利用一种新型异种移植动物模型探讨神经内分泌型前列腺癌形成过程和机制

Neuroendocrine prostate cancer (NEPC) most commonly evolved from prostatic adenocarcinoma after long-term hormone deprivation therapy. NEPC is a highly aggressive and lethal subtype of prostate cancer(PCa) with poor prognostics, death usually ensues within 1 year after NEPC formation. This is an important cause of recurrence and death of a large part of PCa patients, yet its mechanism and dynamic process remains largely unkown. In our pre-study we have established a novel prostatic adenocarcinoma xenograft model, by castration of male NOD-SCID mice, the adenocarinoma type of PCa irrevisbly trans-differentiated into pure NEPC. This provides us with a valuable tool to investigate the molecular mechanism underlying andenocarcinoma-NEPC trans-differentiation process. In this study, we will employ whole genome and transcription next generation sequencing methods to sysmeticly analysis and compare the genetic and molecular characteristics of adenocarcinoma and NEPC xenograft, and we will elucidate the dynamic course of trans-differentiation by observing kenetic changes during the process of adenocarcinoma-NEPC trans-differentiation at a serial of time points. We will also try to abrogate the formation of NEPC in this xenograft animal model by drug that targeting at the key molecules during the trans-differentiation process. This study will providing pre-clinical datas and theretical basis for the prevetion and therapy of NEPC by elucidating the dynamic process and molecular mechanism of the genesis of NEPC evloved from PCa after hormone deprivation therapy.

神经内分泌型前列腺癌多由前列腺癌腺癌长期激素治疗后继发而来，它是一种高度侵袭性的恶性肿瘤，对激素或化学治疗不敏感，预后差，病人多在发生后一年内死亡。这是部分前列腺癌复发和死亡的重要原因。但其发生机制和过程尚不清楚。我们在前期研究中建立了一种新型的前列腺腺癌异种移植动物模型，在雄性小鼠去势处理后可诱导不可逆转的横向转化为神经内分泌型前列腺癌。这为我们研究前列腺腺癌-神经内分泌癌横向分化机制提供了有力的研究工具。本课题拟通过全基因组和转录组测序的方法，系统分析比较该动物模型腺癌和神经内分泌癌的遗传和分子特征，在多个时间段动态观察腺癌向神经内分泌癌分化的系列变化，以阐明神经内分泌型前列腺癌的发生的动态过程。此外，我们还将针对该分化过程中的关键靶点，采用药物干预的方法，以阻断神经内分泌癌的形成。本研究通过阐明神经内分泌型前列腺癌的发生过程和分子机制，其预防和治疗提供临床前实验数据和理论依据。

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