ROLE OF TGF-B IN CARCINOGENESIS AND CHEMOPREVENTION OF PROSTATIC CANCER (DANIELPO

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The purpose of this project is to study the role of TGF- in normal prostatic growth, prostatic carcinogenesis, and chemoprevention of prostatic cancer. In spite of the recognized importance of the chemoprevention of cancer, progress in this area of prostate research has been greatly hampered by inadequate experimental animal models and cell lines. To develop a suitable in vitro model for studying chemoprevention of prostate cancer, we have developed several non- tumorigenic (NRP-152) and tumorigenic (NRP-154 and DP-153) cell lines from the dorsal-lateral prostate of carcinogen-treated Lobund-Wistar rats, the only rodent that spontaneously develops prostatic carcinomas with any significant incidence. The NRP-152 cell line, which has been characterized extensively, is highly responsive to androgens, other steroid hormones and many growth factors, has stem cell-like properties with the ability to transdifferentiate from a basal toward a luminal cell phenotype in vitro, and has the unique property of organizing into prostatic organoids in the presence of urogenital sinus mesenchyme in vivo. The transdifferentiation of this cell line from a basal to a luminal phenotype is tightly coupled to the expression of TGF-s and their receptors, suggesting that TGF- may play some critical role linked to this differentiation process. Indeed, we have shown that TGF-bs can not only arrest growth of NRP-152 cells in culture, they also induce apoptosis and promote differentiation of these cells, albeit under different conditions. Our data suggest that TGF- functions as a key mediator of agents with cancer chemopreventive activity through its ability to relay cellular decisions of whether cells should growth arrest, differentiate, or apoptose. Consistent with our model, retinoids and tamoxifen, which prevents the formation of prostatic tumors induced by N-methyl-nitrosourea and testosterone propionate in Lobund-Wistar rat, induce the expression of autocrine TGF-bs that can mediate most of the growth inhibitory effects of these chemopreventive agents on NRP-152 cells in culture. Moreover, we have shown that ablation of TGF- signaling in these cells can transform them to an adenocarcinoma in vivo. We are further testing our model in vivo by studying prostate development in organoids formed from either wild-type NRP-152 cells or genetically modified NRP-152 cells made defective in TGF- signaling or TGF- expression. In an effort to study the mechanistic basis for apoptosis induced by TGF-, we have recently cloned the gene for a novel serpin whose expression is down-regulated by TGF- and that has a putative role as a regulator of apoptosis. Thus, the NRP-152 cell line is an important tool for mechanistic studies of carcinogenesis and chemoprevention in this tissue.