The recruitment of hematopoietic bone marrow-derived cells by tumors has been previously reported. It has been shown that these precursors can secrete factors that modulate tissue vascularization, or can incorporate directly into the neovasculature acquiring endothelial or periciytic phenotypes. Moreover, once they have homed to the tumor, multipotent bone marrow precursors might also have the potential to become tumor- associated hematopoietic and mesenchymal cells. We have previously reported that under the influence of VEGF and 2-defensin, bone marrow-derived leukocytes expressing dendritic cell markers, are capable of contributing to tumor vasculature in a mouse model of ovarian cancer. A similar population was identified in human ovarian tumors. We called these cells vascular leukocytes (VLCs) since they expressed both hematopoietic and endothelial cell markers, and participate in neoangiogenesis. The co-expression of leukocyte and vascular markers suggests that these cells are part of the early steps of angiogenesis. Thus, we speculated that VLCs may originate from a hematopoietic precursor that could be attracted to the tumor microenvironment where it differentiates. In order to address this issue, we investigated changes in bone marrow populations induced by the development of distant tumors. We have performed preliminary experiments showing that in different mouse tumor models, a dramatic decrease in the proportion of hematopoietic bone marrow precursors is observed as tumor develops. In particular, we have observed relevant changes in the levels of a common precursor for B cells and dendritic cells (PBD). This stem cell population characterized by the coexpression of surface markers CD45, B220 and C1qRp (Early B lineage antigen/AA4.1), can generate B cells or dendritic cells in vitro depending on the cytokine milieu. Moreover, we have also detected PBDs in the microenvironment of mouse and human tumors. In the tumor, these cells express endothelial markers and proangiogenic molecules. Our general hypothesis is that bone marrow PBDs are attracted to the tumor microenvironment by specific chemokines, and there they differentiate into tumor-associated leukocytes with angiogenic capabilities. Involving undergraduate, graduate and medical students, this R15 proposal will critically examine several important mechanisms of the tumor-bone marrow interaction through the following specific aims:
Aim 1. Define the molecular profile of PBD cells recovered from bone marrow of naove animals or from the tumor microenvironment;
Aim 2. Determine the mechanisms involved in PBDs'capability to generate tumor- associated leukocyte populations (i.e., VLCs);
and Aim 3. Determine the mechanisms responsible for PBD migration towards the tumor microenvironment. Ultimately, these data will allow for a better understanding of the mechanisms by which bone marrow precursors participate in tumor development.
Tumor vasculature represents a powerful new target of anti-cancer therapy. Novel targets of anti- angiogenic therapy include molecules which are uniquely expressed on tumor endothelium and/or endothelial precursors. In this project we will define the angiogenic properties of a new bone marrow precursor that can be attracted to the tumor microenvironment and contribute to neoangiogenesis. We believe this precursor represents potential targets for anti-vascular therapeutics.
