Angiopoietin-like 4: A novel molecular hallmark in oral Kaposi’s sarcoma
Introduction
KS is a multifocal vascular neoplasm that often affects the oral cavity in immunosuppressed patients.1 First described as a skin cancer in older men of Jewish or Mediterranean ancestry, a dramatic change in the epidemiology and clinical course of KS occurred with the emergence of the acquired immune deficiency syndrome (AIDS).2 Today, KS remains as one of the most common malignancies affecting HIV-infected individuals and is the most frequent cancer among children and adult men in countries of sub-Saharan Africa.2 Unfortunately, clinical management of KS continues to be a challenge.
A scientific leap in our understanding of the pathogenesis of KS was made possible with the identification of a novel human herpesvirus, HHV8, named Kaposi’s sarcoma associated herpesvirus (KSHV), as the etiological agent for this tumor.3 Subsequent work from several groups suggests that endothelial cell infection with KSHV is indeed a prerequisite for KS development, and results in the formation of the KS tumor (or spindle) cell. These KS spindle cells are the driving force of KS lesion, elaborating angiogenic growth factors and cytokines that promote the formation of this vascular tumor.2
Emerging evidence supports a key role for a viral protein, the KSHV G protein-coupled receptor (vGPCR), in the initiation and promotion of KS.2 vGPCR is a member of the family of CXC chemokine GPCRs, with closest homology to CXCR2, but with ligand-independent (constitutive) activity. Endothelial cells expressing vGPCR elaborate angiogenic growth factors and cytokines that have been suggested to promote tumor formation through a unique paracrine mechanism.2 Indeed, transgenic mice that express vGPCR manifest dermal angioproliferative lesions that closely resemble those seen in KS.[4], [5], [6] These observations have prompted intense investigation into identifying the molecular mechanism(s) whereby vGPCR could play a role in Kaposi’s sarcomagenesis.
Initial work on the contribution of vGPCR to KS development appropriately centered on the upregulation by this viral receptor of the potent endothelial cell mitogen, VEGF, a key player in KSHV pathogenesis.[7], [8] However, we recently identified a novel angiogenic factor, ANGPTL4, which also appears to play an essential role in vGPCR tumorigenesis, promoting angiogenesis and vascular permeability.9 Here we set out to examine the prevalence of ANGPTL4 upregulation in oral KS lesions.
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Cell lines and reagents
pCEFL AU5 vGPCR, pCEFL AU5 GFP, pBIG AU5 vGPCR and pCEFL Tet REV TA have been previously described.[5], [9] HMEC1s were obtained from the CDCs (Atlanta, GA) and grown as described elsewhere.9 Cells were transfected with Polyfect (Qiagen). Conditioned media was prepared as previously described.9 Recombinant proteins were purchased from Pepro Tech. Concentrations used are: IL-8 (50 ng/ml), GROα (50 ng/ml), PDGF (25 ng/ml), IL-1β (10 ng/ml), IL-10 (25 ng/ml), IL-6 (2 ng/ml), TNFα (25 ng/ml), IP-10 (50
Results
KS is a vascular tumor promoted by KSHV infection and the resultant expression of different viral genes and microRNAs.2 Work from several labs has supported a key role for dysregulated expression of the KSHV-encoded GPCR (vGPCR) in the promotion of KS.2 Transgenic mice expressing this viral receptor in endothelial cells manifest vascular tumors (vGPCR tumors) histologically similar to human KS, with expression of vGPCR limited to a few cells, suggestive of a paracrine mechanism for vGPCR
Discussion
KS is a multifocal vascular tumor with lesions predominately affecting the skin and oral mucosa.1 KS tumorigenesis develops in response to infection by KSHV; indeed, expression of KSHV-encoded latent genes (e.g. LANA1) can be detected in most tumor cells within oral KS lesions. Interestingly, the KSHV lytic protein, vGPCR, expressed only in a few tumor cells, appears to be important in KS development through a unique paracrine mechanism.2 The role of vGPCR in KS initiation and maintenance
Conflict of interest statement
The authors declare that they have no conflict of interest.
Acknowledgments
This work was supported by grant R01CA119911 (National Cancer Institute, NIH). B.C.J. is a recipient of a predoctoral fellowship from the CNPq-Brazil. We thank Dr. Gary S. Hayward (Johns Hopkins University) for kindly providing the specific antibody recognizing KSHV vGPCR. We also thank Dr. Akrit Sodhi (Johns Hopkins University) for insightful suggestions and discussion.
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Cited by (31)
KSHV non-structural membrane proteins involved in the activation of intracellular signaling pathways and the pathogenesis of Kaposi's sarcoma
2016, Current Opinion in VirologyCitation Excerpt :Ang-2 can induce vascular remodeling and blood vessel sprouting by increasing proliferation and migration of endothelial cells in concert with other endogenous proangiogenic molecules such as VEGF [59]. AngPTL-4, another novel proangiogenic factor recently shown to be highly expressed in KS lesions more abundantly than VEGF, is also up regulated in response to vGPCR expression and promotes neovascularization and vascular leakage both in vitro and in vivo [60,61]. Additionally, vGPCR-induced activation of PI3K-γ/Rac has been shown to result in an increase internalization of VE-cadherin, loss of cell-cell junction and barrier integrity which in turn increases vascular permeability [62].
Angiopoietin-like 4 enhances metastasis and inhibits apoptosis via inducing bone morphogenetic protein 7 in colorectal cancer cells
2015, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Angiopoietin-like protein 4 (ANGPTL4), a secreted protein, exerts multifunctional roles in many aspects of tumorigenesis, such as motility, metastasis, apoptosis, angiogenesis, tumor-microenvironment, wound healing, vascular permeability and inflammation [2–7]. ANGPTL4 was up-regulated and could promote cancer occurrence and development in glioblastoma, breast cancer, oral Kaposi's sarcoma and clear cell renal-cell carcinoma [8–10]. ANGPTL4 can disrupt vascular endothelial cell–cell junctions and primes breast cancer cells for metastasis to the lungs by TGF-β/smad4 complex-induced expression [9].
Manipulation of endothelial cells by KSHV: Implications for angiogenesis and aberrant vascular differentiation
2014, Seminars in Cancer BiologyCitation Excerpt :Both vGPCR and vIL6 have been shown to induce the expression of Ang2 in LECs through the MAPK pathway, which would provide another mechanism for KSHV to modulate (lymph)angiogenesis by sensitizing ECs to the effect of VEGF [33], as discussed above. ANGPTL4, a multifunctional cytokine that is involved in the regulation of lipid metabolism and angiogenesis, is also strongly expressed in KS tissue [83]. ANGPTL4 expression is induced by vGPCR, and is mediating vGPCR-induced effects in primary ECs, such as increased migration, angiogenic tube formation, increased vascular permeability and angiogenic tumors in mice engrafted with the vGPCR-expressing ECs [84].
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