PTEN and Prostate Cancer Progression

描述（由申请人提供）：前列腺癌是男性中最常见的癌症，是美国男性癌症死亡的第二大原因。尽管前列腺癌对男性健康有着巨大的影响，但与其他常见癌症相比，前列腺癌发病机制的分子机制，特别是与转移和对雄激素消融治疗的耐药性有关的问题，仍然相对未知。PTEN肿瘤抑制基因在30%的原发性前列腺癌和63%的前列腺转移性病变中缺失，使PTEN缺失成为人类前列腺癌中最常见的基因改变之一。这项应用的长期目标是了解前列腺肿瘤发生、进展、转移和激素抵抗的分子机制，并利用我们的基因定义小鼠Pten条件敲除模型，确定药物开发的新靶点以及监测治疗的新生物标志物。目的1将侧重于该模型中疾病病程的特征以及与前列腺癌转移相关的位置和细胞类型。“报告小鼠”已为此目的产生，用于体内非侵入性成像和跟踪肿瘤进展和转移过程中的特定细胞类型。我们将直接验证前列腺癌可能由失调的干细胞/祖细胞引起的假设。由于小鼠Pten前列腺癌模型是目前唯一一种原发性肿瘤病变不受雄激素调节的模型，Aim 2将解剖激素耐药机制并确定激素难治性前列腺癌的细胞起源。最后，肿瘤组织和细胞系将用于全基因组微阵列分析和比较基因组杂交分析。该数据集将与来自人类前列腺癌的类似数据集进行比较，以确定前列腺癌进展、转移和激素抵抗的关键分子事件。候选基因将进一步评估其对前列腺癌发展的生物化学和遗传学贡献。尽管研究重点是前列腺癌，但这里概述的研究和本提案阐明的机制将广泛适用于与PTEN缺失相关的癌症，因为PTEN在我们身体的所有细胞类型中都有表达，并且在许多人类癌症中都观察到PTEN突变。

DESCRIPTION (provided by applicant): Prostate cancer is the most common cancer in men and is the second leading cause of cancer deaths in men in the United States. Despite its enormous impact on male health, the molecular mechanisms underlying the pathogenesis of prostate cancer, especially issues related to metastasis and resistance to androgen ablation therapy, remain relatively unknown in comparison with other common cancers. The PTEN tumor suppressor gene is deleted in 30% of primary prostate cancers and 63% of prostate metastatic lesions, placing PTEN loss among the most common genetic alterations in human prostate cancers. The long term objective of this application is to understand the molecular mechanisms underlying prostate tumor initiation, progression, metastasis, and hormone resistance, and to identify new targets for drug development as well as new biomarkers for monitoring treatment, using our genetically defined murine Pten conditional knock-out model. Aim 1 will focus on characterization of the course of the disease in this model and on the location and the cell types associated with prostate cancer metastasis. "Reporter mice" have been generated for this purpose for in vivo, non-invasive imaging and for tracking specific cell types during tumor progression and metastasis. We will directly test the hypothesis that prostate cancer may arise from dysregulated stem/progenitor cells. Since the murine Pten prostate cancer model is the only model currently available in which the primary tumorigenic lesion is not regulated by androgen, Aim 2 will dissect hormone resistant mechanisms and identify the cellular origin of hormone refractory prostate cancer. Finally, tumor tissues and cell lines will be used for genome-wide microarray analyses and comparative genome hybridization analyses. This dataset will be compared with similar datasets from human prostate cancers to identify key molecular events in prostate cancer progression, metastasis, and hormone resistance. Candidate genes will be further evaluated biochemically and genetically for their contributions to prostate cancer development. Although focused on prostate cancer, the studies outlined here and the mechanisms elucidated in this proposal will be broadly relevant to cancers associated with PTEN loss in general, since PTEN is expressed in all cell types in our body and PTEN mutations are observed in many human cancers.