The central role of gastrin in gastric cancer

Abstract

The prevalence of gastric cancer has markedly declined, but due to the high mortality rates associated with gastric cancer, it is still a serious disease. The preferred classification of gastric cancer is according to Lauren into either the intestinal type, which has a glandular growth pattern, or the diffuse type, which does not have glandular structures. Both types have been classified as adenocarcinomas, with the latter type based on periodic acid–Schiff (PAS) positivity presumed to reflect mucin. However, the presence of mucin in the diffuse type, in contrast to neuroendocrine/enterochromaffin-like (ECL) cell markers, has not been confirmed by immunohistochemistry and in situ hybridization. The ECL cells are probably prone to becoming cancerous because they do not express E-cadherin. Gastric cancer is unique in that a bacterium, Helicobacter pylori, is thought to be its main cause. H. pylori predisposes infected individuals to cancer only after having caused oxyntic atrophy leading to gastric hypoacidity and hypergastrinemia. No single H. pylori factor has been convincingly proved to be carcinogenic. It is probable that gastrin is the pathogenetic factor for gastric cancer due to H. pylori, autoimmune gastritis, and long-term prolonged inhibition of gastric acid secretion. Hypergastrinemia induces ECL cell hyperplasia, which develops into neuroendocrine tumors (NETs) and then into neuroendocrine carcinomas in rodents, a sequence that has also been described in humans. During carcinogenesis, the tumor cells lose specific traits, requiring that sensitive methods be used to recognize their origin. Gastric cancer occurrence may hopefully be prevented by H. pylori eradication at a young age, and by the reduced use of inhibitors of acid secretion and use of a gastrin antagonist in those with previous long-term H. pylori infection and those with autoimmune gastritis.

Clinicopathological Characteristics and Risk Factors of Young-Onset Gastric Carcinoma: A Systematic Review and Meta-analysis

“…For example, neuroendocrine tumors have been recently recognized as significant factors in the pathogenesis of gastric cancer ( 58 ). Moreover, neuroendocrine cells and stem cells have been implicated as the primary sources of diffuse and intestinal-type gastric carcinoma, respectively, which are the 2 most prevalent Lauren type in young patients, thereby elucidating the role of gastrin in cancer development ( 59 ). Further studies are necessary to address this in the future.…”

Autoimmune Gastritis and Hypochlorhydria: Known Concepts from a New Perspective

“…This proliferation first determines hyperplasia (linear and micronodular), which may evolve into dysplasia of the ECL cells and subsequently to the onset of t1-gNETs [119][120][121]. Waldum et al have emphasized the role of hypergastrinemia in the onset not only of t1-gNETs but also of gastric adenocarcinomas [122,123].…”

“…This proliferation first determines hyperplasia (linear and micronodular), which may evolve into dysplasia of the ECL cells and subsequently to the onset of t1-gNETs [119][120][121]. Waldum et al have emphasized the role of hypergastrinemia in the onset not only of t1-gNETs but also of gastric adenocarcinomas [122,123]. The onset of t1-gNETs is significantly higher in the context of AAG compared to Hp gastritis, although ECL hyperplasia and t1-gNETs are not exclusive of AAG but can also occur in Hp gastritis and during long-term treatment with proton pump inhibitors (PPIs) [120,124,125].…”

“…In Hp gastritis, the secretion of gastrin by G cells is partly altered by the Hp infection itself (which primarily affects the gastric antrum); a state of chronic hypergastrinemia may be present, which, analogously to AAG, stimulates ECL cell proliferation, thus possibly favoring the accumulation of mutations and increased risk of GC [122]. In AAG, the state of marked hypergastrinemia may play a role in predisposing to the development of intestinal adenocarcinoma, which has been proposed to originate from stem cells whose proliferation is stimulated directly or indirectly, through ECL cells, by gastrin [123]. A recent multicentric study describing the histopathological and molecular features of GC lesions diagnosed in AAG patients showed a high neuroendocrine component (28%) in corpus GC, supporting this idea [126].…”