VEGF-B promotes cancer metastasis through a VEGF-A–independent mechanism and serves as a marker of poor prognosis for cancer patients

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 22; pp. E2900 - E2909
• Main Authors: Yang, Xiaojuan, Zhang, Yin, Hosaka, Kayoko, Andersson, Patrik, Wang, Jian, Tholander, Fredrik, Cao, Ziquan, Morikawa, Hiromasa, Tegnér, Jesper, Yang, Yunlong, Iwamoto, Hideki, Lim, Sharon, Cao, Yihai
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.06.2015; National Acad Sciences
• Series: PNAS Plus
• Subjects: Animals; Biological Sciences; Biomarkers, Tumor - metabolism; Blotting, Western; Cancer; Cell Hypoxia; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Fluorescent Antibody Technique; Genotype & phenotype; Immunohistochemistry; Injections, Subcutaneous; Kaplan-Meier Estimate; Medicin och hälsovetenskap; Metastasis; Mice; Microvessels - drug effects; Neoplasm Metastasis - physiopathology; Neoplasms - blood supply; PNAS Plus; Polymerase Chain Reaction; Rodents; Survival analysis; Vascular endothelial growth factor; Vascular Endothelial Growth Factor B - administration & dosage; Vascular Endothelial Growth Factor B - metabolism; Vascular Endothelial Growth Factor B - pharmacology; Zebrafish; VEGFR1; VEGF-A; metastasis; VEGF-B; angiogenesis
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1503500112

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. Significance Cancer metastasis is responsible for a majority of the mortality in cancer patients and involves complex interactions, modulated by various factors and cytokines, between malignant and host cells. Vascular structures in solid tumors are crucial for cancer cell intravasation into the circulation. Our present work shows that VEGF-B produced by tumor cells significantly remodels tumor microvasculature, leading to leaky vascular networks that are highly permissive for tumor cell invasion. VEGF-B–promoted cancer metastasis occurs through a VEGF-A–independent mechanism. Thus, inhibition of VEGF-B should be considered an independent approach for the development of new drugs for the treatment of cancer invasion and metastasis. VEGF-B also may be considered as an independent prognostic marker for cancer metastasis.