title: 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.
abstract: 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.
authors.affiliation: Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medizinische Fakultät Mannheim, Universitätsmedizin Mannheim, Universität Heidelberg, TRIDOMUS-Gebäude Haus C, Ludolf-Krehl-Str. 13-17, 68167, Mannheim, Germany.
authors.forename: Luca
authors.initials: L
authors.lastname: Quagliata
authors.forename: Sandra
authors.initials: S
authors.lastname: Klusmeier
authors.forename: Natascha
authors.initials: N
authors.lastname: Cremers
authors.forename: Bronislaw
authors.initials: B
authors.lastname: Pytowski
authors.forename: Alfred
authors.initials: A
authors.lastname: Harvey
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Pettis
authors.forename: Wilko
authors.initials: W
authors.lastname: Thiele
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Sleeman
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis / Q000235:genetics* / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology; D051381:Rats; D015533:Transcriptional Activation / Q000235:genetics; D042582:Vascular Endothelial Growth Factor C / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3