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.
Highlights
Angiogenesis is an important step in the metastatic cascade of tumors
Matrix metalloproteinases (MMPs)-13 is known as collagenase-3 and is active against a wide variety of extracellular matrix (ECM) components [17]
By using Matrix metalloproteinase-13 (MMP-13)-overexpressing cells, we examined the role of MMP-13 in cell growth and invasion
Summary
Angiogenesis is an important step in the metastatic cascade of tumors. Results: MMP-13 itself as well as VEGF-A secretion from fibroblasts promotes angiogenesis. We found a possible correlation between MMP-13 expression and the number of blood vessels in human cancer cases These findings suggest that MMP-13 may directly and indirectly promote tumor angiogenesis. Pro- and anti-angiogenic molecules can be emanated from cancer cells, endothelial cells, stromal cells, blood, and the extracellular matrix (ECM)3 [6] Their relative contribution is likely to change with tumor type and site. The ECM undergoes significant remodeling during tumor progression and this is mediated largely by the extracellular proteinases, the matrix metalloproteinases (MMPs), and the major source of these is from the stromal cells [7]. It has been shown that MMP-13 produced from stromal fibroblasts promotes angiogenesis through increased protein level of VEGF and VEGFR-2 in cancer invasive area [19]. We found that MMP-13 produced by cancer cells directly and indirectly promoted tumor angiogenesis
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