Novel deregulated genes in the etiology and progression of human prostate cancer

摘要 前列腺癌(PC)是最常见的恶性肿瘤之一，也是第二大病因。 与癌症相关的男性死亡人数。尽管在开发早期检测测试方面取得了重大进展 导致改善了对被诊断为器官受限PC的患者的管理，进展到局部 侵袭性和转移性激素耐药PC(HRPC)通常会导致治疗耐药、疾病 复发和病人死亡。因此，更好地了解PC的病因 识别新的分子治疗靶点需要起始和进展以及治疗耐药性。 最近的一系列证据表明，成人前列腺干/祖细胞的恶变 转化为高致瘤性PC启动细胞可能在PC进展、转移 远处组织、治疗耐药和疾病复发。在考虑这些进展时，中央 这一提议的假设是，在PC启动细胞中诱导的特定致癌产物的激活 和他们的后代在PC的病因和进展中，包括EGFR和刺猬的上调 信号元件可协同作用于其持续生长、存活、侵袭、转移、治疗 抵抗力和疾病复发。基于这一假设，长期目标是评估潜在的 同时靶向EGFR和Hedgehog级联以根除PC和转移启动的好处 细胞及其后代与改善当前临床抗雄激素治疗及多西紫杉醇为主 针对局部侵袭性、雄激素非依赖性和转移性PC的化疗。为此，我们将在 体外和体内的人PC细胞模型，以及与前列腺相关的患者前列腺组织的大面板 致癌。提出了三个具体目标。目的建立特定的功能和分子基础 EGFR和Hedgehog通路在PC干/祖细胞恶性转化中的作用机制 以及它们的后代在PC的启动和发展过程中。AIM II将确定与耐药相关的 通过激活EGF-EGFR和PC中的Sonic Hedgehog级联而调节的分子 干细胞/祖细胞与其后代的比较。AIM III将确定联合靶向EGFR的治疗益处 和用于根除PC和转移起始细胞及其后代的声波刺猬通路和 改进目前的临床治疗方法。总之，这些研究应勾勒出所提供的具体职能 通过EGFR和Hedgehog通路获得更恶性的PC表型和耐药性 干细胞/祖细胞及其后代在当前临床治疗中的应用。联合靶向的治疗意义 EGFR和Hedgehog级联根除总PC细胞团并改善当前的抗雄激素作用 治疗和以多西紫杉醇为基础的化疗治疗PC患者，从而防止疾病复发 病人的死亡将被确定。

ABSTRACT Prostate cancer (PC) is among the most commonly diagnosed malignancies and the second leading cause of cancer-related deaths in men. Although significant progress in the development of early detection tests has led to improved management of patients diagnosed with organ-confined PCs, the progression to locally invasive and metastatic hormone-refractory PCs (HRPCs) typically leads to treatment resistance, disease relapse and the death of patients. Therefore, a better understanding of etiological causes responsible for PC initiation and progression and treatment resistance is needed to identify novel molecular therapeutic targets. Recent lines of evidence have revealed that the malignant transformation of adult prostatic stem/progenitor cells into highly tumorigenic PC-initiating cells may provide critical functions in PC progression, metastases at distant tissues, treatment resistance and disease relapse. In considering these advances, the central hypothesis of this proposal is that the activation of specific oncogenic products induced in PC-initiating cells and their progenies during PC etiology and progression, including an up-regulation of EGFR and hedgehog signaling elements, may cooperate for their sustained growth, survival, invasion, metastases, treatment resistance and disease relapse. Based on this hypothesis, the long-term objective is to evaluate the potential benefit to simultaneously target EGFR and hedgehog cascades for eradicating PC- and metastasis-initiating cells and their progenies and improving the current clinical anti-androgenic treatments and docetaxel-based chemotherapies against locally invasive, androgen independent and metastatic PCs. For this, we will use in vitro and in vivo human PC cell models, and a large panel of patient's prostatic tissues relevant to prostate carcinogenesis. Three specific aims are proposed. AIM I will establish the specific functions and molecular mechanisms of EGFR and hedgehog pathways in the malignant transformation of PC stem/progenitor cells and their progenies during PC initiation and progression. AIM II will identify the drug resistance-associated molecules modulated through the activation of EGF-EGFR and sonic hedgehog cascades in PC stem/progenitor cells versus their progenies. AIM III will establish the therapeutic benefit of co-targeting EGFR and sonic hedgehog pathways for eradicating PC- and metastasis-initiating cells and their progenies and improving current clinical therapies. Altogether, these studies should delineate the specific functions provided by EGFR and hedgehog pathways in the acquisition of a more malignant phenotype and resistance of PC stem/progenitor cells and their progenies to current clinical therapies. The therapeutic interest of co-targeting EGFR and hedgehog cascades to eradicate the total PC cell mass and improve current anti-androgenic treatments and docetaxel-based chemotherapies for treating PC patients and thereby prevent disease relapse and the death of patients will be established.