The human herpes virus 8-encoded chemokine receptor is required for angioproliferation in a murine model of Kaposi's sarcoma.
Kaposi's sarcoma (KS)-associated herpesvirus or human herpes virus 8 is considered the etiological agent of KS, a highly vascularized neoplasm that is the most common tumor affecting HIV/AIDS patients. The KS-associated herpesvirus/human herpes virus 8 open reading frame 74 encodes a constitutively active G protein-coupled receptor known as vGPCR that binds CXC chemokines with high affinity. In this study, we show that conditional transgenic expression of vGPCR by cells of endothelial origin triggers an angiogenic program in vivo, leading to development of an angioproliferative disease that resembles KS. This angiogenic program consists partly in the expression of the angiogenic factors placental growth factor, platelet-derived growth factor B, and inducible NO synthase by the vGPCR-expressing cells. Finally, we show that continued vGPCR expression is essential for progression of the KS-like phenotype and that down-regulation of vGPCR expression results in reduced expression of angiogenic factors and regression of the lesions. Together, these findings implicate vGPCR as a key element in KS pathogenesis and suggest that strategies to block its function may represent a novel approach for the treatment of KS.
Jensen
Kristian K
KK
Immunobiology Center, Mount Sinai School of Medicine, New York, NY 10029, USA.
Manfra
Denise J
DJ
Grisotto
Marcos G
MG
Martin
Andrea P
AP
Vassileva
Galya
G
Kelley
Kevin
K
Schwartz
Thue W
TW
Lira
Sergio A
SA
D000818:Animals; D000077214:Becaplermin; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D000072483:Placenta Growth Factor; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011257:Pregnancy Proteins / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D019707:Receptors, Chemokine / Q000235:genetics / Q000502:physiology*; D012514:Sarcoma, Kaposi / Q000098:blood supply / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*
C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D010982:Platelet-Derived Growth Factor; D011257:Pregnancy Proteins; D020574:Proto-Oncogene Proteins c-sis; D019707:Receptors, Chemokine; D014764:Viral Proteins; D000072483:Placenta Growth Factor; D000077214:Becaplermin; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D004318:Doxycycline