MECHANISMS OF KSHV-INDUCED CELLULAR TRANSFORMATION

Oregon Health & Science University, Portland OR

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Abstract

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. Kaposi's sarcoma (KS) is a multi-focal angioproliferative tumor of the skin and visceral organs that, while rare in immunocompetent individuals, is the most frequent AIDS-associated. Human herpesvirus 8 (HHV8/KSHV), the etiologic agent of KS, infects endothelial cells (EC) and spindle cells (SC) and plays an active role in driving tumor development. The goal of this project is to characterize the mechanisms through which KSHV reprograms EC/SC and contributes to tumor formation. We have developed in vitro models based on KSHV-infected dermal microvascular EC, and more recently lineage-committed blood vascular (BEC), lymphatic (LEC) and progenitor (EPC) EC. Our original work in DMVEC used microarray analysis and gene silencing to identify and validate cellular genes that contribute to KS tumorigenesis. The proto-oncogene c-Kit was the first KSHV-induced host gene that we investigated, and this work was aided by the availability of the tyrosine kinase inhibitor Imatinib mesylate. Our in vitro studies show that c-Kit is induced in KSHV[unreadable]infected cells by differential activation of the c-Kit promoter and that downstream signaling pathways are preferentially activated in infected cells by the c-Kit ligand, SCF, which is highly expressed in KS tumors. A phase II clinical trial of Imatinib therapy in AIDS-KS patients is in progress. Current work is focused on elucidating the role of other KSHV-induced host genes in KS pathogenesis. These include the enzyme HO-1 and the chemokine receptors CXCR7 and CXCR4. Our data suggest that these molecules play a role in the seeding and development of KS tumors.