基于肿瘤干细胞免疫微环境TAMs/CCL5通路探讨扶正抑瘤方逆转前列腺癌去势抵抗的分子机制和物质基础

去势抵抗性前列腺癌（CRPC）的发生机制尚不明确。最近研究表明，肿瘤干细胞免疫微环境在前列腺癌发生发展中发挥重要作用，中医药在整体调节肿瘤细胞和微环境治疗前列腺癌方面具有独特优势。前期临床研究显示，扶正抑瘤方显著延长前列腺癌患者激素非依赖性转化时间及总体生存期，其物质基础及作用机制有待阐明。我们预实验发现，扶正抑瘤方对CRPC细胞有显著的增殖抑制和凋亡诱导作用，并且对比卡鲁胺有协同增效作用，抑制TAMs共培养的前列腺癌干细胞的生长，降低TAMs分泌的CCL5 水平。由此我们设想扶正抑瘤方可通过调节TAMs/CCL5信号抑制前列腺癌肿瘤干细胞的自我更新，从而逆转前列腺癌的激素抵抗。本研究拟通过临床标本检测、干细胞培养、体内外基因重组及生物活性导向分离等技术，旨在明确扶正抑瘤方靶向TAMs/CCL5信号通路对前列腺癌干细胞的调控机制及物质基础，为CRPC的发生机制和药物开发提供新的思路。

Castration-resistant (CRPC) progression is the main pathological characteristic of advanced prostate cancer. Recent studies have revealed that immune microenvironment of cancer stem cells (CSCs) plays a critical role in the occurrence and development of prostate cancer. Traditional Chinese Medicine (TCM) has unique priority in the treatment of prostate cancer via regulating cancer cell and its microenvironment. Our previous clinical trials have demonstrated that Fuzheng Yiliu formula could significantly prolong the hormone dependent stage and benefit for the overall survival of prostate cancer. However, its underlying bioactive compounds and molecular mechanisms are still remained largely unknown. Our pilot study revealed that Fuzheng Yiliu formula could significantly inhibit prostate cancer cell growth. More importantly, there was a synergistic effect of Fuzheng Yiliu formula and bicalutamide, an anti-androgen hormone therapeutic agent. Moreover, Fuzheng Yiliu formula could significantly inhibit the growth of prostatic CSCs co-cultured with tumor-associated macrophages (TAMs), as well as reduce the CCL5 level of TAMs. Based on above findings, we hypothesized that FuZhengYiLiu formula might prevent the self-renewal ability of prostatic CSCs via inhibiting TAMs to express CCL5 cytokine which can reverse the anti-androgen resistance of prostate cancer. Taken together, our study will comprehensively explore the significance of CCl5 in regulating prostatic CSCs and the bioactive phytochemicals in Fuzheng Yiliu formula by utilizing multiple techniques including clinical specimen detection, CSCs culture, in vitro and in vivo gene modification and bioactivity-guided fractionation, etc. The study will provide novel strategies and powerful tools for molecular elucidation and therapeutic modalities of CRPC from TCM.