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KSHV, angiogenesis and Kaposi sarcoma

By Di Luca D. and Caselli E.

Abstract

In the HAART era Kaposi’s sarcoma (KS) remains the second\ud most frequent tumor in HIV-infected patients worldwide,\ud and it is the most common cancer in Sub-Saharan Africa. KS\ud is a multicentric angioproliferative disorder characterized by\ud pathognomic spindle cells of endothelial origin, and is casually\ud associated to human herpesvirus 8, known also as KS\ud associated herpesvirus (KSHV).\ud KSHV infects endothelial cells, induces the formation\ud of spindle morphology and promotes angiogenesis. We are\ud studying the molecular mechanisms associated to KSHV\ud angiogenesis. We have determined that KSHV induces angiogenesis\ud with two distinct mechanisms. The first is through\ud NF-kappaB activation, via stimulation of the IkappaB kinase\ud (IKK). KSHV selectively triggers the production of high\ud levels of MCP-1, whereas it does not affect the expression\ud of other NF-kappaB-dependent proinflammatory proteins.\ud Interestingly, inhibition of MCP-1 abrogates KSHV angiogenesis.\ud When NFkB is inhibited, infection still results in a\ud residual angiogenic activity, approximately 30-40% of the\ud maximal level. Our experiments have shown that this second\ud mechanism is dependant upon the transcription factor ATF-4.\ud Infact, KSHV infection of endothelial cells results in a significant\ud upregulation of ATF-4. In addition, transfection of\ud ATF-4 in uninfected endothelial cells induces in vitro angiogenic\ud behaviour. Furthermore, ATF-4 has a direct effect on\ud the activation of MCP-1 promoter.\ud The results show that KSHV promotes angiogenesis by\ud stimulation of two different cellular mechanisms, NFkB and\ud ATF-4, that converge on activating MCP-1. The strict dependance\ud of KSHV angiogenesis on MCP-1 and the elucidation\ud of molecular mechanism involved in this process could result\ud in a better understanding of the angiogenetic process, its\ud involvement in cancer and will help in designing novel therapies\ud to reduce KS growth and vascularizatio

Topics: KSHV, angiogenesis
Publisher: Institute of Human Virology
Year: 2010
OAI identifier: oai:iris.unife.it:11392/1490521
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