Gastrin: From Physiology to Gastrointestinal Malignancies

Abstract

Abetted by widespread usage of acid-suppressing proton pump inhibitors, the mitogenic actions of the peptide hormone gastrin are being revisited as a recurring theme in various gastrointestinal 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 H. pylori infection and the use of proton pump inhibitors. We further explore the molecular biology of gastrin in gastrointestinal 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.

GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming

“… 73 Tumors exhibited reduced expression of mature neuronal and glial cell markers compared with the adjacent BGs from which 60% of these tumors are reported to originate. 9 Collectively, these observations raise the potential for the presence of a potential hybrid transition state, in which reprogrammed enteric neural crest-derived cells escape a glial-restricted lineage and acquire a neuroendocrine phenotype.…”

“… 5 Patients carrying a MEN1 mutation are predisposed to developing gastrinomas, a GI NET that produces excess levels of gastrin, a peptide hormone that stimulates acid secretion and parietal and enterochromaffin cell hyperplasia. 6 , 7 , 8 , 9 Such MEN1 -associated gastrinomas preferentially develop in Brunner’s glands (BGs) located within the duodenal submucosa, with an estimated >50% frequency of MEN1 gastrinomas exhibiting lymph node metastases at the time of diagnosis. 10 , 11 …”

GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming

“…We recently used digital spatial profiling to characterize neuroglial features in a small subset of human duodenal NETs [60] . Tumors exhibited reduced expression of mature neuronal and glial cell markers compared to the adjacent Brunner’s glands from which 60% of these tumors are reported to originate [9] . Collectively, these observations raise the potential for the presence of a potential hybrid transition state, in which reprogrammed enteric neural crest-derived cells escape a mature neuroglial lineage and acquire a neuroendocrine phenotype.…”

“…Inactivation of the MEN1 locus causes loss of the tumor suppressor protein menin and coincides with the development of endocrine tumors in the pancreas, pituitary, and upper GI tract [5] . Patients carrying a MEN1 mutation are predisposed to developing gastrinomas, a GI NET that produces excess levels of gastrin, a peptide hormone that stimulates acid secretion, inflammation, and proliferation [6,7,8,9] . Such MEN1 -associated gastrinomas preferentially develop in Brunner’s glands located within the duodenal submucosa, with an estimated >50% of MEN1 gastrinomas exhibiting lymph node metastases at the time of diagnosis [10,11] .…”

Microanalysis of the stomach of southern white‐breasted hedgehog (Erinaceus concolor): Histological, histochemical, immunohistochemical, and scanning electron microscopic studies

“…For instance, gastrin, which regulates acid secretion, is released from antropyloric G‐cells (Hunt et al, 2015). Gastrin is involved in the differentiation of gastric stem cells and also express multipotent progenitor cells genes such as Sry‐related HMG‐Box gene 8 (SOX8), SOX9, and SOX10 (Duan et al, 2021). Serotonin is a common hormone between the central nervous system (CNS) and the gastrointestinal tract.…”