Transforming growth factor-? in benign and malignant prostate

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.

Relationship between upregulated oestrogen receptors and expression of growth factors in cultured, human, prostatic stromal cells exposed to estradiol or dihydrotestosterone

“…Conversely, TGF-b inhibits growth of prostatic epithelium but appears to have a mitogenic effect on the Oestrogen receptors and stromal growth factors P Smith et al stroma, also inducing these cells to adopt a more smooth muscle-like phenotype. 18,19,21 Our current data indicate that the roles of TGF-b and IGF occur independently of the upregulation of stromal ERa reported in BPH. NGF protein has been identified, by immunohistochemistry, to be expressed by the prostatic stroma while its receptor is confined to the epithelium.…”

“…7 Transforming growth factor beta (TGF-b) isoforms are synthesised by the stroma and their receptors expressed by the epithelium. 18,19 TGF-b 1 , the isoform used in the present study, inhibits growth of the epithelium but is stimulatory on the stroma. [19][20][21] The remaining two growth factors studied, nerve growth factor (NGF) and endothelial nitric oxide synthase (e NOS or NOS 3), have a more speculative role in stromal cell function.…”

“…Isoforms of TGF-b 1 and IGF have been clearly demonstrated within prostatic stromal cells. 7,18,19 IGF appears to have a stimulatory effect on those prostatic epithelial cells that posess receptors to both IGF-1 and IGF-II. 7 Furthermore, the levels of IGF protein and mRNA in stromal cells are particularly increased in elderly men, 17 and by as much as 10 times in cases of BPH, 7 suggesting a likely role for this growth factor in the development of BPH.…”

Adenovirus-mediated interferon-β gene therapy suppresses growth and metastasis of human prostate cancer in nude mice

“…50,51 Malignant transformation of prostate epithelial cells is associated with a reduction of TGF -receptor expression and an overexpression of TGF -. 50 ± 53 The overproduction of TGF -by prostate cancer cells can promote extracellular matrix formation, induce angiogenesis, and inhibit host immune function.…”

“…50 ± 53 The overproduction of TGF -by prostate cancer cells can promote extracellular matrix formation, induce angiogenesis, and inhibit host immune function. 50 By modulating matrix -degrading protease expression and activity, 54,55 TGF -may also promote metastasis in prostate cancers. Therefore, the suppression of tumor progression by AdIFNmay be partially attributable to NO -mediated downregulation of TGF -1.…”