Abstract 3969: Stromal depletion of transforming growth factor receptor 2 promotes the development of forestomach squamous cell carcinoma

Abstract

Abstract Deletion or attenuation of transforming growth factor beta (TGFβ) signaling pathway has significant impact on human tumor development and progression. Specific deletion of transforming growth factor receptor 2 gene (Tgfbr2) in a subset of fibroblast (Tgfbr2fspKO, cre-mediated DNA recombination driven by fibroblast specific protein, FSP) specific promoter, leads to the development of squamous cell carcinoma of the forestomach in 100% of Tgfbr2fspKO mice by 6 Wks of Age. Here we dissect the underlying mechanisms. We first confirmed that deletion of Tgfbr2 is primarly restricted to the stromal components but not epithelial cells using TBR2 (TGFβR2) immunofluorescence and immunohistochemistry, which was done in both tumor tissue sections and cancer epithelial cells derived from tgfbr2fspKO mice. The functionality of TGFβ signaling was further examined in vivo by p-smad2 expression and nuclear localization which was clearly observed in the epithelial but not the stromal components. There was also a clear nuclear localization of p-smad2 protein in cultured cancer epithelial cells when treated with TGFβ1 (10 ng/ml). We further observed that stromal deletion of Tgfbr2 resulted in elevated proliferation of fibroblasts. In addition, there was a significantly increased inflammation in forestomach lesion which was featured by increased CD45+ leukocyte infiltration and elevated expression of inflammatory mediators COX2, NFkB, Akt. Interestingly, the alterations in epithelial cell compartment in Tgfbr2fspKO mice is very evident compared with floxed control littermates Tgfbr2fspKO mice, showing a significant enrichment of epithelial cancer stem cells. Our data demonstrate the importance of stromal TGFβ signaling mediated inflammation and carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3969.