Transforming growth factor-beta1 and prostate cancer.

Abstract

Transforming growth factor-beta1 (TGF-beta1) is an important regulator of the normal and malignant prostate. In the non-malignant prostate, TGF-beta1 stimulates cell differentiation, inhibits epithelial cell proliferation and induces epithelial cell death. TGF-beta1 is secreted into semen and here it is an important immunosuppressive factor. Prostate cancer cells express high levels of TGF-beta1 and it seems to enhance prostate cancer growth and metastasis by stimulating angiogenesis and by inhibiting immune responses directed against tumour cells. Prostate cancer cells frequently lose their TGF-beta receptors and acquire resistance to the anti-proliferative and pro-apoptotic effects of TGF-beta1. Accordingly, high expression of TGF-beta1 and loss of TGF-beta receptor expression have been associated with a particularly bad prognosis in human prostate cancer patients. TGF-beta1 also seems to be a mediator of castration-induced apoptosis in androgen dependent normal and malignant prostate epithelial cells. The ability of some prostate tumours to avoid castration-induced apoptosis is however not simply due to loss of TGF-beta receptor type I or II expression in the tumour cells, but may also be related to an inability of these cells to up-regulate TGF-beta receptor levels in response to castration or possibly due to defects downstream of the receptors. Short-term therapy-induced changes in the TGF-beta system in prostate tumours can probably be used to predict the long-term response to androgen ablation treatment. Further investigations into the TGF-beta system in the prostate are, however, needed to elucidate how alterations in this system affect the behaviour of prostate tumours, and if this system can be manipulated for therapeutical purposes.