Abstract 2710: KSHV-induced PDGF signaling dyregulation drives a Rac1 and ROS-mediated paracrine tumorigenic mechanism necessary for Kaposi's sarcoma

Kaposi9s sarcoma (KS), caused by the Kaposi9s sarcoma-associated herpesvirus (KSHV), is a major AIDS-associated malignancy characterized by angiogenesis and proliferation of spindle cells. KSHV-infected KS lesions are composed of latently-infected cells and a minority of cells expressing lytic genes such as vGPCR, which are implicated the development of KS angioproliferative phenotype via a paracrine mechanism. A key unsolved question is how this minor population of lytically-infected cells expressing vGPCR transduce an angio-proliferative phenotype to latently-infected cells. Here, we describe a Rac1 and ROS driven mechanism of paracrine amplification of viral oncogenesis in the KSHV-induced tumor model mECK36. It is triggered by vGPCR-induced PDGF secretion, which in the presence of high expression of PDGF receptors and NADPH oxidase family members caused by latent KSHV infection, leads to STAT3-mediated transcriptional activation of c-Myc, VEGF and KSHV latent genes. This paracrine loop, driven by PDGF signaling and regulated by Rac1 and ROS, amplifies vGPCR oncogenesis by driving proliferation and angiogenesis in latently-infected cells. Inhibtion of this molecular pathway by either the antioxidant N-acetylcysteine (NAC) or PDGF receptor tyrosine kinase inhibitors impair KSHV-induced tumorigenesis, angiogenesis and lymphangiogenesis, further validating this paracrine oncogenesis mechanism and its components as anti-KS tumor targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2710. doi:10.1158/1538-7445.AM2011-2710