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Genetic reduction of circulating insulin‐like growth factor‐1 inhibits azoxymethane‐induced colon tumorigenesis in mice
Author(s) -
OlivoMarston Susan E.,
Hursting Stephen D.,
Lavigne Jackie,
Perkins Susan N.,
Maarouf Rami S.,
Yakar Shoshana,
Harris Curtis C.
Publication year - 2009
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20577
Subject(s) - azoxymethane , biology , carcinogenesis , endocrinology , growth factor , insulin , cancer research , colorectal cancer , medicine , microbiology and biotechnology , genetics , cancer , receptor
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. © 2009 Wiley‐Liss, Inc.