神经内分泌前列腺癌中谱系可塑性的分子机制研究进展

Research progress on molecular mechanism of lineage plasticity in neuroendocrine prostate cancer

前列腺癌是一种激素驱动的疾病,其发生发展高度依赖于雄激素受体信号通路的活化,因而雄激素剥夺疗法成为晚期前列腺癌的治疗基石。雄激素剥夺疗法在治疗初期一般疗效良好,但随着治疗时间延长,部分患者进展为侵袭性极强的神经内分泌性前列腺癌,其诊断后的中位生存期不足1年。神经内分泌前列腺癌通常表现出雄激素受体的缺失、细胞干性增加以及神经内分泌标记物如嗜铬粒蛋白A、突触素和CD56的表达增加。神经内分泌前列腺癌目前尚未有特定的的治疗策略,主要应用具有相似神经内分泌表型的小细胞肺癌的铂类治疗方案,然而,铂类治疗并未在神经内分泌前列腺癌上取得满意的效果。本综述回顾了在神经内分泌前列腺癌中谱系可塑性发生的分子机制,包括基因突变、转录网络调控、表观遗传修饰改变等,为其潜在治疗策略提供见解。

Prostate cancer is a hormone-driven disease,and its development is highly dependent on the increase of androgen receptor signaling pathway.Therefore,androgen deprivation therapy has become the standard treatment for advanced prostate cancer.With the long-term application of androgen deprivation therapy,some adenocarcinoma transforms to highly invasive neuroendocrine prostate cancer,of that the median survival time after diagnosis is less than one year.Neuroendocrine prostate cancer usually shows loss of androgen receptors and increases expression of stemness markers and neuroendocrine markers such as chromogranin A,synaptophysin and CD56.At present,there is no specific treatment for neuroendocrine prostate cancer.The therapies which are largely based on the treatment of small cell lung cancer with the similar neuroendocrine phenotype,unfortunately,have not achieved satisfactory results in neuroendocrine prostate cancer.Here we review the molecular mechanisms of lineage plasticity in neuroendocrine prostate cancer,including gene mutation,transcriptional network regulation,epigenetic modification changes,etc.,and provide insights into the potential treatment strategies for neuroendocrine prostate cancer.