Mechanisms of Macrophage Mediated Chemoprotection in Breast Cancer

项目描述（申请人提供）：本项目旨在阐明巨噬细胞介导的乳腺癌化学保护机制。我们发现，对紫杉醇（Taxol）治疗有反应的肿瘤相关巨噬细胞（tam）和组织蛋白酶蛋白酶水平在原发性乳腺肿瘤患者和动物模型中增加。在共培养中，表达cathepsin的巨噬细胞对紫杉醇诱导的肿瘤细胞死亡具有保护作用，这种作用被cathepsin抑制完全逆转，部分由cathepsin B和s介导。研究还发现，巨噬细胞对其他化疗药物（特别是依托泊苷和阿霉素）诱导的肿瘤细胞死亡具有保护作用。紫杉醇联合组织蛋白酶抑制在体内显著增强了对原发性和转移性肿瘤的疗效，支持这种效果的治疗相关性。该应用的主要假设是巨噬细胞分泌的组织蛋白酶通过其蛋白水解活性直接调节肿瘤细胞存活信号，迅速诱导化疗耐药状态。本应用程序的目的是确定微环境化学耐药适应的分子机制，并制定治疗策略来阻断肿瘤中的化学保护。第一个目标将是确定巨噬细胞分泌的组织蛋白酶介导化疗诱导的肿瘤细胞死亡的必要性和充分性。第二个目标将是确定由组织蛋白酶活性调节的肿瘤细胞存活信号通路，并确定决定对这种化学保护机制敏感性的基因组改变。第三个目的是评估急性或强化组织蛋白酶抑制剂治疗是否会导致体内化疗反应的更大改善，并确定在辅助治疗方案中添加组织蛋白酶抑制剂的疗效。这项工作的意义超出了乳房肿瘤微环境，通过阐明分子机制，我们希望确定巨噬细胞和组织蛋白酶导致治疗失败的其他癌症类型和器官部位。因此，我们打算进一步证明肿瘤及其微环境的综合治疗靶向的重要性。

DESCRIPTION (provided by applicant): This project aims to elucidate the mechanisms of macrophage-mediated chemoprotection in breast cancer. We have found that in response to paclitaxel (Taxol) treatment there is an increase in tumor-associated macrophages (TAMs) and cathepsin protease levels in primary breast tumors in patients and in animal models. Cathepsin-expressing macrophages protected against Taxol-induced tumor cell death in co-culture, an effect fully reversed by cathepsin inhibition and mediated partially by cathepsins B and S. Macrophages were also found to protect against tumor cell death induced by additional chemotherapeutics, specifically etoposide and doxorubicin. Combining Taxol with cathepsin inhibition in vivo significantly enhanced efficacy against primary and metastatic tumors, supporting the therapeutic relevance of this effect. The main hypothesis of this application is that macrophage-secreted cathepsins directly modulate tumor cell survival signaling through their proteolytic activity, rapidly inducing a chemoresistant state. The objectives of this application are to identify the molecular mechanisms underlying microenvironmental chemoresistance adaptations, and develop therapeutic strategies to block chemoprotection in tumors. The first aim will be to determine the necessity and sufficiency of macrophage-secreted cathepsins to mediate protection against chemotherapy-induced tumor cell death. The second aim will be to identify the tumor cell survival signaling pathway(s) modulated by cathepsin activity, and determine the genomic alterations that dictate sensitivity to this mechanism of chemoprotection. The third aim will be to evaluate whether acute or enhanced cathepsin inhibitor treatment will result in a greater improvement in chemotherapeutic response in vivo, and determine the efficacy of adding cathepsin inhibitors to adjuvant treatment regimens. The implications of this work extend beyond the breast tumor microenvironment and through the elucidation of molecular mechanism we hope to identify other cancer types and organ sites where macrophages and cathepsin proteases contribute to treatment failure. We thereby intend to further demonstrate the critical importance of integrated therapeutic targeting of the tumor and its microenvironment.