Elsevier

Oral Oncology

Volume 47, Issue 5, May 2011, Pages 371-375
Oral Oncology

Angiopoietin-like 4: A novel molecular hallmark in oral Kaposi’s sarcoma

https://doi.org/10.1016/j.oraloncology.2011.02.018Get rights and content

Summary

Kaposi’s sarcoma (KS) remains among the most common causes of oral cancer in HIV-infected individuals. Infection with the KS-associated herpesvirus (KSHV/HHV8) is a necessary event for disease development. Emerging evidence suggests that KSHV infects vascular endothelial (or endothelial progenitor) cells promoting the formation of the KS tumor (or spindle) cell. These cells elaborate angiogenic growth factors and cytokines that promote the dysregulated angiogenesis and profuse edema that characterizes this unusual vascular tumor. Central among these secreted factors is the potent endothelial cell mitogen, vascular endothelial growth factor (VEGF). Indeed, VEGF has proven to be a key player in KSHV pathogenesis and is a molecular hallmark of KS lesions. We have recently shown that a second angiogenic factor, Angiopoietin-like 4 (ANGPTL4), may also play a critical role in KS development. Here we demonstrate that ANGPTL4 is upregulated both directly and indirectly by the KSHV oncogene, vGPCR. We further show that ANGPTL4 is a molecular hallmark of oral KS lesions. Indeed, expression of this protein was observed in more tumor cells and in more biopsies specimens than expression of VEGF (23/25 or 92% vs. 19/25 or 76%, respectively) in oral KS. These surprising results support a key role for ANGPTL4 in Kaposi’s sarcomagenesis and further suggest that this angiogenic factor may provide a novel diagnostic and therapeutic marker for oral KS patients.

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.

Section snippets

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.

References (21)

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