Transforming growth factor-beta1 modulates tumor-stromal cell interactions of prostate cancer through insulin-like growth factor-I

Abstract

Insulin-like growth factor-I (IGF-I) secreted from the prostate stroma mediates tumor-stromal cell interactions in prostate cancer development. We have recently reported that human prostate stromal cells (PrSC) stimulate human prostate cancer DU-145 cell growth via IGF-I. Transforming growth factor-beta1 (TGF-beta1) also plays a critical role in tumor-stromal cell interactions, but TGF-beta1 has pleiotropic effects as it can modulate growth of prostate cancer either positively or negatively. To elucidate the complex behavior of TGF-beta1, the effect of TGF-beta1 on the IGF axis in PrSC was studied. TGF-beta1 increased the expression of IGF-I and IGF binding protein-3 (IGFBP-3). RT-PCR experiments revealed that TGF-beta1 upregulated the mRNA expression of IGF-I and IGFBP-3. However, while TGF-beta1 significantly increased IGFBP-3 secretion by PrSC, it conversely reduced the amounts of biologically active IGF-I unbound to IGFBP-3. Immunohistochemical analyses of 49 human prostate cancer tissues showed that IGF-I expression in the stroma correlated positively with TGF-beta1 expression in the stroma (r = 0.551, p = 0.0001). Furthermore, TGF-beta1 actually suppressed the growth of DU-145 cells in coculture with PrSC. But, IGFBP-3 proteinases, such as prostate specific antigen (PSA) and matrix metalloproteinase-7 (MMP-7), restored the DU-145 cell growth, suggesting that degradation of IGFBP-3 potentiates cancer growth. Taken together, these results indicated that TGF-beta1 modulates the growth of prostate cancer, either positively or negatively, through the balance between the amounts of IGF-I and IGFBP-3. This complex behavior of TGF-beta1 on the IGF axis is one explanation for the pleiotropic activities of TGF-beta1 on the growth of prostate cancer.