Defining the Critical role for the Insulin-Like Growth Factor-1 (IGF-1) axis in prostate cancer using genetically engineered mouse (GEM) models

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The purpose of these studies has been to use genetically engineered mouse (GEM) models to elucidate the molecular mechanisms whereby the IGF signaling axis contributes to the initiation and progression of prostate cancer. The rationale is based on strong epidemiological studies demonstrating that elevated serum IGF-I is associated with cancer risk and, in particular, prostate cancer risk. Indeed, in preliminary studies we demonstrated that the transformed prostate gland could produce IGF-1 and that expression of the IGF-1 receptor (IGF-1R) was reduced in metastatic lesions of intact and castrated TRAMP mice, supporting different roles for IGF-1 signaling in organ confined and disseminated disease. To further investigate the association between localized IGF-1R activity and prostate disease we generated a prostate-specific conditional IGF-1R knockout model using the Cre/LoxP strategy. Mice that express Cre recombinase in terminally differentiated prostate epithelial cells were crossed with mice carrying a LoxP modified IGF-1R allele and /or TRAMP. Using these mice we now demonstrate that (a) IGF-1R is required to maintain terminal differentiation of the prostate epithelium; (b) IGF-1R loss allows epithelial cells to proliferate; (c) proliferation following IGF-1R loss induces a cellular senescence rescue program likely regulated by p53 and (d) IGF-1R depletion or loss subsequent to malignant transformation does not inhibit but might in fact promote progression to more aggressive prostate cancer disease states. Therefore we now believe that IGF-1 action facilitates the genesis of prostate cancer by suppressing cellular senescence and apoptosis thereby allowing the epithelial cells to survive spontaneous transformation while still enforcing a strong differentiation block.