Limited involvement of MMP2, MMP9 and MMP14 in vasculogenic mimicry formation of human tumor cell lines

Vasculogenic mimicry (VM) is a phenomenon in which tumor cells form capillary-like networks without endothelial cells and is associated with tumor progression and poor prognosis. Understanding mechanisms of VM and identifying its reliable biomarkers are critical for developing novel therapeutic strategies. Matrix metalloproteinases (MMPs), which degrade extracellular matrix (ECM) components, have been reported to regulate VM. Indeed, increased expression of MMPs has been reported in VM-positive patients; however, their precise roles in VM formation remain unclear. Therefore, in this study, we investigated the roles of MMPs, particularly MMP2, MMP9, and MMP14, in VM formation and assessed their potential as VM markers. Expression levels of MMP2 and MMP9 in multiple types of cancer cell lines did not correlate with VM-forming ability, and knockout of either gene in HT1080 cells had no significant effect on VM formation. In contrast, MMP14 expression showed a positive correlation with VM formation, although VM structures were still maintained in MMP14-knockout MDA-MB-231 cells. Additionally, treatment with GM6001, a broad-spectrum MMPs inhibitor, had no significant impact on VM formation. Moreover, co-treatment with various known anticancer agents and GM6001 did not synergistically suppress VM. These findings suggest that MMPs inhibition does not give a vulnerability in VM formation. Collectively, our results indicate that MMPs, particularly MMP2, MMP9, and MMP14, are unlikely to play critical roles in VM formation.