Contribution of host MMP-2 and MMP-9 to promote tumor vascularization and invasion of malignant keratinocytes.
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.
Masson
Véronique
V
Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium.
de la Ballina
Laura Rodriguez
LR
Munaut
Carine
C
Wielockx
Ben
B
Jost
Maud
M
Maillard
Catherine
C
Blacher
Silvia
S
Bajou
Khalid
K
Itoh
Takeshi
T
Itohara
Shige
S
Werb
Zena
Z
Libert
Claude
C
Foidart
Jean-Michel
JM
Noël
Agnès
A
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
D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9