Abstract 1340: A mouse model of metastatic intestinal cancers associated with Fbw7- and p53-loss

Abstract

Abstract Colon cancer is a leading cause of cancer deaths in the USA, where it accounts for up to 50,000 deaths per year. Mouse models that recapitulate the genetic changes seen in human colon cancers are useful tools for biological and preclinical applications, but most available models develop adenomatous lesions that rarely metastasize. The Fbw7 tumor suppressor is a core component of a ubiquitin ligase complex that negatively regulates a number of proteins associated with genomic instability and cancer, including cyclin E, c-myc, Mcl-1, and Notch. Our previous work shows that Fbw7 cooperates with the p53 tumor suppressor to control genetic instability in vitro, and both Fbw7 and p53 are frequently deregulated in human colon cancers. We hypothesized that coordinate deletion of these two tumor suppressors would promote intestinal cancers in mice. To accomplish intestine specific deletion of these pathways, we interbred genetically engineered mice encoding conditional Fbw7 and p53 alleles with the VillinCre strain. Examination of normal intestines from the resulting Fbw7(fl/fl); p53(fl/fl); villinCre (FPV) animals showed abnormal proliferation and differentiation along the crypt-villus axis compared to control animals. Strikingly, the majority (55%) of FPV mice developed adenocarcinomas in the small intestine and cecum (median survival 70 weeks of age), and these tumors frequently metastasized to the lymph nodes and liver (in 36% and 14% of tumor bearing animals, respectively). Analysis of cancer tissues showed clear evidence of genetic instability in the majority of tumors. Finally, FPV tumors were readily grown as cell lines in vitro which could, in turn, grow as allografts in both immunodeficient and immunocompetent recipients. Notably, comparison of primary tumors and allografted cell lines showed similar pathological features and patterns of metastasis. This work confirms the critical role of the Fbw7 and p53 pathways in suppressing genetic instability and cancer development. Furthermore, the described FPV models recapitulate critical features of human colon cancer and should prove useful for studies of cancer biology, prevention, and therapy. 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 1340. doi:1538-7445.AM2012-1340