Role of Bone in Primary and Metastatic Cancer

项目负责人/主要研究者（最后，第一，中间）：Faccio，Roberta，PhD 摘要 我们实验室和其他实验室的最新证据表明，原发性肿瘤的发生会导致 影响造血和间充质细胞群的骨微环境。这些 骨微环境的变化发生在肿瘤发展的早期阶段， 转移性播散，并变得更加明显，而原发性肿瘤的进展，即使在肿瘤 不会转移到骨头上我们发现未成熟的骨髓细胞数量增加， 抑制乳腺癌小鼠骨髓T细胞增殖 II-III乳腺癌患者与对照组比较。除了免疫群体的变化外， 通常参与骨形成和骨稳态调节的成骨细胞和骨细胞， 通过上调各种炎性细胞因子以及Wnt信号传导途径的抑制剂， 例如DKK 1。这些骨生成因子中的一些局部作用于改变基础骨稳态，但 也可以有全身性的影响，可以直接或间接地影响原发性肿瘤的生长和未来的发展。 肿瘤扩散到不同部位。 Wnt信号在骨发育、造血和癌症中起重要作用。Dkk1是Wnt/β-连环蛋白 抑制剂，已知抑制骨形成和促进骨吸收。Dkk1水平的增加通常 在癌症患者中观察到，并且与不良预后相关。我们最近报道Dkk1被上调， 通过成骨细胞和骨细胞在小鼠骨原发性乳腺肿瘤和癌症相关 成纤维细胞（CAF）在原发部位，但在一个水平远低于骨。有趣的是，我们发现DKK 1 发挥免疫抑制作用，其中和作用通过减少未成熟的 骨髓群体和增强T细胞免疫监视。基于这些令人兴奋的发现，我们的中央 假设是骨驻留成骨细胞和骨细胞调节原发性乳腺癌生长， 通过建立全身免疫抑制环境， 生产DKK 1。目标1.探索骨微环境在肿瘤进展中的作用。 本研究的目的是确定Dkk 1在骨中缺失与其在肿瘤中缺失的抗肿瘤作用。 绝佳的价钱目标2。确定Dkk1调节免疫抑制的机制。这个目标 目的是确定Dkk1诱导免疫抑制的细胞机制。 OMB编号0925 - 0001/0002（2016年3月批准至2018年10月31日修订版）第1页续格式第页

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