TUMOR MICROENVIRONMENT IN ANGIOGENESIS AND BONE METASTASIS

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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.