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

Abstract

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...

Spontaneous initiation, promotion and progression of colorectal cancer in the novel A/J Min/+ mouse

“…The novel A/J Min/1 mouse model more closely resembles the PIRC (Polyposis In the Rat Colon) rat model for colorectal cancer, in that this rat also develops a greater number of lesions in the colon. 44 Femia et al 46 found that the number of mucin-depleted foci, which are comparable to the flat ACF, and macroscopic tumors in the PIRC rat colon increased with age. This is similar to what was observed for the A/J Min/1 mouse.…”

New insights from animal models of colon cancer: inflammation control as a new facet on the tumor suppressor APC gem

“…151 Apc-mutant (PIRC) rats also show mucin-depleted foci that increase in number as the rats age. 152 Notably, the NSAID sulindac, reduces the number of polyps as well as mucin-depleted foci in PIRC rats. 152 Collectively, these data suggest that Apc mutations predispose to the precancerous mucin-depleted foci.…”

Exploring the role and diversity of mucins in health and disease with special insight into non-communicable diseases

“…Several animal models of mucin depleted foci or mucin therapy have demonstrated the role of mucin in onset and progression of carcinogenesis indicating importance of mucin in cancers [55,56].…”