EXPRESSION OF TRANSFORMING GROWTH-FACTOR-BETA-1 IN PROSTATE-CANCER

Transforming growth factor-beta 1 (TGF beta 1) is a potent modulator of cell proliferation, differentiation, angiogenesis, and the immune system. TGF beta 1 messenger RNA (mRNA) levels were much higher in several rat prostate adenocarcinomas (Dunning R3327 MATLyLu, AT2, G, HI, and H sublines) than in normal prostate. Normal prostate and the well differentiated H and HI tumors produced two TGF beta 1 mRNA transcripts, 2.4 kilobases (major) and 1.6 kilobases (minor). The poorly differentiated MATLyLu and AT2 sublines produced these plus additional TGF beta 1 mRNA transcripts that were present in the primary tumors, metastases, and cultured cell lines. TGF beta 1 mRNA levels were unchanged 2 weeks after castration. Immunohistochemical staining of TGF beta 1 protein was more prominent and more extensive in prostate cancer than in normal prostate. Only extracellular TGF beta 1 staining was detected. In normal prostate and in well differentiated tumors (H and HI), extracellular TGF beta 1 staining was located in the interacinar stroma, suggesting that it may be produced there. In contrast, in the poorly differentiated tumors (MATLyLu, AT2, and G) that contain sheets of epithelial cells, extracellular TGF beta 1 staining was present throughout the tumor, suggesting that TGF beta 1 may be made and secreted by the tumor epithelial cells. MATLyLu, AT2, and G tumor cells were cultured in vitro, and the conditioned medium was analyzed for the presence of TGF beta using a bioassay. TGF beta 1 is produced and secreted as an inactive latent precursor and must be activated to release bioactive TGF beta 1, Cells secreted about 100-500 pg TGF beta/10(6) cells 24 h and were able to activate about 50% of the total TGF beta secreted. Because TGF beta 1 mRNA and protein expression are higher in cancerous than normal tissue and because prostate cancer cells themselves can activate latent TGF beta 1 to a bioactive form, TGF beta 1 produced endogenously by prostate cancer has the potential to affect tumor behavior in vivo. Therefore, TGF beta 1 may represent a new therapeutic target in prostate cancer.