This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Recent findings from our laboratory and others demonstrate that dendritic cells (DCs) have remarkable functional and developmental plasticity. Whereas the antigen uptake and presentation functions of DCs are well described, our recent work establishes that some DC precursors can also participate directly in vasculogenesis. We have defined a novel mechanism of vascularization: beta-defensins produced by tumor cells recruit myeloid leukocytes expressing the chemokine receptor CCR6 to the tumor microenvironment, where they are transformed by VEGF-A into endothelial-like cells, termed Vascular Leukocytes (VLCs). VLCs express markers - and have physiologic characteristics - of both endothelial cells and DCs. Our central hypothesis is that VLCs are a specific lineage of CD11c+ DCs that significantly contributes to vascularization during tumor formation: as such these cells may represent an important and novel therapeutic target in the treatment of cancer, and perhaps in other immunological disease syndromes. To test this hypothesis, we propose the following experimental plan:
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 labeled leukocytes; this will enable us to precisely define which leukocyte subset(s) are capable of contributing to vasculogenesis.
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 in the abrogation of tumor growth.These endeavors will result in a better understanding of the immunobiology and functional potential of DCs and provide a basis for more effective treatment of tumors and immunological disorders.
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