ANTISENSE RNA TO THE TYPE-I INSULIN-LIKE GROWTH-FACTOR RECEPTOR SUPPRESSES TUMOR-GROWTH AND PREVENTS INVASION BY RAT PROSTATE-CANCER CELLS IN-VIVO

Prostate carcinoma is the second leading cause of death from malignanc y in men in the United States. Prostate cancer cells express type I in sulin-like growth factor receptor (IGF-TR) and prostate cancer selecti vely metastazises to bone, which is an environment rich in insulin-lik e growth factors (IGFs), thereby supporting a paracrine action for can cer cell proliferation, We asked whether the IGF-IR is coupled to tumo rigenicity and invasion of prostate cancer. When rat prostate adenocar cinoma cells (PA-III) were stably transfected with an antisense IGF-IR expression construct containing the ZnSO4-inducible metallothionein-l transcriptional promoter, the transfectants expressed high levels of IGF-IR antisense RNA after induction with ZnSO4, which resulted in dra matically reduced levels of endogenous IGF-IR mRNA. A significant redu ction in expression both of tissue-type plasminogen activator and of u rokinase-type plasminogen activator occurred in PA-III cells accompany ing inhibition of IGF-IR, Subcutaneous injection of either nontransfec ted PA-III or PA-III cells transfected with vector minus the IGF-IR in sert into nude mice resulted in large tumors after 4 weeks, However, m ice injected with IGF-IR antisense-transfected PA-III cells either dev eloped tumors 90% smaller than controls or remained tumor free after 6 0 days of observation, When control-transfected PA-III cells were inoc ulated over the abraded calvaria of nude mice, large tumors formed wit h invasion of tumor cells into the brain parenchyma. In contrast, IGF- IR antisense transfectants formed significantly smaller tumors with no infiltration into brain. These results indicate an important role for the IGF/IGF-IR pathway in metastasis and provide a basis for targetin g IGF-IR as a potential treatment for prostate cancer.