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.

Molecular mechanism of inhibition of the abnormal proliferation of human umbilical vein endothelial cells by hydroxysafflor-yellow A

“…There are many studies on the biological function and intracellular signal transduction mechanism of VEGF and its receptors in tumour angiogenesis (Rivera & Bergers 2015), and the possibility of promoting some tumour metastasis (Yang et al 2015;Zarkada et al 2015). The biological activity of VEGF is mainly regulated by two tyrosine kinase receptors of VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1).…”

Microarray expression profile of long non-coding RNAs in paclitaxel-resistant human lung adenocarcinoma cells

“…For example, upregulated lncRNA ENST00000447028 was found to be located near VEGF-B mRNA. VEGF-B mRNA was reported by Yang et al to take part in the resistance of lung cancer cells to the chemotherapeutic drug EGFR-TKI (29). We found that VEGF-B mRNA was strongly upregulated, therefore, ENST00000447028 may influence paclitaxel resistance by regulating VEGF-B mRNA.…”

Vascular endothelial growth factor-B: Impact on physiology and pathology

“…However, the VEGF-B also retarded tumor growth in the RIP1-Tag2 mouse of pancreatic neuroendocrine tumorigenesis, 6 and the reduced blood perfusion in VEGF-B-T241 tumors might explain, at least in part, the anti-tumor growth effect. 105 The antigrowth effect might also be accounted for the approximate 15% heavier weight displayed in the VEGF-B −/− mice. 6 , 13 The VEGFR-1 may explained the antigrowth and antiangiogenic effect, since it is served as the decoy receptor of VEGF-A.…”

“…106 The VEGFR-1 had a negative role in developmental vascularization, and VEGFR-1 −/− embryos died early due to VEGF-A dependent vessels overgrowth and disorganization. 107 Moreover, the VEGF-B advanced tumor invasiveness both in HCC patients 108 and mouse tumors, 105 via remodeling of the tumor microvasculature, leading to leaky vascular networks that are highly permissive for invasion. 105 So, VEGF-B might have paradoxical roles in cancer initiation and further progression, inhibiting growth and promoting metastasis, which insinuated the uncoupling of the metastasis and primary tumor growth.…”

“…105 So, VEGF-B might have paradoxical roles in cancer initiation and further progression, inhibiting growth and promoting metastasis, which insinuated the uncoupling of the metastasis and primary tumor growth. 105 …”