MOLECULAR ANALYSIS OF HUMAN PROSTATE CANCER PROGRESSION

人类前列腺癌进展的分子基础 它的雄激素非依赖性(AI)状态鲜为人知。致信地址 这个问题，我们实验室已经研制出一种人类前列腺癌模型 其中分泌前列腺特异性抗原(PSA)的人前列腺 癌细胞系LNCaP与非致瘤性人共接种 骨基质细胞系MS植入雄性无菌小鼠皮下。这个 共接种的细胞群体相互作用并形成 癌症。最近，我扩展了这些观察，发现 保留在去势宿主体内的诱发前列腺癌 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在缺乏 雄激素)。在分子水平上，我观察到 雄激素上调基因(如PSA)的过度表达，解偶联 来自雄激素对照，在AI肿瘤中被检测到伴随着 几个雄激素抑制基因的增加，如表皮生长 因子受体(EGFR)和纤维连接蛋白(FN)基因。LNCaP亚线派生 单独接种在裸鼠体内时，AI肿瘤成为肿瘤 并产生前列腺特异性自分泌因子(PSAF)，它是 能够诱导PSA过表达。我们的初步数据显示 AI LNCaP亚系合成和分泌PSAF是一种 细胞的自主功能的一部分，并且这种功能可以 被雄激素抑制。我们观察到类似的PSAF活动也可以 在前列腺癌患者的骨髓抽吸物中检测到 骨转移患者。基于这些观察，我们 假设雄激素抑制基因的异常表达 作为PSAF，EGFR和FN可能在AI的自主生长中起关键作用 前列腺癌。为了解决这些问题，我的目标是 建议：第一，从LNCAP中分离和鉴定PSAF 亚系和骨髓标本并克隆相应的cDNAs 序列。同时，探讨PSA基因的分子机制。 在PSAF存在的情况下表达。其次，调查 PSAF、EGFR和FN的功能作用及其可能的相互作用 前列腺癌人工智能进展中的基因。我希望集中我的精力 致力于阐明与之相关的分子机制 前列腺癌从雄激素依赖(AD)进展到AI状态。 对分子和细胞的进一步探索和理解 与从AD向AI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.