Format

Send to

Choose Destination
See comment in PubMed Commons below
Oncogene. 2014 Apr 24;33(17):2264-72. doi: 10.1038/onc.2013.157. Epub 2013 May 27.

Matrix metalloprotease 1a deficiency suppresses tumor growth and angiogenesis.

Author information

1
1] Molecular Oncology Research Institute, Division of Hematology-Oncology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA [2] Program in Genetics at the Sackler School of Graduate Biomedical Sciences, Departments of Biochemistry and Medicine, Tufts University School of Medicine, Boston, MA, USA.
2
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
3
Program in Genetics at the Sackler School of Graduate Biomedical Sciences, Departments of Biochemistry and Medicine, Tufts University School of Medicine, Boston, MA, USA.
4
Molecular Oncology Research Institute, Division of Hematology-Oncology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA.

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.

PMID:
23708660
PMCID:
PMC4221191
DOI:
10.1038/onc.2013.157
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Support Center