Session 5: Enterochromaffin-Like Tumour Cells in the Diffuse but not the Intestinal Type of Gastric Carcinomas

Waldum, Helge L.; Haugen, Øystein; Isaksen, Christin; Mecsei, Reidun; Sandvik, A. K.

doi:10.3109/00365529109093195

Cited by 29 publications

(19 citation statements)

References 25 publications

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“…Some studies have suggested that a proportion of gastric adenocarcinomas develop from the ECL cell (47,49), whereas others have reported that gastric adenocarcinomas in hypergastrinemic patients show signs of neuroendocrine differentiation (25). Moreover, the majority of patients with poorly differentiated, high-grade neuroendocrine carcinomas have hypergastrinemia (29).…”

Section: Discussionmentioning

confidence: 99%

Inducible cAMP early repressor suppresses gastrin-mediated activation of cyclin D1 and c-fosgene expression

Steigedal¹,

Bruland²,

Misund³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Steigedal TS, Bruland T, Misund K, Thommesen L, Laegreid A. Inducible cAMP early repressor suppresses gastrin-mediated activation of cyclin D1 and c-fos gene expression. Am J Physiol Gastrointest Liver Physiol 292: G1062-G1069, 2007. First published December 21, 2006; doi:10.1152/ajpgi.00287.2006.-The gastric hormone gastrin and its precursors promote proliferation in several gastrointestinal cell types. Here we show that gastrin induces transcription of cell cycle gene cyclin D1 and protooncogene c-fos in the neuroendocrine pancreatic cell line AR42J and that this gastrin response is inhibited by endogenous inducible cAMP early repressor (ICER). The transcriptional repressor ICER is known to downregulate both its own expression and the expression of other genes containing cAMPresponsive elements (CREs). Using siRNA, we also show that CRE promoter elements are the targets of endogenous ICER in AR42J cells as well as in the neuroendocrine cell line RIN5F. Our results suggest that ICER plays an important role in molecular mechanisms governing gastrin-mediated growth by modulating gastrin's transcriptional activation of growth-related genes. Our finding that ICER modulates pituitary adenylate cyclase-activating polypeptide-activated gene expression also indicates a regulatory effect of ICER in the responses of neuroendocrine cells to peptides other than gastrin.neuroendocrine gene regulation; gastrointestinal proliferation; gastrin THE PEPTIDE HORMONE GASTRIN is well characterized as a stimulant of gastric acid secretion by stimulation of enterochromaffin-like (ECL) cells to produce histamine, which in turn stimulates the parietal cells in the oxyntic mucosa to release HCl (36,48). Gastrin is an important growth factor for the fetal pancreas (50) and a potent stimulant for the growth of gastric mucosa (4,5,46). Transgenic mice overexpressing gastrin exhibit increased proliferation of the oxyntic mucosa (51), whereas gastrin-deficient mice develop abnormal gastrointestinal (GI) mucosa with immature cells (7,12). In addition, there is abundant evidence to suggest that gastrin may play an important role in tumor biology, as gastrin is shown to regulate tumor cell growth (4, 5) and stimulate tumor cell invasion (4, 5, 13). Hypergastrinemia is associated with the occurrence of gastric ECL cell carcinoid tumors (4,5,28,46) and with an increased risk of gastric and colorectal carcinoma (5), indicating a role in carcinogenesis. The biological actions of gastrin are exerted through binding to the gastrin/cholecystokinin (CCK2) receptor. This receptor has been shown to be coexpressed with gastrin in several GI tumor cell lines (53) and in human gastric carcinoids (38), indicating the existence of an autocrine growth stimulatory loop. The malignant potential of carcinoids is associated with hypergastrinemia (24). These studies suggest that gastrin plays an important role in neuroendocrine tumor biology.Inducible cAMP early repressor (ICER) is a transcriptional repressor encoded by the cAMP-responsive element (CRE) modulatin...

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Section: Discussionmentioning

confidence: 99%

Inducible cAMP early repressor suppresses gastrin-mediated activation of cyclin D1 and c-fosgene expression

Steigedal¹,

Bruland²,

Misund³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In fact, evidence of focal neuroendocrine differentiation has been found in over 50% of tumors otherwise classified as adenocarcinoma 37,38,39,40 . It is particularly common in signet ring cell carcinomas, leading some to propose that signet ring cells derive from a pluripotent neuroendocrine stem cell 41,42,43,44 . Molecular and infectious correlates of neuroendocrine differentiation have not been systematically investigated.…”

Section: Introductionmentioning

confidence: 99%

Three Molecular Subtypes of Gastric Adenocarcinoma Have Distinct Histochemical Features Reflecting Epstein-Barr Virus Infection Status and Neuroendocrine Differentiation

Speck¹,

Tang²,

Morgan

et al. 2015

Applied Immunohistochemistry &Amp; Molecular Morphology

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Current histopathologic classification schemes for gastric adenocarcinoma have limited clinical utility and are difficult to apply due to tumor heterogeneity. Elucidation of molecular subtypes of gastric cancer may contribute to our understanding of gastric cancer biology and to the development of new molecular markers that may lead to improved diagnosis, therapy, or prognosis. We previously demonstrated that Epstein-Barr virus infected gastric cancers have a distinct human gene expression profile compared to uninfected cancers. We now examine the histopathologic features characterizing infected (n=14) and uninfected (n=89) cancers, the latter of which are now further divided into two major molecular subtypes based on expression patterns of 93 RNAs. One uninfected gastric cancer subtype was distinguished by upregulation of three genes with neuroendocrine function (CHGA, GAST, and REG4 encoding chromogranin, gastrin and the secreted peptide REG4 involved in epithelial cell regeneration), implicating hormonal factors in the pathogenesis of a major class of gastric adenocarcinomas. Evidence of neuroendocrine differentiation (molecular, immunohistochemical, or morphologic) was mutually exclusive of EBV infection. EBV infected tumors tended to have solid-type morphology with lymphoid stroma. This study reveals novel molecular subtypes of gastric cancer and their associated morphologies that demonstrate divergent neuroendocrine features.

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“…We can therefore not exclude that this tumor originated from the ECL cell. Alternatively, the cancer originated from stem cells which could have been over-stimulated by mediators from ECL cell carcinoids [42]. Patient 4 showed signs of a metastatic NE tumor (CT scan and SRS).…”

Section: Discussionmentioning

confidence: 99%

Five-year follow-up of patients treated for 1 year with octreotide long-acting release for enterochromaffin-like cell carcinoids

Jianu

Fossmark

Syversen

et al. 2010

Scandinavian Journal of Gastroenterology

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Session 5: Enterochromaffin-Like Tumour Cells in the Diffuse but not the Intestinal Type of Gastric Carcinomas

Cited by 29 publications

References 25 publications

Inducible cAMP early repressor suppresses gastrin-mediated activation of cyclin D1 and c-fosgene expression

Inducible cAMP early repressor suppresses gastrin-mediated activation of cyclin D1 and c-fosgene expression

Three Molecular Subtypes of Gastric Adenocarcinoma Have Distinct Histochemical Features Reflecting Epstein-Barr Virus Infection Status and Neuroendocrine Differentiation

Five-year follow-up of patients treated for 1 year with octreotide long-acting release for enterochromaffin-like cell carcinoids

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