Vascular channels formed by subpopulations of PECAM1+ melanoma cells

Targeting the vasculature remains a promising approach for treating solid tumours; however, the mechanisms of tumour neovascularization are diverse and complex. Here we uncover a new subpopulation of melanoma cells that express the vascular cell adhesion molecule PECAM1, but not VEGFR-2, and participate in a PECAM1-dependent form of vasculogenic mimicry (VM). Clonally derived PECAM1(+) tumour cells coalesce to form PECAM1-dependent networks in vitro and they generate well-perfused, vascular endothelial growth factor (VEGF)-independent channels in mice. The neural crest specifier AP-2 alpha is diminished in PECAM1(+) melanoma cells and is a transcriptional repressor of PECAM1. Re-introduction of AP-2 alpha into PECAM1(+) tumour cells represses PECAM1 and abolishes tube-forming ability, whereas AP-2 alpha knockdown in PECAM1(-) tumour cells upregulates PECAM1 expression and promotes tube formation. Thus, VM-competent subpopulations, rather than all cells within a tumour, may instigate VM, supplant host-derived endothelium, and form PECAM1-dependent conduits that are not diminished by neutralizing VEGF.