title: Matrix metalloproteinase Mmp-1a is dispensable for normal growth and fertility in mice and promotes lung cancer progression by modulating inflammatory responses.
abstract: Human MMP-1 is a matrix metalloproteinase repeatedly associated with many pathological conditions, including cancer. Thus, MMP1 overexpression is a poor prognosis marker in a variety of advanced cancers, including colorectal, breast, and lung carcinomas. Moreover, MMP-1 plays a key role in the metastatic behavior of melanoma, breast, and prostate cancer cells. However, functional and mechanistic studies on the relevance of MMP-1 in cancer have been hampered by the absence of an in vivo model. In this work, we have generated mice deficient in Mmp1a, the murine ortholog of human MMP1. Mmp1a(-/-) mice are viable and fertile and do not exhibit obvious abnormalities, which has facilitated studies of cancer susceptibility. These studies have shown a decreased susceptibility to develop lung carcinomas induced by chemical carcinogens in Mmp1a(-/-) mice. Histopathological analysis indicated that tumors generated in Mmp1a(-/-) mice are smaller than those of wild-type mice, consistently with the idea that the absence of Mmp-1a hampers tumor progression. Proteomic analysis revealed decreased levels of chitinase-3-like 3 and accumulation of the receptor for advanced glycation end-products and its ligand S100A8 in lung samples from Mmp1a(-/-) mice compared with those from wild-type. These findings suggest that Mmp-1a could play a role in tumor progression by modulating the polarization of a Th1/Th2 inflammatory response to chemical carcinogens. On the basis of these results, we propose that Mmp1a knock-out mice provide an excellent in vivo model for the functional analysis of human MMP-1 in both physiological and pathological conditions.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Fanjul-Fernández
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Folgueras
authors.affiliation: Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Fueyo
authors.affiliation: Servicio de Oncología Molecular, Hospital Universitario Central de Asturias, 33006 Oviedo, Spain.
authors.forename: Milagros
authors.initials: M
authors.lastname: Balbín
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: María F
authors.initials: MF
authors.lastname: Suárez
authors.affiliation: Anatomía Patológica, Hospital Universitario Central de Asturias, 33006 Oviedo, Spain.
authors.forename: M Soledad
authors.initials: MS
authors.lastname: Fernández-García
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: José M P
authors.initials: JMP
authors.lastname: Freije
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain. Electronic address: clo@uniovi.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000378:metabolism; D049109:Cell Proliferation; D018450:Disease Progression; D015971:Gene Expression Regulation, Enzymologic; D007249:Inflammation / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D010447:Peptide Hydrolases / Q000378:metabolism; D011379:Prognosis; D014520:Urethane
chemical_list: D014520:Urethane; D010447:Peptide Hydrolases; D020781:Matrix Metalloproteinase 1; C425310:Mmp1a protein, mouse
keywords: Carcinogenesis; Degradome; Inflammation; Invasion; Metastasis; Protease
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