Stem Cell Biology Promotes Intestinal Length and Neoplasia in the ApcMin R se Model for Colorectal Cancer

nloaded mutations cause activation of Wnt/β-catenin signaling, which invariably leads to colorectal cancer. rly, overexpressed Dvl proteins are potent activators of β-catenin signaling. Screening a large tissue array of different staged colorectal tumors by immunohistochemistry, we found that Dvl2 has a strong cy to be overexpressed in colorectal adenomas and carcinomas, in parallel to nuclear β-catenin and (a universal transcriptional target of Wnt/β-catenin signaling). Furthermore, deletion of Dvl2 reduced estinal tumor numbers in a dose-dependent way in the Apc model for colorectal cancer. Interestingly, all intestines of Dvl2 mutants are shortened, reflecting in part a reduction of their crypt diameter and ze. Consistent with this, mammalian target of rapamycin (mTOR) signaling is highly active in normal nal crypts in which Wnt/β-catenin signaling is active, and activated mTOR signaling (as revealed by g for phosphorylated 4E-BP1) serves as a diagnostic marker of Apc mutant adenomas. Inhibition OR signaling in Apc mutant mice by RAD001 (everolimus) reduces their intestinal tumor load, simto Dvl2 deletion. mTOR signaling is also consistently active in human hyperplastic polyps and has a cant tendency for being active in adenomas and carcinomas. Our results implicate Dvl2 and mTOR signifi in the progression of colorectal neoplasia and highlight their potential as therapeutic targets in colorectal cancer. Cancer Res; 70(16); 6629–38. ©2010 AACR.