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.
Highlights
Colorectal cancer (CRC) is a common internal malignancy in affluent countries and is appearing rapidly in developing countries with greater prosperity
Africa and Asia showing lower risk [1]. This suggests that environmental factors are influential in carcinogenesis, a proposition supported by rapid temporal increases in colorectal cancer (CRC) morbidity and mortality in countries such as Japan [3]
There is the paradox of high and rising CRC rates in Australia, despite population-wide intakes of fibre [38]. These discrepancies can be resolved if one considers the food components which contribute to total dietary fibre intakes and which could protect against CRC through altering the colonic environment
Summary
Colorectal cancer (CRC) is a common internal malignancy in affluent countries and is appearing rapidly in developing countries with greater prosperity. Epidemiological data show that there is a major geographical variation in the incidence of CRC, with populations in Africa and Asia showing lower risk [1] This suggests that environmental factors are influential in carcinogenesis, a proposition supported by rapid temporal increases in CRC morbidity and mortality in countries such as Japan [3]. Diets that are low in fibre and unrefined grains, and high in energy (fat) and protein, are associated with increased risk of CRC [5] This dietary pattern is established in developed countries, and becomes apparent in countries traditionally at low risk as they become more affluent. The greater number of cases (by far) is sporadic in origin where both genetic and environmental factors are important [8,9] This implies that at least 80% of CRC are inducible and could be prevented with changes in diet and lifestyle.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
