6-Gingerol stabilized the p-VEGFR2/VE-cadherin/\u03b2-catenin/actin complex promotes microvessel normalization and suppresses tumor progression

Weilong Zhong,Yuanhao Tang,Yanrong Liu,Cheng Yang,Yuan Qin,Hengwei Xu,Huijuan Liu,Honggang Zhou,Bo Sun,Shuang Chen,Wenguang Gu,Yinyin Xue,Tao Sun,Changhua Wang,Hongzhi Wang,Wendong Yang,Chao Zhang

doi:10.1186/s13046-019-1291-z

Abstract

BackgroundAnti-angiogenic therapies demonstrate anti-tumor effects by decreasing blood supply to tumors and inhibiting tumor growth. However, anti-angiogenic therapy may leads to changes in tumor microenvironment and increased invasiveness of tumor cells, which in turn promotes distant metastasis and increased drug resistance.MethodsThe CO-IP assays, N-STORM and cytoskeleton analysis were used to confirm the mechanism that p-VEGFR2/VE-cadherin/β-catenin/actin complex regulates vascular remodeling and improves the tumor microenvironment. 6-gingerol (6G), the major bioactive component in ginger, stabilized this complex by enhancing the binding of VEGFa to VEGFR2 with non-pathway dependent. Biacore, pull down and molecular docking were employed to confirm the interaction between 6G and VEGFR2 and enhancement of VEGFa binding to VEGFR2.ResultsHere, we report that microvascular structural entropy (MSE) may be a prognostic factor in several tumor types and have potential as a biomarker in the clinic. 6G regulates the structural organization of the microvascular bed to decrease MSE via the p-VEGFR2/VE-cadherin/β-catenin/actin complex and inhibit tumor progression. 6G promotes the normalization of tumor vessels, improves the tumor microenvironment and decreases MSE, facilitating the delivery of chemotherapeutic agents into the tumor core and thereby reducing tumor growth and metastasis.ConclusionsThis study demonstrated the importance of vascular normalization in tumor therapy and elucidated the mechanism of action of ginger, a medicinal compound that has been used in China since ancient times.

Highlights

Anti-angiogenic therapies demonstrate anti-tumor effects by decreasing blood supply to tumors and inhibiting tumor growth
High Microvascular structural entropy (MSE) was correlated with low survival time in hepatocellular carcinoma (HCC) patients (Fig. 1f), indicating that more irregular and tortuous microvessels with high MSE values can lead to a poor prognosis
We demonstrated that β-catenin was working as a “bridge” to connect activated VEGFR2 and VE-cad. 6G did not affect the interactions between VE-cad and βcatenin.VE-cad, VEGFR2, and β-catenin were co-localized to the cell membrane (Fig. 5f)

Summary

Introduction

Anti-angiogenic therapies demonstrate anti-tumor effects by decreasing blood supply to tumors and inhibiting tumor growth. Anti-angiogenic therapy may leads to changes in tumor microenvironment and increased invasiveness of tumor cells, which in turn promotes distant metastasis and increased drug resistance. Microvessels deliver oxygen and nutrients and remove waste from the tumor microenvironment [1, 2]. Solid tumors have numerous blood vessels, the function and structure of these vessels are usually abnormal, Microvascular structural entropy (MSE), a measure of the degree of disorder, is used to assess the structural organization of microvessels. MSE combines measurements of the size and distance between vessels. A regular or ordered microvascular distribution improves the tumor microenvironment and decreases malignancy by promoting microvascular normalization [8,9,10,11]

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Results

Discussion

Conclusion