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Matrix Metalloproteinase-8 Functions as a Metastasis Suppressor through Modulation of Tumor Cell Adhesion and Invasion

¹ Departamento de Bioquímica y Biología Molecular and ² Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain; ³ School of Biological Sciences, University of East Anglia, Norwich, United Kingdom; ⁴ Tumor Biology Laboratory, Institute of Cancer, Queen Mary's School of Medicine and Dentistry, London, United Kingdom; and ⁵ Department of Chemical Endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands

Requests for reprints: Carlos Lopez-Otin, Departamento de Bioquímica y Biología Molecular Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain. Phone: 34-985-104201; Fax: 34-985-103564; E-mail: clo{at}uniovi.es.

Key Words: MMP • metastasis • melanoma • animal model • invasion

Collagenase-2 (matrix metalloproteinase-8, MMP-8) is an MMP mainly produced by neutrophils and associated with many inflammatory conditions. We have previously described that MMP-8 plays a protective role in cancer through its ability to regulate the inflammatory response induced by carcinogens. Moreover, it has been reported that experimental manipulation of the expression levels of this enzyme alters the metastatic behavior of human breast cancer cells. In this work, we have used mutant mice deficient in MMP-8 and syngenic melanoma and lung carcinoma tumor cells lines overexpressing this enzyme to further explore the putative antimetastatic potential of MMP-8. We report herein that MMP-8 prevents metastasis formation through the modulation of tumor cell adhesion and invasion. Thus, tumor cells overexpressing MMP-8 have an increased adhesion to extracellular matrix proteins, whereas their invasive ability through Matrigel is substantially reduced when compared with control cells. Analysis of MMP-8 in breast cancer patients revealed that the expression of this metalloproteinase by breast tumors correlates with a lower incidence of lymph node metastasis and confers good prognosis to these patients. On this basis, we propose that MMP-8 is a tumor protective factor, which also has the ability to reduce the metastatic potential of malignant cells in both mice and human. [Cancer Res 2008;68(8):2755–63]