Does dysregulated expression of a deregulated viral GPCR trigger Kaposi's sarcomagenesis?
In 1994, the Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) was identified as the etiologic agent of Kaposi's sarcoma (KS). KSHV has since been associated with two additional AIDS-related malignancies: primary effusion lymphomas (PEL) and multicentric Castleman's disease (MCD). Although molecular characterization of the KSHV genome has revealed several candidate oncogenes, infection with KSHV alone is not sufficient to cause KS, suggestive of an accomplice in KS initiation. Recent experimental evidence supports a key role for a particular KSHV gene, a constitutively-active G-protein-coupled receptor (vGPCR), in the development of KS. However, it is unclear how a lytic gene expressed in cells destined to die can cause cancer. Here we propose that dysregulation of the viral gene program may lead to nonlytic vGPCR expression. Several candidate cofactors (e.g., HIV-1 Tat, inflammation, aborted lytic cycle progression) are identified that may trigger vGPCR dysregulation, enabling oncogenic signaling pathways up-regulated by vGPCR, combined with the paracrine secretions from vGPCR-expressing cells, to promote the initiation of KS. If KS is indeed dependent on vGPCR dysregulation, then the development of new therapeutic modalities specifically targeting this viral protein or its downstream targets may ultimately prove to be the most effective treatment strategy for this enigmatic disease.
Cell Growth Regulation Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental Research, National Institutes of Health, 30 Convent Dr., Building 30, Room 211, Bethesda, Maryland 20892-4330, USA. asodhi@nidcr.nih.gov
Akrit
A
Sodhi
Silvia
S
Montaner
J Silvio
JS
Gutkind
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019898:Autocrine Communication; D002472:Cell Transformation, Viral / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000821:virology; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000502:physiology; D006678:HIV / Q000502:physiology; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000235:genetics; D019899:Paracrine Communication; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012514:Sarcoma, Kaposi / Q000821:virology*; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000235:genetics; D017735:Virus Latency / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus
D016207:Cytokines; C115448:G protein-coupled receptor, Human herpesvirus 8; D015696:Gene Products, tat; D019707:Receptors, Chemokine; D054322:tat Gene Products, Human Immunodeficiency Virus; D040301:Vascular Endothelial Growth Factor Receptor-2