Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis
2012 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 39, 15894-15899 p.Article in journal (Refereed) Published
Interplay between various lymphangiogenic factors in promoting lymphangiogenesis and lymphatic metastasis remains poorly understood. Here we show that FGF-2 and VEGF-C, two lymphangiogenic factors, collaboratively promote angiogenesis and lymphangiogenesis in the tumor microenvironment, leading to widespread pulmonary and lymph-node metastases. Coimplantation of dual factors in the mouse cornea resulted in additive angiogenesis and lymphangiogenesis. At the molecular level, we showed that FGFR-1 expressed in lymphatic endothelial cells is a crucial receptor that mediates the FGF-2-induced lymphangiogenesis. Intriguingly, the VEGFR-3-mediated signaling was required for the lymphatic tip cell formation in both FGF-2- and VEGF-C-induced lymphangiogenesis. Consequently, a VEGFR-3-specific neutralizing antibody markedly inhibited FGF-2-induced lymphangiogenesis. Thus, the VEGFR-3-induced lymphatic endothelial cell tip cell formation is a prerequisite for FGF-2-stimulated lymphangiogenesis. In the tumor microenvironment, the reciprocal interplay between FGF-2 and VEGF-C collaboratively stimulated tumor growth, angiogenesis, intratumoral lymphangiogenesis, and metastasis. Thus, intervention and targeting of the FGF-2- and VEGF-C-induced angiogenic and lymphangiogenic synergism could be potentially important approaches for cancer therapy and prevention of metastasis.
Place, publisher, year, edition, pages
National Academy of Sciences , 2012. Vol. 109, no 39, 15894-15899 p.
neovascularization, growth factors, signaling interplay, cancer spread, antiangiogenic therapy
National CategorySocial Sciences
IdentifiersURN: urn:nbn:se:liu:diva-85089DOI: 10.1073/pnas.1208324109ISI: 000309604500074OAI: oai:DiVA.org:liu-85089DiVA: diva2:564623
Funding Agencies|Swedish Research Council||Swedish Cancer Foundation||Karolinska Institute Foundation||Karolinska Institute distinguished professor award||Torsten Soderbergs Foundation||ImClone Systems/EliLilly||European Union Integrated Project of Metoxia|222741|Nordea Foundation||European Research Council advanced Grant ANGIOFAT|250021|2012-11-022012-11-022014-01-29Bibliographically approved