1. Inflammation, Atrophy, Gastric Cancer: Connecting the Molecular Dots
Juanita L. Merchant 
Gastroenterology 
Volume 129, Issue 3, Pages (September 2005)
DOI: /j.gastro
Copyright © 2005 American Gastroenterological Association Terms and Conditions

2. Figure 1
Regional epithelial and mesenchymal interactions during gastric transformation. Putative genes important for normal corpus and antral homeostasis are shown, with the morphogen sonic hedgehog (Shh) potentially having effects in the mesenchyme, as well as on adjacent cells that express its receptor patched (Ptc).14 Bone morphogenic proteins (BMPs) are regulated by both the Shh and Wnt signaling pathways and can be found in both the mesenchyme and epithelium. BMP 2 and 4 are found in the stomach. In response to bacterial colonization and typically antral inflammation, hypermethylation is one of several epigenetic effects that can alter gene expression. In the case of MLH1 suppression, microsatellite instability (MSI) can result. TGFβ receptor II is a known target of this pathway. Suppression of the gastric specific tumor-suppressor gene Runx3 is regulated by TGFβ and normally stimulates apoptosis. The suppressor of cytokine signaling (SOCS-1) is also a target of hypermethylation and inhibits STAT signaling induced by cytokine receptors and the Janus kinases. As a result, IL-6 levels are high and contribute to elevated levels of pro-proliferative STATs, eg, STAT3. Cdx2 is an intestine specific transcription factor and a member of the caudal gene family. Also the calcium binding protein S100A family is overexpressed in gastric cancer. TFF, trefoil factor; Muc, mucin gene; MGMT, O6-methylguanine DNA methyltransferase; Pep, pepsinogen. Illustration by Jerry Schoerdorf, MAMS.
Gastroenterology  , DOI: ( /j.gastro )
Copyright © 2005 American Gastroenterological Association Terms and Conditions

3. Figure 2
Schematic time line of mucosal phenotypes and genetic changes in response to chronic gastritis. Bacterial colonization generates an immune response. In the acid competent stomach, the microbial trigger is H pylori; whereas, in the hypochlorhydric stomach other bacterial species can flourish. Chronic inflammation in the stomach consists of Th1 interferon gamma-secreting cells, as well as neutrophils and macrophages. Byproducts of inflammation (oxidative stress) stimulate DNA methyltransferases (DNMT). Interferon gamma stimulates mucous neck cell hypertrophy.10 Helicobacter infection stimulates proliferation of mucous neck cells, which are phenotypically similar to antral pyloric glands. Pseudopyloric gland metaplasia represents antral-type glands in the corpus and is a form of glandular atrophy. These pseudopyloric glands are TFF2, Muc6 positive, and thus may be synonomous with the mucous neck cell hypertrophy and hyperplasia that responds to proinflammatory cytokines. Intestinal metaplastic cells expressing enterocyte markers, eg, villin, TFF3, Muc2, Cdx2, can appear in the antrum or corpus emerging from an epithelial landscape of pseudopyloric gland metaplasia.5 The appearance of atrophic glands results in hypochlorhydria due either to loss of oxnytic gland function or cells. Dysplastic cells lose indicators of gastric differentiation. Transformed epithelium will exhibit functional and histologic evidence of unregulated growth, eg, loss of contact inhibition. There can be a 30 to 50 year lag between the appearance of atrophic glands and cancer. However, an exact time line and sequence of genetic alterations has yet to be firmly established.
Gastroenterology  , DOI: ( /j.gastro )
Copyright © 2005 American Gastroenterological Association Terms and Conditions