No abstract

BACKGROUND The present review summarizes the cellular action of TGF‐β in benign and malignant growth of the prostate. METHODS. TGF‐β is a pleiotropic growth factor. It plays an important role in the regulation of growth and differentiation in many cells. In benign prostatic epithelia, its action is mediated through a paracrine mechanism. It inhibits proliferation and induces apoptosis in prostatic epithelia. It provides a mechanism to maintain epithelial homeostasis in the prostate. In prostatic stroma, its continual action leads to smooth muscle differentiation. This effect of TGF‐β may regulate the development of prostatic smooth muscle nodules in benign prostatic hyperplasia. RESULTS As prostatic epithelial cells undergo malignant transformation, two major events occur regarding TGF‐β action. These include the loss of expression of functional TGF‐β receptors and overproduction of TGF‐β in malignant cells. The loss of expression of functional TGF‐β receptors provides a growth advantage to cancer cells over their benign counterparts. The overproduction of TGF‐β by cancer cells has a multitude of adverse consequences. TGF‐β can promote extracellular matrix production, induce angiogenesis, and inhibit host immune function. The biological consequence of these activities is an enhanced tumorigenicity in prostate cancer. Results of our recent studies with a rat prostate cancer model suggest that the immunosuppressive effect of TGF‐β seems to be the primary cause of tumor progression. This is because, if these cancer cells were engineered to reduce the production of TGF‐β, tumor growth was inhibited in syngeneic hosts but not in immune compromised hosts. CONCLUSIONS Our future research should take advantage of this knowledge to devise therapeutic strategies aimed at eradicating prostate cancer. Prostate 39:285–290, 1999. © 1999 Wiley‐Liss, Inc.

The Na+,K(+)-ATPase enzyme through its p-nitrophenyl phosphatase activity was localized in the ductuli efferentes of rats. Enzymatic activity was demonstrated along the cytoplasmic side of the plasmalemma of the ductular epithelial cells. The most intense deposition of reaction products was found on the plasmalemma delimiting the lower lateral and basal regions of the cells. The plasma membranes forming the microvilli, apical junctional complexes were devoid of reaction product while the midlateral membranes showed a weak reaction. The enzyme reaction was potassium-dependent and was abolished by addition of 10 mM ouabain to the incubation media. Enzyme activity decreased significantly from proximal to distal regions of the ductules (8,101.47 +/- 274.53, 6,658.95 +/- 269.53 and 4,668.10 +/- 575.41 pmoles p-nitrophenol/mm/h, respectively in initial, conus vasculosus and terminal zones). A unified model for water absorption is proposed in the efferent ductules based upon this data and that of others.

These results demonstrate that the apoptotic effect of Doxazosin on human prostatic stromal cells is mediated through an autocrine production of TGF-beta1.

In a preliminary study, we observed that TGF-beta1 induced both proliferation and growth arrest in prostatic stromal cells, depending on the concentration of TGF-beta1 used in the culture medium. In this study, we explored possible mechanisms of this dual effect of TGF-beta. Primary cultures of prostatic stromal cells, established from clinical surgical specimens and treated with low doses of TGF-beta1 (0.001-0.01 ng/ml), resulted in an increase in cell proliferation. The addition of neutralizing antibody against platelet-derived growth factor (PDGF)-BB, but not anti-PDGF-AA, abrogated this stimulatory effect of TGF-beta1. TGF-beta1 treatment resulted in a dose-related increase in PDGF-BB production as measured by ELISA. Cells underwent growth arrest at high concentrations of TGF-beta1 (1.0 and 10 ng/ml). An inhibitor of cyclin-dependent kinase (cdk), p15INK4b, was up-regulated at both transcript and protein levels in these cultures by TGF-beta1 in a dose-related manner as determined by RT-PCR and Western blot analysis. The transcript, but not the protein, for another cdk inhibitor, p21Cip1, was up-regulated with treatment of TGF-beta1 to these cells. Levels of other cdk inhibitors, such as p16INK4a and p27Kip1, were constitutively expressed in prostatic stromal cells and were not significantly affected by TGF-beta1 treatment. Finally, the growth arrest effect of TGF-beta1 was abrogated when antisense oligonucleotides to p15INH4b, but not p21Cip1, were added to the culture medium. These data indicate that the dual effect of TGF-beta1 is mediated, at least, by up-regulation of PDGF-BB and p15INK4b, respectively.