Expression of vascular endothelial growth factor receptor-3 and podoplaninsuggests a lymphatic endothelial cell origin of Kaposi's sarcoma tumor cells

Despite intensive research over the past decade, the exact lineage relation ship of Kaposi's sarcoma (KS) tumor cells has not yet been settled. In the present study, we investigated the expression of two markers for lymphatic endothelial cells (EC), ie, vascular endothelial growth factor receptor-3 ( VEGFR-3) and podoplanin, in AIDS and classic KS. Both markers were strongly expressed by cells lining irregular vascular spaces in early KS lesions an d by tumor cells in advanced KS. Double-staining experiments by confocal la ser microscopy established that VEGFR-3-positive and podoplanin-positive ce ll populations were identical and uniformly expressed CD31. By contrast, th ese cells were negative for CD45, CD68, and PAL-E, excluding their hemopoie tic and blood vessel endothelial cell nature. Podoplanin expression in prim ary KS tumor lysates was confirmed by Western blot analysis. Both splice va riants of VEGFR-3 were found in KS-tumor-derived RNA by RT-PCR. In contrast to KS tumor cells in situ, no expression of VEGFR-3 and podoplanin was det ected in any of four KS-derived spindle cell cultures and in one KS-derived autonomously growing cell line (KS Y-1). Our findings that KS tumor cells express two lymphatic EC markers in situ strongly suggest that they are rel ated to or even derived from the lymphatic EC lineage. Lack of these antige ns on cultured cells derived from KS lesions indicates that they might not represent tumor cells that grow in tissue culture, but rather other cell ty pes present in KS lesions.