Multiple mucin depleted foci, high proliferation and low apoptotic response in the onset of colon carcinogenesis of the PIRC rat, mutated in Apc

PIRC rats (F344/NTac-Apc (am1137)) mutated in the Apc gene spontaneously develop colon tumors thus mimicking familial adenomatous polyposis (FAP) and sporadic colorectal cancer (CRC) more closely than Apc-based rodent models developing tumors mostly in the small intestine. To understand whether microscopic dysplastic lesions precede the development of macroscopic tumors, PIRC rat colon was examined for the presence of mucin depleted foci (MDF), microadenomas of the rodent and human colon. Few MDF (about 4/animal) were already present in 1-month-old rats and their number rapidly increases to about 250 in 8-month-old rats. These lesions showed Wnt signaling activation (nuclear -catenin accumulation) and were dramatically decreased by sulindac (320 ppm), a drug with chemopreventive activity (MDF/rat at 4 months: 1568 and 386 in controls and sulindac-treated rats, respectively, means +/- SE, p<0.001). Since altered proliferation and apoptosis could underlie the early phases of carcinogenesis, we studied these processes in the apparently normal colon mucosa (NM) of 1-month-old PIRC and wt rats. Colon proliferation (PCNA expression) was significantly higher in PIRC rats. Notably, PIRC rat NM showed resistance to apoptosis since it sustained proliferation and had lower apoptosis after a cytotoxic insult with 1,2 dimethylhydrazine. Gene expression of Myc, p21, Birc5, Ogg1, Apex1 and Sod2 were significantly up-regulated in the NM of PIRC rat. The overall results put forward PIRC rat as useful model of colon carcinogenesis, either to study the process itself or to test in vivo chemopreventive agents in both short- and long-term studies. What's new? The majority of human colorectal cancers (CRCs) are associated with mutations in APC, which encodes the tumor suppressing APC protein. However, most rodent CRC models that have been engineered with Apc mutations typically develop tumors in the small intestine rather than the colon. An exception is the PIRC (Polyposis In the Rat Colon) model. In this study, PIRC rat colon was found to contain multiple precancerous mucin depleted foci (MDF) with Wnt signaling activation and to display defective proliferation and apoptosis. Treatment with sulindac resulted in MDF reduction. The findings reinforce the utility of the PIRC model.