title: Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis.
abstract: 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.
authors.affiliation: Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Renhai
authors.initials: R
authors.lastname: Cao
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.forename: Ninghan
authors.initials: N
authors.lastname: Feng
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Yang
authors.forename: Patrik
authors.initials: P
authors.lastname: Andersson
authors.forename: Yuping
authors.initials: Y
authors.lastname: Sun
authors.forename: Katerina
authors.initials: K
authors.lastname: Tritsaris
authors.forename: Anker Jon
authors.initials: AJ
authors.lastname: Hansen
authors.forename: Steen
authors.initials: S
authors.lastname: Dissing
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; D016222:Fibroblast Growth Factor 2; D040321:Vascular Endothelial Growth Factor Receptor-3