6-Gingerol Stabilized the P-VEGFR2/VE-cadherin/β-catenin/actin Complex Promotes Microvessel Normalization and Suppresses Tumor Progression

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2019 Jul 4

PMID 31266540

Citations 53

Authors

Weilong Zhong

Wendong Yang

Yuan Qin

WenGuang Gu

Yinyin Xue

Yuanhao Tang

Hengwei Xu

Hongzhi Wang

Chao Zhang

Changhua Wang

Bo Sun

Yanrong Liu

Huijuan Liu

Honggang Zhou

Shuang Chen

Tao Sun

Cheng Yang

Affiliations

Soon will be listed here.

Abstract

Background: Anti-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.

Methods: The 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.

Results: Here, 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.

Conclusions: This 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.

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References

Kayser K, Gabius H . The application of thermodynamic principles to histochemical and morphometric tissue research: principles and practical outline with focus on the glycosciences. Cell Tissue Res. 1999; 296(3):443-55. DOI: 10.1007/s004410051305. View

Jain R . Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001; 7(9):987-9. DOI: 10.1038/nm0901-987. View

Vidal S, Horvath E, Kovacs K, Lloyd R, Scheithauer B . Microvascular structural entropy: a novel approach to assess angiogenesis in pituitary tumors. Endocr Pathol. 2003; 14(3):239-47. DOI: 10.1007/s12022-003-0016-0. View

Tong R, Boucher Y, Kozin S, Winkler F, Hicklin D, Jain R . Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 2004; 64(11):3731-6. DOI: 10.1158/0008-5472.CAN-04-0074. View

Jain R . Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005; 307(5706):58-62. DOI: 10.1126/science.1104819. View

Lee T, Seng S, Sekine M, Hinton C, Fu Y, Avraham H . Vascular endothelial growth factor mediates intracrine survival in human breast carcinoma cells through internally expressed VEGFR1/FLT1. PLoS Med. 2007; 4(6):e186. PMC: 1885450. DOI: 10.1371/journal.pmed.0040186. View

Lee H, Seo E, Kang N, Kim W . [6]-Gingerol inhibits metastasis of MDA-MB-231 human breast cancer cells. J Nutr Biochem. 2007; 19(5):313-9. DOI: 10.1016/j.jnutbio.2007.05.008. View

Zhang Z, Ramirez N, Yankeelov T, Li Z, Ford L, Qi Y . alpha2beta1 integrin expression in the tumor microenvironment enhances tumor angiogenesis in a tumor cell-specific manner. Blood. 2007; 111(4):1980-8. PMC: 2234046. DOI: 10.1182/blood-2007-06-094680. View

Jain R . Lessons from multidisciplinary translational trials on anti-angiogenic therapy of cancer. Nat Rev Cancer. 2008; 8(4):309-16. DOI: 10.1038/nrc2346. View

10.

Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F . Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009; 15(3):220-31. PMC: 2874829. DOI: 10.1016/j.ccr.2009.01.027. View

11.

Jeong C, Bode A, Pugliese A, Cho Y, Kim H, Shim J . [6]-Gingerol suppresses colon cancer growth by targeting leukotriene A4 hydrolase. Cancer Res. 2009; 69(13):5584-91. DOI: 10.1158/0008-5472.CAN-09-0491. View

12.

Sun T, Zhao N, Zhao X, Gu Q, Zhang S, Che N . Expression and functional significance of Twist1 in hepatocellular carcinoma: its role in vasculogenic mimicry. Hepatology. 2009; 51(2):545-56. DOI: 10.1002/hep.23311. View

13.

Cao Z, Jensen L, Rouhi P, Hosaka K, Lanne T, Steffensen J . Hypoxia-induced retinopathy model in adult zebrafish. Nat Protoc. 2010; 5(12):1903-10. DOI: 10.1038/nprot.2010.149. View

14.

Bertuccio C, Veron D, Aggarwal P, Holzman L, Tufro A . Vascular endothelial growth factor receptor 2 direct interaction with nephrin links VEGF-A signals to actin in kidney podocytes. J Biol Chem. 2011; 286(46):39933-44. PMC: 3220571. DOI: 10.1074/jbc.M111.241620. View

15.

Metze K . Fractal dimension of chromatin and cancer prognosis. Epigenomics. 2011; 2(5):601-4. DOI: 10.2217/epi.10.50. View

16.

Goel S, Fukumura D, Jain R . Normalization of the tumor vasculature through oncogenic inhibition: an emerging paradigm in tumor biology. Proc Natl Acad Sci U S A. 2012; 109(20):E1214. PMC: 3356659. DOI: 10.1073/pnas.1203794109. View

17.

Sun Z, Li X, Massena S, Kutschera S, Padhan N, Gualandi L . VEGFR2 induces c-Src signaling and vascular permeability in vivo via the adaptor protein TSAd. J Exp Med. 2012; 209(7):1363-77. PMC: 3405501. DOI: 10.1084/jem.20111343. View

18.

van Malenstein H, Dekervel J, Verslype C, Van Cutsem E, Windmolders P, Nevens F . Long-term exposure to sorafenib of liver cancer cells induces resistance with epithelial-to-mesenchymal transition, increased invasion and risk of rebound growth. Cancer Lett. 2012; 329(1):74-83. DOI: 10.1016/j.canlet.2012.10.021. View

19.

Simoneau B, Houle F, Huot J . Regulation of endothelial permeability and transendothelial migration of cancer cells by tropomyosin-1 phosphorylation. Vasc Cell. 2012; 4(1):18. PMC: 3552968. DOI: 10.1186/2045-824X-4-18. View

20.

Lin B, Zeng Z, Yang S, Zhuang C . Dietary restriction suppresses tumor growth, reduces angiogenesis, and improves tumor microenvironment in human non-small-cell lung cancer xenografts. Lung Cancer. 2012; 79(2):111-7. DOI: 10.1016/j.lungcan.2012.11.001. View