title: Matrix metalloproteinase-13 (MMP-13) directly and indirectly promotes tumor angiogenesis.
abstract: Matrix metalloproteinases (MMPs) are extracellular zinc-dependent endopeptidases involved in the degradation and remodeling of extracellular matrix in physiological and pathological processes. MMPs also have a role in cell proliferation, migration, differentiation, angiogenesis, and apoptosis. We previously identified cancer invasion-related factors by comparing the gene expression profiles between parent and the highly invasive clone of cancer cells. Matrix metalloproteinase-13 (MMP-13) was identified as a common up-regulated gene by cancer invasion-related factors. Although MMP-13 slightly promoted tumor invasion, we found that MMP-13 was involved in tumor angiogenesis. Conditioned medium from MMP-13-overexpressing cells promoted capillary formation of immortalized human umbilical vein endothelial cells. Furthermore, treatment with recombinant MMP-13 protein enhanced capillary tube formation both in vitro and in vivo. MMP-13-promoted capillary tube formation was mediated by activation of focal adhesion kinase and ERK. Interestingly, MMP-13 promoted the secretion of VEGF-A from fibroblasts and endothelial cells. By immunohistochemical analysis, we found a possible correlation between MMP-13 expression and the number of blood vessels in human cancer cases. In summary, these findings suggest that MMP-13 may directly and indirectly promote tumor angiogenesis.
authors.affiliation: Department of Oral and Maxillofacial PathobiologyGraduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8553, Japan. yasusei@tokushima-u.ac.jp
authors.forename: Yasusei
authors.initials: Y
authors.lastname: Kudo
authors.forename: Shinji
authors.initials: S
authors.lastname: Iizuka
authors.forename: Maki
authors.initials: M
authors.lastname: Yoshida
authors.forename: Takaaki
authors.initials: T
authors.lastname: Tsunematsu
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kondo
authors.forename: Ajiravudh
authors.initials: A
authors.lastname: Subarnbhesaj
authors.forename: Elsayed M
authors.initials: EM
authors.lastname: Deraz
authors.forename: Samadarani B S M
authors.initials: SB
authors.lastname: Siriwardena
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tahara
authors.forename: Naozumi
authors.initials: N
authors.lastname: Ishimaru
authors.forename: Ikuko
authors.initials: I
authors.lastname: Ogawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Takata
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D053509:Matrix Metalloproteinase 13