Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 22, Pages E2900-E2909Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1503500112
Keywords
VEGF-B; metastasis; VEGFR1; VEGF-A; angiogenesis
Categories
Funding
- Swedish Research Council
- Swedish Cancer Foundation
- Karolinska Institute Foundation
- Torsten Soderberg Foundation
- European Research Council Advanced Grant ANGIOFAT [250021]
- Novo Nordisk Foundation advanced grant
- Karolinska Institute distinguished professor award
- European Research Council (ERC) [250021] Funding Source: European Research Council (ERC)
- Novo Nordisk Fonden [NNF14OC0012835] Funding Source: researchfish
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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.
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