基于炎-癌关系探讨猪苓对膀胱癌微环境中巨噬细胞极化抑癌的调节作用

In the field of therapy of bladder carcinoma, particular attention has been continuously given to the mechanism of immunotherapy. The connection between inflammation and cancer has developed a new theory to elucidate the mechanism, therefore has become one of the newest directions in the research area of tumor inflammatory microenvironment, in which the tumor-associated macrophage and macrophage-secreted factors are commonly found. Polyporus umbellatus , which has an immunomodulatory effect, has been used for treatment of urologic diseases for over two thousand years. Based on our preliminary experiments, bladder carcinoma cell lines, macrophages and bladder cancer tissue will be used in the present study to investigate the effect of substance released from bladder cancer cells and Polyporus umbellatus combined with BCG on M1/M2 polarization of macrophages, the expression of related cytokines and some signaling pathways, such as TLR-4/NF-ҡB, IFN-γR, IL-4R and P38/C/EBP. The measurement of two marker compounds of Polyporus umbellatus, ergosterol and ergone, will be performed in tissues from bladder, marrow,thymus and spleen to analyze the correlation between drug tissue concentration and macrophage polarization as well as its signaling pathways in inflammatory microenvironment of bladder cancer. By doing these, this study would further elucidate the molecular mechanism of anti-cancer activity of Polyporus umbellatus combined with BCG through bladder cancer cells and macrophage in tumor inflammatory microenvironment. Also,the data from this research may pave the way for searching for new therapeutic targets and strategies for bladder cancer. Thus the innovative theory proposed in this research would help development of new drug, which has important benefits for cancer prevention and treatment.

膀胱癌治疗机理探讨一直是该领域重点课题，炎-癌理论为解决该问题提供了新的理论依据，炎-癌关系研究是肿瘤炎症微环境最新的研究方向，而肿瘤炎症微环境中最常见是肿瘤相关巨噬细胞及其分泌的因子。猪苓治疗泌尿系疾病已有两千多年历史。因此本项目在前期研究基础上，以膀胱癌细胞、巨噬细胞和膀胱癌组织为主要研究对象，研究膀胱癌细胞释放物和猪苓联合BCG对巨噬细胞M1/M2型极化及其相关因子表达和TLR-4/NF-ҡB, IFN-γR与IL-4R，P38/C/EBPβ信号通路的影响以及检测膀胱、骨髓、胸腺和脾脏组织中猪苓指标成分麦角甾酮和麦角甾醇的含量，分析其组织药物浓度与膀胱癌炎症微环境中巨噬细胞极化及其信号通路变化的关联性，进一步阐明猪苓BCG-膀胱癌细胞-巨噬细胞在肿瘤炎症微环境中的抗癌分子机制。对寻找新的膀胱癌治疗靶点和治疗策略具有创新的理论价值，对肿瘤防治和新药开发具有重要意义。

膀胱癌治疗机理探讨一直是该领域的热点问题，炎-癌理论为解决该问题提供了新的理论依据，肿瘤炎症微环境中最常见是肿瘤相关巨噬细胞及其分泌的因子研究。本项目在前期研究和猪苓治疗泌尿系疾病已有两千多年历史基础上，以膀胱癌细胞、巨噬细胞和膀胱癌组织为主要研究对象，研究了膀胱癌细胞释放物和猪苓联合BCG对巨噬细胞M1/M2型极化及其相关因子表达和信号通路的影响以及检测膀胱、免疫相关组织中猪苓指标成分麦角甾酮和麦角甾醇的含量，分析其组织药物浓度与膀胱癌炎症微环境中巨噬细胞极化及其信号通路变化的关联性，进一步阐明了猪苓BCG-膀胱癌细胞-巨噬细胞在肿瘤炎症微环境中的抗癌分子机制。研究结果获得均一猪苓多糖具有明确的调节巨噬细胞M1/M2型极化及其相关因子表达和TLR-4/NF-B, IFN-γR与IL-4R，P38/C/EBPβ信号通路的影响，具有潜在的新药开发前景，申请中国专利2项，国际专利4项，发表相关学术论文6篇，项目实施过程中以广东省中西医结合学会实验医学专业委员会名义主办（申请人是专业委员会主任委员）主办了国家继续教育项目1项，主题是“炎症-癌症-中药”，约有200人参会交流，以大会报告与同行交流本研究的成果和新观点，负责人也被邀请在中国免疫学会中医药免疫分会年会大会报告本项目的研究成果，同时多次被邀请国内和省内相关的组织授课交流，也是国家自然科学基金项目和国家重大专项的会议评审专家。在此项目研究基础上获得获得学校重点学科资助1项和院内专项1项。培养研究生4人，博士后2人，2017年医院优秀博士后出站2人，研究生获得国家奖学金1人，博士一等学业奖学金1人，优秀毕业生1人；第九届全国中医药优秀博士论文2等奖1人。负责人也评为优秀博士生导师及中华中医药学会聘请的青年人才托举工程项目指导老师（2017-2019）。项目研究和实施对肿瘤防治和新药开发以及人才培养都具有重要意义。