KSHV, angiogenesis and Kaposi sarcoma

Abstract

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