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: Xiaojuan Yang, Yin Zhang, Kayoko Hosaka, Patrik Andersson, Jian Wang, Fredrik Tholander, Ziquan Cao, Hiromasa Morikawa, Jesper Tegnér, Yunlong Yang, Hideki Iwamoto, Sharon Lim, Yihai Cao
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 22 Pg. E2900-9 (Jun 02 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 25991856 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Vascular Endothelial Growth Factor B
• vascular endothelial growth factor B, mouse

Topics

• Animals
• Biomarkers, Tumor (metabolism)
• Blotting, Western
• Cell Hypoxia
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Fluorescent Antibody Technique
• Immunohistochemistry
• Injections, Subcutaneous
• Kaplan-Meier Estimate
• Mice
• Microvessels (drug effects)
• Neoplasm Metastasis (physiopathology)
• Neoplasms (blood supply)
• Polymerase Chain Reaction
• Vascular Endothelial Growth Factor B (administration & dosage, metabolism, pharmacology)
• Zebrafish