Signaling for lymphangiogenesis via VEGFR-3 is required for the early events of metastasis
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RESEARCH PAPER
Signaling for lymphangiogenesis via VEGFR-3 is required for the early events of metastasis Masataka Matsumoto • Sally Roufail • Rachael Inder • Carol Caesar • Tara Karnezis • Ramin Shayan • Rae H. Farnsworth • Teruhiko Sato • Marc G. Achen • G. Bruce Mann • Steven A. Stacker
Received: 28 September 2012 / Accepted: 2 April 2013 Ó Springer Science+Business Media Dordrecht 2013
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-Ddependent 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-Dmediated tumor spread precedes angiogenesis-induced growth. Small but highly metastatic primary human breast cancers had significantly higher lymphatic vessel density (23.1 vessels/mm2) than size-matched (11.7) or larger nonmetastatic 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. Keywords Lymphatic vessels Lymph nodes Angiogenesis Breast cancer
Steven A. Stacker and Marc G. Achen are on the Scientific Advisory Board of Vegenics Ltd, a wholly owned subsidiary of Circadian Technologies, are stock holders and consultants. M. Matsumoto S. Roufail R. Inder C. Caesar T. Karnezis R. Shayan R. H. Farnsworth T. Sato M. G. Achen S. A. Stacker Ludwig Institute for Cancer Research, Royal Melbourne Hospital, P.O. Box 2008, Parkville, VIC 3050, Australia Present Address: M. Matsumoto Department of Surgical Oncology and Digestive Surgery, Field of Oncology Course of Advanced Therapeutics, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8520, Japan S. Roufail C. Caesar T. Karnezis R. Shayan R. H. Farnsworth M. G. Achen S. A. Stacker (&) Tumour Angiogenesis Program, Peter MacCallum Cancer Centre, Locked bag 1, A’Beckett Street, East Melbourne, VIC 8006, Australia e-mail: [email protected]
R. Shayan R. H. Farnsworth G. B. Mann Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC 3050, Aus
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