Abstract
Tumor invasion requires intense interactions with stromal cells and a profound extracellular matrix remodelling by matrix metalloproteinases (MMPs). Here, we assessed the specific contribution of fibroblasts to tumor invasion, MMPs, tissue inhibitors of MMPs and angiogenesis-related cytokine expression in organotypic cultures of highly malignant HaCaT-ras A-5RT3 cells, with and without MMP inhibition. Collagen degradation, the hallmark of tumor invasion, was dependent on fibroblasts and active MMP-2. Additionally, MMP blockade down-regulated VEGF-A and up-regulated PDGF-BB. These results were paralleled in xenotransplants in vivo, demonstrating strong inhibitory effects of MMP blockade on tumor invasion and vascularization, as shown by the almost complete absence of VEGF-A and MMP-14 and by the decrease in relative blood volume. MMP blockade also increased the fraction of mature vessels, as demonstrated by an increased mean tumor vessel diameter and a higher ratio of Ng2-positive vessels. Thus, this study highlights the importance of targeting the tumor stroma to defeat cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Becaplermin
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Carcinoma, Squamous Cell / blood supply
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Cell Line, Tumor
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Collagen / metabolism
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Fibroblasts / enzymology
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Fibroblasts / pathology
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Humans
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Matrix Metalloproteinases, Secreted / antagonists & inhibitors*
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Matrix Metalloproteinases, Secreted / biosynthesis
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Matrix Metalloproteinases, Secreted / metabolism
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Mice
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Mice, Nude
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Neoplasm Invasiveness
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Organic Chemicals / pharmacology
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Piperazines / pharmacology
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Platelet-Derived Growth Factor / biosynthesis*
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Proto-Oncogene Proteins c-sis
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Pyrimidines / pharmacology
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Skin Neoplasms / blood supply
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Skin Neoplasms / drug therapy
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Skin Neoplasms / metabolism*
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Skin Neoplasms / pathology
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Tissue Inhibitor of Metalloproteinase-1 / biosynthesis
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Tissue Inhibitor of Metalloproteinase-1 / metabolism
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Tissue Inhibitor of Metalloproteinase-2 / biosynthesis
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Tissue Inhibitor of Metalloproteinase-2 / metabolism
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Vascular Endothelial Growth Factor A / biosynthesis*
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Xenograft Model Antitumor Assays
Substances
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Organic Chemicals
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Piperazines
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins c-sis
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Pyrimidines
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Ro 28-2653
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Tissue Inhibitor of Metalloproteinase-1
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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prinomastat
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Tissue Inhibitor of Metalloproteinase-2
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Becaplermin
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Collagen
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Matrix Metalloproteinases, Secreted