six (6.6%) and nine (1.8%) patients, respectively. The cumulative prevalence of MGC after PG was significantly higher than that after DG; P = 0.005. Univariate and multivariate analysis revealed male sex and PG as significant risk factors for MGC (P = 0.014 and P = 0.026, respectively). Five of the six patients who underwent PG were treated by endoscopic submucosal dissection. CONCLUSIONS The incidence of MGC after PG was significantly higher than that after DG. However, most of the MGCs that developed after PG could be treated by endoscopic submucosal dissection.
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The role of enteric neurons in the development and progression of colorectal cancer. Biochim Biophys Acta Rev Cancer 2017; 1868:420-434. [PMID: 28847715 DOI: 10.1016/j.bbcan.2017.08.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 08/16/2017] [Accepted: 08/17/2017] [Indexed: 02/06/2023]
Abstract
The enteric nervous system (ENS) is the intrinsic neural network of the gastrointestinal tract, which is essential for regulating gut functions and intestinal homeostasis. The importance of the ENS is underscored by the existence of severe gastrointestinal diseases, such as Hirschsprung's disease and intestinal pseudo-obstruction, which arise when the ENS fails to develop normally or becomes dysregulated. Moreover, it is known that enteric neurons are involved in intestinal inflammation. However, the role of the ENS in colorectal cancer (CRC) carcinogenesis remains poorly understood, even though processes like perineural invasion and neoneurogenesis are important factors in CRC. Here we summarize how enteric neurons are affected during CRC and discuss the influence of enteric neurons, either direct or indirect, on the development and/or progression of CRC. Finally, we illustrate how the ENS could be targeted as a potential anti-cancer therapy, establishing the ENS as an integral part of the tumor microenvironment.
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9
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Abstract
Gastric cancer is the third leading cause of cancer-related mortality worldwide. Despite progress in understanding its development, challenges with treatment remain. Gastrin, a peptide hormone, is trophic for normal gastrointestinal epithelium. Gastrin also has been shown to play an important role in the stimulation of growth of several gastrointestinal cancers including gastric cancer. We sought to review the role of gastrin and its pathway in gastric cancer and its potential as a therapeutic target in the management of gastric cancer. In the normal adult stomach, gastrin is synthesized in the G cells of the antrum; however, gastrin expression also is found in many gastric adenocarcinomas of the stomach corpus. Gastrin's actions are mediated through the G-protein-coupled receptor cholecystokinin-B (CCK-B) on parietal and enterochromaffin cells of the gastric body. Gastrin blood levels are increased in subjects with type A atrophic gastritis and in those taking high doses of daily proton pump inhibitors for acid reflux disease. In experimental models, proton pump inhibitor-induced hypergastrinemia and infection with Helicobacter pylori increase the risk of gastric cancer. Understanding the gastrin:CCK-B signaling pathway has led to therapeutic strategies to treat gastric cancer by either targeting the CCK-B receptor with small-molecule antagonists or targeting the peptide with immune-based therapies. In this review, we discuss the role of gastrin in gastric adenocarcinoma, and strategies to block its effects to treat those with unresectable gastric cancer.
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10
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Alsubai J, Matters GL, McGovern CO, Liao J, Gilius EL, Smith JP. Germline Mutation of the CCK Receptor: A Novel Biomarker for Pancreas Cancer. Clin Transl Gastroenterol 2016; 7:e134. [PMID: 26741064 PMCID: PMC4737870 DOI: 10.1038/ctg.2015.61] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 11/03/2015] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVES Today, genetic biomarkers have been demonstrated to play an important role in identifying at-risk subjects for familial or inherited cancers. We have identified a single-nucleotide polymorphism (SNP) that results in missplicing of the cholecystokinin (CCK) receptor gene and expressing a larger mutated receptor in pancreatic cancer. The purpose of this study was to evaluate the significance and specificity of this SNP as a potential biomarker in patients with pancreatic cancer compared with other gastrointestinal (GI) cancers that also have CCK receptors. METHODS DNA was isolated and genotyped for the CCK receptor SNP from frozen tumor tissue from banked specimens of patients with pancreas, gastric, or colon cancer and from human cancer cell lines. Genotype and allelic frequencies were compared between the cancer cohort and two normal control databases using Fisher's exact test and odds ratio (OR). The Kaplan-Meier method was used to estimate the survival for patients with the CCK-B receptor SNP compared with those with the wild-type genotype. Immunohistochemical staining of cancer cells was done to detect the mutated receptor. RESULTS Colon and gastric cancer patients had similar genotype frequencies for the CCK receptor SNP as that reported in the normal population. In contrast, the prevalence of the SNP in subjects with pancreatic cancer was twice that of controls and other GI cancers. Survival was adversely affected by the presence of the SNP only in those with pancreatic cancer. Immunoreactivity for the mutated receptor was positive in pancreatic cancer tissues with the SNP but absent in other GI cancers. CONCLUSIONS A SNP of the CCK receptor is significantly increased in patients with pancreatic cancer but not in those with other GI malignancies. Therefore, this SNP may be a potential biomarker for pancreatic cancer.
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Affiliation(s)
- Jelal Alsubai
- Department of Medicine, Pennsylvania State University School of Medicine, Hershey, Pennsylvania, USA
| | - Gail L Matters
- Department of Biochemistry and Molecular Biology, Pennsylvania State University School of Medicine, Hershey, Pennsylvania, USA
| | - Christopher O McGovern
- Department of Biochemistry and Molecular Biology, Pennsylvania State University School of Medicine, Hershey, Pennsylvania, USA
| | - Jiangang Liao
- Department of Public Health Sciences, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania, USA
| | - Evan L Gilius
- The National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Jill P Smith
- Department of Medicine, Pennsylvania State University School of Medicine, Hershey, Pennsylvania, USA
- Department of Medicine/Gastroenterology Georgetown University School of Medicine, Washington, District of Columbia, USA
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11
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Expression of cholecystokinin receptors in colon cancer and the clinical correlation in Taiwan. Tumour Biol 2015; 37:4579-84. [DOI: 10.1007/s13277-015-4306-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 10/20/2015] [Indexed: 10/22/2022] Open
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12
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Westwood DA, Patel O, Baldwin GS. Gastrin mediates resistance to hypoxia-induced cell death in xenografts of the human colorectal cancer cell line LoVo. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1843:2471-80. [DOI: 10.1016/j.bbamcr.2014.06.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 06/11/2014] [Accepted: 06/24/2014] [Indexed: 10/25/2022]
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13
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A network map of the gastrin signaling pathway. J Cell Commun Signal 2014; 8:165-70. [PMID: 24584707 DOI: 10.1007/s12079-014-0224-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Accepted: 01/28/2014] [Indexed: 12/14/2022] Open
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14
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He AR, Marshall JL. Clinical experiences with G17DT in gastrointestinal malignancies. Expert Rev Anticancer Ther 2014; 6:487-92. [PMID: 16613537 DOI: 10.1586/14737140.6.4.487] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The development of new agents for the treatment of gastrointestinal malignancies is increasing in pace and importance. The discovery of novel targets, namely the epidermal growth factor receptor and vascular endothelial growth factor, have sparked an explosion of new agents being tested in gastrointestinal malignancies. Clearly, novel agents and approaches are required. G17DT is a novel immunoconjugate designed to elicit a humoral response against the N-terminal end of G17 gastrin. In this overview, the authors summarize the clinical research focused on gastrointestinal tract cancers to date. In total, there is a clear signal of efficacy with this compound, although further testing is required in order for this efficacy to be demonstrated in a manner that will support regulatory approval.
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Affiliation(s)
- Aiwu R He
- Vincent T Lombardi Cancer Research Center, Georgetown University Medical Center, Podium Level, Corridor B, 3800 Reservoir Road, NW Washington, DC 20007, USA.
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Tatishchev SF, VanBeek C, Wang HL. Helicobacter pylori infection and colorectal carcinoma: is there a causal association? J Gastrointest Oncol 2012; 3:380-385. [PMID: 23205318 PMCID: PMC3492471 DOI: 10.3978/j.issn.2078-6891.2012.058] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Accepted: 10/30/2012] [Indexed: 12/21/2022] Open
Affiliation(s)
- Sergei F. Tatishchev
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, California, USA
| | - Christine VanBeek
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Hanlin L. Wang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, California, USA
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16
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Rai R, Chandra V, Tewari M, Kumar M, Shukla HS. Cholecystokinin and gastrin receptors targeting in gastrointestinal cancer. Surg Oncol 2012; 21:281-92. [PMID: 22801592 DOI: 10.1016/j.suronc.2012.06.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Revised: 05/16/2012] [Accepted: 06/21/2012] [Indexed: 12/12/2022]
Abstract
Cholecystokinin and Gastrin are amongst the first gastrointestinal hormone discovered. In addition to classical actions (contraction of gallbladder, growth and secretion in the stomach and pancreas), these also act as growth stimulants for gastrointestinal malignancies and cell lines. Growth of these tumours is inhibited by antagonists of the cholecystokinin and gastrin receptors. These receptors provides most promising approach in clinical oncology and several specific radiolabelled ligands have been synthesized for specific tumour targeting and therapy of tumours overexpressing these receptors. Therefore, definition of the molecular structure of the receptor involved in the autocrine/paracrine loop may contribute to novel therapies for gastrointestinal cancer. Hence, this review tries to focus on the role and distribution of these hormones and their receptors in gastrointestinal cancer with a brief talk about the clinical trial using available agonist and antagonist in gastrointestinal cancers.
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Affiliation(s)
- Rajani Rai
- Department of Surgical Oncology, Banaras Hindu University, 7 SKG Colony, Lanka, Varanasi 221005, Uttar Pradesh, India
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17
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Fino KK, Matters GL, McGovern CO, Gilius EL, Smith JP. Downregulation of the CCK-B receptor in pancreatic cancer cells blocks proliferation and promotes apoptosis. Am J Physiol Gastrointest Liver Physiol 2012; 302:G1244-52. [PMID: 22442157 PMCID: PMC3378167 DOI: 10.1152/ajpgi.00460.2011] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Gastrin stimulates the growth of pancreatic cancer cells through the activation of the cholecystokinin-B receptor (CCK-BR), which has been found to be overexpressed in pancreatic cancer. In this study, we proposed that the CCK-BR drives growth of pancreatic cancer; hence, interruption of CCK-BR activity could potentially be an ideal target for cancer therapeutics. The effect of CCK-BR downregulation in the human pancreatic adenocarcinoma cells was examined by utilizing specific CCK-BR-targeted RNA interference reagents. The CCK-BR receptor expression was both transiently and stably downregulated by transfection with selective CCK-BR small-interfering RNA or short-hairpin RNA, respectively, and the effects on cell growth and apoptosis were assessed. CCK-BR downregulation resulted in reduced cancer cell proliferation, decreased DNA synthesis, and cell cycle arrest as demonstrated by an inhibition of G(1) to S phase progression. Furthermore, CCK-BR downregulation increased caspase-3 activity, TUNEL-positive cells, and decreased X-linked inhibitor of apoptosis protein expression, suggesting apoptotic activity. Pancreatic cancer cell mobility was decreased when the CCK-BR was downregulated, as assessed by a migration assay. These results show the importance of the CCK-BR in regulation of growth and apoptosis in pancreatic cancer. Strategies to decrease the CCK-BR expression and activity may be beneficial for the development of new methods to improve the treatment for patients with pancreatic cancer.
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Affiliation(s)
| | - Gail L. Matters
- Departments of 1Medicine and ,2Biochemistry and Molecular Biology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania
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Abstract
Gastric cancer is the most common cancer in Korea, with an age-standardized rate of 61.2 in males and 23.9 in females (in 2007), one of the highest in the world. Using a large gastric tissue depository and the extensive clinical experience gained from gastric cancer surgery, we work as a 'translational researcher' to apply basic research tools and results to the clinical field. We are also interested in providing answers to the questions in the operating room using the methods of basic research. I would like to introduce our research activities in this review paper.
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Affiliation(s)
- Han-Kwang Yang
- Department of Surgery, Seoul National University College of Medicine and Gastric Cancer Center, Seoul National University Cancer Hospital, Korea.
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19
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Glycogen Synthase Kinase-3beta regulates Snail and beta-catenin during gastrin-induced migration of gastric cancer cells. J Mol Signal 2010; 5:9. [PMID: 20637111 PMCID: PMC2912299 DOI: 10.1186/1750-2187-5-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2010] [Accepted: 07/16/2010] [Indexed: 01/08/2023] Open
Abstract
Background The gastrointestinal peptide hormone gastrin is known to regulate various cellular processes including proliferation, migration and metastasis in gastrointestinal (GI) cells. The studies described here were undertaken to elucidate in detail the signaling pathways mediating the migratory responses of amidated gastrin (G17) and to understand the involvement of the serine/threonine kinase Glycogen Synthase Kinase-3 beta (GSK3β) in this. Results Our results indicate that incubation of gastric cancer cells overexpressing CCK2 receptor (AGSE cells) with G17 results in a dose and time dependent increase of GSK3βSer9 phosphorylation, indicative of an inhibition of the kinase. Pretreatment with a pharmacological inhibitor of PI3Kinase pathway (Wortmannin) was unable to antagonize G17-induced GSK3βSer9 phosphorylation, suggesting that this might involve PI3Kinase-independent pathways. Treatment with G17 was also associated with increased Snail expression, and β-catenin nuclear translocation, both of which are GSK3β downstream targets. Pretreatment with a pharmacological inhibitor of GSK3β (AR-A014418) augmented Snail expression and β-catenin nuclear translocation in the absence of G17, whereas overexpression of a phosphorylation deficient mutant of GSK3β (S9A) abrogated Snail promoter induction. These suggested that G17 modulates Snail and β-catenin pathways via inhibiting GSK3β. In addition, overexpression of GSK3β wild type (WT) or S9A mutant inhibited G17-induced migration and MMP7 promoter induction. G17 studies designed following small interference RNA (siRNA)-mediated knockdown of Snail and β-catenin expression indicated a significant reduction of G-17-induced migration and MMP7 promoter induction following combined knockdown of both proteins. Conclusion Our studies indicate that inhibition of GSK3β is necessary to activate G17-induced migratory pathways in gastric cancer cells. Inhibition of GSK3β leads to an induction of Snail expression and β-catenin nuclear translocation, both of which participate to promote G17-induced migration.
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20
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Copps J, Murphy RF, Lovas S. The production and role of gastrin-17 and gastrin-17-gly in gastrointestinal cancers. Protein Pept Lett 2010; 16:1504-18. [PMID: 20001914 DOI: 10.2174/092986609789839269] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The gastrointestinal peptide hormone gastrin is responsible for initiating the release of gastric acid in the stomach in response to the presence of food and/or humoral factors such as gastrin releasing peptide. However, it has a role in the growth and maintenance of the gastric epithelium, and has been implicated in the formation and growth of gastric cancers. Hypergastrinemia resulting from atrophic gastritis and pernicious anemia leads to hyperplasia and carcinoid formation in rats, and contributes to tumor formation in humans. Additionally, gastrin has been suspected to play a role in the formation and growth of cancers of the colon, but recent studies have instead implicated gastrin processing intermediates, such as gastrin-17-Gly, acting upon a putative, non-cholecystokinin receptor. This review summarizes the production and chemical structures of gastrin and of the processing intermediate gastrin-17-Gly, as well as their activities in the gastrointestinal tract, particularly the promotion of colon cancers.
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Affiliation(s)
- Jeffrey Copps
- Department of Biomedical Sciences, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA
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21
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Matters GL, Harms JF, McGovern CO, Jayakumar C, Crepin K, Smith ZP, Nelson MC, Stock H, Fenn CW, Kaiser J, Kester M, Smith JP. Growth of human pancreatic cancer is inhibited by down-regulation of gastrin gene expression. Pancreas 2009; 38:e151-61. [PMID: 19465883 PMCID: PMC2704379 DOI: 10.1097/mpa.0b013e3181a66fdc] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVES This study evaluated the effects of gastrin messenger RNA (mRNA) down-regulation on growth of human pancreatic cancer. METHODS Gastrin expression was examined in human pancreatic cancer cell lines by reverse transcriptase-polymerase chain reaction, and peptide expression was assessed by immunocytochemistry. Gastrin was down-regulated using either stable transfection of an antisense gastrin cDNA or 1 of 3 shRNA (short hairpin RNA) constructs. Tumor formation was evaluated after either subcutaneous or orthotopic injections into nude mice. The effect of nanoliposomes loaded with gastrin siRNA (small interfering RNA) was tested in mice bearing pancreatic tumors. RESULTS Stable transfection of gastrin antisense or shRNAs into BxPC-3 cells resulted in clones with more than 90% reduction in gastrin mRNA. Tumor growth rate and incidence of metastases in both wild-type and transfected pancreatic cancer cells were directly proportional to the degrees of gastrin mRNA expression. Immunofluorescence analysis confirmed that gastrin peptide levels were decreased in antisense and shRNA tumors. Gastrin knockdown clones had lower Ki-67 and increased cleaved caspase-3 staining, consistent with known effects of gastrin on proliferation and apoptosis. Tumors in mice treated with gastrin siRNA were smaller than controls. CONCLUSIONS These results suggest that RNAi targeting of gastrin could serve as an effective treatment for pancreatic cancer.
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Affiliation(s)
- Gail L Matters
- Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17011, USA
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22
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23
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Watson S. Section Review: Oncologic, Endocrine & Metabolic: Gastrin antagonists and gastrointestinal tumours. Expert Opin Investig Drugs 2008. [DOI: 10.1517/13543784.4.12.1253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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24
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Sun WH, Zhu F, Chen GS, Su H, Luo C, Zhao QS, Zhang Y, Shao Y, Sun J, Zhou SM, Ding GX, Cheng YL. Blockade of cholecystokinin-2 receptor and cyclooxygenase-2 synergistically induces cell apoptosis, and inhibits the proliferation of human gastric cancer cells in vitro. Cancer Lett 2008; 263:302-11. [PMID: 18258354 DOI: 10.1016/j.canlet.2008.01.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2007] [Revised: 12/28/2007] [Accepted: 01/03/2008] [Indexed: 12/21/2022]
Abstract
Gastrin and cyclooxygenase-2 (COX-2) play important roles in the carcinogenesis and progression of gastric cancer. However, it remains unknown whether the combination of cholecystokinin-2 (CCK-2) receptor antagonist plus COX-2 inhibitor exerts synergistic anti-tumor effects on human gastric cancer. Here, we demonstrated that the combination of AG-041R (a CCK-2 receptor antagonist) plus NS-398 (a selective COX-2 inhibitor) treatment had synergistic effects on proliferation inhibition, apoptosis induction, down-regulation of Bcl-2 and up-regulation of Bax expression in MKN-45 cells. These results indicate that simultaneous targeting of CCK-2 receptor and COX-2 may inhibit gastric cancer development more effectively than targeting either molecule alone.
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Affiliation(s)
- Wei-Hao Sun
- Department of Geriatrics, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu, PR China.
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25
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Singh M, Dhindsa G, Friedland S, Triadafilopoulos G. Long-term use of proton pump inhibitors does not affect the frequency, growth, or histologic characteristics of colon adenomas. Aliment Pharmacol Ther 2007; 26:1051-61. [PMID: 17877512 DOI: 10.1111/j.1365-2036.2007.03450.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The clinical significance of the trophic effects of long-term proton pump inhibitors (PPI)-related hypergastrinemia on colon polyps remains unknown. AIM To study the frequency, growth, and histology of colon polyps in patients on chronic PPI therapy (cases), compared to those not receiving acid suppression (controls). METHODS Medical records of 2868 consecutive patients who underwent two or more colonoscopies, performed 3 or more months apart were reviewed. Cases (116) that used PPIs between the two colonoscopies were then compared to controls (194). RESULTS Demographics and risk factors for colon cancer were comparable between the two groups. At baseline the mean frequency and size of adenomatous polyps were similar in cases and controls (P > 0.05) and at follow-up, these were 0.89 and 1.18 (P > 0.05; 95% CI of -0.08 to 0.66) and 4.09 mm and 4.00 mm (P > 0.05; 95% CI -2.29 to 2.11), respectively with no significant change. However, control group had a higher mean frequency and size of hyperplastic polyps at baseline as well as at follow-up colonoscopy (P < 0.05). CONCLUSIONS The long-term use of PPI does not influence the frequency, growth, or histology of adenomatous polyps, but is associated with a reduction in both baseline and interval development of hyperplastic polyps.
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Affiliation(s)
- M Singh
- Gastroenterology Section, Veterans Affairs Health Care System, Palo Alto, CA, USA
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26
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Grabowska AM, Watson SA. Role of gastrin peptides in carcinogenesis. Cancer Lett 2007; 257:1-15. [PMID: 17698287 DOI: 10.1016/j.canlet.2007.06.017] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2007] [Revised: 06/25/2007] [Accepted: 06/28/2007] [Indexed: 01/22/2023]
Abstract
Gastrin gene expression is upregulated in a number of pre-malignant conditions and established cancer through a variety of mechanisms. Depending on the tissue where it is expressed and the level of expression, differential processing of the polypeptide product leads to the production of different biologically active peptides. In turn, acting through the classical CCK-2R receptor, CCK-2R isoforms and alternative receptors, these peptides trigger signalling pathways which influence the expression of downstream genes that affect cell survival, angiogenesis and invasion. Here we review this network of events, highlighting the importance of cellular context for interpreting the role of gastrin peptides and a possible role for gastrin in supporting the early stage of carcinogenesis.
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Affiliation(s)
- Anna M Grabowska
- Division of Pre-Clinical Oncology, D Floor, West Block, Queen's Medical Centre, University Hospital, Nottingham NG7 2UH, UK.
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27
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Grabowska AM, Hughes J, Watson SA. Use of interfering RNA to investigate the role of endogenous gastrin in the survival of gastrointestinal cancer cells. Br J Cancer 2007; 96:464-73. [PMID: 17262081 PMCID: PMC2360027 DOI: 10.1038/sj.bjc.6603588] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Gastrin isoforms, acting through a variety of receptors, have proliferative and anti-apoptotic effects on gastrointestinal (GI) cancers. A small interfering RNA (siRNA) targeting the gastrin gene was used to investigate the role of endogenous gastrin in GI cancer cell survival. Downregulation of the gastrin gene in siRNA-transfected cells was measured using real-time reverse transcriptase–PCR. The most effective siRNA was tested in a panel of GI cancer cell lines at various concentrations and time points, and the effect on cell survival and apoptosis was measured using methyl thiazoyl tetrazolium (MTT) and caspase 3 activation assays. Gastrin siRNA reduced gene expression by more than 90% in a range of GI cancer cell lines. Downregulation of the gastrin gene was dose-dependent and effective over approximately 1 week in vitro. However, downregulation at the protein level was delayed by 3–4 days. Gastrin siRNA-transfected cells showed up to a 60% reduction in growth and up to a 50% increase in apoptosis compared with control siRNA-transfected cells. The effects were most marked in the cell line with the highest constitutive level of gastrin gene expression (human metastatic colon, C170HM2) and in epidermal growth factor (EGF)-treated cells as the gastrin promoter contains an EGF-response element, gERE. The ability of the siRNAs to reduce survival of these GI cell lines is further evidence of the importance of autocrine and/or intracrine gastrin loops in GI cancer, where expression of the gastrin gene and autonomous gastrin appears widespread.
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Affiliation(s)
- A M Grabowska
- Academic Unit of Cancer Studies, D Floor, West Block, Queen's Medical Centre, University Hospital, Nottingham NG7 2UH, UK.
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28
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Chao C, Goluszko E, Lee YT, Kolokoltsov AA, Davey RA, Uchida T, Townsend CM, Hellmich MR. Constitutively active CCK2 receptor splice variant increases Src-dependent HIF-1 alpha expression and tumor growth. Oncogene 2006; 26:1013-9. [PMID: 16909104 DOI: 10.1038/sj.onc.1209862] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Gastrointestinal (GI) cancers ectopically express multiple splice variants of the cholecystokinin-2 (CCK(2))/gastrin receptor; however, their relative contributions to the cancer phenotype are unknown. The aim of this study was to compare the effects of CCK(2) receptor (CCK(2)R) and CCK(2i4sv)R expression on cell growth both in vitro and in vivo using a human epithelial cell model, HEK239. In vitro, receptor variant expression did not affect cell proliferation either in the absence or presence of agonist. However, in vivo, the expression of CCK(2i4sv)R, but not CCK(2)R, increases HEK293 tumor growth in a constitutive, Src-dependent manner. Enhanced tumorigenicity of CCK(2i4sv)R is associated with an Src-dependent increase in the transcription factor, hypoxia-inducible factor-1alpha, its downstream target, vascular endothelial growth factor and tumor micro-vessel density, suggesting that CCK(2i4sv)R may contribute to the growth and spread of GI cancers through agonist-independent mechanisms that enhance tumor angiogenesis.
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Affiliation(s)
- C Chao
- Department of Surgery, University of Texas Medical Branch, Galveston, TX77555, USA
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29
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Ajani JA, Hecht JR, Ho L, Baker J, Oortgiesen M, Eduljee A, Michaeli D. An open-label, multinational, multicenter study of G17DT vaccination combined with cisplatin and 5-fluorouracil in patients with untreated, advanced gastric or gastroesophageal cancer: the GC4 study. Cancer 2006; 106:1908-16. [PMID: 16568451 DOI: 10.1002/cncr.21814] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Gastrin hormone is trophic to in vitro gastric cancer, and the antigastrin antibodies (AGAs) are antiproliferative and antimetastatic. Human gastric cancers overexpress gastrin genes and receptors that react to gastrin's trophic effects. Immunogen G17DT elicits a specific and high-affinity AGA. The authors evaluated G17DT vaccination given with cisplatin plus 5-fluorouracil for the treatment gastric adenocarcinoma. METHODS In this multicenter, Phase II study, patients received G17DT vaccination intramuscularly on Weeks 1, 5, 9 and 25 and cisplatin plus 5-fluorouracil every 28 days. Eligible patients had untreated, metastatic, or unresectable gastric or gastroesophageal adenocarcinoma with near-normal organ function. The primary endpoint of the study was the over response rate (ORR), and secondary endpoints included overall survival (OS), safety, and the impact of successful vaccination on patient outcome. RESULTS In total, 103 patients were enrolled in 5 countries. Seven patients who were overdosed inadvertently with 5-fluorouracil (a major protocol violation) were removed from the analysis. The confirmed ORR was 30% in 79 patients who were evaluated for response. The median time-to-progression (TTP) was 5.4 months, and the median survival (MS) was 9.0 months (n = 96 patients). Sixty-five of 94 patients who were vaccinated (69%) had 2 consecutive AGA titers of > or =1 units (successfully vaccinated patients or immune-responders). The TTP was longer in immune-responders than in immune-nonresponders (P = .0005). Similarly, the MS was longer in immune-responders than in immune-nonresponders (10.3 months vs. 3.8 months; P < or =.0001). In a multivariate analysis, successful vaccination was an independent OS prognosticator (P = .0001). G17DT did not have an adverse effect on safety. CONCLUSIONS The results demonstrated that successful G17DT vaccination was correlated with longer TTP and MS. AGA response was an independent OS prognosticator. A Phase III evaluation of G17DT in gastric cancer is warranted.
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Affiliation(s)
- Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
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Chang AJ, Song DH, Wolfe MM. Attenuation of Peroxisome Proliferator-activated Receptor γ (PPARγ) Mediates Gastrin-stimulated Colorectal Cancer Cell Proliferation. J Biol Chem 2006; 281:14700-10. [PMID: 16574647 DOI: 10.1074/jbc.m602623200] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Peroxisome proliferators-activated receptor gamma (PPARgamma) has been shown to suppress cell proliferation and tumorigenesis, whereas the gastrointestinal regulatory peptide gastrin stimulates the growth of neoplastic cells. The present studies were directed to determine whether changes in PPARgamma expression might mediate the effects of gastrin on the proliferation of colorectal cancer (CRC). Initially, using growth assays, we determined that the human CRC cell line DLD-1 expressed both functional PPARgamma and gastrin receptors. Amidated gastrin (G-17) attenuated the growth suppressing effects of PPARgamma by decreasing PPARgamma activity and total protein expression, in part through an increase in the rate of proteasomal degradation. G-17-induced degradation of PPARgamma appeared to be mediated through phosphorylation of PPARgamma at serine 84 by a process involving the biphasic phosphorylation of ERK1/2 and activation of the epidermal growth factor receptor (EGFR). These results were confirmed through the use of EGFR antagonist AG1478 and MEK1 inhibitor PD98059. Furthermore, mutation of PPARgamma at serine 84 reduced the effects of G-17, as evident by inability of G-17 to attenuate PPARgamma promoter activity, degrade PPARgamma, or inhibit the growth suppressing effects of PPARgamma. The results of these studies demonstrate that the trophic properties of gastrin in CRC may be mediated in part by transactivation of the EGFR and phosphorylation of ERK1/2, leading to degradation of PPARgamma protein and a decrease in PPARgamma activation.
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Affiliation(s)
- Albert J Chang
- Section of Gastroenterology, Boston University School of Medicine and Boston Medical Center, 650 Albany Street, Boston, MA 02118, USA
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31
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Hur K, Kwak MK, Lee HJ, Park DJ, Lee HK, Lee HS, Kim WH, Michaeli D, Yang HK. Expression of gastrin and its receptor in human gastric cancer tissues. J Cancer Res Clin Oncol 2005; 132:85-91. [PMID: 16228228 DOI: 10.1007/s00432-005-0043-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2005] [Accepted: 09/12/2005] [Indexed: 01/28/2023]
Abstract
PURPOSE Gastrin is a growth factor of cancerous and normal cells of the gastrointestinal tract, and its effect is known to be mediated by gastrin/cholecystokinin B (CCKB) receptor. This study was performed to investigate the prognostic significance and the expression profiles of gastrin and gastrin receptor in human gastric carcinoma tissues. METHODS We analyzed the expressions of gastrin and gastrin receptor by immunohistochemical staining using anti-gastrin Ab (Sigma, St. Louis, MO, USA) and anti-gastrin receptor Ab (Aphton Corp., Woodland, CA, USA) in 279 gastric adenocarcinoma patients. Patients' clinicopathologic features and prognoses were analyzed. RESULTS The gastrin expression rate in these patients was 47.7% (133/279) and the gastrin receptor expression rate was 56.5% (158/279). Gastrin expression was significantly higher in men than in women (54.3% vs. 34.1%), and higher in differentiated gastric adenocarcinoma than in the undifferentiated type (55.1% vs. 43.0%). The gastrin receptor expression rate was also significantly higher in men than in women (61.2% vs. 47.3%), and was higher in the differentiated type than in the undifferentiated type (72.9% vs. 46.5%), and significantly higher in the intestinal type than in the diffuse type (75.2% vs. 42.9%). Gastrin and gastrin/CCKB receptor expressions were not found to be significant prognostic factors in themselves. When focused on correlation between the co-expression of gastrin and gastrin/CCKB receptor and the survival, the prognosis of patients positive for both gastrin and gastrin receptor was significantly poorer than for those negative for gastrin and gastrin receptor in diffuse-type gastric cancer patients. However, multivariate analysis showed that only TNM stage was an independent prognostic factor of survival in diffuse-type gastric cancer patients. CONCLUSIONS This study shows that the expression rates of gastrin and gastrin receptor are high (about a half) in gastric carcinoma tissues, and that there is an association between gastrin and gastrin receptor expression. We also found that patients with diffuse-type gastric carcinoma tissues expressing both gastrin and gastrin receptor have a poorer prognosis than those negative for both, which suggests that gastrin acts as an autocrine growth factor in a subgroup of gastric carcinomas.
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Affiliation(s)
- Keun Hur
- Cancer Research Institute, Seoul National University College of Medicine, Chongno-gu, Seoul, 110-744, Republic of Korea
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Zhao MD, Hu XM, Sun DJ, Zhang Q, Zhang YH, Meng W. Expression of some tumor associated factors in human carcinogenesis and development of gastric carcinoma. World J Gastroenterol 2005; 11:3217-21. [PMID: 15929170 PMCID: PMC4316051 DOI: 10.3748/wjg.v11.i21.3217] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effect of IGF-1/IGF-1R and gastrin/CCK-BR on carcinogenesis and development of human gastric carcinoma and to explore its mechanism and provide a credible theoretical foundation for early diagnosis and molecular therapy of gastric carcinoma.
METHODS: mRNA expression levels of IGF-1/IGF-1R and gastrin/CCK-BR were assessed by RT-PCR method in gastric cancer tissues, adjacent mucosa, and tumor-free tissues from 56 patients with gastric carcinoma and normal gastric mucosae from 56 healthy controls. Tissue specimens were obtained by biopsy and confirmed by histological evaluation.
RESULTS: The mRNA levels of IGF-1/IGF-1R were increased in gastric cancer tissues compared with normal tissues from healthy controls and successively increased in tumor-free tissues, adjacent mucosa, and gastric cancer tissues. The mRNA levels of gastrin/CCK-BR were increased in gastric cancer tissues compared with normal tissues from healthy controls. There was a significant difference between gastric cancer tissues and adjacent mucosa and tumor-free tissues, but the mRNA levels of gastrin were not significantly increased in adjacent mucosa and gastric cancer tissues compared with tumor-free tissues. The mRNA levels of CCK-BR were increased in gastric cancer tissues and adjacent mucosa compared with tumor-free tissues, but not significantly increased in adjacent mucosa and gastric cancer tissues compared with gastric cancer tissues.
CONCLUSION: Overexpression of IGF-1/IGF-1R and gastrin/CCK-BR promotes the disorderly proliferation of gastric mucosa epithelia and it is of great significance in the carcinogenesis and development of gastric carcinoma.
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Affiliation(s)
- Ming-Dong Zhao
- Department of Radiology, Affiliated Hospital of Binzhou Medical College, Binzhou 256-603, Shandong Province, China
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Abstract
AIM: Patients with advanced stage cardiac adenocarcinoma have a very poor prognosis. Surgery is the first choice of treat-ment for this kind of patients. Peptide hormone gastrin is a recognized growth factor for gastric cancer, and gastrin receptor antagonist proglumide can block the effects of gastrin. The aim of this study was to investigate the actions of proglumide as an adjuvant treatment to improve the postoperative long-term survival rate of patients with cardiac adenocarcinoma.
METHODS: We performed a randomized, controlled study of gastrin receptor antagonist proglumide in 301 patients with cardiac adenocarcinoma after proximal subtotal gastrectomy. The oral dose of 0.4 g proglumide thrice daily preprandially was maintained for more than 5 years in 153 cases (proglumide treatment group). In the control group, 148 patients underwent operation only. In clinicopathologic features, there was no significant difference between the two groups (P>0.05). All patients were followed up during their lifetime, and the survival rates were analyzed combined with clinicopathologic factors by SPSS 11.5 statistical software.
RESULTS: The 1, 3, 5 and 10-year survival rate of the patients was 88.4%, 48.8%, 22.6% and 13.4%, respectively. The 1, 3, 5 and 10-year survival rate of the proglumide treatment group was 90.2%, 49.7%, 26.8% and 17.6% compared to 86.5%, 48.0%, 18.2% and 8.9% of the control group. There was a significant difference between the two groups (P = 0.0460). The patients in proglumide treatment group had no obvious side effects after administration of the drug, and no definite hepatic and renal function damage was found. According to single factor log-rank analysis, the long-term survival rate was correlated with the primary tumor position (P = 0.0205), length of the tumor (P = 0.0000), property of the operation (P = 0.0000), histopathologic grading (P = 0.0003), infiltrating degree of the tumor (P = 0.0000), influence of lymph node metastasis (P = 0.0000), clinicopathologic staging (P = 0.0000) and administration of proglumide (P = 0.0460). Cox regression analysis demonstrated the infiltrating degree of tumor (P = 0.000), influence of lymph node metastasis (P = 0.039) and the clinicopathologic staging (P = 0.003) were independent prognostic factors. Administration of proglumide (P = 0.081), length of the tumor (P = 0.304), radical status of the resection (P = 0.224) and histopathologic types (P = 0.072) were not the independent prognostic factors.
CONCLUSION: Proglumide is convenient to use with no obvious toxic side effects, and prolonged postoperative administration of proglumide as a postoperative adjuvant treatment can increase the survival rate of patients after resection of cardiac adenocarcinoma. Proglumide may provide a new effective approach of endocrinotherapy for patients with gastric cardiac cancer.
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Affiliation(s)
- Yu-Ping Chen
- Department of Thoracic Surgery, Tumor Hospital of Shantou University Medical College, Shantou 515031, Guangdong Province, China.
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Zavros Y, Eaton KA, Kang W, Rathinavelu S, Katukuri V, Kao JY, Samuelson LC, Merchant JL. Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma. Oncogene 2005; 24:2354-66. [PMID: 15735748 DOI: 10.1038/sj.onc.1208407] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The current study tests the hypothesis that chronic atrophic gastritis from hypochlorhydria in the gastrin-deficient mouse predisposes the stomach to gastric cancer. Gross morphology and histology of 12-month-old wild-type (WT), gastrin-deficient (G-/-) and somatostatin-deficient (SOM-/-) mice were examined. Parietal and G cells, Ki67, TUNEL, villin and MUC2 expression were analysed by immunohistochemistry. RUNX3 and STAT3 expression was analysed by Western blot. Anchorage-independent growth was determined by cell cluster formation in soft agar. Compared to the WT and SOM-/- mice, hypochlorhydric G-/- mice developed parietal cell atrophy, significant antral inflammation and intestinal metaplasia. Areas of metaplasia within the G-/- mouse stomach showed decreased RUNX3 expression with elevated MUC2 and villin expression. Cells isolated from the tumor grew in soft agar. However, the cells isolated from WT, nontransformed G-/- and SOM-/- gastric tissue did not form colonies in soft agar. Consistent with elevated antral proliferation, tumor tissue isolated from the G-/- mice showed elevated phosphorylated STAT3 expression. We then examined the mechanism by which STAT3 was constitutively expressed in the tumor tissue of the G-/- mice. We found that IFNgamma expression was also significantly higher in the tumor tissue of G-/- mice compared to WT and SOM-/- animals. To determine whether STAT3 was regulated by IFNgamma, MKN45 cells were cocultured with IFNgamma or gastrin. IFNgamma significantly stimulated phosphorylation of STAT3 in the MKN45 cell line, but not gastrin. Therefore, we show here that in the hypochlorhydric mouse stomach, the chronic gastritis, atrophy, metaplasia, dysplasia paradigm can be recapitulated in mice. Moreover, neoplastic transformation of the antral gastric mucosa does not require gastrin.
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Affiliation(s)
- Yana Zavros
- Department of Gastroenterology, University of Michigan, Ann Arbor, MI 48109-0650, USA
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Moore TC, Jepeal LI, Boylan MO, Singh SK, Boyd N, Beer DG, Chang AJ, Wolfe MM. Gastrin stimulates receptor-mediated proliferation of human esophageal adenocarcinoma cells. ACTA ACUST UNITED AC 2005; 120:195-203. [PMID: 15177938 DOI: 10.1016/j.regpep.2004.03.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2003] [Revised: 03/01/2004] [Accepted: 03/15/2004] [Indexed: 01/12/2023]
Abstract
The prevalence of esophageal adenocarcinoma in the setting of Barrett's metaplasia continues to increase in Western nations at a rate greater than any other cancer. The trophic properties of gastrin have been documented in gastric, pancreatic and colon cancer cell lines, suggesting a potential role for this regulatory peptide in the growth of these malignancies. The aims of these studies were to identify and characterize the presence of functional cholecystokinin type-2 (gastrin) receptors on the membranes of human esophageal adenocarcinoma cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated the presence of cholecystokinin type-2 receptor transcripts in human esophageal adenocarcinoma cell lines. Competitive binding assays revealed specific binding of gastrin in SEG-1 cells (IC50 of 2.4 x 10(-8) M). This finding was confirmed by laser scanning confocal microscopy through internalization of rhodamine green labeled gastrin heptapeptide in SEG-1 cells. Gastrin caused a dose-dependent increase in proliferation of SEG-1 cells when compared to controls. This effect was abolished by co-incubation with L365,260, a CCK-2-specific receptor antagonist. Gastrin-induced phosphorylation of the p44 and p42 mitogen-activated protein kinases was demonstrated by Western blot analysis. In conclusion, the studied human esophageal adenocarcinoma cell lines possess cholecystokinin type-2 (gastrin) receptors. Receptors bind gastrin, resulting in increased proliferation in SEG-1 cells.
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Affiliation(s)
- T Carlton Moore
- Section of Gastroenterology, Boston University School of Medicine and Boston Medical Center, 650 Albany Street, EBRC Fifth Floor, MA 02118, USA
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Smith JP, Stanley WB, Verderame MF, Zagon IS. The functional significance of the cholecystokinin-C (CCK-C) receptor in human pancreatic cancer. Pancreas 2004; 29:271-7. [PMID: 15502642 DOI: 10.1097/00006676-200411000-00005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES The aim of this study was to evaluate whether the CCK-C receptor, a splice variant of the CCK-B receptor, in human pancreatic cancer cells was associated with accelerated cancer cell growth. METHODS In vitro, BxPC-3 cells were transfected with the antisense cDNA for the CCK-C receptor and growth of transfected cells was compared with that of wild-type (WT) and empty vector (EV)-transfected cells; expression was confirmed by RT-PCR and immunocytochemistry. In vivo, athymic nude mice bearing human BxPC-3 pancreatic cancers were treated for 28 days with either an antisense oligonucleotide specific to the CCK-C receptor, the same nucleotide sequence arranged in a scrambled fashion (nucleotide control), or vehicle (control). RESULTS In culture, BxPC-3 cells transfected with the antisense cDNA for the CCK-C receptor were reduced in cell number 65% compared with WT and EV-transfected cell cultures at 6 days; this difference was statistically significant (P = 0.002). Transfected cells did not respond to exogenous gastrin with growth as did WT cells. Tumors of mice treated with the antisense oligonucleotide for CCK-C were 75% smaller in volume and 83% reduced in weight (P = 0.03) compared with the control tumors. CONCLUSION These studies indicate that the CCK-C receptor is functional and plays a crucial role in growth of human pancreatic cancer.
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MESH Headings
- Animals
- Cell Line, Tumor
- Cell Proliferation/drug effects
- DNA, Antisense/genetics
- DNA, Complementary/genetics
- DNA, Neoplasm/genetics
- Humans
- Mice
- Mice, Nude
- Neoplasm Transplantation/methods
- Oligonucleotides, Antisense/genetics
- Oligonucleotides, Antisense/pharmacology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Receptors, Cholecystokinin/genetics
- Receptors, Cholecystokinin/metabolism
- Receptors, Cholecystokinin/physiology
- Reverse Transcriptase Polymerase Chain Reaction/methods
- Transfection/methods
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Affiliation(s)
- Jill P Smith
- Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
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Smith JP, Verderame MF, Ballard EN, Zagon IS. Functional significance of gastrin gene expression in human cancer cells. ACTA ACUST UNITED AC 2004; 117:167-73. [PMID: 14749036 DOI: 10.1016/j.regpep.2003.10.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The gastrointestinal peptide, gastrin, stimulates the growth of human pancreatic cancer. A receptor for gastrin activity, the cholecystokinin-C (CCK-C) receptor, has been identified in binding assays, cloned and sequenced, and is a splice variant of the CCK-B receptor. The relationship of gastrin and the CCK-C receptor to the growth of cancer cells was examined in vitro and in vivo. Stable transfection of the sense cDNA of gastrin into human MDA Amp-7 ampullary cancer cells, which normally lack gastrin gene expression but possess CCK-C receptors, increased cell growth up to 10-fold over wild type (WT) and vector-transfected (VT) cells. MDA Amp-7 tumors of gastrin-transfected cells reduced latency time for a visible tumor by 35%, decreased the timetable of tumor incidence, and increased tumor size by at least 2-fold in comparison to WT and VT groups. Transfection of human BxPC-3 pancreatic cancer cells, which normally express gastrin and possess CCK-C receptors, with the antisense cDNA to human gastrin decreased cell number by 30% in culture and tumor size by 53% compared to the WT and VT groups. Transfection of sense gastrin cDNA to monkey COS-1 cells, which normally lack both the gastrin and the CCK-C receptor genes, had no effect on growth. These studies demonstrate that gastrin and the CCK-C receptor form an autocrine loop in human pancreatic cancer that plays a role in regulating growth.
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Affiliation(s)
- Jill P Smith
- Department of Medicine, Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
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Ahmed S, Budai B, Herédi-Szabó K, Farkas J, Tóth G, Murphy RF, Lovas S. High and low affinity receptors mediate growth effects of gastrin and gastrin-Gly on DLD-1 human colonic carcinoma cells. FEBS Lett 2004; 556:199-203. [PMID: 14706850 DOI: 10.1016/s0014-5793(03)01408-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Gastrin (G17) and N-carboxymethylgastrin (G17-Gly) have been shown to stimulate the growth of colon cancer cells both in vivo and in vitro. The identity of the receptor mediating these effects is controversial. A recent study demonstrated the presence of a low affinity binding site for G17 and G17-Gly on the DLD-1 human colon cancer cell line. The goal of the current study was to further investigate the role of this receptor in mediating the growth-promoting effects of gastrin peptides. Binding of [Leu(15)]G17 and [Leu(15)]G17-Gly to DLD-1 cell membranes in competition with [(3)H]G17-Gly was examined. Binding of [(3)H]cholecystokinin-8 (CCK8) to DLD-1 cell membranes was also assessed. Whole cell binding experiments were carried out using [(125)I-Tyr(12),Leu(15)]G17-Gly. In addition, the ability of [Leu(15)]G17 and [Leu(15)]G17-Gly to stimulate cell growth, as determined by cell counting, was tested. [Leu(15)]G17 and [Leu(15)]G17-Gly competed with [(3)H]G17-Gly at both a high and a low affinity site on DLD-1 membranes. The IC(50) values for [Leu(15)]G17 were 6.0 x 10(-8) M and 6.9 x 10(-6) M while those for [Leu(15)]G17-Gly were 3.2 x 10(-9) M and 4.9 x 10(-6) M. [(3)H]CCK8 did not bind to either site. [Leu(15)]G17-Gly also competed with [(125)I-Tyr(12),Leu(15)]G17-Gly at both a high and a low affinity site on DLD-1 cells with similar affinities as observed with membranes. [Leu(15)]G17 and [Leu(15)]G17-Gly significantly stimulated the growth of DLD-1 cells in a dose-dependent and biphasic manner. The binding profiles of the peptides tested suggest that these sites are different from previously identified wild-type and mutant CCK(1) or CCK(2) receptors.
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Affiliation(s)
- Shawn Ahmed
- Creighton University School of Medicine, Department of Biomedical Sciences, 2500 California Plaza, Omaha, NE 68137, USA
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Sharma C, Pradeep A, Pestell RG, Rana B. Peroxisome proliferator-activated receptor gamma activation modulates cyclin D1 transcription via beta-catenin-independent and cAMP-response element-binding protein-dependent pathways in mouse hepatocytes. J Biol Chem 2004; 279:16927-38. [PMID: 14764597 DOI: 10.1074/jbc.m309045200] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) following exposure to PPARgamma-specific ligands resulted in growth inhibition in various carcinoma cell lines. Our aim was to elucidate the pathway of PPARgamma2 activation-mediated modulation of cyclin D1 transcription in mouse hepatocytes. To address this we utilized stable control and PPARgamma hepatocyte cell lines created via retroviral overexpression utilizing AML-12 hepatocytes. Addition of PPARgamma ligand troglitazone (TZD) activated PPARgamma2 in proliferating hepatocytes and resulted in growth arrest accompanied by a down-regulation of proliferating cell nuclear antigen, cyclin D1, and beta-catenin expression. Furthermore activation of PPARgamma2 attenuated cyclin D1 promoter activity indicating a transcriptional regulation of cyclin D1. Since beta-catenin plays a pivotal role in regulating cyclin D1 transcription, we studied whether PPARgamma2-mediated inhibition of cyclin D1 transcription involved beta-catenin. Interestingly overexpression of either wild-type or S37A mutant beta-catenin was unable to rescue PPARgamma2-mediated suppression of cyclin D1 transcription, whereas overexpression of cAMP-response element-binding protein (CREB) was capable of antagonizing this inhibitory effect of PPARgamma2. Additionally pretreatment with okadaic acid antagonized PPARgamma2-mediated inhibition of cyclin D1 transcription without any effect on beta-catenin expression. These studies also showed a TZD-mediated inhibition of total and phospho-CREB(Ser133) levels, CREB promoter activity, and cAMP-response element-mediated transcription in PPARgamma hepatocytes. Pretreatment of PPARgamma hepatocytes with okadaic acid, however, maintained higher total and phospho-CREB(Ser133) levels in the presence of TZD. These results indicated that PPARgamma2 activation inhibited cyclin D1 transcription in hepatocytes via CREB-dependent and beta-catenin-independent pathways.
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Affiliation(s)
- Chandan Sharma
- Division of Molecular Cardiology, The Texas A&M University System Health Science Center, College of Medicine, Temple, Texas 76504, USA
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Olszewska-Pazdrak B, Ives KL, Park J, Townsend CM, Hellmich MR. Epidermal Growth Factor Potentiates Cholecystokinin/Gastrin Receptor-mediated Ca2+ Release by Activation of Mitogen-activated Protein Kinases. J Biol Chem 2004; 279:1853-60. [PMID: 14602717 DOI: 10.1074/jbc.m309481200] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Small differences in amplitude, duration, and temporal patterns of change in the concentration of free intracellular Ca2+ ([Ca2+](i)) can profoundly affect cell physiology, altering programs of gene expression, cell proliferation, secretory activity, and cell survival. We report a novel mechanism for amplitude modulation of [Ca2+](i) that involves mitogen-activated protein kinase (MAPK). We show that epidermal growth factor (EGF) potentiates gastrin-(1-17) (G17)-stimulated Ca2+ release from intracellular Ca2+ stores through a MAPK-dependent pathway. G17 activation of the cholecystokinin/gastrin receptor (CCK(2)R), a G protein-coupled receptor, stimulates release of Ca2+ from inositol 1,4,5-triphosphate-sensitive Ca2+ stores. Pretreating rat intestinal epithelial cells expressing CCK(2)R with EGF increased the level of G17-stimulated Ca2+ release from intracellular stores. The stimulatory effect of EGF on CCK(2)R-mediated Ca2+ release requires activation of the MAPK kinase (MEK)1,2/extracellular signal-regulated kinase (ERK)1,2 pathway. Inhibition of the MEK1,2/ERK1,2 pathway by either serum starvation or treatment with selective MEK1,2 inhibitors PD98059 and U0126 or expression of a dominant-negative mutant form of MEK1 decreased the amplitude of the G17-stimulated Ca2+ release response. Activation of the MEK1,2/ERK1,2 pathway either by pretreating cells with EGF or by expression of constitutively active K-ras (K-rasV12G) or MEK1 (MEK1*) increased the amplitude of G17-stimulated Ca2+ release. Although EGF, MEK1*, and K-rasV12G activated the MEK1,2/ERK1,2 pathway, they did not increase [Ca2+](i) in the absence of G17. These data demonstrate that the activation state of the MEK1,2/ERK1,2 pathway can modulate the amplitude of the CCK(2)R-mediated Ca2+ release response and identify a novel mechanism for cross-talk between EGF receptor- and CCK(2)R-regulated signaling pathways.
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Affiliation(s)
- Barbara Olszewska-Pazdrak
- Department of Surgery, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA
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Bombski G, Gasiorowska A, Orszulak-Michalak D, Neneman B, Kotynia J, Strzelczyk J, Janiak A, Malecka-Panas E. Differences in plasma gastrin, CEA, and CA 19-9 concentration in patients with proximal and distal colorectal cancer. INTERNATIONAL JOURNAL OF GASTROINTESTINAL CANCER 2003; 31:155-63. [PMID: 12622427 DOI: 10.1385/ijgc:31:1-3:155] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM We investigated whether there are differences in plasma gastrin, as compared with carcinoembryonic antigen (CEA) and cancer antigen (CA) 19-9 between patients with proximal and distal colorectal cancer. Gastrin concentration has also been analyzed, dependent on the tumor stage, in order to evaluate the possible prognostic role of this measurement. METHODS In 50 patients with colon cancer-fasting gastrin, CA 19-9 and CEA levels were evaluated. RESULTS Mean plasma-gastrin level in patients with distal tumor yielded 105.31 +/- 12.5 microU/L and was significantly higher than in patients with the proximal tumor site (42.2 +/- 3.1 microU/L) as well as in controls (p < 0.001). No significant difference was observed between mean plasma gastrin in patients with proximal tumors and the control group. The mean CEA plasma level was significantly higher (p < 0.01) in patients with distal tumors (9.1 +/- 1.1 ng/mL) than in those with proximal tumors (1.48 +/- 0.1 ng/mL). Similarly, the mean CA 19-9 plasma level was significantly higher (p < 0.01) in patients with distal tumor (19.9 +/- 2.1 U/mL) than in those with proximal tumor: 1.8 +/- 0.2 U/mL. The mean gastrin plasma, CA 19-9, and CEA level was significantly higher in group of Duke's stage C and D as compared to A and B. CONCLUSION We speculate that observed differences in gastrin concentration in patients with distal and proximal tumors may contribute to the distinct pathogenesis and biological properties of those cancers. The significance of gastrin as a marker for diagnostic or prognostic purposes in colorectal cancer requires further study.
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Affiliation(s)
- Grzegorz Bombski
- Gastroenterology Ward, Regional Hospital, Piotrkow Trybunalski, Poland
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Abstract
BACKGROUND A stepwise progression through premalignant stages has been identified for the intestinal type of gastric carcinoma. As gastrin has been identified as a growth factor for the intestinal type of gastric adenocarcinoma, the aim of this study was to investigate whether gastrin is expressed in premalignant gastric conditions. METHODS Ninety archival samples of atrophic gastritis, intestinal metaplasia, mild gastric epithelial dysplasia, moderate gastric epithelial dysplasia, severe gastric epithelial dysplasia and intestinal-type gastric adenocarcinoma were obtained. Immunocytochemistry was performed using antibodies directed against gastrin and its post-translational precursors, and the gastrin/cholecystokinin B receptor. Positive staining was identified using the avidin--biotin immunoperoxidase method and quantified using an image analysis system. RESULTS Gastrin and its receptor were shown to be expressed in specimens of atrophic gastritis, intestinal metaplasia, epithelial dysplasia and the intestinal type of gastric carcinoma. CONCLUSION Gastrin seems to be an important growth factor in gastric carcinogenesis.
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Affiliation(s)
- M Henwood
- Academic Unit of Cancer Studies, Section of Surgery, University Hospital, Nottingham, UK
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Petit T, Davidson KK, Lawrence RA, von Hoff DD, Izbicka E. Neuropeptide receptor status in human tumor cell lines. Anticancer Drugs 2001; 12:133-6. [PMID: 11261886 DOI: 10.1097/00001813-200102000-00006] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Tumor types expressing a neuroendocrine phenotype secrete neuropeptides with paracrine or autocrine growth factor activity. The efficacy of these paracrine or autocrine loops depends on the expression of specific receptors on tumor cells. Once specific receptors are identified, specific neuropeptide antagonists disrupting paracrine and autocrine loops could be potential treatments in neuropeptide-secreting tumors. In the present study, 11 human tumor cell lines representing astrocytoma, lymphoma, and pancreatic, prostate, lung and colon carcinomas were examined for expression of five different neuropeptide receptors (cholecystokinin, neurotensin, vasopressin, tachykinine substance P and cannabinoid) using RT-PCR and radioligand binding. The presence of various neuropeptide receptors in different human cancer cell lines supports development of new antitumor treatments based on disruption of neuropeptide autocrine growth pathways.
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Affiliation(s)
- T Petit
- Institute for Drug Development, Cancer Therapy Research Center, San Antonio, TX 78245, USA
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Siddheshwar RK, Muhammad KB, Gray JC, Kelly SB. Seroprevalence of Helicobacter pylori in patients with colorectal polyps and colorectal carcinoma. Am J Gastroenterol 2001; 96:84-8. [PMID: 11197293 DOI: 10.1111/j.1572-0241.2001.03355.x] [Citation(s) in RCA: 68] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The role of Helicobacter pylori in the pathogenesis of colorectal polyps and colorectal carcinoma is unknown. H. pylori infection causes fasting and meal stimulated hypergastrinemia. Gastrin increases colorectal mucosal proliferation and promotes tumor growth. We performed a prospective study to determine the seroprevalence of H. pylori in patients with colorectal polyps and colorectal carcinoma and in controls. METHODS Blood samples were collected from 189 patients with colorectal carcinoma, 57 patients with colorectal polyps, and 179 controls. H. pylori serology was determined by an ELISA assay. RESULTS Logistic regression showed no difference in seroprevalence of H. pylori between patients with colorectal cancer and controls (odds ratio, 1.1; 95% confidence interval, 0.7 to 1.8) or between patients with colorectal polyps and controls (odds ratio 1.3; 95% confidence interval, 0.7 to 2.5). Age and sex were not found to be associated with H. pylori infection. Patients in social classes IV and V were 2.3 times more likely to have H. pylori infection than those in social classes I, II, and III (95% confidence interval, 1.3 to 4.2). CONCLUSIONS This study shows that there is no increase in the seroprevalence of H. pylori in patients with colorectal polyps or colorectal carcinoma compared with controls. These results do not support the hypothesis that there is a relationship between H. pylori infection and the development of colorectal neoplasia.
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Affiliation(s)
- R K Siddheshwar
- Department of Surgery, Regional School of Medicine, North Tyneside General Hospital, Tyne & Wear, North Shields, England
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Abstract
The polypeptide hormone gastrin was identified nearly a hundred years ago and its role in the regulation of acid secretion is well established. Gastrin also acts as a growth factor and is trophic for the normal gastric oxyntic mucosa. This growth promoting action has led to the extensive investigation of its role in carcinogenesis, in particular colorectal neoplasia. The relationship between gastrin and colorectal adenocarcinoma has been subject to controversy, however the findings from several recent studies have resulted in a clearer understanding of the mechanism of action of gastrin in this is common cancer. The majority of colorectal cancers produce their own gastrin, which may act in an autocrine manner. The tumour cells also express gastrin/CCKB receptors (and/or a combination of isoforms) which mediate the proliferative action. This locally produced gastrin gives rise to a small increase in systemic gastrin levels. Autocrine gastrin may also have a role in tumour development, as expression occurs early in the adenoma-carcinoma sequence. In addition, several studies using animal models have shown that systemic hypergastrinaemia promotes the proliferation of both normal and neoplastic colonic epithelium. Hyperproliferative colonic epithelium in the presence of hypergastrinaemia has been recorded in humans and a well-designed epidemiological study has demonstrated an increased incidence of colorectal cancer. Gastrin is a potential therapeutic target in the treatment of colorectal cancer and several approaches have been assessed. Receptor antagonists and antisecretory agents have been demonstrated to be ineffectual. Novel methods of inhibition, including the use of anti-gastrin antibodies, are currently being evaluated.
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Affiliation(s)
- A M Smith
- The Academic Unit of Cancer Studies, Department of Surgery, University Hospital, Nottingham, UK.
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Szabó I, Rumi G, Bódis B, Németh P, Mózsik G. Gastrin and pentagastrin enhance the tumour proliferation of human stable cultured gastric adenocarcinoma cells. JOURNAL OF PHYSIOLOGY, PARIS 2000; 94:71-4. [PMID: 10761693 DOI: 10.1016/s0928-4257(00)00156-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
The effect of gastrin on stimulating tumour proliferation has been evaluated on human pancreas cancer cells in culture and in tumours transplanted to nude mice. The presence of CCK-B/gastrin-like receptor responsible for that effect of gastrin has been proved in colonic (WiDr, HT-29, YAMC) and pancreatic (PANC-1, BON) cell lines. The aim of our study was to examine the stimulating effect of gastrin and pentagastrin on the growth of human gastric adenocarcinoma cell line. The human gastric adenocarcinoma cell line (AGS, CRL-1739) was purchased from ATCC (Rockville, MA, USA). Gastrin-17 was purchased from Sigma-Aldrich (Budapest, Hungary), pentagastrin was from Zeneca Limited (Macclasfield, UK). The cells were incubated in DMEM containing 10% FCS on 96-well culturing plate with 10(4) cells/well starting cell number at 37 degrees C with 5% CO2. The proliferation rates were detected: by the measurements of the metabolically active cells with Owen's reagent and the determination of protein content, and by cell counting in a haemocytometer at several incubation times. As a result, we detected similar proliferation rates using gastrin-17 or pentagastrin in the incubation medium. The stimulating effect of gastrin/pentagastrin on cell line proliferation was in correlation with its concentration. Our results proved that pentagastrin is a 10 times less effective stimulator of proliferation of gastric cancer than gastrin-17, and that AGS human adenocarcinoma cell line might be CCK receptor positive.
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Affiliation(s)
- I Szabó
- First Department of Medicine, University Medical School of Pécs, Hungary
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Watson SA, Morris TM, Varro A, Michaeli D, Smith AM. A comparison of the therapeutic effectiveness of gastrin neutralisation in two human gastric cancer models: relation to endocrine and autocrine/paracrine gastrin mediated growth. Gut 1999; 45:812-7. [PMID: 10562577 PMCID: PMC1727758 DOI: 10.1136/gut.45.6.812] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Gastrin is a growth factor for established tumours. AIMS To investigate the therapeutic effect of antibodies, raised against the Gastrimmune immunogen, which neutralise the glycine extended and carboxy amidated forms of gastrin 17 in two human gastric cancer models. METHODS MGLVA1 cells (which have a gastrin autocrine/paracrine phenotype) and ST16 cells (which have an endocrine phenotype) were injected into the peritoneal cavity of SCID mice. Peritoneal tumours, ascites, and cachexia formation occurred, with the monitored endpoint being morbidity. RESULTS In MGLVA1 cells, intravenous administration of antibodies raised against Gastrimmune increased the 50% median survived by 25% at three different initial cell seeding concentrations (1 x 10(6)-5 x 10(5) per mouse). In ST16 cells, the effect of Gastrimmune induced antibodies on time to morbidity was greatest at the lowest cell seeding concentration (5 x 10(5) cells/mouse) with the 50% median survival increased by 74% and overall survival achieved in 38% of the mice. CONCLUSIONS Gastrimmune may have potential therapeutic benefit on gastrin sensitive gastric tumours and may interact with both endocrine and autocrine mediated growth pathways.
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Affiliation(s)
- S A Watson
- Academic Unit of Cancer Studies, Department of Surgery, University of Nottingham, UK
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Watson SA, Michaeli D, Grimes S, Morris TM, Varro A, Clarke PA, Smith AM, Justin TA, Hardcastle JD. A comparison of an anti-gastrin antibody and cytotoxic drugs in the therapy of human gastric ascites in SCID mice. Int J Cancer 1999; 81:248-54. [PMID: 10188727 DOI: 10.1002/(sici)1097-0215(19990412)81:2<248::aid-ijc14>3.0.co;2-g] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The therapeutic effect of antibodies raised by the immunogen Gastrimmune was compared with both a CCKB/gastrin receptor antagonist, CI-988, and 5-Fluorouracil/leucovorin in a gastric cancer model. The human gastric ascites cell line, MGLVA1asc, produced and secreted progastrin and glycine-extended gastrin as determined by radioimmunoassay and immunocytochemistry. Cells were also stained with an antiserum directed against the human CCKB/gastrin receptor. MGLVAI asc cells were injected i.p. into SCID mice. Antibodies raised by Gastrimmune immunization of rabbits (affinity for G17 of 0.15 nM and GlyG17 of 0.47 nM) were passively infused i.p. and significantly enhanced survival by up to 5 days (p=0.0024 from vehicle controls). The enhancement in survival was not significantly different from that achieved by treatment with 5-Fluorouracil and leucovorin. A CCKB/gastrin receptor antagonist, CI-988, did not affect survival with cells injected at 7.5 x 10(5) cells/mouse but significantly increased the survival of mice injected with a lower cell innoculum of 5 x 10(5) cells/mouse from 30 to 35 days (p=0.0186). At this lower innoculum antibodies raised by Gastrimmune induced complete survival in 2 animals with the remaining dead by day 36 (p=0.0022). Thus, both endocrine and autocrine pathways mediated by precursor and mature gastrin molecules may be jointly operational in the gastric cancer scenario and may be important targets for therapeutic agents.
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Affiliation(s)
- S A Watson
- Department of Surgery, University of Nottingham, UK.
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Smith JP, Verderame MF, Zagon IS. Antisense oligonucleotides to gastrin inhibit growth of human pancreatic cancer. Cancer Lett 1999; 135:107-12. [PMID: 10077228 DOI: 10.1016/s0304-3835(98)00279-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Human pancreatic cancer is stimulated by the autocrine production of gastrin. In this study, the effects of administration of antisense oligonucleotides to gastrin on growth of pancreatic cancer were evaluated in vitro and in vivo. Log phase BxPC-3 human pancreatic cancer cells in culture were exposed to increasing concentrations (0.5-10 microM) of a synthetic 20-mer antisense phosphorothioate oligonucleotide to gastrin for 48 h and growth was assessed by the cellular proliferation assay. Growth was inhibited up to 88% by anti-gastrin oligonucleotides in a dose-related fashion compared to cells treated with diluent or a randomized sequence with the same composition as the anti-gastrin oligonucleotide. In vivo nude mice bearing BxPC-3 xenografts were treated daily for 14 days with a 0.1-ml intratumoral injection of either anti-gastrin (5 microM), the scrambled sequence control phosphorothioate oligonucleotide (5 microM), or buffer. Tumors from the anti-gastrin-treated mice were significantly smaller in volume and weight and had less gastrin detected by radioimmunoassay than either controls. These results support the role of gastrin as a stimulatory peptide for growth of human pancreatic cancer. Antisense oligonucleotide to gastrin may have a role in the future treatment of patients with pancreatic cancer.
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Affiliation(s)
- J P Smith
- Department of Medicine, The Milton S. Hershey Medical Center, Pennsylvania State University 17033, USA
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Abstract
In addition to its fundamental role in stimulating gastric acid secretion, the peptide hormone gastrin induces growth-promoting effects on diversity of target cells. Various mechanisms, including endocrine, paracrine, and autocrine, have been proposed for gastrin's growth-promoting actions. The mitogenic effects of gastrin are mediated by specific cell surface receptors activated after gastrin binding. The functionally defined receptors for gastrin include cholecystokinin A (CCKA) receptor, which is discriminating for sulfated CCK8; cholecystokinin B (CCKB)/gastrin receptor, which binds gastrin17 sulfated, and nonsulfated CCK8 with nearly equal affinities; cholecystokinin C (CCKC), which is a low-affinity gastrin binding protein; and novel, high-affinity receptors selective for amidated gastrin, processing intermediates of gastrin, or both. The signaling pathways mediating gastrin's stimulation of the CCKB/gastrin receptor have been progressively outlined, and the pathways mediating other receptors have been slowly emerging. Engagement of the gastrin receptor initiates various biochemical and molecular events, including recruitment and activation of tyrosine kinases, activation of the phospholipase C signaling pathway leading to phosphoinositide breakdown, intracellular calcium mobilization and protein kinase C stimulation, activation of the mitogen-activated protein kinase pathway, and induction of early response genes. Current emphasis is on understanding the functional significance of processing intermediate forms of gastrin, and the receptor subtypes and pathways that promote the trophic/mitogenic effects of the different molecular forms of gastrin.
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Affiliation(s)
- R R Yassin
- Department of Medicine, MCP Hahnemann University, Philadelphia, PA 19102-1192, USA
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