The Kaposi's sarcoma‐associated herpesvirus G protein‐coupled receptor: Lessons on dysregulated angiogenesis from a viral oncogene

Abstract

Tumor viruses can induce cell transformation by overcoming cellular defense mechanisms and promoting the ungoverned proliferation of infected cells. To this end, functionally related viral oncogenes have evolved in disparate viruses to override key proliferative and survival intracellular pathways, thus assuring efficient viral replication and contributing to tumor formation. Indeed, the study of viral oncogenes has been a powerful tool for disclosing fundamental insights into these basic cellular processes. In this regard, the Kaposi’s sarcoma-associated Herpesvirus (KSHV or HHV8), the etiological agent of Kaposi’s sarcoma (KS), is an exemplary model of an oncogenic virus that includes within its genome several homologues of cellular genes implicated in the regulation of cell proliferation and apoptosis. However, emerging evidence now points to a single KSHV gene, ORF74, encoding for the viral G protein-coupled receptor (vGPCR), as essential for KS development. Expressed in only a fraction of cells within KS lesions, this viral receptor induces tumorigenesis through both autocrine and paracrine mechanisms. Indeed, work from several labs has demonstrated that vGPCR can promote cell proliferation, enhance cell survival, modulate cell migration, stimulate angiogenesis, and recruit inflammatory cells, both in expressing cells, as well as in neighboring (bystander) cells. Examination of this powerful viral oncogene may expose novel targets for the treatment of patients with KS and could ultimately provide a unique perspective into how GPCRs, and specifically chemokine receptors, contribute to angiogenesis and tumorigenesis.

KSHV Paracrine Effects on Tumorigenesis

“…Concordantly, in all KS mouse models, expression of vGPCR is restricted to a small subset of cells within the lesions, which is similar to the part of lytically replicating cells in human KS. This supports the hypothesis that vGPCR influences tumour growth by paracrine mechanisms promoted by the cytokines, chemokines, and growth factors secreted by vGPCR-expressing cells (Jham & Montaner, 2010). However, it remains to be proven if the vGPCR alone (together with latently infected cells) is sufficient to trigger KS tumorigenesis or additional factors are necessary.…”

Viral G protein-coupled receptor up-regulates Angiopoietin-like 4 promoting angiogenesis and vascular permeability in Kaposi's sarcoma

“…This viral protein is expressed in a limited number of cells within KS lesions but is thought to induce tumorigenesis by promoting the secretion of angiogenic and inflammatory molecules (8). Among all of the cytokines, chemokines, and growth factors secreted by vGPCR-expressing cells, it is believed that VEGF is critical to KS progression through the promotion of neovascularization and vessel permeability (9)(10)(11)(12).…”

“…Compelling data suggests that vGPCR induces sarcomagenesis through the release of pro-and antiangiogenic cytokines, chemokines, and growth factors that ultimately promote the proangiogenic and proexudative response induced by this viral receptor (8,13). In this regard, ANGPTL proteins have been previously shown to regulate multiple aspects of endothelial cell function, including endothelial cell proliferation, migration, differentiation, and endothelial cell adhesion (19).…”

“…These features are also responsible for the morbidity often associated with these lesions. Of note, the prominent vascularity of KS tumors has been attributed to the paracrine release of angiogenic mediators (e.g., vascular endothelial growth factor, or VEGF) by the KS spindle cells (8). Indeed, VEGF and its receptor, VEGFR2 (KDR), are up-regulated in AIDS-KS primary lesions as well as in AIDS-KS spindle-cell cultures (9)(10)(11)(12).…”

The unsulfated extracellular N-terminus of vGPCR reduces the tumorigenicity of hGRO-α in nude mice

“…However, unlike its cellular counterpart, it is constitutively activated even in the absence of ligand association [8]. vGPCR triggers downstream signaling components including the phospholipase C pathway, and PI3 kinase/AKT axis, and has broad signaling effects in vitro, activating NF-B, NFAT and AP-1 [9][10][11][12][13][14]. Emerging evidence supports that this KHSV lytic gene is an oncogene: vGPCR-transformed cells led to tumorigenesis in nude mice and vGPCR transgenic mice developed the human KS-like disease [15,16].…”