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Latent KSHV Infection of Endothelial Cells Induces Integrin Beta3 to Activate Angiogenic Phenotypes

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PLoS Pathogens

Public Library of Science

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      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.

      Author Summary

      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.

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      Most cited references 73

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      Integrins in cancer: biological implications and therapeutic opportunities.

      The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumours. The importance of integrins in several cell types that affect tumour progression has made them an appealing target for cancer therapy. Integrin antagonists, including the alphavbeta3 and alphavbeta5 inhibitor cilengitide, have shown encouraging activity in Phase II clinical trials and cilengitide is currently being tested in a Phase III trial in patients with glioblastoma. These exciting clinical developments emphasize the need to identify how integrin antagonists influence the tumour and its microenvironment.
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        Integrins can alter cellular behavior through the recruitment and activation of signaling proteins such as non-receptor tyrosine kinases including focal adhesion kinase (FAK) and c-Src that form a dual kinase complex. The FAK-Src complex binds to and can phosphorylate various adaptor proteins such as p130Cas and paxillin. In normal cells, multiple integrin-regulated linkages exist to activate FAK or Src. Activated FAK-Src functions to promote cell motility, cell cycle progression and cell survival. Recent studies have found that the FAK-Src complex is activated in many tumor cells and generates signals leading to tumor growth and metastasis. As both FAK and Src catalytic activities are important in promoting VEGF-associated tumor angiogenesis and protease-associated tumor metastasis, support is growing that FAK and Src may be therapeutically relevant targets in the inhibition of tumor progression.
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          Angiogenesis depends on the adhesive interactions of vascular cells. The adhesion receptor integrin alpha v beta 3 was identified as a marker of angiogenic vascular tissue. Integrin alpha v beta 3 was expressed on blood vessels in human wound granulation tissue but not in normal skin, and it showed a fourfold increase in expression during angiogenesis on the chick chorioallantoic membrane. In the latter assay, a monoclonal antibody to alpha v beta 3 blocked angiogenesis induced by basic fibroblast growth factor, tumor necrosis factor-alpha, and human melanoma fragments but had no effect on preexisting vessels. These findings suggest that alpha v beta 3 may be a useful therapeutic target for diseases characterized by neovascularization.

            Author and article information

            Department of Microbiology, University of Washington, Seattle, Washington, United States of America
            University of North Carolina at Chapel Hill, United States of America
            Author notes

            Conceived and designed the experiments: TAD ML. Performed the experiments: TAD KDG. Analyzed the data: TAD ML. Wrote the paper: TAD ML.

            Role: Editor
            PLoS Pathog
            PLoS Pathogens
            Public Library of Science (San Francisco, USA )
            December 2011
            December 2011
            8 December 2011
            : 7
            : 12
            DiMaio et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Pages: 12
            Research Article
            Viral Persistence and Latency
            Viruses and Cancer
            Molecular Cell Biology
            Cell Adhesion
            Cellular Types
            Endothelial Cells
            Extracellular Matrix
            Signal Transduction
            Signaling in Cellular Processes
            Cell Movement Signaling
            Vascular Biology
            Basic Cancer Research
            Tumor Physiology
            Cancer Treatment
            Antiangiogenesis Therapy
            Cancers and Neoplasms
            AIDS-related cancers

            Infectious disease & Microbiology


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