Vascular channel formation by human melanoma cells in vivo and in vitro: Vasculogenic mimicry

Tissue sections from aggressive human intraocular (uveal) and metastatic cu taneous melanomas generally lack evidence of significant necrosis and conta in patterned networks of interconnected loops of extracellular matrix. The matrix that forms these loops or networks may be solid or hollow. Red blood cells have been detected within the hollow channel components of this patt erned matrix histologically, and these vascular channel networks have been detected in human tumors angiographically, Endothelial cells were not ident ified within these matrix-embedded channels by light microscopy, by transmi ssion electron microscopy, or by using an immunohistochemical panel of endo thelial cell markers (Factor VIII-related antigen, Ulex, CD31, CD34, and KD R[Flk-1]). Highly invasive primary and metastatic human melanoma cells form ed patterned solid and hollow matrix channels (seen in tissue sections of a ggressive primary and metastatic human melanomas) in three-dimensional cult ures containing Matrigel or dilute Type I collagen, without endothelial cel ls or fibroblasts. These tumor cell-generated patterned channels conducted dye, highlighting looping patterns visualized angiographically in human tum ors. Neither normal melanocytes nor poorly invasive melanoma cells generate d these patterned channels in vitro under identical culture conditions, eve n after the addition of conditioned medium from metastatic pattern-forming melanoma cells, soluble growth factors, or regimes of hypoxia, Highly invas ive and metastatic human melanoma cells, but clot poorly invasive melanoma cells, contracted and remodeled floating hydrated gels, providing a biomech anical explanation for the generation of microvessels in vitro. cDNA microa rray analysis of highly invasive versus poorly invasive melanoma tumor cell s confirmed a genetic reversion to a pluripotent embryonic-like genotype in the highly aggressive melanoma cells. These observations strongly suggest that aggressive melanoma cells may generate vascular channels that facilita te tumor perfusion independent of tumor angiogenesis.