MECHANISMS OF PROSTATE EPITHELIAL CELL TRANFORMATION

本提案的总体目标是通过以下方式确定关键机制： 成年人非肿瘤性前列腺上皮细胞 恶性表型越来越严重 分子表征 以及可能与恶性肿瘤相关的细胞遗传学修饰 将承担人前列腺肿瘤细胞的潜力。 以下 这一建议的具体目标是：（10）使成年人永生 非肿瘤性前列腺上皮细胞体外转染 SV40或人乳头瘤病毒（HPV）的特异性转化基因。 获得组织学证实的非肿瘤性前列腺组织 手术将是细胞的来源。 (2)为了进一步驱动这些细胞 通过体外暴露于化学试剂而达到完全致瘤性 与前列腺癌发生有关。 重点将放在 直接（MNNG）和间接（苯并[a]芘）处理影响 致癌物质。 (3)在肿瘤演变的每个阶段， 将在形态学，体外生长能力， 细胞遗传学和免疫细胞化学可检测的标记蛋白 （上皮细胞角蛋白、前列腺特异性抗原、前列腺酸 磷酸酶、表皮生长因子受体、雄激素受体等）。 此外，将通过生长能力评价致瘤性 在无胸腺裸鼠中作为肿瘤进行性。 (4)了解前列腺 通过这些实验产生的上皮细胞转化将是 调查了人类良性疾病的自然历史， 恶性肿瘤 这些研究将有助于我们了解 美国男性中最常见的肿瘤，因此可能导致 新的机会，治疗干预疾病， 没有令人满意的治疗选择。

The overall objective of this proposal is to identify key mechanisms by which adult human non-neoplastic prostate epithelial cells are driven towards increasingly malignant phenotypes. Characterization of molecular and cytogenetic modifications which may correlate with the malignant potential of human prostate tumor cells will be undertaken. The following are the specific aims of this proposal: (10 To immortalize adult human non-neoplastic prostatic epithelial cells from in vitro by transfection of specific transforming genes of SV40 or Human Papilloma Viruses (HPV). Histopathologically confirmed nonneoplastic prostatic tissue obtained surgically will be the source of cells. (2) To drive these cells further toward complete tumorigenicity by exposure in vitro to chemical agents implicated in prostatic carcinogenesis. Emphasis will be placed upon the impact of treatment with both direct (MNNG, ) and indirect (benzo[a]pyrene) carcinogens. (3) At each stage of tumor evolution, the resulting cells will be characterized in terms of morphology, in vitro growth capacity, cytogenetics, and immunocytochemically detectable marker proteins (epithelial cytokeratins, prostate specific antigen, prostatic acid phosphatase, epidermal growth factor receptor, androgen receptor, etc.). In addition, tumorigenicity will be evaluated by ability to grow progressively as a tumor in athymic nude mice. (4) Insights into prostatic epithelial cell transformation generated by these experiments will be investigated for relevence to the natural history of human benign and malignant neoplasms. These studies will facilitate our understanding of the most common tumor occurring among American men, and thus may lead to new opportunities for therapeutic intervention in a disease for which there are no satisfactory treatment options.