The PI's previous work unveiled a novel mechanism of vascularization in human and mouse ovarian carcinoma: beta-defensins were shown to massively recruit CD45+CD11c+CCR6+ myeloid cells to the tumor microenvironment, where they were transformed by VEGF in vivo into endothelial-like cells, termed Vascular Leukocytes (VLCs). VLCs express markers - and have physiologic characteristics - of both endothelial cells and dendritic cell precursors. Our central hypothesis is that VLCs are a specific lineage of CD11c+ myeloid cells that significantly contributes to vascularization during tumor formation;as such, these cells may represent important and novel therapeutic targets in the treatment of cancer. This hypothesis is based on the following observations: First, mouse and human VLCs sorted from tumor specimens can create perfusable blood vessels in vivo under angiogenic conditions. Second, our results show that CD45+CD11c+ cells labelled with GFP accumulate within tumor blood vessels. Third, the depletion of CD11c+ cells in suitable ITGAX-DTR-GFP mouse model resulted in a dramatic decrease in tumor growth. The long-term objectives of our research are to determine the exact origin of VLCs and their involvement in tumor vasculogenesis, in order to design new clinically effective cancer interventions.
In Specific Aim 1, we will determine the origin of leukocytes with vasculogenic potential. Mice will be depleted of VLCs, and then challenged with tumors admixed with different subsets of labelled leukocytes, enabling us to precisely define which leukocyte subset(s) are capable of contributing to vascularization.
Specific Aim 2 will assess the stage in tumor development at which VLCs contribute to tumor vascularization. We propose to generate a transgenic mouse with permanently """"""""tagged"""""""" VLCs, permitting the ready identification of this subset over time, even if they lose their leukocyte phenotype during the process of endothelialization.
Specific Aim 3 will evaluate the effectiveness of VLC depletion as a therapeutic intervention in cancer, focusing on the efficacy of anti-VLC immunotoxins homed to the tumor microenvironment. These endeavours will lead to new insights into the mechanisms of tumor vasculogenesis and provide a basis for a more effective targeting of the ovarian cancer microenvironment, focused on triggering an effective immune response while impeding tumor vascularization.
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