VEGF-D Promotes Tumor Metastasis by Regulating Prostaglandins Produced by the Collecting Lymphatic Endothelium

Cancer Cell. 2012 Feb 14;21(2):181-95. doi: 10.1016/j.ccr.2011.12.026.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Cell Transformation, Neoplastic*
  • Endothelium, Lymphatic / metabolism*
  • Endothelium, Lymphatic / pathology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lymphangiogenesis / drug effects
  • Lymphatic Metastasis / genetics
  • Lymphatic Metastasis / physiopathology*
  • Lymphatic System / drug effects
  • Lymphatic System / pathology
  • Lymphatic Vessels / metabolism
  • Lymphatic Vessels / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Prostaglandins / metabolism*
  • Vascular Endothelial Growth Factor D / genetics
  • Vascular Endothelial Growth Factor D / metabolism
  • Vascular Endothelial Growth Factor D / physiology*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism

Substances

  • Anti-Inflammatory Agents
  • Prostaglandins
  • Vascular Endothelial Growth Factor D
  • Vascular Endothelial Growth Factor Receptor-2
  • Vascular Endothelial Growth Factor Receptor-3