title: Contribution of host MMP-2 and MMP-9 to promote tumor vascularization and invasion of malignant keratinocytes.
abstract: The matrix metalloproteinases (MMPs) play a key role in normal and pathological angiogenesis by mediating extracellular matrix degradation and/or controlling the biological activity of growth factors, chemokines, and/or cytokines. Specific functions of individual MMPs as anti- or proangiogenic mediators remain to be elucidated. In the present study, we assessed the impact of single or combined MMP deficiencies in in vivo and in vitro models of angiogenesis (malignant keratinocyte transplantation and the aortic ring assay, respectively). MMP-9 was predominantly expressed by neutrophils in tumor transplants, whereas MMP-2 and MMP-3 were stromal. Neither the single deficiency of MMP-2, MMP-3, or MMP-9, nor the combined absence of MMP-9 and MMP-3 did impair tumor invasion and vascularization in vivo. However, there was a striking cooperative effect in double MMP-2:MMP-9-deficient mice as demonstrated by the absence of tumor vascularization and invasion. In contrast, the combined lack of MMP-2 and MMP-9 did not impair the in vitro capillary outgrowth from aortic rings. These results point to the importance of a cross talk between several host cells for the in vivo tumor promoting and angiogenic effects of MMP-2 and MMP-9. Our data demonstrate for the first time in an experimental model that MMP-2 and MMP-9 cooperate in promoting the in vivo invasive and angiogenic phenotype of malignant keratinocytes.
authors.affiliation: Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium.
authors.forename: Véronique
authors.initials: V
authors.lastname: Masson
authors.forename: Laura Rodriguez
authors.initials: LR
authors.lastname: de la Ballina
authors.forename: Carine
authors.initials: C
authors.lastname: Munaut
authors.forename: Ben
authors.initials: B
authors.lastname: Wielockx
authors.forename: Maud
authors.initials: M
authors.lastname: Jost
authors.forename: Catherine
authors.initials: C
authors.lastname: Maillard
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.forename: Khalid
authors.initials: K
authors.lastname: Bajou
authors.forename: Takeshi
authors.initials: T
authors.lastname: Itoh
authors.forename: Shige
authors.initials: S
authors.lastname: Itohara
authors.forename: Zena
authors.initials: Z
authors.lastname: Werb
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
authors.forename: Agnès
authors.initials: A
authors.lastname: Noël
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015603:Keratinocytes / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency / Q000502:physiology*; D019278:Matrix Metalloproteinase 3 / Q000172:deficiency / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009368:Neoplasm Transplantation / Q000379:methods / Q000473:pathology; D009369:Neoplasms / Q000098:blood supply* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9