title: Matrix metalloprotease 1a deficiency suppresses tumor growth and angiogenesis.
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.
authors.affiliation: 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.
authors.forename: C J
authors.initials: CJ
authors.lastname: Foley
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Fanjul-Fernández
authors.affiliation: Program in Genetics at the Sackler School of Graduate Biomedical Sciences, Departments of Biochemistry and Medicine, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bohm
authors.affiliation: Molecular Oncology Research Institute, Division of Hematology-Oncology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Nguyen
authors.affiliation: Molecular Oncology Research Institute, Division of Hematology-Oncology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: 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.
authors.forename: K
authors.initials: K
authors.lastname: Austin
authors.affiliation: 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.
authors.forename: G
authors.initials: G
authors.lastname: Koukos
authors.affiliation: 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.
authors.forename: L
authors.initials: L
authors.lastname: Covic
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
authors.forename: C
authors.initials: C
authors.lastname: López-Otín
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Kuliopulos
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D063646:Carcinogenesis / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000201:enzymology* / Q000556:secondary; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004792:Enzyme Precursors / Q000737:chemistry / Q000172:deficiency* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000556:secondary; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D021382:Protein Sorting Signals; D047368:Tumor Burden
chemical_list: D004792:Enzyme Precursors; D021382:Protein Sorting Signals; D020781:Matrix Metalloproteinase 1; C425310:Mmp1a protein, mouse