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Blood, 1 January 2009, Vol. 113, No. 1, pp. 254-263. Prepublished online as a Blood First Edition Paper on October 3, 2008; DOI 10.1182/blood-2008-02-140020. This Article Full Text (PDF) All Versions of this Article: blood-2008-02-140020v1 113/1/254    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Scehnet, J. S Articles by Gill, P. S Search for Related Content PubMed PubMed Citation Articles by Scehnet, J. S Articles by Gill, P. S Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 26, 2008 Accepted July 16, 2008 The role of Ephs, Ephrins and growth factors in Kaposi sarcoma and implications of EphrinB2 blockade Jeffrey S Scehnet, Eric J Ley, Valery Krasnoperov, Ren Liu, Parmeet K. Manchanda, Eric Sjoberg, Anna P. Kostecke, Sachin Gupta, S. Ram Kumar, and Parkash S Gill* Department of Pathology, University of Southern California, Los Angeles, CA, United States Department of Medicine, University of Southern California, Los Angeles, CA, United States Vasgene Therapeutics Inc., Los Angeles, CA, United States Department of Surgery, University of Southern California, Los Angeles, CA, United States * Corresponding author; email: parkashg{at}usc.edu. Kaposi sarcoma (KS) is associated with human herpesvirus (HHV)-8 and dependent on induction of vascular endothelial growth factors including VEGF, VEGF-C and their cognate receptors VEGFR1,-2,-3. VEGF regulates genes that provide arterial or venous identity to endothelial cells, such as induction of EphrinB2 that phenotypically defines arterial endothelial cells and pericytes, and represses EphB4 that defines venous endothelial cells. We conducted a comprehensive analysis of the Eph receptor tyrosine kinases to determine which members are expressed and therefore contribute to KS pathogenesis. We demonstrated limited Eph/Ephrin expression, notably, the only ligand highly expressed is EphrinB2. We next studied the biological effects of blocking EphrinB2 using the extracellular domain of EphB4 fused with human serum albumin (sEphB4-HSA). sEphB4-HSA inhibited migration and invasion of the KS cells in vitro in response to various growth factors. Lastly, we determined the biological effects of combining sEphB4-HSA and an antibody to VEGF. sEphB4-HSA was substantially more active than the VEGF antibody and the combination of the two had at least additive activity. sEphB4-HSA reduced blood vessel density, pericyte recruitment, vessel perfusion, and increased hypoxia with an associated increase in VEGF and DLL4 expression. Combiniation of sEphB4-HSA and VEGF antibody is a rational treatment combination for further investigation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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