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

Matrix metalloproteinase (MMP) 14 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 (EC) expression of MMP14 in skin physiology and pathology in vivo after birth is yet unknown. Using a mouse model with constitutive EC-specific deletion of Mmp14 (Mmp14EC(-/-)), we showed that mice developed and bred normal, but melanoma growth and metastasis were reduced. Although vascularity was unaltered, vessel permeability was decreased. Deletion of MMP14 in ECs led to increased vessel coverage by pericytes and vascular endothelialecadherin expression in mice in vivo and in vitro but not in human ECs. Endothelial nitric oxide synthase expression and nitric oxide production were significantly reduced in Mmp14EC(-/-) ECs and MMP14-silenced human umbilical vein ECs. A direct correlation between endothelial nitric oxide synthase 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-derived MMP14 direct targeting alone or with vascular stabilizing agents may be therapeutically crucial in inhibiting melanoma growth and metastasis.

Automated summary

MMP14 plays a critical role in skin physiological and pathological processes, and its deletion in endothelial cells leads to reduced melanoma growth and metastasis through decreased vessel permeability. This suggests that targeting EC-derived MMP14 may be therapeutically crucial in inhibiting melanoma growth and metastasis.