Colorectal carcinogenesis: a cellular response to sustained risk environment

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 propo...

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Bibliographic Details
Published in:	International Journal of Molecular Sciences Vol. 14; no. 7; pp. 13525 - 13541
Main Authors:	Fung, Kim Y C, Ooi, Cheng Cheng, Zucker, Michelle H, Lockett, Trevor, Williams, Desmond B, Cosgrove, Leah J, Topping, David L
Format:	Journal Article Book Review
Language:	English
Published:	Switzerland MDPI AG 27-06-2013 Molecular Diversity Preservation International (MDPI)
Subjects:	ammonia Ammonia - metabolism Cell Transformation, Neoplastic - metabolism Cellular Microenvironment colorectal cancer Colorectal Neoplasms - etiology Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Dietary Carbohydrates - adverse effects Dietary Carbohydrates - metabolism dietary protein Dietary Proteins - adverse effects Dietary Proteins - metabolism Humans Hydrogen-Ion Concentration Intestinal Mucosa - metabolism Intestinal Mucosa - pathology Oxygen - metabolism resistant starch Review Risk Factors short chain fatty acid
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Summary:	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.
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms140713525