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

Author:
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
Source:
Proceedings of the National Academy of Sciences of the United States of America 2015 v.112 no.22 pp. E2900
ISSN:
0027-8424
Subject:
cell invasion, cytokines, metastasis, mortality, neoplasm cells, neoplasms, new drugs, patients, prognosis, vascular endothelial growth factor B
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.
Agid:
2304648