Abstract
Lymphatic metastasis is facilitated by lymphangiogenic growth factors VEGF-C and VEGF-D that are secreted by some primary tumors. We identified regulation of PGDH, the key enzyme in prostaglandin catabolism, in endothelial cells of collecting lymphatics, as a key molecular change during VEGF-D-driven tumor spread. The VEGF-D-dependent regulation of the prostaglandin pathway was supported by the finding that collecting lymphatic vessel dilation and subsequent metastasis were affected by nonsteroidal anti-inflammatory drugs (NSAIDs), known inhibitors of prostaglandin synthesis. Our data suggest a control point for cancer metastasis within the collecting lymphatic endothelium, which links VEGF-D/VEGFR-2/VEGFR-3 and the prostaglandin pathways. Collecting lymphatics therefore play an active and important role in metastasis and may provide a therapeutic target to restrict tumor spread.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / pharmacology
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Cell Transformation, Neoplastic*
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Endothelium, Lymphatic / metabolism*
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Endothelium, Lymphatic / pathology
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Lymphangiogenesis / drug effects
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Lymphatic Metastasis / genetics
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Lymphatic Metastasis / physiopathology*
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Lymphatic System / drug effects
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Lymphatic System / pathology
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Lymphatic Vessels / metabolism
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Lymphatic Vessels / pathology
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Prostaglandins / metabolism*
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Vascular Endothelial Growth Factor D / genetics
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Vascular Endothelial Growth Factor D / metabolism
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Vascular Endothelial Growth Factor D / physiology*
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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Vascular Endothelial Growth Factor Receptor-3 / metabolism
Substances
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Anti-Inflammatory Agents
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Prostaglandins
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Vascular Endothelial Growth Factor D
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Vascular Endothelial Growth Factor Receptor-2
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Vascular Endothelial Growth Factor Receptor-3