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 b-catenin accumulation) and were dramatically decreased by sulindac (320 ppm), a drug with chemopreventive activity (MDF/rat at 4 months: 156 6 8 and 38 6 6 in controls and sulindac-treated rats, respectively, means 6 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.Mutations in the Apc gene, responsible for the inherited predisposition to intestinal carcinogenesis in familial adenomatous polyposis (FAP) and present in the majority of sporadic colorectal cancers (CRC), are considered early, necessary events in the development of the disease. 1 Rodent models carrying mutations in Apc have been thus developed and widely used. 2,3 However, at variance with human pathology, the majority of these strains, including Apc Min (Min) mice, develops tumors predominantly in the small intestine and not in the colon. [2][3][4] This characteristic is a considerable drawback given the inherent diversity of these two parts of the intestine in terms of anatomy, lumen environment, physiology and propensity to tumor development. [2][3][4] Few years ago, the PIRC rat (Polyposis In the Rat Colon) with a germline mutation in one allele of the Apc gene (F344/NTac-Apc am1137 ) has been described. 5 Notably, at variance with pre-existing Apcbased mouse models, PIRC rats spontaneously develop tumors in the small intestine but also in the colon, thus mimicking more closely FAP and CRC and potentially standing for as a robust model of colon cancer. 5 Here we were interested in the early phases of PIRC rat colon carcinogenesis studying (i) the presence and the biology of early-appearing precancerous lesions in the colon and (ii) the morphologically normal mucosa (NM). Small ad...

BackgroundRecently, we showed that Sulindac (SU; 320 ppm) reduces precancerous lesions in the colon of Pirc rats, mutated in the Apc gene. Surprisingly, previous data in Apc-mutated mice showed that SU, with reported efficacy in Familial Adenomatous Polyposis (FAP), increases colon carcinogenesis. Therefore, we assessed the effect of SU 320 ppm in a long-term carcinogenesis experiment in Pirc rats. Moreover, since side effects of SU hamper its chronic use and a combination of drugs could be more effective and less toxic than single agents, we also studied whether two natural compounds, 3,3’-diindolylmethane (DIM; 250 ppm) and curcumin (CUR; 2000 ppm), with or without lower doses of SU could affect carcinogenesisMethodsPirc rats were fed an AIN76 diet containing SU, DIM and CUR and sacrificed at 8 months of age to measure intestinal tumours. Apoptosis and proliferation in the normal colon mucosa, as well as gene expression profile were studiedResultsColon tumours were significantly reduced by SU 320 ppm (62 % reduction over Controls), by DIM and CUR without or with SU 80 and 160 ppm (50, 53 and 58 % reduction, respectively) but not by SU 80 ppm alone. Total tumours (colon and small intestine) were reduced by SU (80 and 320 ppm) and by DIM and CUR. Apoptosis in the normal mucosa was significantly increased by SU 320 ppm, and slightly increased by DIM and CUR with or without SU. A slight reduction in Survivin-Birc5 expression was observed with all the treatments compared to Controls. Proliferative activity was not variedConclusionsThe results on SU reinforce the validity of Pirc rats to identify chemopreventive products. Moreover, the efficacy of the DIM and CUR combination to lower colon tumours, suggests an alternative strategy to be exploited in patients at risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1627-9) contains supplementary material, which is available to authorized users.

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