Angiopoietin-like 4: a novel molecular hallmark in oral Kaposi's sarcoma.

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.