Genetic reduction of circulating insulin-like growth factor-1 inhibits azoxymethane-induced colon tumorigenesis in mice.
High levels of insulin-like growth factor-1 (IGF-1) have been associated with a significant increase in colon cancer risk. Additionally, IGF-1 inhibits apoptosis and stimulates proliferation of colonic epithelial cells in vitro. Unfortunately, IGF-1 knockout mice have severe developmental abnormalities and most do not 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 preexisting 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 display a 50-75% reduction in circulating IGF-1 levels. We conducted a pilot study to assess the impact of liver-specific IGF-1 deficiency on azoxymethane (AOM)-induced colon tumors. LID mice had a significant inhibition of colon tumor multiplicity in the proximal area of the colon compared to their wild-type littermates. We examined markers of proliferation and apoptosis in the colons of the LID and wild-type mice to see if these were consistent with tumorigenesis. We observed a decrease in proliferation in the colons of the LID mice and an increase in apoptosis. Finally, we examined cytokine levels to determine whether IGF-1 interacts with inflammatory pathways to affect colon tumorigenesis. We observed a significant reduction in the levels of 7 out of 10 cytokines that were measured in the LID mice as compared to wild-type littermates. Results from this pilot study support the hypothesis that reductions in circulating IGF-1 levels may prevent colon tumorigenesis and affect both proliferation and apoptosis. Future experiments will investigate downstream genes of the IGF-1 receptor.
Olivo-Marston
Susan E
SE
Laboratory of Human Carcinogenesis, National Cancer Institute, Center for Cancer Research, NIH, Bethesda, Maryland 20892-4258, USA.
Hursting
Stephen D
SD
Lavigne
Jackie
J
Perkins
Susan N
SN
Maarouf
Rami S
RS
Yakar
Shoshana
S
Harris
Curtis C
CC
D000818:Animals; D017209:Apoptosis; D001397:Azoxymethane / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D007124:Immunoenzyme Techniques; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D019426:Integrases / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic
D002273:Carcinogens; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; C045073:Cre recombinase; D019426:Integrases; D001397:Azoxymethane