Abstract
Flt-4, a VEGF receptor, is activated by its specific ligand, VEGF-C. The resultant signaling pathway promotes angiogenesis and/or lymphangiogenesis. This report provides evidence that the VEGF-C/Flt-4 axis enhances cancer cell mobility and invasiveness and contributes to the promotion of cancer cell metastasis. VEGF-C/Flt-4-mediated invasion and metastasis of cancer cells were found to require upregulation of the neural cell adhesion molecule contactin-1 through activation of the Src-p38 MAPK-C/EBP-dependent pathway. Examination of tumor tissues from various types of cancers revealed high levels of Flt-4 and VEGF-C expression that correlated closely with clinical metastasis and patient survival. The VEGF-C/Flt-4 axis, through upregulation of contactin-1, may regulate the invasive capacity in different types of cancer cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology*
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Animals
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Cell Adhesion Molecules, Neuronal / metabolism
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Cell Movement
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Contactin 1
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Contactins
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Female
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Humans
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Immunohistochemistry
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In Situ Hybridization, Fluorescence
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology*
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Lymphatic Metastasis / pathology
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Male
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Mice
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Middle Aged
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Mitogen-Activated Protein Kinases / metabolism
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Neoplasm Invasiveness / pathology*
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Reverse Transcriptase Polymerase Chain Reaction
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Vascular Endothelial Growth Factor C / metabolism*
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Vascular Endothelial Growth Factor Receptor-3 / metabolism*
Substances
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CNTN1 protein, human
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Cell Adhesion Molecules, Neuronal
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Cntn1 protein, mouse
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Contactin 1
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Contactins
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Vascular Endothelial Growth Factor C
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Vascular Endothelial Growth Factor Receptor-3
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Mitogen-Activated Protein Kinases