PECAM-1-dependent vascular mimicry in melanoma: Contributions to anti-angiogenic resistance

The development of a perfused blood vasculature is a requirement both in development and for many human pathologies. Critically, the formation of new blood vessels through angiogenesis has been identified as a hallmark of cancer progression. A major effort has been undertaken to target the blood vessels of nascent and metastatic tumors to inhibit tumor growth. Therapies targeting the blood vasculature have shown limited efficacy, and multiple modes or resistance have been proposed. While attempting to characterize endothelial cells from mouse models of melanoma, we discovered a novel subpopulation of tumor cells expressing the endothelial cell marker PECAM-1. PECAM-1 + melanoma participate in a tumor cell derived vasculature in a form of vasculogenic mimicry (VM). PECAM-1+ tumor cells form PECAM-1 -- dependent vascular-like networks in vitro and generate perfused vascular networks in vivo in a VEGF-independent fashion. Transcriptional activator AP-2a is diminished in PECAM-1+ melanoma and represses PECAM-1 expression. Re-expression of AP-2a in PECAM-1+ tumor cells blocks PECAM-1 expression and inhibits tube-forming ability, and knockdown of AP-2a upregulates PECAM-1 in PECAM-1-- tumor cells. We identified PECAM-1+ tumor cells in both murine and human melanoma, and propose that PECAM-1+ melanoma cells may instigate VM, collaborate with host endothelial cells, and form PECAM-1-dependent vascular channels which are refractory to VEGF inhibition.