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Int. J. Mol. Sci. 2013, 14(7), 13525-13541; doi:10.3390/ijms140713525

Colorectal Carcinogenesis: A Cellular Response to Sustained Risk Environment

1,* , 1,2
1 CSIRO Preventative Health National Research Flagship, P.O. Box 10041, Adelaide, SA 5001, Australia 2 Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, GPO Box 2471, Adelaide, SA 5001, Australia 3 CSIRO Food Futures National Research Flagship, P.O. Box 10041, Adelaide, SA 5001, Australia
* Author to whom correspondence should be addressed.
Received: 13 May 2013 / Revised: 7 June 2013 / Accepted: 14 June 2013 / Published: 27 June 2013
(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)
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The current models for colorectal cancer (CRC) are essentially linear in nature with a sequential progression from adenoma through to carcinoma. However, these views of CRC development do not explain the full body of published knowledge and tend to discount environmental influences. This paper proposes that CRC is a cellular response to prolonged exposure to cytotoxic agents (e.g., free ammonia) as key events within a sustained high-risk colonic luminal environment. This environment is low in substrate for the colonocytes (short chain fatty acids, SCFA) and consequently of higher pH with higher levels of free ammonia and decreased mucosal oxygen supply as a result of lower visceral blood flow. All of these lead to greater and prolonged exposure of the colonic epithelium to a cytotoxic agent with diminished aerobic energy availability. Normal colonocytes faced with this unfavourable environment can transform into CRC cells for survival through epigenetic reprogramming to express genes which increase mobility to allow migration and proliferation. Recent data with high protein diets confirm that genetic damage can be increased, consistent with greater CRC risk. However, this damage can be reversed by increasing SCFA supply by feeding fermentable fibre as resistant starch or arabinoxylan. High protein, low carbohydrate diets have been shown to alter the colonic environment with lower butyrate levels and apparently greater mucosal exposure to ammonia, consistent with our hypothesis. Evidence is drawn from in vivo and in vitro genomic and biochemical studies to frame experiments to test this proposition.
Keywords: ammonia; colorectal cancer; dietary protein; resistant starch; short chain fatty acid ammonia; colorectal cancer; dietary protein; resistant starch; short chain fatty acid
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Fung, K.Y.C.; Ooi, C.C.; Zucker, M.H.; Lockett, T.; Williams, D.B.; Cosgrove, L.J.; Topping, D.L. Colorectal Carcinogenesis: A Cellular Response to Sustained Risk Environment. Int. J. Mol. Sci. 2013, 14, 13525-13541.

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