Loss of Endothelial Cell Matrix Metalloproteinase 14 Reduces Melanoma Growth and Metastasis by Increasing Tumor Vessel Stability
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 de...
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Published in | Journal of investigative dermatology |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
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United States
27.12.2021
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Abstract | 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 (Mmp14
), 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 endothelial-cadherin 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 Mmp14
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. |
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AbstractList | 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 (Mmp14
), 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 endothelial-cadherin 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 Mmp14
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. |
Author | Zamek, Jan Hessenthaler, Sabrina Mauch, Cornelia Kümper, Maike Pach, Elke Zigrino, Paola Niland, Stephan |
Author_xml | – sequence: 1 givenname: Maike surname: Kümper fullname: Kümper, Maike organization: Department of Dermatology and Venereology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany – sequence: 2 givenname: Sabrina surname: Hessenthaler fullname: Hessenthaler, Sabrina organization: Department of Dermatology and Venereology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany – sequence: 3 givenname: Jan surname: Zamek fullname: Zamek, Jan organization: Department of Dermatology and Venereology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany – sequence: 4 givenname: Stephan surname: Niland fullname: Niland, Stephan organization: Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany – sequence: 5 givenname: Elke surname: Pach fullname: Pach, Elke organization: Department of Dermatology and Venereology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany – sequence: 6 givenname: Cornelia surname: Mauch fullname: Mauch, Cornelia organization: Department of Dermatology and Venereology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany – sequence: 7 givenname: Paola surname: Zigrino fullname: Zigrino, Paola email: paola.zigrino@uni-koeln.de organization: Department of Dermatology and Venereology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. Electronic address: paola.zigrino@uni-koeln.de |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34968503$$D View this record in MEDLINE/PubMed |
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Title | Loss of Endothelial Cell Matrix Metalloproteinase 14 Reduces Melanoma Growth and Metastasis by Increasing Tumor Vessel Stability |
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