The insulin-like growth factor axis and prostate cancer: Lessons from the transgenic adenocarcinoma of mouse prostate (TRAMP) model

We have characterized the temporal expression of the insulin-like growth fa ctor (IGF) axis in the transgenic adenocarcinoma of mouse prostate (TRAMP) model as prostate cancer progression in this model closely mimics that obse rved in the human disease, and the model provides samples representing the earliest stages of prostate cancer that are clinically the most difficult t o obtain. We report that prostate-specific IGF-I mRNA expression increased during prostate cancer progression in TRAMP mice and was elevated in the ac companying metastatic lesions, whereas prostatic IGF I mRNA remained at non transgenic levels in androgen-independent disease. Expression of IGF-II mRN A, however, was reduced in primary prostate cancer, metastatic lesions, and androgen-independent disease. Expression of type-1 IGF receptor (IGF1R) mR NA, encoding the cognate receptor for both IGF-I and IGF-II, as well as typ e-2 IGF receptor (IGF2R) mRNA was not found to be altered during primary pr ostate cancer progression in intact TRAMP mice but was dramatically reduced in metastatic lesions and in androgen-independent disease. Similar to repo rts from clinical disease, serum IGF-I levels were observed to increase pre cociously in TRAMP mice early in disease progression but remained at nontra nsgenic levels after castration. Elevated serum levels of IGF-binding prote in 2 were observed to correlate with advanced prostate cancer in the TRAMP model. Together these observations implicate IGF-I as an important factor d uring the initiation and progression of primary prostate cancer and provide evidence that there is a strong selection against expression of IGF1R and IGF2R in metastatic and androgen-independent disease.