Research Perspectives:

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

Tara Karnezis, Ramin Shayan, Stephen Fox, Marc G. Achen and Steven A. Stacker _

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Oncotarget. 2012; 3:893-906. https://doi.org/10.18632/oncotarget.593

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Tara Karnezis1, Ramin Shayan1, 2,3, Stephen Fox 1,4, Marc G. Achen1,2,4 and Steven A. Stacker1,2,4

1 Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, East Melbourne, Victoria, Australia.

2 Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Victoria, Australia.

3 Jack Brockhoff Reconstructive Plastic Surgery Research Unit, Royal Melbourne Hospital and Department of Anatomy, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Victoria, Australia.

4 Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia


Steven Stacker, email:

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

Received: August 07, 2012, Accepted: August 17, 2012, Published: August 19, 2012


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.

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