The connection between lymphangiogenic signalling and prostaglandin biology: a missing link in the metastatic pathway

Oncotarget. 2012 Aug;3(8):893-906. doi: 10.18632/oncotarget.593. Epub 2012 Aug 19.


Substantial evidence supports important independent roles for lymphangiogenic growth factor signaling and prostaglandins in the metastatic spread of cancer. The significance of the lymphangiogenic growth factors, vascular endothelial growth factor (VEGF)-C and VEGF-D, is well established in animal models of metastasis, and a strong correlation exits between an increase in expression of VEGF-C and VEGF-D, and metastatic spread in various solid human cancers. Similarly, key enzymes that control the production of prostaglandins, cyclooxygenases (COX-1 and COX-2, prototypic targets of Non-steroidal anti-inflammatory drugs (NSAIDs)), are frequently over-expressed or de-regulated in the progression of cancer. Recent data have suggested an intersection of lymphangiogenic growth factor signaling and the prostaglandin pathways in the control of metastatic spread via the lymphatic vasculature. Furthermore, this correlates with current clinical data showing that some NSAIDs enhance the survival of cancer patients through reducing metastasis. Here, we discuss the potential biochemical and cellular basis for such anti-cancer effects of NSAIDs through the prostaglandin and VEGF signaling pathways.

Keywords: Angiogenesis; Aspirin; COX-1; COX-2; Cancer; Lymphangiogenesis; Lymphatics; Metastasis; NSAID; PGDH; Prostaglandin; VEGF-D.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Cyclooxygenase 1 / biosynthesis
  • Cyclooxygenase 2 / biosynthesis
  • Humans
  • Lymphangiogenesis*
  • Lymphatic Metastasis*
  • Lymphatic System / blood supply
  • Lymphatic Vessels / metabolism*
  • Lymphatic Vessels / pathology
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Prostaglandins / metabolism*
  • Signal Transduction
  • Vascular Endothelial Growth Factor C / metabolism*
  • Vascular Endothelial Growth Factor D / biosynthesis
  • Vascular Endothelial Growth Factor D / metabolism*


  • Anti-Inflammatory Agents, Non-Steroidal
  • Prostaglandins
  • VEGFC protein, human
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor D
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • PTGS1 protein, human
  • PTGS2 protein, human