title: VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium.
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.
authors.affiliation: Tumour Angiogenesis Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Tara
authors.initials: T
authors.lastname: Karnezis
authors.forename: Ramin
authors.initials: R
authors.lastname: Shayan
authors.forename: Carol
authors.initials: C
authors.lastname: Caesar
authors.forename: Sally
authors.initials: S
authors.lastname: Roufail
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Harris
authors.forename: Kathryn
authors.initials: K
authors.lastname: Ardipradja
authors.forename: You Fang
authors.initials: YF
authors.lastname: Zhang
authors.forename: Steven P
authors.initials: SP
authors.lastname: Williams
authors.forename: Rae H
authors.initials: RH
authors.lastname: Farnsworth
authors.forename: Ming G
authors.initials: MG
authors.lastname: Chai
authors.forename: Thusitha W T
authors.initials: TW
authors.lastname: Rupasinghe
authors.forename: Dedreia L
authors.initials: DL
authors.lastname: Tull
authors.forename: Megan E
authors.initials: ME
authors.lastname: Baldwin
authors.forename: Erica K
authors.initials: EK
authors.lastname: Sloan
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
authors.forename: Marc G
authors.initials: MG
authors.lastname: Achen
authors.forename: Steven A
authors.initials: SA
authors.lastname: Stacker
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic; D004729:Endothelium, Lymphatic / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects; D008207:Lymphatic Metastasis / Q000235:genetics / Q000503:physiopathology*; D008208:Lymphatic System / Q000187:drug effects / Q000473:pathology; D042601:Lymphatic Vessels / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011453:Prostaglandins / Q000378:metabolism*; D042643:Vascular Endothelial Growth Factor D / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D011453:Prostaglandins; D042643:Vascular Endothelial Growth Factor D; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3