Transforming growth factor-β1 modulates tumor-stromal cell interactions of prostate cancer through insulin-like growth factor-I

B186

Insulin-like growth factor-I (IGF-I) secreted from prostate stroma mediates tumor-stromal cell interactions to develop prostate cancer. Transforming growth factor-β1 (TGF-β1) also plays a critical role in tumor-stromal cell interactions, but it has pleiotropic effects and modulates growth of prostate cancer either positively or negatively. To understand such complexity of its actions, we have studied the effect of TGF-β1 on IGF axis in human prostate stromal cells (PrSC). TGF-β1 induced myofibroblasts differentiation of PrSC and upregulated mRNA expression of both IGF-I and IGFBP-3. TGF-β1 significantly increased IGFBP-3 secretion from PrSC, but it conversely reduced amounts of biologically active IGF-I unbound to IGFBP-3. PSA and MMP-7 acted as IGFBP-3 proteinases, degraded IGFBP-3, and restored the IGF-I action. TGF-β1 actually suppressed the growth of human prostate cancer DU-145 cells capable to respond to IGF-I in the coculture with PrSC, but PSA and MMP-7 restored the suppressed growth of DU-145 cells. Furthermore, immunohistochemical analyses of 29 human prostate cancer tissues showed that IGF-I expression in stroma significantly correlated positively with TGF-β1 expression in stroma (r=0.797, P<0.0001). Taken together, these results indicate that TGF-β1 modulates the tumor growth either positively or negatively through the balance between the amounts of IGF-I and IGFBP-3. Furthermore, degradation of IGFBP-3 potentially results in the tumor promotion and will be a therapeutic target.