Signaling for lymphangiogenesis via VEGFR-3 is required for the early events of metastasis
AuthorMatsumoto, M; Roufail, S; Inder, R; Caesar, C; Karnezis, T; Shayan, R; Farnsworth, RH; Sato, T; Achen, MG; Mann, GB; ...
Source TitleCLINICAL & EXPERIMENTAL METASTASIS
University of Melbourne Author/sMann, Gregory; Stacker, Steven; Shayan, Ramin; Achen, Marc; Farnsworth, Rae; Karnezis, Tara
AffiliationMedicine (St Vincent's)
Sir Peter MacCallum Department of Oncology
Science Collected Works
Document TypeJournal Article
CitationsMatsumoto, M; Roufail, S; Inder, R; Caesar, C; Karnezis, T; Shayan, R; Farnsworth, RH; Sato, T; Achen, MG; Mann, GB; Stacker, SA, Signaling for lymphangiogenesis via VEGFR-3 is required for the early events of metastasis, CLINICAL & EXPERIMENTAL METASTASIS, 2013, 30 (6), pp. 819 - 832
Access StatusOpen Access
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.
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