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

本课题的目的是研究TGF-β在正常人乳腺癌中的作用， 前列腺生长、前列腺癌发生和前列腺癌的化学预防 前列腺癌。尽管公认的重要性， 前列腺癌的化学预防，研究进展 由于实验动物模型不足， 细胞系建立一个合适的体外研究模型 前列腺癌的化学预防，我们已经开发了几种非- 致瘤性（NRP-152）和致瘤性（NRP-154和DP-153）细胞系 来自致癌剂处理的Lobund-Wistar大鼠的背侧前列腺 大鼠是唯一一种会自发发生前列腺癌的啮齿动物 有任何重大的影响。NRP-152细胞系，已被 特征广泛，对雄激素高度敏感，其他 类固醇激素和许多生长因子，具有干细胞样特性 具有从基底细胞向管腔细胞转分化的能力， 细胞表型在体外，并具有独特的性质，组织成 存在尿生殖窦间充质的前列腺类器官 vivo.该细胞系从基底细胞到基底细胞的转分化 管腔表型与TGF-β的表达紧密相关， 他们的受体，这表明TGF-β可能发挥一些关键作用， 这个分化过程。事实上，我们已经证明TGF-β可以 它们不仅能抑制培养物中NRP-152细胞的生长， 凋亡和促进这些细胞的分化，尽管在 不同条件我们的数据表明，TGF-β是一个关键的功能， 具有癌症化学预防活性的介质， 传递细胞决定细胞是否应该生长的能力 停止、分化或分解。与我们的模型一致，维甲酸 和他莫昔芬，它可以防止前列腺肿瘤的形成， 通过N-甲基-亚硝基脲和丙酸睾酮在Lobund-Wistar中 大鼠，诱导自分泌TGF-β的表达，可以介导大部分的 这些化学预防剂对NRP-152的生长抑制作用 细胞培养。此外，我们已经表明，TGF-β的消融， 这些细胞中的信号可以将它们转化为腺癌， vivo.我们正在进一步测试我们的模型在体内研究前列腺 在由野生型NRP-152细胞或 基因修饰的NRP-152细胞在TGF-β信号传导中有缺陷， TGF-β表达。为了研究 TGF-β 1诱导的细胞凋亡，我们最近克隆了一个新的基因， 丝氨酸蛋白酶抑制剂，其表达被TGF-β下调， 作为细胞凋亡调节因子的假定作用。因此，NRP-152细胞系 是研究致癌机理的重要工具， 化学预防

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.