The role of bone marrow macrophages in skeletal metastasis

项目4 项目摘要 骨转移是晚期前列腺癌的最终和不可避免的后果。以前的研究旨在 为了提高对癌症和骨的理解，主要集中在肿瘤细胞和骨细胞的相互作用上。 其他关键的细胞相互作用一直没有得到充分的研究。髓系细胞在肿瘤浸润性病变中的作用 组织和促进肿瘤生长；然而，对髓系细胞在肿瘤中的作用机制知之甚少 骨髓相对于肿瘤在骨中的占有率。肿瘤细胞在生长过程中不可避免地遇到这些细胞 在原发灶、休眠期间和直肠转移灶中的轨迹。最感兴趣的是 癌症中的髓系细胞集中在它们产生的细胞因子和/或它们的免疫反应上 精心编排。巨噬细胞介导一种特殊的凋亡细胞吞噬过程，称为胞吐作用。 巨噬细胞用来识别细胞泡腾的不同信号通路正在出现。 作为自身免疫性疾病和动脉粥样硬化的治疗靶点。调查小组的初步调查 项目实验室证明，巨噬细胞泡沫化诱导极化向M2型肿瘤- 通过激活STAT3-relA信号轴促进细胞。此外，M2型巨噬细胞耗竭 通过一种新的治疗方法，显著减少骨微环境中的实验性肿瘤进展。 这项提案的目标是勾勒出与前列腺癌细胞凋亡和肿瘤生长相关的途径。 在骨转移过程中使用体外策略，新的动物模型以及人类细胞和组织 验证靶向治疗的翻译和临床潜力。总体假设是骨头 骨髓巨噬细胞通过吞噬/胞吐作用支持前列腺癌在骨中的生长 凋亡的肿瘤细胞。三个目标将解决这个有趣的问题，即髓系/巨噬细胞如何 推动骨髓中肿瘤的形成。第一个将鉴定吞噬/泡出巨噬细胞。 骨转移的肿瘤微环境，并决定其支持肿瘤生长的能力。这个 第二个将确定乳脂球EGF-8(MFGE8)的作用机制，MFGE8是 胞吐作用，支持肿瘤生长。第三个目标将阐明巨噬细胞的靶向机制。 使用可直接转化为临床的策略的泡腾作用和前列腺癌肿瘤进展 治疗潜力

Project 4 Project Summary Skeletal metastasis is a final and inevitable consequence of advanced prostate cancer. Previous studies aimed to improve understanding of cancer and bone focused primarily on interactions of tumor cells and bone cells. Other critical cellular interactions have been understudied. Myeloid cells play intriguing roles infiltrating tumor tissue and promoting tumor growth; however little is known of the mechanisms of action of myeloid cells in the bone marrow relative to tumor occupation in bone. Tumor cells inevitably encounter these cells during their trajectory from the primary lesion, during dormancy, and in the frank metastatic lesion. Most of the interest in myeloid cells in cancer has centered on the cytokines they produce and/or immune reactions that they orchestrate. Macrophages mediate a specialized process of apoptotic cell phagocytosis termed efferocytosis. The distinct signaling pathways that macrophages use to identify apoptotic cells for efferocytosis are emerging as therapeutic targets for autoimmune conditions and atherosclerosis. Preliminary investigations from the project laboratory demonstrate that macrophage efferocytosis induces polarization towards M2-type tumor- promoting cells with activation of the Stat3-RelA signaling axis. Furthermore, M2-type macrophage depletion with a novel therapeutic, significantly reduces experimental tumor progression in the bone microenvironment. This proposal sets a goal to delineate pathways relative to prostate cancer cell apoptosis and tumor growth during skeletal metastasis using in vitro strategies, novel animal models, as well as human cells and tissues to validate the translation and clinical potential for targeted therapies. The overall hypothesis is that bone marrow macrophages support prostate cancer growth in bone via phagocytosis/efferocytosis of apoptotic tumor cells. Three aims will address the intriguing question as to how myeloid/macrophage cells drive tumor establishment in the bone marrow. The first will identify the phagocytic/efferocytotic macrophage in the tumor microenvironment of skeletal metastases and determine its ability to support tumor growth. The second will determine the mechanisms of action of milk fat globule EGF-8 (MFGE8), a mediator of efferocytosis, in supporting tumor growth. The third aim will elucidate targetable mechanisms of macrophage efferocytosis and prostate cancer tumor progression using strategies that directly translate to clinical therapeutic potential