OBESITY, HYPERINSULINEMIA, THE INSULIN AND INSULIN-LIKE GROWTH FACTOR 1 RECEPTORS, AND RISK OF COLORECTAL CANCER

Insulin resistance and hyperinsulinemia associated with obesity or type 2 diabetes are strongly associated with increased risk of colorectal cancer (CRC). Elevated plasma insulin can increase the levels of "free" insulin-like growth factor 1 (IGF1) in the circulation. Both insulin and IGF1 can bind and activate the insulin receptor (IR) or the related IGF1 receptor (IGF1R). IGF1R is traditionally viewed as a major mediator of growth and anti-apoptosis and has been linked to cancer. IR is expressed as two isoforms, IR-A and IR-B. IR-A promotes growth of fetal and possibly cancer cells, while IR-B mediates the metabolic actions of insulin and promotes differentiation in some tissues. However, the specific roles of IGF1R, IR-A, and IR-B in colon physiology and tumorigenesis are unclear. This dissertation combined translational and pre-clinical approaches to explore the roles of IGF1R and IR in colorectal adenoma risk, tumorigenesis, and reduced apoptosis of genetically damaged colonocytes during obesity and hyperinsulinemia. Our studies showed that increased IR-A:IR-B ratio due to decreased IR-B mRNA predicted colorectal adenomas in patients with elevated plasma insulin. In a mouse model of inflammation-induced CRC, genetic deletion of IR in colon epithelial cells (CECs) enhanced tumor number in vivo and tumor cell growth in vitro and this was associated with enhanced IGF1-induced AKT activation. Obesity/hyperinsulinemia resulted in reduced apoptosis of CECs in normal colon after radiation-induced DNA damage. Surprisingly, loss of IGF1R in CECs had no effects on apoptosis, but loss of IR dramatically increased apoptosis of genetically-damaged CECs. However, IR loss did not prevent the anti-apoptotic effects of obesity/hyperinsulinemia. Overall, this dissertation provides novel evidence that maintained IR expression and function may protect against early stage colon tumorigenesis. Since IR-B expression is reduced in colon tumors in mice and normal mucosa of hyperinsulinemic patients with adenomas, we propose that in the colon, IR-B normally attenuates the proliferative, anti-apoptotic, or tumorigenic actions of IGF1R or IR-A. Our studies suggest that therapeutic strategies to increase or maintain IR-B expression may improve prevention of CRC, particularly when IR-B function is impaired as occurs during insulin resistance associated with obesity or type 2 diabetes.Doctor of Philosoph