TUMOR MICROENVIRONMENT IN ANGIOGENESIS AND BONE METASTASIS

现在很清楚，在被指定为肿瘤微环境的细胞边界之外发生了什么 会对肿瘤的进展产生重大影响。宿主来源的细胞被活跃地招募到肿瘤中 由肿瘤细胞表达的多种趋化因子和生长因子所致的微环境 从邻近组织或骨髓中提取。反之亦然，骨髓积极招募肿瘤细胞， 提供独特的环境，通过成骨细胞和破骨细胞的激活，肿瘤细胞建立骨骼 转移。在过去的四年里，通过这笔赠款，我们已经证明了神经母细胞瘤细胞 招募骨髓来源细胞作为内皮祖细胞和基质金属蛋白酶-9的来源 (基质金属蛋白酶-9)表达CD45阳性的炎性细胞，以及基质金属蛋白酶-9在 通过促进周细胞覆盖内皮细胞而形成成熟的血管系统。我们还获得了证据表明 缺乏破骨细胞激活因子表达能力的神经母细胞瘤细胞可刺激破骨细胞活化因子的表达 白介素6(IL-6)，破骨细胞的激活剂，骨髓间充质干细胞(BM-MSC)。在此基础上 在这些观察中，我们假设骨髓来源的细胞对 神经母细胞瘤的肿瘤进展通过两个特定的机制，首先是通过作为EPC和 炎性细胞有助于在原发肿瘤中建立成熟的血管系统，以及 第二，作为表达骨髓间充质干细胞和破骨细胞的IL-6的来源，允许恶性骨侵袭。 我们的两个具体目标是：目标1：研究神经母细胞瘤细胞吸收骨髓来源的机制 细胞，它们在血管形态发生中的作用，以及血管上缺乏周细胞覆盖的后果 渗透性、药物释放和临床结果。目的#2：研究骨髓间充质干细胞 由神经母细胞瘤细胞刺激，激活破骨细胞，触发骨侵袭，并测试干预治疗 在这个过程中。该项目旨在从根本上了解神经母细胞瘤之间的相互作用。 细胞和骨髓来源的细胞将根据这些交互作用识别治疗干预的新靶点 小路。

It is now clear that what happens outside the cell boundaries in what is designated as the tumor microenvironment can have a significant impact on tumor progression. Host-derived cells are actively recruited into the tumor microenvironment by a large variety of chemokines and growth factors expressed by tumor cells, either from neighboring tissues or from the bone marrow. Vice versa, the bone marrow actively recruits tumor cells and provides a unique environment where through osteoblast and osteoclast activation, tumor cells establish bone metastasis. Over the last four years of funding through this grant we have demonstrated that neuroblastoma cells recruit bone marrow-derived cells as a source of endothelial precursor cells (EPC) and matrix metalloproteinase-9 (MMP-9) expressing CD45 positive inflammatory cells, and that MMP-9 plays a critical role in the establishment of a mature vasculature by promoting endothelial cell coverage with pericytes. We have also obtained evidence that neuroblastoma cells, which lack the ability to express osteoclast activating factors, can stimulate the expression of interleukin-6 (IL-6), an activator of osteoclasts, by bone marrow mesenchymal stem cells (BM-MSC). On the basis of these observations, we hypothesize that bone marrow-derived cells positively contribute to neuroblastoma tumor progression by two specific mechanisms, first by being a source of EPC and inflammatory cells that contribute to the establishment of a mature vasculature in the primary tumor, and second by being a source of IL-6 expressing BM-MSC and of osteoclasts, allowing malignant bone invasion. Our two specific aims are: Aim #1: To examine the mechanisms by which neuroblastoma cells recruit bone marrowderived cells, their role in vascular morphogenesis, and the consequences of a lack of pericyte coverage on vascular permeability, drug delivery and clinical outcome. Aim #2: To examine the mechanisms by which BM-MSC are stimulated by neuroblastoma cells to activate osteoclasts and trigger bone invasion, and to test therapies interfering with this process. This project aimed at a fundamental understanding of the interactions between neuroblastoma cells and bone marrow-derived cells will identify novel targets for therapeutic intervention based on these interactive pathways.