Colon cancer: Intestinal stem cells and bile acids
Cancer researchers at Flinders are looking to uncover mechanisms that control the risk and progression of colon cancer.
Associate Professor Robyn Meech has been awarded a Flinders Foundation Health Seed Grant to investigate a novel pathway that controls the behaviour of intestinal stem cells, which are essential for the normal regular turnover of the lining of the gut.
Colon cancer - the most common type of cancer in the gut - occurs when intestinal stem cells overgrow and transform, giving rise to polyps and subsequently tumours. Conversely, some degenerative and inflammatory bowel diseases involve disruption to the regenerative capacity of these stem cells, and results in loss of the gut’s ability to renew and repair its lining.
“Bile acids play multiple roles in the gut, and are increasingly recognized as critical signalling molecules that act via a transcription factor called FXR to control the behaviour of intestinal stem cells,” A/Prof Meech explains.
“Excessive amounts of bile acids display toxic effects: they contribute to DNA damage and inflammation, and thus colon cancer risk.
“However, recent studies on their roles as signalling molecules suggests a new model whereby an imbalance in the levels of different bile acids can also disrupt the normal behaviour of stem cells, leading to overgrowth and polyp formation. Maintaining a healthy balance between bile acid forms involves not only host factors, but also bile acid modifying enzymes produced by gut bacteria.”
A/Prof Meech’s team has identified a new factor – an enzyme called UGT8 - that modifies bile acids within intestinal stem cells to produce variant forms that may have unique signalling properties. Importantly, a change in the amount of UGT8 in the gut is linked to inflammatory bowel disease, and to colon cancer outcomes.
“This project will study in depth how the modification of bile acids by UGT8 alters signalling in intestinal cells, which can explain its links to cancer and other gut diseases,” A/Prof Meech explains.
“The findings are also intended to inform the design of new bile acid-based drugs that can target these signalling pathways.”
The team that Dr. Meech has assembled to tackle this problem is cross-disciplinary and includes early career pharmacology researchers, Dr Julie-Ann Hulin and Dr Pramod Nair, and chemist Dr Mike Perkins, as well as international collaborators.
Research category: Cancer
Project title: Developing selective bile acid receptor modulators (SBARMs): has nature done the work for us?
Lead researcher: Associate Professor Robyn Meech