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Matrix metalloprotease 1a deficiency suppresses tumor growth and angiogenesis

Oncogene volume 33, pages 2264–2272 (2014)Cite this article

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Abstract

Matrix metalloprotease-1 (MMP1) is an important mediator of tumorigenesis, inflammation and tissue remodeling through its ability to degrade critical matrix components. Recent studies indicate that stromal-derived MMP1 may exert direct oncogenic activity by signaling through protease-activated receptor-1 (PAR1) in carcinoma cells; however, this has not been established in vivo. We generated an Mmp1a knockout mouse to ascertain whether stromal-derived Mmp1a affects tumor growth. Mmp1a-deficient mice are grossly normal and born in Mendelian ratios; however, deficiency of Mmp1a results in significantly decreased growth and angiogenesis of lung tumors. Coimplantation of lung cancer cells with wild-type Mmp1a+/+ fibroblasts completely restored tumor growth in Mmp1a-deficient animals, highlighting the critical role of stromal-derived Mmp1a. Silencing of PAR1 expression in the lung carcinoma cells phenocopied stromal Mmp1a-deficiency, thus validating tumor-derived PAR1 as an Mmp1a target. Mmp1a secretion is controlled by the ability of its prodomain to facilitate autocleavage, whereas human MMP1 is efficiently secreted because of stable pro- and catalytic domain interactions. Taken together, these data demonstrate that stromal Mmp1a drives in vivo tumorigenesis and provide proof of concept that targeting the MMP1-PAR1 axis may afford effective treatments of lung cancer.

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Acknowledgements

We are grateful to Sheida Sharifi for her expertise in quantifying tumor angiogenesis, and Rutika V Pradhan and Namrata Nammi for the analysis of endothelial tube formation. This work was supported, in part, by NIH grants F30-HL104835 (to CJF), CA122992, HL64701 (to AK) and CA104406 (to LC).

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Authors and Affiliations

  1. Division of Hematology-Oncology, Molecular Oncology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA

    C J Foley, N Nguyen, A Agarwal, K Austin, G Koukos, L Covic & A Kuliopulos

  2. Departments of Biochemistry and Medicine, Program in Genetics at the Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA

    C J Foley, A Bohm, K Austin, G Koukos, L Covic & A Kuliopulos

  3. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain

    M Fanjul-Fernández & C López-Otín

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Correspondence to A Kuliopulos.

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Foley, C., Fanjul-Fernández, M., Bohm, A. et al. Matrix metalloprotease 1a deficiency suppresses tumor growth and angiogenesis. Oncogene 33, 2264–2272 (2014). https://doi.org/10.1038/onc.2013.157

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