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Genetic suppression of inflammation blocks the tumor-promoting effects of TGF-? in gastric tissue.

ABSTRACT: The contributions of TGF-? signaling to cancer are complex but involve the inflammatory microenvironment as well as cancer cells themselves. In mice encoding a TGF-? mutant that precludes its binding to the latent TGF-? binding protein (Tgfb1(-/C33S)), we observed multiorgan inflammation and an elevated incidence of various types of gastrointestinal solid tumors due to impaired conversion of latent to active TGF-?1. By genetically eliminating activators of latent TGF-?1, we further lowered the amount of TGF-?, which enhanced tumor frequency and multiorgan inflammation. This model system was used to further investigate the relative contribution of TGF-?1 to lymphocyte-mediated inflammation in gastrointestinal tumorigenesis. Toward this end, we generated Tgfb1(-/C33S);Rag2(-/-) mice that lacked adaptive immune function, which eliminated tumor production. Analysis of tissue from Tgfb1(-/C33S) mice indicated decreased levels of P-Smad3 compared with wild-type animals, whereas tissue from Tgfb1(-/C33S);Rag2(-/-) mice had normal P-Smad3 levels. Inhibiting the inflammatory response normalized levels of interleukin (IL)-1? and IL-6 and reduced tumor cell proliferation. In addition, Tgfb1(-/C33S);Rag2(-/-) mice exhibited reduced paracrine signaling in the epithelia, mediated by hepatocyte growth factor produced by gastric stroma. Together, our results indicate that many of the responses of the gastric tissue associated with decreased TGF-?1 may be directly or indirectly affected by inflammatory processes, which accompany loss of TGF-?1, rather than a direct effect of loss of the cytokine.

SUBMITTER: Ota M

PROVIDER: S-EPMC4158836 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Genetic suppression of inflammation blocks the tumor-promoting effects of TGF-β in gastric tissue.

Ota Mitsuhiko M Horiguchi Masahito M Fang Victoria V Shibahara Kotaro K Kadota Kyuichi K Loomis Cynthia C Cammer Michael M Rifkin Daniel B DB

Cancer research 20140303 9

The contributions of TGF-β signaling to cancer are complex but involve the inflammatory microenvironment as well as cancer cells themselves. In mice encoding a TGF-β mutant that precludes its binding to the latent TGF-β binding protein (Tgfb1(-/C33S)), we observed multiorgan inflammation and an elevated incidence of various types of gastrointestinal solid tumors due to impaired conversion of latent to active TGF-β1. By genetically eliminating activators of latent TGF-β1, we further lowered the a ...[more]

PMID: 24590056

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Project description:Although Helicobacter-induced gastric inflammation is the major predisposing factor for gastric carcinogenesis, the precise mechanism by which chronic gastritis causes gastric cancer remains unclear. Intestinal and spasmolytic polypeptide-expressing metaplasia (SPEM) is considered as precancerous lesions, changes in epithelial tissue stem/progenitor cells after chronic inflammation has not been clarified yet. In this study, we utilized three-dimensional gastric epithelial cell culture systems that could form organoids, mimicking gastric epithelial layer, and characterized the changes in epithelial cells after chronic Helicobacter felis infection.We used three mice model; 1) long-term H. felis infection, 2) H. felis eradication, and 3) MNU chemical carcinogenesis model. We performed cRNA microarray analysis after organoid culture, and analyzed the effects of chronic gastric inflammation on tissue stem cells, by the size of organoid, mRNA expression profile and immunohistochemical analysis.The number of organoids cultured from gastric epithelial cells was significantly higher in organoids isolated from H. felis-infected mice compared with those from uninfected gastric mucosa. Based on the mRNA expression profile, we found that possible stem cell markers such as Cd44, Dclk1, and genes associated with the intestinal phenotype, such as Villin, were increased in organoids isolated from H. felis-infected mucosa compared with the control. The upregulation of these genes were cancelled after H. felis eradication. In a xenograft model, tumors were generated only from organoids cultured from carcinogen-treated gastric mucosa, not from H. felis infected mucosa or control organoids.Our results suggested that, as a possible mechanism of gastric carcinogenesis, chronic inflammation induced by H. felis infection increased the number of tissue stem/progenitor cells and the expression of stem cell markers. These findings suggest that chronic inflammation may alter the direction of differentiation toward undifferentiated state and that drawbacks may enable cells to redifferentiate to intestinal metaplasia or neoplasia.

Dataset Information

Genetic suppression of inflammation blocks the tumor-promoting effects of TGF-? in gastric tissue.

Publications

Genetic suppression of inflammation blocks the tumor-promoting effects of TGF-β in gastric tissue.

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