Viral G protein-coupled receptor up-regulates Angiopoietin-like 4 promoting angiogenesis and vascular permeability in Kaposi's sarcoma.
Kaposi's sarcoma (KS) is an enigmatic vascular tumor thought to be a consequence of dysregulated expression of the human herpesvirus-8 (HHV-8 or KSHV)-encoded G protein-coupled receptor (vGPCR). Indeed, transgenic animals expressing vGPCR manifest vascular tumors histologically identical to human KS, with expression of the viral receptor limited to a few cells, suggestive of a paracrine mechanism for vGPCR tumorigenesis. Both human and vGPCR experimental KS lesions are characterized by prominent angiogenesis and vascular permeability attributed to the release of angiogenic molecules, most notably vascular endothelial growth factor. However, the relative contribution of these paracrine mediators to the angiogenic and exudative phenotype of KS lesions remains unclear. Here we show that vGPCR up-regulation of Angiopoietin-like 4 (ANGPTL4) plays a prominent role in promoting the angiogenesis and vessel permeability observed in KS. Indeed, ANGPTL4 expression is a hallmark of vGPCR experimental and human KS lesions. Inhibition of ANGPTL4 effectively blocks vGPCR promotion of the angiogenic switch and vascular leakage in vitro and tumorigenesis in vivo. These observations suggest that ANGPTL4 is a previously unrecognized target for the treatment of patients with KS. As angiogenesis and increased vessel permeability are common themes in all solid tumors, these findings may have a broad impact on our understanding and treatment of cancer.
Ma
Tao
T
Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, MD 21201, USA.
Jham
Bruno C
BC
Hu
Jiadi
J
Friedman
Eitan R
ER
Basile
John R
JR
Molinolo
Alfredo
A
Sodhi
Akrit
A
Montaner
Silvia
S
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000096:biosynthesis* / Q000235:genetics; D002199:Capillary Permeability; D002460:Cell Line; D054884:Host-Pathogen Interactions; D006801:Humans; D009389:Neovascularization, Pathologic; D019899:Paracrine Communication; D019707:Receptors, Chemokine / Q000502:physiology*; D012514:Sarcoma, Kaposi / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A
C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C115448:G protein-coupled receptor, Human herpesvirus 8; D019707:Receptors, Chemokine; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A