TRANSFORMING GROWTH FACTOR-BETA-1 OVERPRODUCTION IN PROSTATE-CANCER - EFFECTS ON GROWTH-INVIVO AND INVITRO

We found previously that transforming growth factor-beta-1 (TGF-beta-1) mRNA levels are markedly elevated in rat prostate cancer (Dunning R3327 sublines) compared to levels in normal prostate. Our goal was to determine whether elevated expression of TGF-beta-1 is biologically relevant to prostate cancer growth in vivo. We chose as our model the R3327-MATLyLu prostate cancer epithelial cell line, which produces metastatic anaplastic tumors when reinoculated in vivo. Our approach was to stably transfect MATLyLu cells with an expression vector that codes for latent TGF-beta-1 and to isolate subclones of cells that over-expressed TGF-beta-1 mRNA. We also isolated a subclone of MATLyLu cells transfected with a control vector lacking the TGF-beta-1 mRNA. We also isolated a subclone of MATLyLu cells transfected with a control vector lacking the TGF-beta-1 cDNA insert. We then studied the growth of these cells in vivo and in vitro. Twenty days after sc inoculation of 10(6) cells in vivo, TGF-beta-1-overproducing MATLyLu tumors were 50% larger, markedly less necrotic, and produced more extensive metastatic disease (lung metastases in 73% of all lobes and lymph node metastases in 88% of animals) compared to control MATLyLu tumors (lung metastases, 21%; lymph node metastases, 7%). Thus, TGF-beta-1 produced in vivo is biologically active and can promote prostate cancer growth, viability, and aggressiveness, perhaps via effects on the host and/or on the tumor cells themselves. When followed in vitro, TGF-beta-1-overproducing cells became growth inhibited, but this effect was transient as cells subsequently resumed proliferating. Growth inhibition was due to TGF-beta, because it could be prevented by TGF-beta-neutralizing antibody. Therefore, prostate cancer cells can activate and respond to secreted latent TGF-beta-1, and although the cells are transiently inhibited in vitro, there is no net inhibition of growth. The ability of the cells to respond to endogenously produced TGF-beta-1 suggests that TGF-beta-1 overexpression enhances tumor growth in vivo at least in part via an effect of TGF-beta-1 on the tumor cells themselves.