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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.</jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2012,"id":637554,"datarank":0.8124150603306631,"base_score":5.41610040220442,"endowment":5.41610040220442,"self_citation_contribution":0.8124150603306631,"citation_network_contribution":0.0,"self_endowment_contribution":0.8124150603306631,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":224,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":357072,"name":"Hong Ji","orcid":"0000-0002-9558-0620","position":1,"is_corresponding":false},{"id":653052,"name":"Ninghan Feng","orcid":"0000-0002-0892-6102","position":2,"is_corresponding":false},{"id":148243,"name":"Yin Zhang","orcid":null,"position":3,"is_corresponding":false},{"id":1203968,"name":"Xiaojuan Yang","orcid":"0000-0002-7534-011X","position":4,"is_corresponding":false},{"id":1025653,"name":"Patrik Andersson","orcid":"0000-0002-8454-3963","position":5,"is_corresponding":false},{"id":36918,"name":"Yuping Sun","orcid":null,"position":6,"is_corresponding":false},{"id":1655508,"name":"Katerina Tritsaris","orcid":null,"position":7,"is_corresponding":false},{"id":1655509,"name":"Anker Jon Hansen","orcid":null,"position":8,"is_corresponding":false},{"id":1655510,"name":"Steen Dissing","orcid":null,"position":9,"is_corresponding":false},{"id":615925,"name":"Yihai Cao","orcid":"0000-0003-1308-0065","position":10,"is_corresponding":false},{"id":1655507,"name":"Renhai Cao","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis","abstract":"<jats:p>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. 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