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

本课题的目的是研究转化生长因子-α在正常组织中的作用。 前列腺癌的发生与前列腺癌的化学预防 前列腺癌。尽管人们认识到 癌症的化学预防，前列腺癌研究领域的进展 已经受到实验动物模型不足的严重阻碍 细胞系。建立一种适合于研究的体外模型 前列腺癌的化学预防，我们已经开发出几种非 致瘤(NRP-152)和致瘤(NRP-154和DP-153)细胞系 来自致癌药物治疗的Lobund-Wistar大鼠的前列腺背侧 老鼠，唯一自发患前列腺癌的啮齿动物 有没有重大的意外事件。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 具有从基底向腔内转化的能力 体外细胞表型，并具有独特的组织成 前列腺腺样体与泌尿生殖窦间充质 活着。该细胞系从基细胞向基细胞的转分化 子宫腔表型与转化生长因子-S和 它们的受体，提示转化生长因子-α可能发挥着一些关键作用联系 这一分化过程。事实上，我们已经证明了转化生长因子-b可以 它们不仅能抑制NRP-152细胞在培养中的生长，还能诱导 促进这些细胞的凋亡和分化，尽管在 不同的条件。我们的数据表明，转化生长因子-1是一种 具有癌症化学预防活性的物质的介体 能够传递细胞对细胞是否应该生长的决定 阻止、区分或放弃。与我们的模型一致，维甲酸 和他莫昔芬，防止前列腺癌的形成 Lobund-Wistar中N-甲基亚硝脲和丙酸睾丸酮的作用 诱导大鼠自分泌转化生长因子-b的表达，该转化生长因子-b可介导大部分 这些化学预防性药物对NRP-152细胞的生长抑制作用 培养中的细胞。此外，我们还表明，消融转化生长因子-1 这些细胞中的信号可以将它们转化为腺癌 活着。我们正在通过研究前列腺在体内进一步测试我们的模型 野生型NRP-152细胞形成的有机体的发育 转基因NRP-152细胞在转化生长因子信号转导或 转化生长因子-表达。为了研究它的机制基础 由转化生长因子-1诱导的细胞凋亡，我们最近克隆了一个新的基因 它的表达被转化生长因子下调--它有一个 被认为是细胞凋亡的调节因子。因此，NRP-152细胞系 是致癌机制研究的重要工具 在这个组织中进行化学预防。

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.