In Vivo-Restricted and Reversible Malignancy Induced by Human Herpesvirus-8 KSHV: A Cell and Animal Model of Virally Induced Kaposi's Sarcoma

Mutlu, Agata D.Agostino; Cavallin, Lucas E.; Vincent, Loı̈c; Chiozzini, Chiara; Eroles, Pîlar; Duran, Elda M.; Asgari, Zahra; Hooper, Andrea T.; Perle, Krista M. D. La; Hilsher, Chelsey; Gao, Shou‐Jiang; Dittmer, Dirk P.; Rafii, Shahin; Mesri, Enrique A.

doi:10.1016/j.ccr.2007.01.015

Cited by 151 publications

(261 citation statements)

References 66 publications

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“…Among the HHV8 lytic genes, the ORF74, which encodes vGPCR can be expressed in the endothelial cell compartment where it provokes the apparition of KS-like lesions in mice (Montaner et al, 2003;Grisotto et al, 2006;Mutlu et al, 2007). However, the molecular mechanisms by which vGPCR alters endothelial homeostasis are not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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: Discussionmentioning

confidence: 99%

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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“…But as many investigators have experienced, this is a difficult task, and this explains, at least in part, why our initial efforts have focused on the use of the 293T cell line. Very recently, however, a published report has indicated the formation of KS-like tumors in nude mice following the transfection of the HHV-8 BAC into murine bone marrow endothelial-lineage (mECK36) cells [17]. The model presented by Mutlu et al elegantly demonstrates the oncogenic properties of the HHV-8 BAC and an essential role for v-GPCR in angiogenesis and sarcomagenesis [17].…”

Section: Discussionmentioning

confidence: 99%

“…Very recently, however, a published report has indicated the formation of KS-like tumors in nude mice following the transfection of the HHV-8 BAC into murine bone marrow endothelial-lineage (mECK36) cells [17]. The model presented by Mutlu et al elegantly demonstrates the oncogenic properties of the HHV-8 BAC and an essential role for v-GPCR in angiogenesis and sarcomagenesis [17]. Unlike our 293T-E1 cells, which have comparable latent and lytic HHV-8 transcript levels under in vitro and in vivo conditions, mECK36 tumors express lytic genes much more than in vitro-cultured mECK36 cells.…”

Section: Discussionmentioning

confidence: 99%

Increased tumorigenicity of cells carrying recombinant human herpesvirus 8

et al. 2007

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SummaryHuman herpesvirus 8 (HHV-8) infection is associated with the development of Kaposi's sarcoma and primary effusion lymphoma. The cloning of the HHV-8 genome into a bacterial artificial chromosome (BAC) allows researchers to mutate and identify the relative importance of HHV-8 genes essential for growth and replication in tissue culture systems. However, in vivo models to study the impact of such mutations are very limited. Consequently, the objective of this study was to determine whether cells carrying the HHV-8 BAC would form tumors when injected into mice, enabling the use of this model to assess the influence of viral gene mutation on tumorigenesis. To do so, 293T and 293T-E1 cells carrying recombinant HHV-8 were injected into SCID mice and tumor growth was analyzed. Our results clearly show that mice injected with 293T-E1 cells had a significantly higher tumor incidence level as well as increased tumor volumes and weights compared to mice injected with 293T control cells. Cells carrying the HHV-8 genome grew faster and more aggressively in SCID mice than control 293T cells, highlighting the oncogenic properties of HHV-8. The model presented could therefore be used for the identification of HHV-8 genes contributing to tumorigenesis in the context of the entire viral genome.

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“…Many of the 80 most highly significant EBNA3C-regulated RNAs encode proteins that are implicated in IQGAP and RAC1 signaling. Interestingly, RAC1 signaling is also implicated in Kaposi's sarcoma herpes virus and human papilloma virus (HPV) tumor pathogenesis (57)(58)(59). The principal EBNA3C up-regulated pathway components are RNAs downstream of LYN or TNF.…”

Section: Ebna3c-regulated Genes Overlap With Ebna2-and Ebna3a-regulatedmentioning

confidence: 99%

Epstein–Barr virus nuclear antigen 3C regulated genes in lymphoblastoid cell lines

Mar¹,

Maruo

Lee

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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EBV nuclear antigen 3C (EBNA3C) is an essential transcription factor for EBV transformed lymphoblast cell line (LCL) growth. To identify EBNA3C-regulated genes in LCLs, microarrays were used to measure RNA abundances in each of three different LCLs that conditionally express EBNA3C fused to a 4-OH-Tamoxifen-dependent estrogen receptor hormone binding domain (EBNA3CHT). At least three RNAs were assayed for each EBNA3CHT LCL under nonpermissive conditions, permissive conditions, and nonpermissive conditions with wild-type EBNA3C transcomplementation. Using a two-way ANOVA model of EBNA3C levels, we identified 550 regulated genes that were at least 1.5-fold up-or down-regulated with false discovery rates < 0.01. EBNA3C-regulated genes overlapped significantly with genes regulated by EBNA2 and EBNA3A consistent with coordinated effects on cell gene transcription. Of the 550 EBNA3C-regulated genes, 106 could be placed in protein networks. A seeded Bayesian network analysis of the 80 most significant EBNA3C-regulated genes suggests that RAC1, LYN, and TNF are upstream of other EBNA3C-regulated genes. Gene set enrichment analysis found enrichment for MAP kinase signaling, cytokine-cytokine receptor interactions, JAK-STAT signaling, and cell adhesion molecules, implicating these pathways in EBNA3C effects on LCL growth or survival. EBNA3C significantly up-regulated the CXCL12 ligand and its CXCR4 receptor and increased LCL migration. CXCL12 up-regulation depended on EBNA3C's interaction with the cell transcription factor, RBPJ, which is essential for LCL growth. EBNA3C also up-regulated MYC 1.3-fold and down-regulated CDKN2A exons 2 and 3, shared by p16 and p14, 1.4-fold, with false discovery rates < 5 × 10 −4 . lymphoma | Notch

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In Vivo-Restricted and Reversible Malignancy Induced by Human Herpesvirus-8 KSHV: A Cell and Animal Model of Virally Induced Kaposi's Sarcoma

Cited by 151 publications

References 66 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

Increased tumorigenicity of cells carrying recombinant human herpesvirus 8

Epstein–Barr virus nuclear antigen 3C regulated genes in lymphoblastoid cell lines

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