Alternative tumor irrigation: The extracellular matrix promotes the process of vasculogenic mimicry

Vasculogenic mimicry (VM) describes a process by which cancer cells establish an alternative perfusion pathway in an endothelial cell-free manner. Despite its strong correlation with reduced patient survival, the mechanisms by which a tumor can create a self-generated irrigation system remain unknown. We demonstrate using X-microtomography, confocal microscopy and Imaris reconstruction, the most convincing evidence to date of the formation of fluid conducting tubular networks from cultured (in vitro assay) cancer cell lines, cancer spheres, primary cancer cultures and a mouse xenograft. Interestingly, unlike blood vessels, the lumen of a cancer-generated tubular structure is bordered by a glycoprotein-rich matrix upon which the malignant cells rest. These structures are not disrupted by anti-angiogenic compounds. Two further phenomena were observed. Firstly, VM only occurs when cells are grown on matrigel and secondly, only 30% of primary cancer cultures undergo VM. We demonstrate that a specific component of the extracellular matrix (ECM) promotes the process of VM and present a molecular pathway within the cancer cell. As VM is strongly associated with poor patient survival, understanding the mechanisms of VM formation may deliver new druggable targets.