Viral G protein-coupled receptor up-regulates Angiopoietin-like 4 promoting angiogenesis and vascular permeability in Kaposi's sarcoma

Abstract

Kaposi's sarcoma (KS) is an enigmatic vascular tumor thought to be a consequence of dysregulated expression of the human herpesvirus-8 (HHV-8 or KSHV)-encoded G protein-coupled receptor (vGPCR). Indeed, transgenic animals expressing vGPCR manifest vascular tumors histologically identical to human KS, with expression of the viral receptor limited to a few cells, suggestive of a paracrine mechanism for vGPCR tumorigenesis. Both human and vGPCR experimental KS lesions are characterized by prominent angiogenesis and vascular permeability attributed to the release of angiogenic molecules, most notably vascular endothelial growth factor. However, the relative contribution of these paracrine mediators to the angiogenic and exudative phenotype of KS lesions remains unclear. Here we show that vGPCR up-regulation of Angiopoietin-like 4 (ANGPTL4) plays a prominent role in promoting the angiogenesis and vessel permeability observed in KS. Indeed, ANGPTL4 expression is a hallmark of vGPCR experimental and human KS lesions. Inhibition of ANGPTL4 effectively blocks vGPCR promotion of the angiogenic switch and vascular leakage in vitro and tumorigenesis in vivo. These observations suggest that ANGPTL4 is a previously unrecognized target for the treatment of patients with KS. As angiogenesis and increased vessel permeability are common themes in all solid tumors, these findings may have a broad impact on our understanding and treatment of cancer.

Emerging Roles of Angiopoietin-like 4 in Human Cancer

“…This increase in ANGPTL4 expression enhanced endothelial cell migration and differentiation, both of which are important processes in angiogenesis, resulting in markedly enhanced neovascularization. The inhibition of ANGPTL4 using siRNA prevented the neovascularization process and reduced vascular permeability as well as vGPCR-induced tumorigenesis in vivo (43). In subsequent studies, Huang and colleagues revealed that ANGPTL4-knockdown allograft tumors express consistently lower levels of endothelial cell marker CD31 compared with wild-type allograft tumors, which is indicative of impaired angiogenesis, further confirming the proangiogenic role of ANGPTL4 in tumors (21).…”

“…Using a transgenic mouse model expressing a viral Gprotein coupled receptor (vGPCR), ANGPTL4 expression was upregulated by vGPCR in Kaposi sarcoma (43). This increase in ANGPTL4 expression enhanced endothelial cell migration and differentiation, both of which are important processes in angiogenesis, resulting in markedly enhanced neovascularization.…”

“…Unfortunately, numerous studies that have attempted to decipher the role of ANGPTL4 in cancer have failed to address the posttranslational modifications and proteolytic processing of ANGPTL4, which clearly have a significant influence on the functions of ANGPTL4 (10,30,37,(47)(48)(49). For example, the expression of either the nANGPTL4 or the cANGPTL4 truncation in transgenic mice remains unknown (43). The differential processing of ANGPTL4 has a major effect on the different biological functions of ANGPTL4 under various contexts and may have contributed to the observed discrepancies (11,21,50).…”

Advanced glycation end products upregulate angiopoietin-like protein 4 expression by activating the renin-angiotensin system in endothelial cells

“…Previous studies suggest that ANGPTL4 has complex and contradictory roles in vascular biology and tumor metastasis (3)(4)(5). However, the effects of AGEs on ANGPTL4 in endothelial cells remain uncertain and not fully understood.…”

“…Galaup et al (3) found that ANGPTL4 prevents tumor metastasis through inhibition of vascular permeability, tumor cell motility and invasiveness. However, more recent studies (4,5) showed that ANGPTL4 in cancer cells disrupts vascular endothelial cell-cell junctions, increases the permeability of lung capillaries and facilitates the transendothelial passage of tumor cells. Upregulation of ANGPTL4 has a prominent effect on promoting the angiogenesis and vessel permeability in Kaposi's sarcoma (8).…”