title: Signaling for lymphangiogenesis via VEGFR-3 is required for the early events of metastasis.
abstract: Metastasis to regional lymph nodes is an important and early event in many tumors. Vascular endothelial growth factor-C (VEGF-C), VEGF-D and their receptor VEGFR-3, play a role in tumor spread via the lymphatics, although the timing of their involvement is not understood. In contrast, VEGFR-2, activated by VEGF-A, VEGF-C and VEGF-D, is a mediator of angiogenesis and drives primary tumor growth. We demonstrate the critical role for VEGFR-3, but not VEGFR-2, in the early events of metastasis. In a tumor model exhibiting both VEGF-D-dependent angiogenesis and lymphangiogenesis, an antibody to VEGFR-2 (DC101) was capable of inhibiting angiogenesis (79 % reduction in PECAM + blood vessels) and growth (93 % reduction in tumor volume). However, unlike an anti-VEGFR-3 Mab (mF4-31C1), DC101 was not capable of eliminating either tumor lymphangiogenesis or lymphogenous metastasis (60 % reduction of lymph node metastasis by DC101 vs 95 % by mF4-31C1). Early excision of the primary tumors demonstrated that VEGF-D-mediated tumor spread precedes angiogenesis-induced growth. Small but highly metastatic primary human breast cancers had significantly higher lymphatic vessel density (23.1 vessels/mm(2)) than size-matched (11.7) or larger non-metastatic tumors (12.4) thus supporting the importance of lymphatic vessels, as opposed to angiogenesis-mediated primary tumor growth, for nodal metastasis. These results suggest that lymphangiogenesis via VEGF-D is more critical than angiogenesis for nodal metastasis.
authors.affiliation: Ludwig Institute for Cancer Research, Royal Melbourne Hospital, P.O. Box 2008, Parkville, VIC, 3050, Australia.
authors.forename: Masataka
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Sally
authors.initials: S
authors.lastname: Roufail
authors.forename: Rachael
authors.initials: R
authors.lastname: Inder
authors.forename: Carol
authors.initials: C
authors.lastname: Caesar
authors.forename: Tara
authors.initials: T
authors.lastname: Karnezis
authors.forename: Ramin
authors.initials: R
authors.lastname: Shayan
authors.forename: Rae H
authors.initials: RH
authors.lastname: Farnsworth
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Sato
authors.forename: Marc G
authors.initials: MG
authors.lastname: Achen
authors.forename: G Bruce
authors.initials: GB
authors.lastname: Mann
authors.forename: Steven A
authors.initials: SA
authors.lastname: Stacker
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D042583:Lymphangiogenesis / Q000502:physiology*; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D018919:Neovascularization, Physiologic; D015398:Signal Transduction / Q000502:physiology*; D042643:Vascular Endothelial Growth Factor D / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000502:physiology*
chemical_list: D042643:Vascular Endothelial Growth Factor D; C581309:FLT4 protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3