VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism and serves as a marker of poor prognosis for cancer patients
2015 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 22, E2900-E2909 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
National Academy of Sciences , 2015. Vol. 112, no 22, E2900-E2909 p.
VEGF-B; metastasis; VEGFR1; VEGF-A; angiogenesis
IdentifiersURN: urn:nbn:se:liu:diva-120054DOI: 10.1073/pnas.1503500112ISI: 000355832200011PubMedID: 25991856OAI: oai:DiVA.org:liu-120054DiVA: diva2:839985
Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Torsten Soderberg Foundation; European Research Council Advanced Grant ANGIOFAT ; Novo Nordisk Foundation advanced grant; Karolinska Institute distinguished professor award2015-07-062015-07-062016-04-25