Towards Understanding of Gastric Cancer Based upon Physiological Role of Gastrin and ECL Cells

Abstract

The stomach is an ideal organ to study because the gastric juice kills most of the swallowed microbes and, thus, creates rather similar milieu among individuals. Combined with a rather easy access to gastric juice, gastric physiology was among the first areas to be studied. During the last century, a rather complete understanding of the regulation of gastric acidity was obtained, establishing the central role of gastrin and the histamine producing enterochromaffin-like (ECL) cell. Similarly, the close connection between regulation of function and proliferation became evident, and, furthermore, that chronic overstimulation of a cell with the ability to proliferate, results in tumour formation. The ECL cell has long been acknowledged to give rise to neuroendocrine tumours (NETs), but not to play any role in carcinogenesis of gastric adenocarcinomas. However, when examining human gastric adenocarcinomas with the best methods presently available (immunohistochemistry with increased sensitivity and in-situ hybridization), it became clear that many of these cancers expressed neuroendocrine markers, suggesting that some of these tumours were of neuroendocrine, and more specifically, ECL cell origin. Thus, the ECL cell and its main regulator, gastrin, are central in human gastric carcinogenesis, which make new possibilities in prevention, prophylaxis, and treatment of this cancer.

NF-κB in Gastric Cancer Development and Therapy

“…Infection with H. pylori affects paracrine loops between parietal cells, gastrin-secreting G cells, histamine-secreting ECL cells, and somatostatin-secreting D cells [ 137 , 138 ]. In H. pylori -infected human gastric tissue, the expression of ATP4A, a subunit of H, K-ATPase, is suppressed in a T4SS-dependent and NF-κB-dependent manner [ 137 ].…”

“…The suppression of H, K-ATPase intensifies gastrin production, which stimulates the oxyntic mucosa, and contributes to its atrophy, promoting further hypergastrinemia and ECL cell hyperplasia [ 104 , 138 ]. There is an indication that gastrin and released factors by ECL cells promote the proliferation of gastric cells, including cell precursors, which is also relevant for gastric cancer pathogenesis [ 138 ]. Further, cytokines contribute to these functional disorders [ 139 ].…”

Clear Cell Renal Cancer, a Tumour with Neuroendocrine Features Originating from the Erythropoietin-Producing Cell

“…HIFs are released during hypoxia, and HIF-2 is being the main stimulator of erythropoietin release [25]. Our experience is that it is a close correlation between regulation of function and growth [73], which in this case will indicate that HIF-2 will not only stimulate erythropoietin release but also proliferation of EPC. Lack of proteolysis of HIFs will accordingly lead to chronic overstimulation of proliferation explaining the carcinogenic effect.…”

Gastritis, Gastric Polyps and Gastric Cancer

“…Antigenic mimicry between H. pylori and the oxyntic mucosa [ 15 ] including parietal cells [ 16 ] was discussed as a possibility for the development of gastritis in the late nineties, but has not been followed up later. Since H. pylori seems mainly to be acquired in childhood [ 17 ] and since atrophic gastritis secondary to H. pylori requires decades to develop, as indicated by the decline in gastric acid secretory capacity with age [ 18 ], the logic strategy to prevent H. pylori induced gastric cancer is to test young adults for H. pylori by serology and eradicate the bacterium from positive individuals [ 19 ].…”