Role of Bone in Primary and Metastatic Cancer

项目主任/首席研究员(最后、第一、中间)：法西奥，罗伯塔，博士 摘要 我们实验室和其他实验室的最新证据表明，原发肿瘤的暴发会导致变化 在影响居住的造血细胞和间充质细胞群体的骨骼微环境中。这些 骨微环境的改变发生在肿瘤发展的早期阶段，在任何证据出现之前。 转移扩散，并在原发肿瘤进展时变得更加明显，即使在肿瘤中也是如此 不会转移到骨头里。我们发现越来越多的未成熟髓系细胞可以活跃地 抑制初诊及初诊乳腺癌小鼠骨髓T细胞增殖 II-III级乳腺癌患者与对照组比较。除了免疫群体的变化，骨骼驻留 成骨细胞和骨细胞，通常参与骨形成和骨稳态的调节，反应 通过上调各种炎性细胞因子和Wnt信号通路的抑制物来促进远端肿瘤， 例如Dkk1。这些骨生成因子中的几个局部作用于改变基础骨稳态，但是 也可能产生全身性影响，直接或间接影响原发肿瘤的生长和未来 肿瘤扩散到不同的部位。 WNT信号在骨发育、造血和癌症中发挥重要作用。DKK1是一种WNT/β连锁蛋白 已知的抑制骨形成和促进骨吸收的抑制剂。Dkk1水平的升高通常是 在癌症患者中观察到，并与不良预后相关。我们最近报道了Dkk1基因上调 成骨细胞和骨细胞在原发乳腺癌及其相关肿瘤小鼠骨骼中的表达 成纤维细胞(CAF)位于原发部位，但水平远低于骨骼。有趣的是，我们发现Dkk1 发挥免疫抑制作用，中和通过减少幼稚减少原发肿瘤生长 并加强T细胞免疫监测。基于这些令人兴奋的发现，我们的中央 假说是骨居住的成骨细胞和骨细胞调节原发乳腺癌的生长和 通过以下途径创造全身免疫抑制环境而转移到多个部位 Dkk1的生产。目的：1.探讨骨微环境在肿瘤进展中的作用。 其目的是确定Dkk1在骨中的缺失与其在肿瘤中的缺失的抗肿瘤效果 地点。AIM2.确定Dkk1调节免疫抑制的机制。这样做的目的是 目的是确定Dkk1诱导免疫抑制的细胞机制。 OMB编号0925-0001/0002(截至2018年10月31日批准的03/16修订版)第1页续格式页

Program Director/Principal Investigator (Last, First, Middle): Faccio, Roberta, PhD ABSTRACT Recent evidence from our lab and others indicates that the insurgence of a primary tumor leads to changes in the bone microenvironment that affect the residing hematopoietic and mesenchymal populations. These changes in the bone microenvironment occur during the early stages of tumor development, prior to any evidence of metastatic dissemination, and become more pronounced while the primary tumor progresses, even in tumors that do not metastasize to the bone. We find increased numbers of immature myeloid cells that can actively suppress T cell proliferation in bone marrow of mice bearing primary breast tumors and in newly diagnosed stage II-III breast cancer patients compared with controls. In addition to changes in immune populations, bone residing osteoblasts and osteocytes, normally involved in bone formation and regulation of bone homeostasis, respond to distal tumors by upregulating various inflammatory cytokines as well as inhibitors of the Wnt signaling pathway, such as Dkk1. Several of these bone-produced factors act locally to change the basal bone homeostasis, but can also have systemic effects that can impact, either directly or indirectly, primary tumor growth and future tumor dissemination to various sites. Wnt signaling plays important roles in bone development, hematopoiesis and cancer. Dkk1 is a Wnt/β-catenin inhibitor, known to suppress bone formation and promote bone resorption. Increased levels of Dkk1 are often observed in cancer patients and correlate with poor prognosis. We recently reported that Dkk1 is upregulatated by osteoblasts and osteocytes in the bone of mice with primary breast tumors and in cancer associated fibroblasts (CAFs) in the primary site, but at a level much lower than in the bone. Intriguingly, we found that Dkk1 exerts immune suppressive effects and its neutralization decreases primary tumor growth by reducing immature myeloid populations and enhancing T cell immune surveillance. Based on these exciting findings, our central hypothesis is that bone residing osteoblasts and osteocytes modulate primary breast cancer growth and metastatic dissemination to multiple sites by creating a systemic immune suppressive environment via production of Dkk1. Aim1. Exploring the role of the bone microenvironment during tumor progression. The goal of this aim is to determine the anti-tumor effects of Dkk1 deletion in bone versus its deletion at tumor site. Aim2. Determine the mechanism by which Dkk1 modulates immune suppression. The goal of this aim is to determine the cellular mechanism by which Dkk1 induces immune suppression. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page 1 Continuation Format Page