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(The FASEB Journal. 2004;18:422-427.)
© 2004 FASEB

Does dysregulated expression of a deregulated viral GPCR trigger Kaposi’s sarcomagenesis?

AKRIT SODHI1, SILVIA MONTANER and J. SILVIO GUTKIND1

Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA

1Correspondence: 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, MD 20892-4330, USA. E-mail: sg39v@nih.gov; asodhi{at}nidcr.nih.gov

ABSTRACT

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.—Sodhi, A., Montaner, S., Gutkind, J. S. Does dysregulated expression of a deregulated viral GPCR trigger Kaposi’s sarcomagenesis?


Key Words: Kaposi’s sarcoma-associated herpesvirus • human herpesvirus-8 • G-protein-coupled receptor • HIV

KAPOSI’S SARCOMA-ASSOCIATED HERPESVIRUS

KAPOSI'S SARCOMA (KS) remains the most frequent neoplasm in AIDS patients, and has tragically emerged as the most prevalent cancer in children and adult men in parts of the developing world (1) . The recent identification of the Kaposi’s sarcoma-associated herpesvirus (KSHV) as the etiologic agent for KS (2) has promised a new era in KS research (3) . Within only a few years of its initial discovery, the combined work from several labs has firmly established KSHV as the cause of KS. Current efforts have since focused on defining the mechanism whereby this virus causes cancer. KSHV contains >80 open reading frames (ORFs), including several homologues to mammalian proteins likely pirated by KSHV from its cellular host (Fig. 1 ); further investigation proved that several of these genes bear potential for KSHV pathogenesis. However, reasonable disagreement exists as to which KSHV gene(s) may be responsible for the initiation of cell transformation. Ironically, this is due not to the lack of candidate viral oncogenes, but rather to the remarkable redundancy in KSHV genes that bear transforming potential. This is further exacerbated by an inability to effectively generate KSHV deletion mutants due in part to the limited ability to culture recombinant virus in vitro.



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  		Figure 1. KSHV genome. Latent genes in blue, lytic genes in red. *Genes previously shown to be transforming in vivo.

KSHV LATENT GENES

Initial efforts to identify the KSHV gene(s) responsible for the initiation of KS focused primarily on viral latent genes (LANA-1, LANA-2, vCyclin, vFlip, and Kaposin). These genes are expressed in almost all spindle cells in late KS lesions, and were therefore predicted to play a critical role in Kaposi’s sarcomagenesis. Several recent studies have suggested that many of the KSHV latent genes bear potential for the initiation of KS through myriad of mechanisms (Table 1 ). However, despite mounting experimental evidence that KSHV latent genes may harbor oncogenic potential, it remained to be determined which of these genes contributes to the initiation of KS.


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  		Table 1. Proliferative advantage of KSHV latent genes

To address this question, Montaner et al. recently engineered a transgenic mouse line expressing the avian leucosis virus (ALV) receptor, tv-a, under the direction of the vascular endothelial cell-specific TIE2 promoter (TIE2-tva mice), enabling the somatic introduction of candidate KSHV oncogenes in a tissue-specific manner (4) . Surprisingly, although several of the latent genes were expected to play an important role in driving Kaposi’s sarcomagenesis, none appeared to be sufficient alone to initiate endothelial cell transformation in this system. Endothelial infection with virus expressing both vCyclin and vFlip similarly failed to initiate KS lesions. Although they may promote cell proliferation, latent genes, either individually or in combination, do not appear to be sufficient to initiate Kaposi’s sarcomagenesis. Indeed, latent gene expression is readily detected in most KSHV-infected patients, who only rarely go on to develop KS (5 , 6) . Collectively, these results raised the unexpected possibility that the gene(s) responsible for the initiation of KSHV-associated tumors may not be latent genes.

KSHV LYTIC GENES

Lytic genes are expressed during the phase of the viral life cycle when viral progeny are produced. Consequently, these viral genes are expressed in cells ultimately destined to die (lyse). It is therefore generally believed that lytic genes are not likely to play a significant role in oncogenesis. However, emerging evidence supports a role for lytic genes in the genesis of KSHV-associated malignancies. Among the lytic genes, the KSHV G-protein-coupled receptor (vGPCR) is perhaps the leading candidate for the gene responsible for the initiation of KS (4) .

The KSHV vGPCR is a member of the family of CXC chemokine G-protein-linked receptors (7 , 8) , with significant homology to CXCR1 and CXCR2. However, this receptor exhibits ligand-independent activities (9) . Different intracellular signaling molecules have been shown to be activated by vGPCR, including MAPK, p38, and JNK (10 , 11) , which in turn may control the expression of growth-promoting genes. In addition, activation of the serine-threonine kinase Akt by vGPCR may represent a critical intracellular pathway in the blockade of cell death (12) as this kinase acts on a large number of target molecules involved in the control of apoptotic signals and in the promotion of cell survival (13) . It has also been shown that vGPCR induces the secretion of angiogenic growth factors from expressing cells, including VEGF, IL-8, and Gro-{alpha} (10 , 14 15 16 17) , suggesting that vGPCR may serve a role both in direct cell transformation and indirect (paracrine) cell transformation (Fig. 2 ). Recent evidence further supports a role for chemokines in the potentiation of vGPCR signaling (12 , 18) , suggesting that chemokines secreted by vGPCR-expressing cells may play an additional role in enhancing vGPCR direct cell transformation in an autocrine fashion. Equally intriguing is the observation that human endothelial cells infected by KSHV or ectopically expressing vGPCR up-regulate the expression of the VEGF receptor KDR2, which will be activated by tumor-released VEGF (19 , 20) . Taken together, these results point to a complex interplay between direct and autocrine/paracrine cell transformation that, together with yet-to-be identified additional molecular mechanisms, may explain the potent oncogenic potential of vGPCR.



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  		Figure 2. Transforming pathways activated by vGPCR.

Work by several labs has provided convincing evidence implicating vGPCR in KSHV oncogenesis (4 , 10 , 12 , 14 , 20 21 22) . Most notably, when a KS model in which endothelial-specific retroviral transduction was used, vGPCR produced vascular tumors in mice that were strikingly similar to human KS lesions (Fig. 3 ) (4) , suggestive of an important role for vGPCR in the initiation of KS. In addition to their histological and ultrastructural similarity to human lesions, vGPCR-induced tumors had a unique predilection for the dermis, similar to human KS, suggesting that dermal endothelial cells may be particularly vulnerable to vGPCR-induced sarcomagenesis; this may help explain why systemic infection with KSHV often manifests only with dermal KS lesions. Furthermore, by the use of immortalized murine endothelial cells expressing key latent KSHV genes, it has been reported that cells expressing vGPCR cooperate with cells expressing latent genes to promote tumorigenesis in a KS allograft model (4) . These results further implicate vGPCR in the progression of Kaposi’s sarcomagenesis.



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  		Figure 3. H- and E-stained sections of a vGPCR-induced experimental tumor using the TIE2-tva KS mouse model (A) and a biopsy from a patient with AIDS-associated KS (B). Both experimental and human KS have a unique predilection for the skin.

Of note, two transgenic animals that express vGPCR under either a ubiquitous (SV40) promoter (22) or a T cell-specific (CD2) promoter (21) only manifest vascular tumors. This unexpected observation is consistent with a unique susceptibility of vascular endothelial cells to the combined direct and paracrine transforming pathways activated by vGPCR. However, this further suggests that vGPCR may not be the viral gene responsible for the initiation of the two other KSHV-associated malignancies, PEL and MCD. Thus, although these three disparate malignancies share the same viral etiologic origins, their viral oncogenic origins may be distinct. Nonetheless, experimental evidence strongly supports a role for vGPCR as the KSHV gene responsible for the initiation and progression of KS.

HYPOTHESIS: DYSREGULATION OF VIRAL GENE PROGRAMS TRIGGERS KAPOSI’S SARCOMAGENESIS

These observations raise an intriguing question: How can a viral lytic gene, normally expressed only in cells destined for lysis, induce a tumor? This conundrum assumes that KSHV respectfully adheres to our strict definitions for latent and lytic viral gene expression. It is certainly possible that KSHV is not so well behaved, at least under unique circumstances, thus enabling cells expressing vGPCR to defy their lytic destiny. It is under these circumstances that dysregulation of the normal viral gene program-evolved to promote efficient viral replication and propagation, but not host death—may trigger KS.

Transient lytic expression of vGPCR
During the normal viral life cycle, vGPCR is indeed a lytic gene. Its potent transforming potential is kept in check through multiple mechanisms. 1) vGPCR is transcribed within the 3' end of a bicistronic mRNA, thus restricting its expression (23) . 2) Host cytokines (e.g., SDF-1 {alpha}, IP-10) act as antagonists to vGPCR signaling (24 , 25) . 3) KSHV itself encodes a lytic gene, vMIP2, whose protein product acts as an antagonist to vGPCR signaling (25) . 4)As mentioned above, as a lytic gene, vGPCR is expressed in cells ultimately destined to die.

Consequently, proliferative signals initiated by vGPCR (in cooperation with other KSHV lytic genes) may serve only to prolong lytic cell survival to ensure efficient viral replication. Concomitantly, proangiogenic growth factors secreted by vGPCR-expressing cells may function to recruit neighboring endothelial cells, which are then infected by the newly formed progeny virion. Of note, the highly related murine gammaherpesvirus-68 also encodes a GPCR (ORF74) that functions by promoting efficient viral replication (26) . Newly infected endothelial cells may either repeat this lytic cycle or enter latency, during which KSHV latent genes are expressed (Fig. 4 A). Thus, transient lytic expression of vGPCR may ensure successful viral propagation but is not likely to be sufficient to trigger KS.



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  		Figure 4. Consequences of normal (lytic) (A) and dysregulated (nonlytic) (B) expression and signaling of vGPCR. A) Proliferative signals initiated by vGPCR prolong lytic cell survival to ensure efficient viral replication. Concomitantly, proangiogenic growth factors secreted by vGPCR-expressing cells recruit neighboring endothelial cells that are then infected by the newly formed progeny virion. B) Unregulated vGPCR signaling to survival pathways promote direct cell transformation while continuous secretion of chemokines and growth factors induce the recruitment and subsequent indirect (paracrine) cell transformation of neighboring endothelial cells.

Dysregulation of vGPCR
How can vGPCR be responsible for the initiation of KS tumors if its expression and signaling are so tightly controlled? We hypothesize that under special circumstances (e.g., HIV co-infection, inflammation, aborted lytic cycle progression), dysregulation of the normal viral program may result in nonlytic expression and enhanced signaling of vGPCR, ultimately manifesting as KS.

Several studies suggest that this attractive, albeit unconventional, paradigm may prove true. 1) HIV Tat increases expression of KSHV lytic genes, including vGPCR, whose expression is significantly enhanced in aggressive AIDS-KS as compared with the more benign classical KS lesions (27) . 2) Several inflammatory cytokines released by HIV infected cells (including IL-8 and Gro-{alpha}; ref 28 ) can increase vGPCR signaling (18) . The critical role for these locally released inflammatory cytokines for vGPCR oncogenesis was recently confirmed by a transgenic animal encoding a mutant vGPCR lacking a ligand binding domain that failed to manifest tumors despite its constitutive activity (29) . Ultimately, co-infection with other pathogens, including (but not limited to) HIV as well as inflammatory processes that result in increased release of inflammatory cytokines, may promote KS by stimulating vGPCR signaling. This may help explain the extensive prevalence of endemic KS in sub-Saharan African countries, regardless of HIV co-infection, and may account for the occurrence of KS lesions at the site of surgical wounds (30) . 3) Finally, it is possible that a disruption of the normal lytic program may result in an aborted lytic cycle and the consequent deregulated expression of vGPCR.

Regardless of the nature of the triggering event, which is likely to be different in different forms of KS (in both etiology and efficiency), the end result is (over-) expression of and increased signaling by vGPCR in nonlytic cells. Under these circumstances, we propose that unregulated vGPCR signaling to survival pathways may promote direct cell transformation while the continuous secretion of chemokines and growth factors may induce the recruitment and subsequent indirect (paracrine) cell transformation of neighboring endothelial cells (Fig. 4B ). As a fraction of cells may continue to produce new viral progeny, recruited endothelial cells in late-stage KS lesions could ultimately be latently infected with KSHV, thus explaining the expression of latent genes in the bulk of nodular KS tumors. Although alone not transforming, latent genes may nonetheless enhance tumor cell proliferation (4) , contributing to the more aggressive nature of late-stage or "nodular" KS tumors.

This theory further predicts a second function for immunosuppression in Kaposi’s sarcomagenesis. It is reasonable to speculate that in immunocompetent KSHV-infected individuals, the host immune system readily detects and clears KSHV-infected endothelial cells expressing high levels of this viral transmembrane protein, thereby preventing vGPCR from promoting KS development. Conversely, in addition to facilitating KSHV replication, immunosuppression may further enable KSHV-infected cells overexpressing vGPCR to escape detection by the host immune system, allowing these cells to facilitate Kaposi’s sarcomagenesis. This may help explain the strong correlation between increased or decreased levels of immunosuppression and the rapid progression or regression of KS lesions, respectively, in organ transplant and HIV-infected patients.

TESTING THE HYPOTHESIS OF vGPCR DYSREGULATION

The theory that Kaposi’s sarcoma is triggered by dysregulation of a lytic gene, vGPCR, makes two assumptions: 1) dysregulated expression and activity of vGPCR in a fraction of tumor cells is necessary and sufficient to initiate KS; and 2) an event must occur to trigger vGPCR dysregulation.

The first assumption was recently addressed in animal models and appears to hold true (4 , 21 , 22) . If so, treating KS patients with drugs that specifically target vGPCR could help establish the importance of vGPCR in human Kaposi’s sarcomagenesis. Recent studies demonstrating that a point mutation rendering vGPCR agonist-dependent abrogates its tumorigenic potential (A. Sodhi et al., unpublished results) suggest that peptide analogs of vGPCR antagonists (e.g., IP-10 and SDF-1{alpha}) may be suitable candidates for anti-KS therapy. Indeed, as G-protein-coupled receptors are the targets of more than half of all drugs currently available in the market, vGPCR may prove to be a vulnerable target for the treatment of KS.

The second assumption, the dysregulating or activating event, requires further investigation. Although lytic expression of vGPCR may itself contribute to KS, we suggest it is unlikely that the transient expression associated with normal viral lytic genes (i.e., expression for only a few hours prior to cell lysis) would be sufficient for vGPCR to initiate KS. Indeed, all current vGPCR KS animal models mimic dysregulated vGPCR expression in nonlytic cells (4 , 21 , 22) . Thus, an unidentified triggering event leading to dysregulated vGPCR expression is almost certainly required for vGPCR sarcomagenesis. Identifying this dysregulating event may be difficult. Leading candidates include HIV-1 Tat, inflammation, and aborted lytic cycle progression. Regardless of which of these candidate(s) endure experimental challenge, their identification could expose additional targets for therapeutic intervention.

One corollary to the dysregulation hypothesis is that there must be two populations of vGPCR-expressing cells: normal lytic cells, and dysregulated nonlytic cells. Indeed, the response of KS patients to the two anti-viral drugs acyclovir and ganciclovir—potent inhibitors of herpesvirus lytic cycle progression—may be limited due in part to the persistent dysregulated (nonlytic) expression of vGPCR in these lesions. This could be tested in human lesions by the presence of persistent vGPCR expression despite treatment with these anti-lytic drugs. Of note, two vGPCR-encoding transcripts were recently identified in KSHV-induced lesions: the lytic 2.7 kb bicistronic K14/vGPCR transcript and a previously unrecognized 1.4 kb monocistronic vGPCR transcript (31) . Whereas the former (bicistronic) transcript is regulated by the KSHV lytic transcription factor ORF50 (Rta), the latter may prove to be a nonlytic transcript of dysregulated vGPCR-expressing cells. These two cell populations could be distinguished in human lesions using in situ hybridization and transmission electron microscopy. In addition to supporting the dysregulation hypothesis, identification of two vGPCR-expressing cell populations would demonstrate that viruses may not always conform to our conventional definitions of lytic vs. latent gene expression.

CONCLUSIONS

Evidence for increasingly aggressive disseminated KS in sub-Saharan Africa (32) , along with the recent outbreaks of highly pathogenic multi-drug resistant forms of other AIDS-associated pathogens in the developed world (33) , suggests there is a real potential for a re-emergence of more aggressive forms of KS on a pandemic scale. It is therefore critical that we rapidly take steps toward identifying the gene(s) responsible for KSHV pathogenesis. Emerging evidence supporting a role for dysregulated expression of a lytic gene in the initiation and progression of KS may ultimately lead to a path toward understanding the origin of this enigmatic tumor. Indeed, this intriguing theory could resolve many unanswered questions regarding Kaposi’s sarcomagenesis and may represent a new paradigm in viral oncology. If proved true, it may prompt us to reconsider our current approaches for identifying potential viral oncogenes. This will undoubtedly have a broad impact on how researchers and clinicians think about viral oncogenesis and may further facilitate the identification of novel treatment modalities to help patients in desperate need of effective therapies.

Received for publication September 26, 2003. Accepted for publication November 10, 2003.

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R. Yarchoan
Key role for a viral lytic gene in Kaposi's sarcoma.
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S. Montaner, A. Sodhi, A. K. Ramsdell, D. Martin, J. Hu, E. T. Sawai, and J. S. Gutkind
The Kaposi's Sarcoma-Associated Herpesvirus G Protein-Coupled Receptor as a Therapeutic Target for the Treatment of Kaposi's Sarcoma
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M. Cannon, E. Cesarman, and C. Boshoff
KSHV G protein-coupled receptor inhibits lytic gene transcription in primary-effusion lymphoma cells via p21-mediated inhibition of Cdk2
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S. J. Paulsen, M. M. Rosenkilde, J. Eugen-Olsen, and T. N. Kledal
Epstein-Barr Virus-Encoded BILF1 Is a Constitutively Active G Protein-Coupled Receptor
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S. Montaner, A. Sodhi, J.-M. Servitja, A. K. Ramsdell, A. Barac, E. T. Sawai, and J. S. Gutkind
The small GTPase Rac1 links the Kaposi sarcoma-associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia
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