Abstract 4014: The gp130/Stat3 pathway enables Wnt induced regeneration and tumorigenesis in the mouse intestine

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Abstract The transcription factor Stat3 is frequently activated in human intestinal tumors. Using a hyperactive gp130 mutant mouse, gp130Y757F (in which the Socs3 site of the gp130 receptor is mutated leading to constitutive activation of Stat3), we have recently demonstrated a key role for Stat3 during inflammation associated colonic cancer (1). However, although gp130Y757F mice are predisposed to gastric adenomas due to hyper Stat3 activation, they do not develop intestinal tumors. Deregulated Wnt signaling is also a key event in intestinal tumorigenesis. Mice which are heterozygous for the negative Wnt regulator Apc (ApcMin/+) develop multiple intestinal neoplasia, and in humans, constitutive heterozygosity for Apc underlies familial adenomatous polyposis (FAP) syndrome. To investigate a possible interaction between Stat3 and Wnt signaling in intestinal cancer we generated compound ApcMin/+ mutant mice to modulate expression and/or activation of Stat3. Compared to ApcMin/+ or gp130Y757F mice, corresponding gp130Y757F ApcMin/+ mice have a significantly reduced lifespan associated with an increase in the number of intestinal tumors. Conversely, when Stat3 is reduced in ApcMin/+Stat3+/− mice the number of polyps in both the small and large intestine is significantly reduced. Tumor initiation, but not tumor growth, is promoted in gp130Y757F ApcMin/+ mice compared to ApcMin/+ littermates. These results suggest that Stat3 is rate limiting for Wnt induced intestinal tumourigenesis. In support of this data we found that the in vitro colony forming potential of human colonic cancer cells (SW480 cells) was reduced when gp130/Stat3 signaling was inhibited. Importantly, inhibition of gp130/Stat3 did not reduce the colony forming potential of SW480 colon cancer cells expressing full-length APC (by stable transfection of APC), suggesting that Stat3 is only rate limiting during cellular conditions of high Wnt signaling. We have recently demonstrated that intestinal regeneration is characterized by high Wnt signaling and requires an intact Wnt signaling pathway (2). Stat3 is also rate limiting for intestinal regeneration in vivo and for intestinal organoid assays in vitro. Together these data provide a novel role for gp130/Stat3 signaling, which becomes rate limiting in situations of high Wnt signaling in the intestinal epithelium including regeneration and tumourigenesis. Mechanistically we find that Stat3 up-regulates Bcl2 (an apoptosis inhibitor protein) expression and allows cells to evade apoptosis, providing a survival advantage. Thus, compound gp130Y757F Bcl2+/− mice have reduced regenerative capacity in vitro and in vivo. (1) Bollrath and Phesse et al. 2009. Cancer Cell (2) Ashton and Phesse et al. 2010. Dev Cell Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4014. doi:1538-7445.AM2012-4014