Ronald M. Evans, Ph.D.
Salk Institute

Molecular Mechanisms and the Role of Inflammation in Diet-Induced Intestinal Cancer

Colorectal cancer is the third most common cancer and the second leading cause of cancer-related death in the Western world. Western life-style, which is characterized by high fat diet, lack of exercise and obesity is considered to be a leading contributing factor through both altered metabolism and inflammation in the initiation and progression of intestinal cancer. Under normal dietary conditions, the metabolically dysregulated SMRT mRID1 mouse is asymptomatic. However, these miss develop colon polyps on a high fat diet. This is a unique model for dieted-induced cancer.

Dr. Evans' lab tested a second CRC model; mice with reduced expression of the tumor suppressor LKB1 develop spontaneous intestinal tumors. LKB1 regulates cellular metabolism by controlling glucose and lipid consumption in response to alterations in nutrients and intracellular energy levels. Both of these models will be subjected to high fat diet or inflammatory stress that will allow them to establish molecular gene signatures associated with the initiation and progression of intestinal cancer.

Finally, they will determine the susceptibility of each of these models to drug treatment of either Rapamycin or Pioglitazone. They suggest that Rapamycin can rescue the LKB1 defect by inhibiting mTOR, a protein kinase that promotes cell growth in a variety of human cancers. Pioglitazone is a PPARy activator that modulates the gene network that controls glucose and lipid metabolism and the inflammatory response associated with innate immunity. It is envisioned that this project will provide insights into two new approaches to treat colorectal cancer.