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Gastrin and Gastric Cancer

Open AccessPublished:March 16, 2017DOI:https://doi.org/10.1016/j.jcmgh.2017.03.004
      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.

      Keywords

      Abbreviations used in this paper:

      CCK-BR (cholecystokinin-B receptor), ECL (enterochromaffin-like), EGFR (epidermal growth factor receptor), ERK (extracellular signal–regulated kinase), HER2 (human epidermal growth factor receptor 2), IHC (immunohistochemistry), PAS (polyclonal antibody stimulator), PPI (proton pump inhibitor), TCGA (The Cancer Genome Atlas)
      The gastrointestinal peptide, gastrin, stimulates growth of gastric adenocarcinoma (gastric cancer) through the cholecystokinin-B receptors that are overexpressed in this malignancy. Serum gastrin levels may be increased secondary to chronic administration of proton pump inhibitors, atrophic gastritis, Helicobacter pylori infection, or from de novo gastrin expression from the gastric cancer epithelial cells. Strategies to interrupt the interaction of gastrin at the cholecystokinin-B receptor may provide a novel approach to the treatment of gastric cancer.
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      Risk Factors for Gastric Cancer

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      Figure thumbnail gr1
      Figure 1Physiologic and pathologic role of gastrin. (A) Under physiologic conditions gastrin is released from antrum G cells in response to food, decreased acid, and gastric distension. Gastrin circulates in the peripheral blood and binds to the CCK-B receptors on the parietal and ECL cells of the body. The ECL cells release histamine, which activates the H2 receptors on parietal cells and HCl (H+) is released. The increased H+ feeds back to the D cells of the antrum to release somatostatin to turn off the gastrin release. Gastrin also is responsible for basal growth and renewal of the gastric epithelium. Normal signaling through the CCK-B receptor occurs through the activation of the phospholipase C-β/diacylglycerol/Ca2+/protein kinase C. (B) Increased gastrin levels can result from achlorhydria, chronic use of PPIs, or H pylori infection. Gastric cancer epithelial cells that express CCK-B receptors also produce their own gastrin de novo, which in turn stimulates growth and metastases of gastric cancer by an autocrine mechanism.
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      Gastrin Mediates its Effects Through the Cholecystokinin-B Receptor

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      Expression of Gastrin and the CCK-B Receptors in Gastric Cancer and Stem Cells

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      showed that infection of canine G cells with H pylori increased endogenous gastrin secretion from the G cells by 17%–27%. In addition, patients with asymptomatic H pylori infection were found to have increased gastrin levels by enzyme-linked immunosorbent assay.
      • Smith J.T.
      • Pounder R.E.
      • Nwokolo C.U.
      • et al.
      Inappropriate hypergastrinaemia in asymptomatic healthy subjects infected with Helicobacter pylori.
      Although hypergastrinemia is associated with the development of gastric neuroendocrine tumors and gastric adenocarcinoma,
      • Waldum H.L.
      • Sagatun L.
      • Mjones P.
      Gastrin and gastric cancer.
      both animal and human studies have shown the greater incidence of gastric carcinoids in patients with increased gastrin levels. One possible explanation for the more frequent neuroendocrine tumors over gastric adenocarcinoma in patients with hypergastrinemia may be related to the finding that although the CCK-B receptor is present on parietal cells, it is expressed more abundantly in ECL cells of the stomach.
      • Asahara M.
      • Kinoshita Y.
      • Nakata H.
      • et al.
      Gastrin receptor genes are expressed in gastric parietal and enterochromaffin-like cells of Mastomys natalensis.
      • Kinoshita Y.
      • Ishihara S.
      Mechanism of gastric mucosal proliferation induced by gastrin.
      In addition to responding to the proliferative effects of gastrin, studies also have shown that the parietal cells respond to other trophic factors secreted by the ECL-like cells by a paracrine mechanism including secretion of Reg protein,
      • Watanabe T.
      • Yonekura H.
      • Terazono K.
      • et al.
      Complete nucleotide sequence of human reg gene and its expression in normal and tumoral tissues. The reg protein, pancreatic stone protein, and pancreatic thread protein are one and the same product of the gene.
      heparin-binding EGF,
      • Bordi C.
      • Falchetti A.
      • Buffa R.
      • et al.
      Production of basic fibroblast growth factor by gastric carcinoid tumors and their putative cells of origin.
      and even histamine.
      • Waldum H.L.
      • Brenna E.
      • Sandvik A.K.
      • et al.
      Trophic effect of histamine on the stomach.
      With more sophisticated technology using lineage tracing, researchers have confirmed the presence of CCK-B receptors on the antrum stem cells that do not respond to gastrin-17.
      • Hayakawa Y.
      • Jin G.
      • Wang H.
      • et al.
      CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis.
      These studies also help us understand that hypergastrinemia selectively increases the risk of gastric corpus cancers and low gastrin levels may increase the risk for antral cancers. Whether hypergastrinemia enhances the growth of gastric carcinoids more frequently than gastric adenocarcinoma seems irrelevant when the long-term prognosis differs between these 2 lesions, with adenocarcinoma doing more poorly. Clinical investigations in human subjects also have shown that hypergastrinemia adversely affects survival from subjects with stages 2–4 gastric adenocarcinomas.
      • Fossmark R.
      • Sagatun L.
      • Nordrum I.S.
      • et al.
      Hypergastrinemia is associated with adenocarcinomas in the gastric corpus and shorter patient survival.
      Therefore, strategies to decrease gastrin levels in subjects with gastric cancers may be useful.

      Gastrin-CCK-B Receptor Pathway

      Treatment of cancer is improved significantly when a cancer-specific target or cell surface receptor is identified. Because gastrin has been shown to stimulate growth of gastric cancer and other gastrointestinal malignancies, researchers have been studying means to block the ligand:receptor interaction in an attempt to slow or arrest tumor growth. Numerous investigations have been conducted in cell culture and animal models of gastric cancer using small-molecule CCK-B receptor antagonists,
      • Xu W.
      • Chen G.S.
      • Shao Y.
      • et al.
      Gastrin acting on the cholecystokinin2 receptor induces cyclooxygenase-2 expression through JAK2/STAT3/PI3K/Akt pathway in human gastric cancer cells.
      • Grabowska A.M.
      • Morris T.M.
      • McKenzie A.J.
      • et al.
      Pre-clinical evaluation of a new orally-active CCK-2R antagonist, Z-360, in gastrointestinal cancer models.
      and their use in human trials has been reviewed.
      • Baldwin G.S.
      • Shulkes A.
      CCK receptors and cancer.
      • Berna M.J.
      • Jensen R.T.
      Role of CCK/gastrin receptors in gastrointestinal/metabolic diseases and results of human studies using gastrin/CCK receptor agonists/antagonists in these diseases.
      • Rai R.
      • Chandra V.
      • Tewari M.
      • et al.
      Cholecystokinin and gastrin receptors targeting in gastrointestinal cancer.
      Clinical trials in human subjects with agents directed to the gastrin:CCK-B–receptor pathway are rare and most studies have investigated agents in other gastrointestinal cancers rather than in gastric cancer, such as gastrazole in pancreatic cancer
      • Chau I.
      • Cunningham D.
      • Russell C.
      • et al.
      Gastrazole (JB95008), a novel CCK2/gastrin receptor antagonist, in the treatment of advanced pancreatic cancer: results from two randomised controlled trials.
      or netazepide
      • Boyce M.
      • Moore A.R.
      • Sagatun L.
      • et al.
      Netazepide, a gastrin/cholecystokinin-2 receptor antagonist, can eradicate gastric neuroendocrine tumours in patients with autoimmune chronic atrophic gastritis.
      in gastric neuroendocrine tumors.
      Polyclonal antibody stimulator (PAS), formerly called G17DT and gastrimmune, was developed as an immunogen containing a 9–amino acid epitope derived from the amino-terminal sequence of gastrin-17 conjugated to diphtheria toxoid (Figure 2A). PAS elicits specific and high-affinity antibodies that bind gastrin-17 and gly-gastrin, thus preventing its trophic activity. Unlike tumor-associated antigen-based vaccines, PAS is unique in that it produces neutralizing antibodies to gastrin with peak titers occurring by week 6 and persisting after vaccination for up to 40 weeks. Preclinical studies were performed in several animal models that have CCK-B receptors,
      • Singh P.
      • Walker J.P.
      • Townsend Jr., C.M.
      • et al.
      Role of gastrin and gastrin receptors on the growth of a transplantable mouse colon carcinoma (MC-26) in BALB/c mice.
      • Smith J.P.
      • Solomon T.E.
      Effects of gastrin, proglumide, and somatostatin on growth of human colon cancer.
      • Smith J.P.
      • Stock E.A.
      • Wotring M.G.
      • et al.
      Characterization of the CCK-B/gastrin-like receptor in human colon cancer.
      • Upp Jr., J.R.
      • Singh P.
      • Townsend Jr., C.M.
      • et al.
      Clinical significance of gastrin receptors in human colon cancers.
      • Rehfeld J.F.
      • Bardram L.
      • Hilsted L.
      Gastrin in human bronchogenic carcinomas: constant expression but variable processing of progastrin.
      • Smith J.P.
      • Kramer S.T.
      • Solomon T.E.
      CCK stimulates growth of six human pancreatic cancer cell lines in serum-free medium.
      • Smith J.P.
      • Solomon T.E.
      • Bagheri S.
      • et al.
      Cholecystokinin stimulates growth of human pancreatic adenocarcinoma SW-1990.
      • Smith J.P.
      • Fantaskey A.P.
      • Liu G.
      • et al.
      Identification of gastrin as a growth peptide in human pancreatic cancer.
      including gastric cancer.
      • Smith J.P.
      • Shih A.H.
      • Wotring M.G.
      • et al.
      Characterization of CCK-B/gastrin-like receptors in human gastric carcinoma.
      • Watson S.
      • Durrant L.
      • Morris D.
      Gastrin: growth enhancing effects on human gastric and colonic tumor cells.
      In these animal models, PAS-generated anti-G17 antibodies have been shown to reduce growth and metastases.
      • Watson S.A.
      • Michaeli D.
      • Grimes S.
      • et al.
      Anti-gastrin antibodies raised by gastrimmune inhibit growth of the human colorectal tumour AP5.
      • Watson S.A.
      • Michaeli D.
      • Grimes S.
      • et al.
      Gastrimmune raises antibodies that neutralize amidated and glycine-extended gastrin-17 and inhibit the growth of colon cancer.
      • Watson S.A.
      • Michaeli D.
      • Grimes S.
      • et al.
      A comparison of an anti-gastrin antibody and cytotoxic drugs in the therapy of human gastric ascites in SCID mice.
      Passive immunization with PAS antibodies raised in rabbits improved survival of severe combined immunodeficiency disease mice bearing gastric cancers compared with diluent-treated controls
      • Watson S.A.
      • Morris T.M.
      • Varro A.
      • et al.
      A comparison of the therapeutic effectiveness of gastrin neutralisation in two human gastric cancer models: relation to endocrine and autocrine/paracrine gastrin mediated growth.
      (Figure 2B). To date, 5 open-labeled clinical trials have been conducted using PAS in subjects with gastric cancer in doses ranging from 10 to 500 μg intramuscularly (Table 1).
      • Ajani J.A.
      • Hecht J.R.
      • Ho L.
      • et al.
      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.
      • Gilliam A.D.
      • Watson S.A.
      • Henwood M.
      • et al.
      A phase II study of G17DT in gastric carcinoma.
      One gastric cancer study, GC2,
      • Gilliam A.D.
      • Watson S.A.
      • Henwood M.
      • et al.
      A phase II study of G17DT in gastric carcinoma.
      was a dose-finding study and tested 3 doses and analyzed response according to stage of disease. Only 1 study, GC4, evaluated the safety and survival of PAS in combination with standard chemotherapy.
      • Ajani J.A.
      • Hecht J.R.
      • Ho L.
      • et al.
      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.
      The median survival of those with advanced gastric cancer after PAS administration was prolonged significantly (10.8 mo) in subjects who mounted a circulating antibody titer against gastrin (ie, responders) compared with subjects who failed to generate an antibody response (6.2 mo) (ie, nonresponders) (Figure 2C). The only notable PAS-related adverse events when compared with placebo were injection-site reaction and pyrexia.
      Figure thumbnail gr2
      Figure 2Polyclonal antibody stimulator. (A) Diagram showing the structure of PAS with the gastrin epitope linked to diphtheria toxoid with a peptide spacer. Characteristics include a molecular weight of 84 kilodaltons; an appearance that is clear, colorless, to slightly yellow solution; and a pH of 7.0–7.4. PAS is water-soluble and administered as an intramuscular injection. (B) Treatment of severe combined immunodeficiency disease mice with gastric cancer showed greater survival compared with mice treated with nonimmune antibody. **P = .015.
      • Watson S.A.
      • Michaeli D.
      • Grimes S.
      • et al.
      A comparison of an anti-gastrin antibody and cytotoxic drugs in the therapy of human gastric ascites in SCID mice.
      (C) Human subjects with gastric cancer treated with PAS vaccination that elicit circulating antibody titers (CAT) have a significantly prolonged survival when compared with subjects who do not elicit an antibody response (P < .0001). (Adapted with permission from Ajani JA, Hecht JR, Ho L, et al. 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;106:1908–1916).
      Table 1Summary of Clinical Trials With PAS in Gastric Cancer
      Study nameStudy designSubjects, nDose(s), mcgSchedule, wkResults
      GC2
      • Gilliam A.D.
      • Watson S.A.
      • Henwood M.
      • et al.
      A phase II study of G17DT in gastric carcinoma.
      Open-label, dose ranging5210, 100, 2500, 2, 6250 μg gave a 92% Ab response
      GC3Open-label, dose ranging33100, 250, 5000, 1, 3Dosing schedule was poorly tolerated
      GC4
      • Ajani J.A.
      • Hecht J.R.
      • Ho L.
      • et al.
      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.
      Open-label, combination of cisplatin and 5-fluorouracil in chemotherapy-naive subjects, safety and survival study1035001, 5, 9, 2567% Ab titers Survival Ab responders 10.3 mo
      GC5Open-label75000, 2, 6Stopped prematurely because of poor tolerability
      GC12Open, dosing study40125, 2500, 2, 685% Ab response, 250 μg was more effective than 125 μg
      Ab, antibody; GC, gastric cancer.

      Conclusions

      Survival from advanced gastric cancer is poor and new strategies are needed for therapy. CCK-B receptors are overexpressed in many gastric cancers and when these receptors are activated by gastrin, the result is tumor proliferation. Furthermore, many gastric cancers also express gastrin, which stimulates cancer growth by an autocrine mechanism. Understanding the mechanisms and receptor-mediated pathways that regulate the growth of gastric cancer is important. Novel therapeutic agents that target the gastrin:CCK-B–receptor pathways are promising and may help improve survival of advanced gastric cancer.

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