MOLECULAR ANALYSIS OF HUMAN PROSTATE CANCER PROGRESSION

人前列腺癌向恶性转化的分子基础 其雄激素非依赖性（AI）状态知之甚少。 解决 这个问题，我们的实验室已经开发了一个人类前列腺癌模型， 其中分泌前列腺特异性抗原（PSA）的人前列腺 将癌细胞系LNCaP与非致瘤性人 骨基质细胞系MS皮下植入雄性无胸腺小鼠。 的 共接种的细胞群相互作用， carcinoma. 最近，我扩展了这些观察，发现 当在去势宿主中维持时诱导的前列腺肿瘤 经历了明显的表型变化，这与外观有关， AI前列腺癌（即，血清PSA反弹， 雄激素）。 在分子水平上，我观察到 雄激素上调基因（如PSA）过表达，解偶联 在AI肿瘤中检测到雄激素对照， 几种雄激素抑制基因的增加，如表皮生长 因子受体（EGFR）和纤连蛋白（FN）基因。 LNCaP亚系衍生 当单独接种于裸鼠时， 并产生了前列腺特异性自分泌因子（PSAF）， 能够诱导PSA过度表达。 我们的初步数据显示 AI LNCaP亚系合成和分泌PSAF是一个重要的机制。 小区的自主功能的一部分，并且这种功能可以是 被雄激素抑制 我们已经观察到类似的PSAF活性也可以 在前列腺癌的骨髓抽吸物中检测到 骨转移患者。 根据这些观察，我们 假设雄激素抑制基因的异常表达， 由于PSAF、EGFR和FN可能在AI的自主生长中发挥关键作用， 前列腺癌 为了解决这些问题，我的目标是 我们的建议是：首先，从LNCaP中分离并鉴定PSAF 亚系和骨髓标本，并克隆相应的cDNA 顺序 探讨PSA基因表达的分子机制 在PSAF存在下的表达。 第二，调查 PSAF、EGFR和FN的功能作用以及它们之间可能的相互作用 基因在前列腺癌AI进展中的作用。 我希望能集中精力 致力于阐明相关的分子机制 前列腺癌从雄激素依赖性（AD）发展到AI状态。 进一步探索和理解分子和细胞 与从AD到AI的过渡相关的事件将有助于未来 开发新的治疗方法来治疗人类 前列腺癌

The molecular basis of the progression of human prostate cancer toward its androgen-independent (AI) state is poorly understood. To address this question, our laboratory has developed a human prostate cancer model in which a prostate-specific antigen (PSA)-secreting human prostate carcinoma cell line, LNCaP, was coinoculated with a nontumorigenic human bone stromal cell line, MS into male athymic mice subcutaneously. The coinoculated cell populations interacted reciprocally and formed carcinoma. Recently, I have extended these observations and found that the induced prostate tumors when maintained in the castrated hosts underwent marked phenotypic changes, which associated with the appearance of the AI prostate cancer (i.e., rebound of serum PSA in the absence of androgen). At the molecular level, I have observed that the overexpression of androgen-upregulated gene (such as PSA), uncoupling from androgen control, was detected in AI tumors which accompanied with the increase in several androgen-repressed genes such as epidermal growth factor receptor (EGFR) and fibronectin (FN) genes. LNCaP subline derived from the AI tumors became tumorigenic when inoculated alone in nude mice and produced the prostate-specific autocrine factor (PSAF) which is capable of inducing PSA overexpression. Our preliminary data indicate that the synthesis and secretion of PSAF by the AI LNCaP subline is a part of the autonomous function of the cells and such function may be repressed by androgen. We have observed similar PSAF activity can also be detected in bone marrow aspirates obtained from prostate cancer patients with bony metastasis. Based on these observations, we hypothesize that the aberrant expression of androgen-repressed genes such as PSAF, EGFR and FN may play a key role in the autonomous growth of AI prostate cancer. To address these questions, the objectives of my proposal are: First, to isolate and characterize the PSAF from LNCaP subline and bone marrow specimens and clone the corresponding cDNA sequence. Also, to determine the molecular mechanisms of PSA gene expression in the presence of PSAF. Secondly, to investigate the function role of PSAF, EGFR and FN, and possible interaction among these genes in the AI progression of prostate cancer. I hope to focus my effort on the elucidation of molecular mechanisms associated with prostate cancer progression from androgen-dependent (AD) to AI state. Further exploration and understanding of the molecular and cellular events associated with the transition from AD to AI will aid future development of new therapeutic approaches to the treatment of human prostate cancer.