Gastrin and Gastric Cancer

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.

Keywords: CCK-B Receptor; CCK-BR, cholecystokinin-B receptor; ECL, enterochromaffin-like; EGFR, epidermal growth factor receptor; ERK, extracellular signal–regulated kinase; G17DT; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; PAS, polyclonal antibody stimulator; PPI, proton pump inhibitor; PPIs; Proton Pump Inhibitors; TCGA, The Cancer Genome Atlas.

Figure 1

Physiologic 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.

Figure 2

Polyclonal 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. (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).