Gastrin: From Physiology to Gastrointestinal Malignancies

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.

Keywords: G-cell; GEP-NET; Helicobacter pylori; MEN1; gastrinoma; hypergastrinemia; neuroendocrine tumor; somatostatin.

Figure 1.

Mechanisms of gastrin signaling under physiological and specific pathological conditions. Under normal physiological conditions, gastrin participates in negative feedback regulation that involves acid-induced release of somatostatin from the antral D cell. Chronic inhibition of parietal cell acid secretion by proton pump inhibitors (PPIs), stimulates hypergastrinemia in human and mice. In genetically engineered mice exhibiting conditional loss of menin and somatostatin, PPIs can promote gastric carcinoid development. Gastrin stimulates enterochromaffin-like (ECL) cell proliferation through the cholecystokinin B receptor (CCKBR) and expands CCKBR + stem/progenitor cells in the corpus. By contrast in the antrum, gastrin inhibits the expansion of CCKBR + stem/progenitor cells. Therefore, gastrin's effects are likely site and context-dependent, eg, during chronic infection with Helicobacter pylori. Helicobacterpylori-elicited cytokines can positively or negatively regulate gastrin gene expression and antral hyperplasia by modulating GLI2 activation through primary cilia. Figure created with Biorender.com.

Figure 2.

Proposed model of cytokine-elicited epithelial reprogramming events that precede gastrinoma development in the duodenum. Duodenal gastrinomas (DGAST) arise within the Brunner's glands of the proximal duodenum, raising the likelihood that this hormone producing tumor arises from a reprogrammed cell and does not arise directly from enteroendocrine cells. Here, we propose that stromal-derived inflammatory cytokines, such as TNFα or IL-17, activate STAT3 phosphorylation and NFκB signaling pathways that reprogram the Brunner's glands toward a neuroendocrine phenotype. STAT3 and NFκB signaling induce transcription factor NKX6.3, a homeobox transcription factor required for gastrin gene expression and master regulator of gastric differentiation.^, Figure created with Biorender.com and adapted from Rico et al. (2021), BMJ Open Gastroenterology.