Effect of Grape Seed Proanthocyanidins on Tumor Vasculogenic Mimicry in Human Triple-negative Breast Cancer Cells

  • Luan, Yun-Yan (Department of Oncology, Affiliated Hospital of Qingdao University) ;
  • Liu, Zi-Min (Department of Oncology, Affiliated Hospital of Qingdao University) ;
  • Zhong, Jin-Yi (Institute of Nutrition, Medical College of Qingdao University) ;
  • Yao, Ru-Yong (Central Laboratory, Affiliated Hospital of Qingdao University) ;
  • Yu, Hong-Sheng (Department of Oncology, Affiliated Hospital of Qingdao University)
  • Published : 2015.02.25


Vasculogenic mimicry (VM) refers to the unique ability of highly aggressive tumor cells to mimic the pattern of embryonic vasculogenesis, which was associated with invasion and metastasis. The grape seed proanthocyanidins (GSPs) had attracted much attention as a potential bioactive anti-carcinogenic agent. However, GSPs regulation of VM and its possible mechanisms in a triple-negative breast cancer cells (TNBCs) remain not clear. Therefore, we examined the effect of GSPs on VM information in HCC1937 cell model. In this study, we identified the VM structure via the three-dimensional (3D) matrix in vitro. Cell viability was measured using the CCK8 assay. The effects of GSPs on human triple-negative breast cancer cells (TNBCs) HCC1937 in terms of related proteins of VM information were determined using western blot analysis. In vitro, the tubular networks were found in highly invasive HCC1937 cells but not in the non-invasive MCF-7 cells when plated on matrigel. The number of vascular channels was significantly reduced when cells were exposed in GSPs ($100{\mu}g$/ml) and GSPs ($200{\mu}g/mL$) groups (all p<0.001). Furthermore, we found that treatment with GSPs promoted transition of the mesenchymal state to the epithelial state in HCC1937 cells as well as reducing the expression of Twist1 protein, a master EMT regulator.GSPs has the ability to inhibit VM information by the suppression of Twist1 protein that could be related to the reversal of epithelial-to-mesenchymal (EMT) process. It is firstly concluded that GSPs may be an p otential anti-VM botanical agent for human TNBCs.



  1. Basu GD, Liang WS, Stephan DA, et al (2006). A novel role for cyclooxygenase-2 in regulating vascular channel formation by human breast cancer cells. Breast Cancer Res, 8, 69.
  2. Bergers G, Hanahan D (2008). Modes of resistance to antiangiogenic therapy. Nat Rev Cancer, 8, 592-603.
  3. Chen Y, Jing Z, Luo C, et al (2012). Vasculogenic mimicrypotential target for glioblastoma therapy: an in vitro and in vivo study. Med Oncol, 29, 324-31.
  4. Di Cosimo S, Baselga J (2010). Management of breast cancer with targeted agents: importance of heterogeneity. [corrected]. Nat Rev Clin Oncol, 7, 139-47.
  5. Feng L-L, Liu B-X, Zhong J-Y, et al (2014). Effect of grape procyanidins on tumor angiogenesis in liver cancer xenograft models. Asian Pac J Cancer Prev, 15, 737-41.
  6. Han J, Bae SY, Oh SJ, et al (2014). Zerumbone suppresses IL-1beta-induced cell migration and invasion by inhibiting IL-8 and MMP-3 expression in human triple-negative breast cancer cells. Phytother Res.
  7. Hendrix MJ, Seftor EA, Hess AR, et al (2003). Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer, 3, 411-21.
  8. Huang S, Yang N, Liu Y, et al (2012). Grape seed proanthocyanidins inhibit colon cancer-induced angiogenesis through suppressing the expression of VEGF and Ang1. Int J Mol Med, 30, 1410-6.
  9. Lee CH, Wu YT, Hsieh HC, et al (2014). Epidermal growth factor/heat shock protein 27 pathway regulates vasculogenic mimicry activity of breast cancer stem/progenitor cells. Biochimie, 104, 117-26.
  10. Liu TJ, Sun BC, Zhao XL, et al (2013). CD133+ cells with cancer stem cell characteristics associates with vasculogenic mimicry in triple-negative breast cancer. Oncogene, 32, 544-53.
  11. Lu XS, Sun W, Ge CY, et al (2013). Contribution of the PI3K/MMPs/Ln-5gamma2 and EphA2/FAK/Paxillin signaling pathways to tumor growth and vasculogenic mimicry of gallbladder carcinomas. Int J Oncol, 42, 2103-15.
  12. Ma JL, Han SX, Zhu Q, et al (2011). Role of Twist in vasculogenic mimicry formation in hypoxic hepatocellular carcinoma cells in vitro. Biochem Biophys Res Commun, 408, 686-91.
  13. Maniotis AJ, Folberg R, Hess A, et al (1999). Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol, 155, 739-52.
  14. Mantena SK, Baliga MS, Katiyar SK (2006). Grape seed proanthocyanidins induce apoptosis and inhibit metastasis of highly metastatic breast carcinoma cells. Carcinogenesis, 27, 1682-91.
  15. Meeran SM, Vaid M, Punathil T, et al (2009). Dietary grape seed proanthocyanidins inhibit 12-O-tetradecanoyl phorbol-13-acetate-caused skin tumor promotion in 7, 12-dimethylbenz[a]anthracene-initiated mouse skin, which is associated with the inhibition of inflammatory responses. Carcinogenesis, 30, 520-8.
  16. Nandakumar V, Singh T, Katiyar SK (2008). Multi-targeted prevention and therapy of cancer by proanthocyanidins. Cancer Lett, 269, 378-87.
  17. Redig AJ, McAllister SS (2013). Breast cancer as a systemic disease: a view of metastasis. J Intern Med, 274, 113-26.
  18. Rhodes LV, Tate CR, Segar HC, et al (2014). Suppression of triple-negative breast cancer metastasis by pan-DAC inhibitor panobinostat via inhibition of ZEB family of EMT master regulators. Breast Cancer Res Treat, 145, 593-604.
  19. Seftor RE, Hess AR, Seftor EA, et al (2012). Tumor cell vasculogenic mimicry: from controversy to therapeutic promise. Am J Pathol, 181, 1115-25.
  20. Soda Y, Myskiw C, Rommel A, et al (2013). Mechanisms of neovascularization and resistance to anti-angiogenic therapies in glioblastoma multiforme. J Mol Med, 91, 439-48.
  21. Sun Q, Prasad R, Rosenthal E, et al (2011a). Grape seed proanthocyanidins inhibit the invasive potential of head and neck cutaneous squamous cell carcinoma cells by targeting EGFR expression and epithelial-to-mesenchymal transition. BMC Complement Altern Med, 11, 134.
  22. Sun T, Sun BC, Zhao XL, et al (2011b). Promotion of tumor cell metastasis and vasculogenic mimicry by way of transcription coactivation by Bcl-2 and Twist1: a study of hepatocellular carcinoma. Hepatology, 54, 1690-706.
  23. Sun T, Zhao N, Zhao XL, et al (2010). Expression and functional significance of Twist1 in hepatocellular carcinoma: its role in vasculogenic mimicry. Hepatol, 51, 545-56.
  24. Takano S (2012). Glioblastoma angiogenesis: VEGF resistance solutions and new strategies based on molecular mechanisms of tumor vessel formation. Brain Tumor Pathol, 29, 73-86.
  25. Taylor MA, Davuluri G, Parvani JG, et al (2013). Upregulated WAVE3 expression is essential for TGF-beta-mediated EMT and metastasis of triple-negative breast cancer cells. Breast Cancer Res Treat, 142, 341-53.
  26. van der Schaft DW, Seftor RE, Seftor EA, et al (2004). Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells. J Natl Cancer Inst, 96, 1473-7.
  27. Xu Y, Li Q, Li XY, et al (2012). Short-term anti-vascular endothelial growth factor treatment elicits vasculogenic mimicry formation of tumors to accelerate metastasis. J Exp Clin Cancer Res, 31, 16.
  28. Yang J, Mani SA, Donaher JL, et al (2004). Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell, 117, 927-39.
  29. Yoshida T, Ozawa Y, Kimura T, et al (2014). Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states. Br J Cancer, 110, 1497-505.
  30. Yue L, Wang Y, Wang H, et al (2012). Inhibition of hepatocellular carcinoma cell growth by an anti-insulin-like growth factor-I receptor monoclonal antibody. Oncol Rep, 28, 1453-60.
  31. Zhang JT, Sun W, Zhang WZ, et al (2014). Norcantharidin inhibits tumor growth and vasculogenic mimicry of human gallbladder carcinomas by suppression of the PI3-K/MMPs/Ln-5gamma2 signaling pathway. BMC Cancer, 14, 193.
  32. Zhao XL, Sun T, Che N, et al (2011). Promotion of hepatocellular carcinoma metastasis through matrix metalloproteinase activation by epithelial-mesenchymal transition regulator Twist1. J Cell Mol Med, 15, 691-700.

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