Mechanisms of Macrophage Mediated Chemoprotection in Breast Cancer

描述（由申请人提供）：本项目旨在阐明巨噬细胞介导的乳腺癌化学保护机制。我们已经发现，在患者和动物模型中的原发性乳腺肿瘤中，对紫杉醇（Taxol）治疗的响应存在肿瘤相关巨噬细胞（TAM）和组织蛋白酶蛋白酶水平的增加。表达组织蛋白酶的巨噬细胞在共培养中保护紫杉醇诱导的肿瘤细胞死亡，该作用可被组织蛋白酶抑制剂完全逆转，并部分由组织蛋白酶B和S介导。还发现巨噬细胞保护免受由另外的化疗剂（特别是依托泊苷和多柔比星）诱导的肿瘤细胞死亡。联合紫杉醇与组织蛋白酶抑制剂在体内显著增强了对原发性和转移性肿瘤的疗效，支持了该效应的治疗相关性。本申请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传导，快速诱导化学抗性状态。本申请的目的是确定微环境化学抗性适应的分子机制，并开发阻断肿瘤化学保护的治疗策略。第一个目标是确定巨噬细胞分泌的组织蛋白酶介导对化疗诱导的肿瘤细胞死亡的保护的必要性和充分性。第二个目标是鉴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。第三个目的是评价急性或增强的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，并确定将组织蛋白酶抑制剂添加到辅助治疗方案中的功效。这项工作的意义超出了乳腺肿瘤微环境，通过阐明分子机制，我们希望确定其他癌症类型和器官部位，其中巨噬细胞和组织蛋白酶蛋白酶导致治疗失败。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至关重要性。 公共卫生相关性：该项目的长期目标是了解免疫系统的特定细胞如何有助于实体瘤的治疗耐药性，并确定耐药性发生的分子机制。本文描述的研究将为肿瘤微环境如何调节对治疗的反应提供重要的新见解，并确定微环境靶向可能改善临床结果的疾病状态。

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. PUBLIC HEALTH RELEVANCE: The long-term goals of this project are to understand how specific cells of the immune system contribute to therapeutic resistance in solid tumors and to identify the molecular mechanisms by which resistance occurs. The research described here will provide important new insights into how the tumor microenvironment regulates response to therapy and identify disease states where targeting of the microenvironment may improve clinical outcome.