title: VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism and serves as a marker of poor prognosis for cancer patients.
abstract: The biological functions of VEGF-B in cancer progression remain poorly understood. Here, we report that VEGF-B promotes cancer metastasis through the remodeling of tumor microvasculature. Knockdown of VEGF-B in tumors resulted in increased perivascular cell coverage and impaired pulmonary metastasis of human melanomas. In contrast, the gain of VEGF-B function in tumors led to pseudonormalized tumor vasculatures that were highly leaky and poorly perfused. Tumors expressing high levels of VEGF-B were more metastatic, although primary tumor growth was largely impaired. Similarly, VEGF-B in a VEGF-A-null tumor resulted in attenuated primary tumor growth but substantial pulmonary metastases. VEGF-B also led to highly metastatic phenotypes in Vegfr1 tk(-/-) mice and mice treated with anti-VEGF-A. These data indicate that VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism. High expression levels of VEGF-B in two large-cohort studies of human patients with lung squamous cell carcinoma and melanoma correlated with poor survival. Taken together, our findings demonstrate that VEGF-B is a vascular remodeling factor promoting cancer metastasis and that targeting VEGF-B may be an important therapeutic approach for cancer metastasis.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden; Laboratory of Oral Biomedical Science and Translational Medicine, School of Stomatology, Tongji University, Shanghai 200072, Republic of China;
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Kayoko
authors.initials: K
authors.lastname: Hosaka
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Patrik
authors.initials: P
authors.lastname: Andersson
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Fredrik
authors.initials: F
authors.lastname: Tholander
authors.affiliation: Department of Medicine and Health Sciences, Linköping University, 581 83 Linköping, Sweden;
authors.forename: Ziquan
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Unit of Computational Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institute, 171 76 Stockholm, Sweden;
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Morikawa
authors.affiliation: Unit of Computational Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institute, 171 76 Stockholm, Sweden;
authors.forename: Jesper
authors.initials: J
authors.lastname: Tegnér
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Hideki
authors.initials: H
authors.lastname: Iwamoto
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Sharon
authors.initials: S
authors.lastname: Lim
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden; Department of Medicine and Health Sciences, Linköping University, 581 83 Linköping, Sweden; Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, United Kingdom; National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, United Kingdom yihai.cao@ki.se.
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D015687:Cell Hypoxia; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D053208:Kaplan-Meier Estimate; D051379:Mice; D055806:Microvessels / Q000187:drug effects*; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009369:Neoplasms / Q000098:blood supply*; D016133:Polymerase Chain Reaction; D042561:Vascular Endothelial Growth Factor B / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D015027:Zebrafish
chemical_list: D014408:Biomarkers, Tumor; D042561:Vascular Endothelial Growth Factor B; C467482:vascular endothelial growth factor B, mouse
keywords: VEGF-A; VEGF-B; VEGFR1; angiogenesis; metastasis