High levels of insulin-like growth factor-1 (IGF-1) have been associated with a significant increase in colon cancer risk. Additionally IGF-1, which activates the phosphtidylinositiol-3-kinase/Akt pathway through the IGF-1 receptor, inhibits apoptosis and stimulates proliferation of colonic epithelial cells in vitro. Unfortunately, IGF-1 knockout mice have severe developmental abnormalities and most don't survive, making it difficult to study how genetic ablation of IGF-1 affects colon tumorigenesis. To test the hypothesis that inhibition of IGF-1 prevents colon tumorigenesis, we utilized a pre-existing mouse model containing a deletion of the igf1 gene in the liver through a Cre/loxP system. These liver-specific IGF-1 deficient (LID) mice develop normally but display a 75% reduction in circulating IGF-1 levels. To our knowledge, the LID mouse has never been used as part of a chemically-induced colon tumorigenesis model so we conducted a pilot study to assess the impact of liver-specific IGF-1 deficiency on azoxymethane (AOM)-induced colon tumors. LID mice (n=30) had a significant inhibition of colon tumorigenesis compared to their wildtype littermates (n=11, p<0.0001). The wildtype mice had an average of 13.0 + 3.2 colon tumors, while the LID mice had an average of 7.2 + 3.4 colon tumors. Additionally, the colon tumors in the LID mice were less likely to be present in the proximal colon, compared to the wildtype mice (p<0.0001). In the LID mice, 25% of the tumors were in the proximal colon, versus 60% in the wildtype mice. IGF-1 signaling activates several growth-related pathways, resulting in an increase in proliferation and a decrease in apoptosis. Therefore, we examined markers of proliferation and apoptosis in the colons of the LID and wildtype mice to see if these correlated with tumorigenesis. We observed a decrease in proliferation in the colons of the LID mice as measured by proliferating cell nuclear antigen (PCNA) immunohistochemistry. LID mice had a proliferative index of 25.6% + 5.7% while the wildtype mice had a proliferative index of 34.3% + 7.8 (p=0.0003). Additionally, inhibition of IGF-1 resulted in a significant increase in apoptosis (as measured by TUNEL assay) in the crypts of the colons of the LID mice (p<0.0001). Results from this pilot study support the hypothesis that reductions in circulating IGF-1 levels may prevent colon tumorigenesis. Additionally, inhibition of IGF-1 affects both proliferation and apoptosis in the colon. Future experiments will investigate downstream genes of the IGF-1 receptor to further determine the changes associated with inhibition of colon cancer due to IGF-1.
[Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006]