Abstract
The molecular mechanism of tissue-specific metastasis in tumors endogenously expressing members of the vascular endothelial growth factor (VEGF) family is not yet clear. Here we demonstrate that MMP9 is specifically induced in premetastatic lung endothelial cells and macrophages by distant primary tumors via VEGFR-1/Flt-1 tyrosine kinase (TK) and that it significantly promotes lung metastasis. In a genetic approach using mice, suppression of MMP9 induction by deletion of either VEGFR-1TK or MMP9 markedly reduced lung metastasis. Furthermore, the MMP9 levels in endothelial cells of normal lung lobes from patients carrying distant tumors were significantly elevated as compared with those from patients without tumors. Thus, a block of MMP9 induction via VEGFR-1 inhibition could be useful for the prevention of tumor metastasis in lung.
MeSH terms
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Animals
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Carcinoma, Lewis Lung / metabolism
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Carcinoma, Lewis Lung / pathology
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Carcinoma, Lewis Lung / secondary*
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Case-Control Studies
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DNA Primers / chemistry
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Endothelium, Vascular / enzymology
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Enzyme Induction
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Humans
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Immunoenzyme Techniques
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In Vitro Techniques
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Lung / blood supply
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Macrophage-1 Antigen / metabolism
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Macrophages, Alveolar / enzymology
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Matrix Metalloproteinase 9 / biosynthesis*
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Matrix Metalloproteinase Inhibitors
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Melanoma, Experimental / metabolism
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Melanoma, Experimental / pathology
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Melanoma, Experimental / secondary*
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Mice
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Mice, Inbred C57BL
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Up-Regulation
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Vascular Endothelial Growth Factor Receptor-1 / metabolism*
Substances
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DNA Primers
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Macrophage-1 Antigen
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Matrix Metalloproteinase Inhibitors
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RNA, Messenger
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Vascular Endothelial Growth Factor Receptor-1
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Matrix Metalloproteinase 9