Colorectal carcinogenesis: a cellular response to sustained risk environment

Area of Science:

• Gastroenterology
• Oncology
• Cell Biology

Background:

• Current colorectal cancer (CRC) models are linear and overlook environmental factors.
• A high-risk colonic luminal environment, characterized by low short-chain fatty acids (SCFA) and high ammonia, is proposed.
• This environment leads to reduced mucosal oxygen and increased cytotoxic agent exposure.

Purpose of the Study:

• To propose a new hypothesis for colorectal cancer (CRC) development.
• To explain CRC as a cellular survival response to a cytotoxic colonic environment.
• To link dietary factors to the colonic environment and CRC risk.

Main Methods:

• Review of in vivo and in vitro genomic and biochemical studies.
• Analysis of existing data on high-protein diets and their effect on the colonic environment.
• Framing experiments to test the proposed hypothesis.

Main Results:

• Prolonged exposure to cytotoxic agents in a low-SCFA, high-ammonia environment can induce colonocyte transformation.
• Epigenetic reprogramming allows colonocytes to migrate and proliferate, characteristic of CRC cells.
• High-protein, low-carbohydrate diets alter the colonic environment, increasing ammonia exposure and potentially CRC risk.
• Increasing SCFA supply via fermentable fiber can reverse diet-induced genetic damage.

Conclusions:

• Colorectal cancer (CRC) may be a cellular adaptation to a hostile colonic environment.
• Dietary interventions, particularly increasing SCFA through fermentable fiber, show promise in mitigating CRC risk.
• Further research is needed to validate this hypothesis and explore therapeutic strategies.