Kaposi's Sarcoma (KS), the most common tumor of AIDS patients, is a highly vascularized tumor supporting large amounts of angiogenesis. The main cell type of KS tumors is the spindle cell, a cell of endothelial origin, the primary cell type involved in angiogenesis. Kaposi's Sarcoma-associated herpesvirus (KSHV) is the etiologic agent of KS and is likely involved in both tumor formation and the induction of angiogenesis. Integrins, and specifically integrin αVβ3, have known roles in both tumor induction and angiogenesis. αVβ3 is also important for KSHV infection as it has been shown to be involved in KSHV entry into cells. We found that during latent infection of endothelial cells KSHV induces the expression of integrin β3 leading to increased surface levels of αVβ3. Signaling molecules downstream of integrins, including FAK and Src, are activated during viral latency. Integrin activation by KSHV is necessary for the KSHV-associated upregulation of a number of angiogenic phenotypes during latent infection including adhesion and motility. Additionally, KSHV-infected cells become more reliant on αVβ3 for capillary like formation in three dimensional culture. KSHV induction of integrin β3, leading to induction of angiogenic and cancer cell phenotypes during latency, is likely to be important for KS tumor formation and potentially provides a novel target for treating KS tumors.
Kaposi's Sarcoma (KS) is the most common tumor of AIDS patients world-wide and is characterized by very high vascularization. The main KS tumor cell type is the spindle cell, a cell of endothelial origin. Kaposi's Sarcoma-associated herpesvirus (KSHV), the etiologic agent of KS, is found predominantly in the latent state in spindle cells. In this study we examined how KSHV alters endothelial cells to induce phenotypes common to angiogenesis and tumor formation. Integrins are cell surface adhesion and signaling proteins that can be involved in tumor growth and tumor angiogenesis. We found that KSHV infection of endothelial cells leads to increased expression of integrin β3, a molecule that, when paired with its cognate α subunit, αV, has been shown to be critical for tumor-associated angiogenesis. KSHV infection promotes angiogenic phenotypes in endothelial cells including adhesion, motility and capillary morphogenesis, and these phenotypes require expression and signaling through integrin β3. Therefore, KSHV induction of integrin beta3 and downstream signaling is required for the induction of phenotypes thought to be critical for KS tumor formation. αVβ3 inhibitors are in clinical trials for inhibition of tumors and we propose that these inhibitors may be clinically relevant for treatment of KS tumors.