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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E2900-E2909
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number22
DOIs
StatePublished - Jun 2 2015

Keywords

  • Angiogenesis
  • Metastasis
  • VEGF-A
  • VEGF-B
  • VEGFR1

ASJC Scopus subject areas

  • General

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