雄激素受体在膀胱癌细胞和肿瘤相关巨噬细胞间的介导作用及其机制研究

Tumor-associated macrophages (TAM) account for a considerable proportion in bladder cancer tissues, as much as 6-14%. TAM can promote cancer cell proliferation, angiogenesis, and metastasis, while cancer cells can attractive more TAM into tumor tissue. So the interaction between the two cells forms a self-amplifying loop to enhance the cancer cell proliferatoon. Finding and blocking the "bridge" mediating this interaction may pave the new way for tumor therapy. In our previous work, TAM can activate the androgen receptor (AR) of bladder cancer cells; meanwhile, blocking AR can significantly inhibited TAM induced- cancer cell proliferation. This suggests that the AR of cancer cell may be the "bridge" mediating the TAM and cancer cell interaction. In this subject, firstly we examine the changes of co-cultured TAM and bladder cancer cells after enhancing or inhibiting AR function in cancer cells, in order to explicitly certify AR as a "bridge" mediating the interaction. Then, on this basis, we utilize genome expression profile and CHIP technology to find out the AR downstream genes in bladder cancer cell which have been significantly changed after co-culture. And after the examination of these genes' function, we want to explain the mechanism of AR's "bridge" role. In all, we hope to find key clues for elucidating the mechanisms of bladder cancer progression.

膀胱癌组织中，肿瘤相关巨噬细胞(TAM)占癌组织细胞总数的比例高达6-14%，TAM能促进癌细胞的增殖及转移，癌细胞又能诱使更多的TAM进入肿瘤组织，两者相互作用，形成自我放大的环路促进肿瘤进展。寻找并阻断这种细胞间相互作用的介导"桥梁"可能为肿瘤的治疗提供新的思路。我们前期工作中发现，TAM能激活膀胱癌细胞的雄激素受体（AR）；而阻断AR，则TAM对癌细胞的促增殖能力受到明显抑制。这就提示我们癌细胞的AR可能是介导TAM和癌细胞的 "桥梁"之一。本课题利用条件培养基将TAM与癌细胞共培养，通过阻断癌细胞中AR的功能，分析两种细胞各自的改变，明确AR在两者相互作用间的"桥梁"功能。在此基础上，通过PCR芯片与CHIP等技术，筛选出共培养后癌细胞中发生显著改变的AR下游基因，通过对它们的功能分析，明确AR"桥梁"作用的具体机制。期望能为膀胱癌进展机制的阐明寻找到关键线索。

膀胱癌雄激素受体在膀胱癌进展中的价值及作用机制尚不明确。本项目明确了雄激素受体（AR）促进膀胱癌细胞迁移能力，下调自噬水平，与肿瘤相关巨噬细胞形成正反馈环路促进癌细胞增殖。并对这三方面的机制进行了进一步的明确。膀胱癌中AR通过β-catenin/WNT通路，增强slug的表达，进而抑制E-cadherin表达，促使癌细胞向间质转化，最终增强癌细胞转移能力。激活的AR能够通过抑制ULK2表达来下调膀胱癌细胞自噬水平，进而促进膀胱癌进展。肿瘤相关巨噬细胞激活膀胱癌AR通路促进肿瘤细胞增殖，激活的AR通路进一步促进癌细胞分泌CCL3和IL10，进一步招募和诱导TAM的聚集，形成正反馈循环，促进肿瘤增殖。