Loss of Endothelial Cell Matrix Metalloproteinase 14 Reduces Melanoma Growth and Metastasis by Increasing Tumor Vessel Stability

MMP14 belongs to a large family of zinc-dependent endopeptidases and plays a critical role in skin physiological and pathological processes. Complete loss of the protease resulted in severe developmental defects leading to early death. However, because of the premature death of the mice, the functional significance for endothelial cell expression of MMP14 in skin physiology and pathology in vivo postnatal is yet unknown. Using a mouse model with constitutive endothelial cell-specific deletion of MMP14 (MMP14), we demonstrated that mice developed and bred normal, but melanoma growth and metastasis were reduced. While vascularity was unaltered, vessel permeability was decreased. Deletion of MMP14 in ECs led to increased vessel coverage by pericytes and VE-cadherin expression in mice in vivo and in vitro, but not human ECs. eNOS expression and nitric oxide production were significantly reduced in MMP14 ECs and MMP14-silenced HUVECs. A direct correlation between eNOS and MMP14 expression was detected in intratumoral vessels of human malignant melanomas. Altogether, we show that endothelial MMP14 controls tumor vessel function during melanoma growth. These data suggest that EC-MMP14 direct targeting alone or with vascular stabilizing agents may be therapeutically crucial in inhibiting melanoma growth and metastasis.