Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes

Montaner, Silvia; Sodhi, Akrit; Molinolo, Alfredo A.; Bugge, Thomas H.; Sawai, Earl T.; Yunsheng, He; Li, Yang; Ray, Patricio E.; Gutkind, J. Silvio

doi:10.1016/s1535-6108(02)00237-4

Cited by 332 publications

(409 citation statements)

References 53 publications

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“…However, the ORF74 gene, which encodes a viral G-protein-coupled receptor (vGPCR), has the unique ability to recapitulate KS-like tumor progression when expressed in the endothelial cell compartment in mice models (Montaner et al, 2003;Grisotto et al, 2006;Mutlu et al, 2007). HHV8 vGPCR is a seven span transmembrane constitutively active receptor coupled to a heterotrimeric G protein, whose closest homologue is the chemokine receptor CXCR2 (Bais et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

et al. 2010

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Kaposi Sarcoma (KS) are opportunistic tumors, associated with human herpes virus 8 (HHV8) infection. KS development is highly favored by immune-depression and remains the second most frequent tumor in acquired immune deficiency syndrome patients. Although it has been shown that experimental expression of the HHV8 G-proteincoupled receptor (vGPCR) in the endothelial compartment is alone sufficient to recapitulate the formation and progression of KS-like lesions, its functional effects on endothelial homeostasis are not fully understood. Here we show that vGPCR expression in endothelial cells induces an increase in paracellular permeability both in vivo and in vitro. By using pharmacological inhibitors and small interference RNA-based knockdown, we demonstrate an essential role for the PI(3)Kinase-c/Rac nexus in vGPCRmediated permeability. This was further accompanied by dramatic remodeling of VE-cadherin-dependent cell-cell junctions. Importantly, this in vitro vGPCR-initiated signaling signature was observed in a large panel of human KS. Altogether, our results support the hypothesis that endothelial vGPCR signaling is co-opted in KS, and unveil new key cellular targets for therapeutic intervention.

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Section: Introductionmentioning

confidence: 99%

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

et al. 2010

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“…Most viral 7TM receptors characterized to date are dispensable for viral replication in vitro but are important for viral success in vivo (Davis-Poynter et al, 1997;Vieira et al, 1998;Beisser et al, 1999), presumably because of their function as immune-evasion molecules and/or their involvement in viral dissemination (Bodaghi et al, 1998;. It has been shown previously that ORF74 from KSHV is a potential oncogene because of its ability to transform cells in vitro (Bais et al, 1998;Pati et al, 2001) and induce Kaposi's sarcoma-like lesions in mice (Yang et al, 2000;Montaner et al, 2003). Interestingly, US28 has also been shown to transform cells in vitro and form tumors in nude mice (Maussang et al, 2006).…”

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confidence: 99%

Cell transformation mediated by the Epstein–Barr virus G protein-coupled receptor BILF1 is dependent on constitutive signaling

et al. 2010

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Epstein-Barr virus (EBV) open reading frame BILF1encodes a seven trans-membrane (TM) G protein-coupled receptor that signals with high constitutive activity through Ga i Paulsen et al., 2005). In this paper, the transforming potential of BILF1 is investigated in vitro in a foci formation assay using retrovirally transduced NIH3T3 cells, as well as in vivo by using nude mice. BILF1 revealed a substantial transforming potential that was dependent on constitutive signaling, as a signaling-deficient mutant completely lost its ability to transform cells in vitro, and an intermediately active triple-mutated receptor possessed an intermediate transforming potential. Furthermore, BILF1 expression induced vascular endothelial growth factor secretion in a constitutively active manner. In nude mice, BILF1 promoted tumor formation in 90% of cases, ORF74 (from Kaposi's sarcoma-associated herpes virus) in 100% of cases, whereas the signaling-deficient receptor resulted in tumor establishment in 40% of cases. These data suggest that BILF1, when expressed during EBV infection, could indeed be involved in the pathogenesis of EBV-associated diseases and malignancies. Furthermore, the correlation between receptor activity and the ability to mediate cell transformation in vitro and tumor formation in vivo supports the idea that inverse agonists for BILF1 could inhibit cell transformation and be relevant therapeutic candidates.

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“…48 In an animal model, transduction of the vGPCR gene played a critical role in inducing angioproliferative tumors very similar to human KS. 50 Immunohistochemical staining did not find significant VEGF in KS lesions. 51 However, Cornali et al 52 found high amounts of VEGF mRNA and protein present in KS spindle cells.…”

Section: Cutaneous Lymphoma Key Points Dmentioning

confidence: 83%

Angiogenesis in cutaneous disease: Part II

Laquer

Hoang

Nguyen

et al. 2009

Journal of the American Academy of Dermatology

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This review will discuss the role of angiogenesis in specific cutaneous diseases. Scientific evidence now points to the role of angiogenesis in tumor development and many other cutaneous disorders. Angiogenesis is a complex process that involves angiogenic growth factors and inhibitors, many of which could be a potential target for pharmacologic intervention. Antiangiogenic agents have recently been applied to dermatologic diseases with promising efficacy. ( J Am Acad Dermatol 2009;61:945-58.)Learning objectives: After completing this learning activity, participants should be able to recognize cutaneous diseases where angiogenesis is likely to be an important factor, recognize scenarios where angiogenic therapy may be useful in conjunction with traditional therapies, and be able to use angiogenicmediating agents in the treatment of dermatologic disease.

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Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes

Cited by 332 publications

References 53 publications

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

Cell transformation mediated by the Epstein–Barr virus G protein-coupled receptor BILF1 is dependent on constitutive signaling

Angiogenesis in cutaneous disease: Part II

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