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Blood vessels supply all body tissues with nutrients and oxygen, take away waste products and allow the arrival of immune cells and other cells (pericytes, smooth muscle cells) that form part of these vessels around the principal endothelial cells. Vasculogenic mimicry (VM) is a tumor blood supply system that takes place independently of angiogenesis or endothelial cells, and is associated with poor survival in cancer patients. Aberrant expression of VE-cadherin has been strongly associated with VM. Even more, VE-cadherin has constitutively high phosphorylation levels on the residue of Y658 in human malignant melanoma cells. In this review we focus on non-endothelial VE-cadherin and its post-translational modifications as a crucial component in the development of tumor VM, highlighting the signaling pathways that lead to their pseudo-endothelial and stem-like phenotype and the role of tumor microenvironment. We discuss the importance of the tumor microenvironment in VM acquisition, and describe the most recent therapeutic targets that have been proposed for the repression of VM.

Vasculogenic Mimicry: Become an Endothelial Cell “But Not So Much”