MECHANISMS OF PROSTATE EPITHELIAL CELL TRANFORMATION

这项提案的总体目标是通过以下方式确定关键机制 哪些成人非肿瘤性前列腺上皮细胞 越来越恶性的表型。分子的表征 以及可能与恶性肿瘤相关的细胞遗传学修饰 人类前列腺癌细胞的潜能将被承担。以下是 这项建议的具体目标是：(10)使成人永垂不朽 转染人前列腺癌非肿瘤性前列腺上皮细胞 SV40或人乳头瘤病毒(HPV)的特异性转化基因。 经组织病理学证实的非肿瘤性前列腺组织 外科手术将成为细胞的来源。(2)进一步推动这些细胞 通过体外接触化学物质实现完全致瘤性 与前列腺癌的发生有关。重点将放在 直接(MNNG)和间接(苯并[a]芘)处理的影响 致癌物质。(3)在肿瘤进化的每个阶段，所产生的细胞 将在形态、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，肿瘤的致瘤性将通过生长能力进行评估。 在裸鼠体内呈进行性肿瘤。(4)对前列腺癌的洞察 这些实验产生的上皮细胞转化将是 研究与人类良性和非传染性疾病自然历史的相关性 恶性肿瘤。这些研究将有助于我们理解 最常见的肿瘤发生在美国男性中，因此可能导致 对一种疾病进行治疗干预的新机会 都没有令人满意的治疗方案。

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.