Abstract 2738: PIK3CA and APC mutations are synergistic in the development of intestinal cancers

Background: Human colorectal cancers are known to possess multiple mutations, though how these mutations interact in tumor development and progression has not been thoroughly investigated. We have previously described the FC PIK3ca* murine colon cancer model which expresses a constitutively activated phosphoinositide-3 kinase (PI3K) in the intestinal epithelium. The expression of this dominantly active form of PI3K results in hyperplasia and invasive mucinous adenocarcinomas in the proximal colon. These cancers form via a non-canonical mechanism without aberrations in Wnt signaling. Since the Adenomatous Polyposis Coli (APC) gene is mutated in the vast majority of human colon cancers and often occurs concurrently with PIK3CA mutations, we sought to better understand the interaction between APC and PIK3CA mutations in the mammalian intestine using novel murine models. Methods: B6 females carrying a transgene encoding for a chimeric protein with the iSH2 domain of the p85 subunit of PI3K fused to the N-terminus of p110 (PIK3ca*) were crossed to B6 males carrying the Min allele of Apc (ApcMin/+). The resulting B6 PIK3ca* ApcMin/+ mice were then crossed to mice carrying a transgene in which the fatty acid binding protein promoter is fused to Cre recombinase (FC). (FVB x B6)F1 FC PIK3ca* ApcMin/+ progeny express this constitutively active form of PI3K in epithelial cells of the distal small bowel and colon, as well as having lost one allele of Apc. An additional novel model system was developed to induce mutations in the cells of the mid to distal colon using a minimally invasive technique to instil adenovirus expressing the Cre recombinase. These tumors could then be monitored over time with colonoscopy with biopsies taken for histological and molecular analyses. Results: FC PIK3ca* ApcMin/+ mice develop multiple small intestinal and colon tumors, including invasive adenocarcinomas with lymphatic and mesenteric metastases. Tumor multiplicity and size were increased. Moreover, the tumors appeared less differentiated and were more invasive as compared to those in controls. Advanced adenomas and adenocarcinomas were easily detectible with a novel near-infrared phospholipid ether analog, CLR1502, that selectively accumulates in tumors. In the proximal colon, mucinous adenocarcinomas that were initiated by the dominant active PI3K rarely exhibited nuclear β-catenin and when observed, this localization was limited to select areas. This indicates that in these tumors