Amplification of the Angiogenic Signal through the Activation of the TSC/mTOR/HIF Axis by the KSHV vGPCR in Kaposi's Sarcoma

Abstract

BackgroundKaposi's sarcoma (KS) is a vascular neoplasm characterized by the dysregulated expression of angiogenic and inflammatory cytokines. The driving force of the KS lesion, the KSHV-infected spindle cell, secretes elevated levels of vascular endothelial growth factor (VEGF), essential for KS development. However, the origin of VEGF in this tumor remains unclear.Methodology/Principal FindingsHere we report that the KSHV G protein-coupled receptor (vGPCR) upregulates VEGF in KS through an intricate paracrine mechanism. The cytokines secreted by the few vGPCR-expressing tumor cells activate in neighboring cells multiple pathways (including AKT, ERK, p38 and IKKβ) that, in turn, converge on TSC1/2, promoting mTOR activation, HIF upregulation, and VEGF secretion. Conditioned media from vGPCR-expressing cells lead to an mTOR-dependent increase in HIF-1α and HIF-2α protein levels and VEGF upregulation. In a mouse allograft model for KS, specific inhibition of the paracrine activation of mTOR in non-vGPCR-expressing cells was sufficient to inhibit HIF upregulation in these cells, and abolished the ability of the vGPCR-expressing cells to promote tumor formation in vivo. Similarly, pharmacologic inhibition of HIF in this model blocked VEGF secretion and also lead to tumor regression.Conclusions/SignificanceOur findings provide a compelling explanation for how the few tumor cells expressing vGPCR can contribute to the dramatic amplification of VEGF secretion in KS, and further provide a molecular mechanism for how cytokine dysregulation in KS fuels angiogenesis and tumor development. These data further suggest that activation of HIF by vGPCR may be a vulnerable target for the treatment of patients with KS.

High prevalence of specific KIR types in patients with HHV-8 positive cutaneous vascular lesions: a possible predisposing factor?

“…Indeed, many HHV8 genes, including v-GPCR [18], ORF50 [4,5] and vIL-6 [21], have been recognized as important transforming factors inducing a potent neoangiogenic capability in infected endothelial cells. Moreover, HHV8 infection causes a reprogramming of cell transcription, inducing the expression of cellular factors with proangiogenic activity, including VEGF, MCP-1, ATF4, mTOR, and ANGPTL4 [4,5,12,16,21,22]. In line with this, previous observations by our group evidenced a relevant presence of HHV8 in cutaneous vascular proliferative lesions, especially in eruptive cherry angiomas (CAs), and suggested that immunosuppression could be a substratum for HHV8 to explicate its neoangiogenic potential at skin level [1,2].…”

Latency-Associated Nuclear Antigen of Kaposi Sarcoma–Associated Herpesvirus Promotes Angiogenesis through Targeting Notch Signaling Effector Hey1

“…Multiple KSHV-encoded viral proteins have been demonstrated to activate the Notch pathway (3,6,12,(16)(17)(18)(38)(39)(40). We reported previously that KSHV LANA stabilizes ICN and contributes to cell proliferation (30).…”

Molecular Mechanisms Deployed by Virally Encoded G Protein–Coupled Receptors in Human Diseases

“…Of interest, direct and paracrine AKT activation of the TSC2/mTOR pathway has been shown to be necessary and sufficient for vGPCR oncogenesis (37). Although the different downstream mechanisms by which vGPCR-mediated mTOR drives vGPCR sarcomagenesis are still unclear, one includes the dramatic amplification of VEGF secretion, through the activation by vGPCR cytokines of multiple kinases including AKT, ERK, p38 and IKKβ, all of which can ultimately converge in TSC/mTOR activation and hypoxia-inducible factor (HIF) upregulation in (neighboring) non-vGPCR expressing cells (38). Another novel pro-angiogenic and pro-tumorigenic factor highly upregulated through vGPCR direct and paracrine HIF activation is Angiopoietin-like 4, a novel factor recently found to be involved in tumor progression and tumor metastasis through the regulation of endothelial cell-cell junctions (39; 40).…”