Apc‐driven colon carcinogenesis in pirc rat is strongly reduced by polyethylene glycol

Abstract

Polyethylene glycol (PEG) is one of the most powerful agents in reducing chemically induced carcinogenesis in rat colon. However, contrasting results in Min mice dampened the enthusiasm on this potentially strong and virtually safe, cancer chemopreventing agent. Pirc (F344/NTac-Apc am1137 ) rats carrying a germline heterozygous mutation in the Apc gene, spontaneously develop multiple tumours in the colon thus modelling both familial adenomatous polyposis (FAP) and sporadic colorectal cancer (CRC). Given this similarity, we thought that these rats could be appropriate to test the efficacy of PEG 8000 in reducing carcinogenesis. Pirc male rats aged one month were treated with 5% PEG in drinking water for 2 or 6 months. Precancerous lesions were dramatically reduced after 2 months of PEG treatment (Mucin depleted foci (MDF)/colon were 99 617 and 126 8 in Controls and PEG-treated rats, respectively; p < 0.001; mean 6 SD). Similarly, colon tumors were significantly reduced after 6 months of treatment (tumors/rat were 8.1 6 2.3 and 3.6 6 2.2 in Controls and PEG-treated rats, respectively; p < 0.05; mean 6 SD). Colon proliferation, a parameter correlated to cancer risk, was also significantly lower in PEG-treated rats than in Controls, while apoptosis was not significantly affected. In conclusion, PEG markedly reduces colon carcinogenesis in Pirc rats mutated in Apc; we thus suggest that PEG may be used as chemopreventive agent to reduce cancer risk in FAP and CRC patients.

Prevention of colonic neoplasia with polyethylene glycol: A short term randomized placebo-controlled double-blinded trial

“…Several groups, including our own, have replicated this work in rat the carcinogen-models [ 11 , 12 ]. Furthermore, we recapitulated these findings in genetic rodent models (MIN mouse [ 13 ] and Pirc rat [ 14 , 15 ]), which has germline truncations in the adenomatous polyposis coli (APC) tumor suppressor gene, the most common initiating driver mutation in human colorectal carcinogenesis. From a mechanistic perspective, our laboratory has demonstrated that PEG 8000 downregulated epidermal growth factor receptor (EGFR) with concomitant downregulation of SNAIL, induction of E-cadherin leading to β-catenin sequestration away from the nucleus and hence suppressing TCF/LEF-1 transcriptional activity [ 14 ].…”

“…While the preclinical data provides compelling evidence of the of CRC preventive effects of PEG (~20 publications by at least 4 independent groups [ 8 , 10 , 14 , 15 ]) the only clinical data available is from a case-control study that had a number of methodological shortcomings [ 17 ]. Since epidemiological studies are often confounded by the indications for use of PEG (i.e.…”

High Sensitivity to Cholic Acid-induced Colonic Tumorigenesis Makes Female PIRC Rats (F344/NTac-Apcam1137) a Suitable Model for Studying CRC-promoting Agents

“…This model shows a strong gender effect, with male rats developing many more tumors than do females (4). Accordingly, studies aimed at the identification of dietary components or drugs with chemopreventive activity against colonic carcinogenesis, mostly used males, which provides a stronger statistical power when assessing a reducing effect on tumorigenesis (5,6). On the other hand, female rats developing fewer intestinal tumors might be exploited for the identification of substances increasing carcinogenesis such as carcinogens present in the diet (or in toxicological studies), a possibility, to our knowledge, not tested to date.…”