Inhibition of VEGFR-3 activation in tumor-draining lymph nodes suppresses the outgrowth of lymph node metastases in the MT-450 syngeneic rat breast cancer model

• Published in: Clinical & experimental metastasis 2014-03, Vol.31 (3), p.351-365
• Main Authors: Quagliata, Luca, Klusmeier, Sandra, Cremers, Natascha, Pytowski, Bronislaw, Harvey, Alfred, Pettis, Ronald J., Thiele, Wilko, Sleeman, Jonathan P.
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer Research; Female; Hematology; Humans; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Lymph Nodes - pathology; Lymphatic Metastasis - genetics; Lymphatic Metastasis - pathology; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - pathology; Oncology; Rats; Research Paper; Surgical Oncology; Transcriptional Activation - genetics; Vascular Endothelial Growth Factor C - antagonists & inhibitors; Vascular Endothelial Growth Factor C - genetics; Vascular Endothelial Growth Factor C - metabolism; Vascular Endothelial Growth Factor Receptor-3 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-3 - genetics
• ISSN: 0262-0898; 1573-7276
• DOI: 10.1007/s10585-013-9633-2

For many types of human cancer, the expression of vascular endothelial growth factor-C (VEGF-C) correlates with enhanced tumor-associated lymphatic vessel density, metastasis formation and poor prognosis. In experimental animals, VEGF-C produced by primary tumors can induce lymphangiogenesis within and/or at the periphery of the tumor, and promotes metastasis formation. Tumor-induced lymphangiogenesis is therefore thought to expedite entry of tumor cells into the lymphatic vasculature and their trafficking to regional lymph nodes, thereby fostering metastatic dissemination. Tumour-produced VEGF-C can also drain to the regional lymph nodes and induce lymphangiogenesis there. Whether this activity promotes metastasis formation remains unclear. To address this issue we manipulated VEGF-C activity and VEGFR-3 activation in the lymph nodes draining syngeneic rat breast cancers using intra-dermal delivery of either recombinant VEGF-C or VEGFR-3 blocking antibodies to induce or suppress lymph node lymphangiogenesis, respectively. Recombinant VEGF-C induced lymph node lymphangiogenesis, but was not sufficient to promote metastasis formation by poorly metastatic NM-081 breast tumours. Conversely, inhibition of lymph node lymphangiogeneis induced by highly metastatic MT-450 breast tumours suppressed the outgrowth of lymph node metastases, but not the initial colonization of the lymph nodes. Lung metastasis was also not affected. We conclude that tumor-derived VEGF-C draining to regional lymph nodes promotes the outgrowth of lymph node metastases. VEGF-C may induce lung metastasis independently of its effects on lymph node metastasis.