This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background: Our previous work unveiled a novel mechanism of tumor vascularization by beta-defensins and VEGF-A: Defb29 was shown to recruit myeloid CCR6+ leukocytes to the tumor microenvironment, where they were transformed by VEGF into endothelial-like cells, termed Vascular Leukocytes (VLCs). We propose that VLCs are active contributors to tumor vascularization and therefore represent novel anti-cancer therapeutic targets. This hypothesis is based on the fact that mouse and human VLCs sorted from tumor specimens can create perfusable blood vessels in vivo under angiogenic conditions. Methods: To determine the origin of VLCs and their involvement in tumor vascularization, mice depleted of VLCs are challenged with tumors admixed with different subsets of labeled leukocytes; to assess the effectiveness of VLC depletion as a therapeutic intervention in cancer, anti-VLC immunotoxins, T cell chimeric receptors and constructs for endothelial-specific delivery of cyotokines using VLCs as ?Trojan Horses? are being investigated. Finally, the transcriptional profile of human VLCs sorted from 10 different ovarian carcinoma specimens was compare to that of classical endothelial cells. Results: We identified several extracellular markers of vasculogenic VLCs which are not present in physiological endothelial cells, thus allowing specific targeting of tumor vasculature. A novel anti-VLC immunotoxin was produced for that purpose. We are currently generating a transgenic mouse expressing Cre under the control of a myeloid-specific promoter. Conclusions: Vascular Leukocytes represent significant contributors to tumor vascularization. They exhibit a specific profile of markers that makes them promising targets of immunotherapies directed to impede tumor vascularization.
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