VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium

Tara Karnezis, Ramin Shayan, Carol Caesar, Sally Roufail, Nicole C Harris, Kathryn Ardipradja, You F Zhang, Steven P Williams, Rae H Farnsworth, Ming Gene Chai, Thusitha Wasantha Thilaka Rupasinghe, Dedreia Tull, Megan E Baldwin, Erica Kate Sloan, Stephen B Fox, Marc G Achen, Steven A Stacker

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178 Citations (Scopus)

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-DNEGFR-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.
Original languageEnglish
Pages (from-to)181 - 195
Number of pages15
JournalCancer Cell
Volume21
Issue number2
DOIs
Publication statusPublished - 2012

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