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Review
. 2013 Jun 27;14(7):13525-41.
doi: 10.3390/ijms140713525.

Colorectal carcinogenesis: a cellular response to sustained risk environment

Kim Y C Fung  1 , Cheng Cheng Ooi, Michelle H Zucker, Trevor Lockett, Desmond B Williams, Leah J Cosgrove, David L Topping
Affiliations
Review

Colorectal carcinogenesis: a cellular response to sustained risk environment

Kim Y C Fung et al. Int J Mol Sci. .

Abstract

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.

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Figures

Figure 1
Figure 1
Low risk versus high risk colonic environment. A low risk colonic environment is characterised by well perfused mucosa and relatively high luminal concentration of SCFA, low levels of ammonia, and has low pH. In this low risk environment, mucosal cells utilise butyrate as the primary energy source and have low requirement for glucose. Conversely, a high risk environment is higher in pH and ammonia and low in SCFA. Mucosal cells adapt to these conditions, and acquire epigenetic and genetic changes to survive, predisposing to tumorigenesis.
Figure 2
Figure 2
Cellular environment of low risk versus high risk of CRC.
See this image and copyright information in PMC

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