TY - JOUR
T1 - Signaling for lymphangiogenesis via VEGFR-3 is required for the early events of metastasis
AU - Matsumoto, Masataka
AU - Roufail, Sally
AU - Inder, Rachael
AU - Caesar, Carol
AU - Karnezis, Tara
AU - Shayan, Ramin
AU - Farnsworth, Rae Helen
AU - Sato, Teruhiko
AU - Achen, Marc G
AU - Mann, Gregory B
AU - Stacker, Steven A
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
UR - http://download-v2.springer.com/static/pdf/672/art%253A10.1007%252Fs10585-013-9581-x.pdf?token2=exp=1431577277~acl=%2Fstatic%2Fpdf%2F672%2Fart%25253A1
U2 - 10.1007/s10585-013-9581-x
DO - 10.1007/s10585-013-9581-x
M3 - Article
VL - 30
SP - 819
EP - 832
JO - Clinical and Experimental Metastasis
JF - Clinical and Experimental Metastasis
SN - 0262-0898
ER -