Aberrations in Wnt signaling are considered to be the gatekeeper events that drive the development of colorectal cancer. Alterations in this pathway lead to the nuclear translocation of beta catenin and formation of beta catenin/TCF-4 transcription complexes. These complexes activate genes that disrupt intestinal epithelial cell homeostasis and colon crypt maturation. Thus, agents that inhibit the Wnt cascade may also halt or reverse tumorigenesis. Animal models that parallel human cancer are essential for the preclinical evaluation of potential chemopreventive and chemotherapeutic agents. A unique strain of multiple intestinal neoplasia mice (Apc+/Min-FCCC) has been established by this group that exhibits a higher multiplicity of colorectal adenomas than the commercial Apc+/Min-JAX strain (Mol Carcinogenesis 44:31-41, 2005). Histopathological features of colorectal adenomas from Apc+/Min-FCCC mice are similar to human adenomas, making this model well suited for preclinical studies. To further characterize this model, the gene expression profile of adenoma tissue from Apc+/Min-FCCC mice was evaluated. Adenomas were excised from the distal colon of five male Apc+/Min-FCCC mice at the time of sacrifice. Nonneoplastic tissue was also obtained from the distal colon of two Apc+/Min-FCCC mice matched for age and gender. Laser capture microdissection was used to obtain pure populations of colonic epithelial cells from frozen tissue sections for analysis. The expression profile of 14 Wnt pathway genes was measured by quantitative real-time PCR using the TaqMan® Preamplification System and TaqMan® Gene Expression Assays. The normalized expression level of each gene in nonneoplastic and neoplastic cells from Apc+/Min-FCCC mice was compared using the ΔΔCT method. A 2-3-fold increase in expression was found for beta catenin and cyclin D1 in neoplastic cells. In addition, Ptgs-2 and Mmp7 were upregulated more than 10-fold. Similar findings for the TCF-4 target genes, cyclin D1, Ptgs-2 and Mmp7, have been reported for human colorectal adenomas. These results further validate the Apc+/Min-FCCC strain as an ideal model for studying colorectal tumorigenesis and evaluating potential chemopreventive and chemotherapeutic agents.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA