Molecular Basis of Kaposi's Sarcoma Herpesvirus vGPCR-induced Paracrine Neoplasia

Abstract

Kaposi's sarcoma (KS), one of the most common AIDS-associated neoplasms, is a multifocal vascular tumor invariably associated with infection with the KS-associated herpesvirus (KSHV or HHV8). KS has a complex histopathology with respect to its cellular composition, origin and pathogenesis. The driving force of the KS lesion is the KSHV-infected spindle-shaped tumor cell, thought to have a vascular endothelial or endothelial precursor origin. KS tumors are also characterized by infiltrating inflammatory cells, slit-like blood vessels, and extravasated erythrocytes. The recruitment of these cells and the promotion of the angiogenic phenotype in these lesions are thought to be mediated by elevated levels of pro-inflammatory and pro-angiogenic secretions (cytokines, chemokines and growth factors) from the KS tumor cells. We have previously found that expression of a single KSHV gene, the viral G protein-coupled receptor (vGPCR) is able to recapitulate KS-like lesions in mice. Indeed, our results suggest that vGPCR may be responsible for KS initiation, progression and tumor maintenance, underscoring the key role of this viral oncogene in Kaposi's sarcomagenesis. vGPCR has proven to be a powerful oncogene and a potent angiogenic activator by inducing intracellular signaling pathways that promote the survival and transformation of expressing cells and by releasing secreted factors (cytokines, chemokines and growth factors), that may promote the recruitment and subsequent paracrine transformation of neighboring endothelial cells. However, the role of these vGPCR angiogenic factors, and their relative contribution to KS development, remains unclear. Here we describe 1) the molecular mechanism by which vGPCR paracrine secretions upregulate vascular endothelial growth factor (VEGF) in KS lesions; 2) the upregulation by vGPCR of a novel angiopoietin-related factor, angiopoietin-like 4 (ANGPTL4), that plays a critical role in promoting vGPCR-induced angiogenesis and vascular permeability; and 3) the essential role of the transcription factor hypoxia inducible factor (HIF) in vGPCR sarcomagenesis, highlighting the therapeutic potential of HIF inhibitors as an alternative treatment for KS.