Medical Oncology

, Volume 28, Supplement 1, pp 228–238 | Cite as

Prognostic significance and mechanisms of patterned matrix vasculogenic mimicry in hepatocellular carcinoma

  • Wen-bin Liu
  • Ge-liang XuEmail author
  • Wei-dong Jia
  • Jian-sheng Li
  • Jin-liang Ma
  • Ke Chen
  • Zhi-hua Wang
  • Yong-sheng Ge
  • Wei-hua Ren
  • Ji-hai Yu
  • Wei Wang
  • Xiu-jun Wang
Original paper


Vasculogenic mimicry (VM), including tubular VM and patterned matrix VM, has been generally recognized as a new pattern of tumor neovascularization. Pilot studies of tubular VM showed that it was present in hepatocellular carcinoma (HCC) and associated with poor clinical prognosis. However, whether patterned matrix VM is clinically significant in HCC is unknown. To elucidate the effects of patterned matrix VM on prognosis of HCC and the mechanisms involved in VM formation, we examined 151 cases of surgically resected human HCC by immunohistochemistry and transmission electron microscopy and conducted hypoxic experiments on human HCC cell line MHCC97-H. We observed 31 of 151 (20.5%) cases exhibited evidence of patterned matrix VM. The expression of patterned matrix VM was associated with larger tumors (P = 0.042), vascular invasion (P = 0.016), high-grade HCC (P = 0.022), and late-stage HCC (P = 0.013). Kaplan–Meier survival analysis revealed that cases of the VM group had lower overall survival (OS) rate (P < 0.001) and disease-free survival (DFS) rate (P = 0.002) than that of the non-VM group. Univariate and multivariate analysis indicated that the presence of patterned matrix VM was independent adverse prognostic factor for both OS (P = 0.004) and DFS (P = 0.011). Expression of hypoxia-inducible factor 1 alpha (HIF-1alpha), matrix metalloproteinase (MMP)-2, and MMP-9 were higher in the VM group than in the non-VM group (P = 0.001, P = 0.030, P = 0.007, respectively). After VM formation was induced by hypoxia, up-regulated expression of HIF-1α, MMP-2, and MMP-9 was also detected in cells cultured under hypoxia condition. Our results indicate that patterned matrix VM exists in HCC, and it might serve as an unfavorable prognostic factor for HCC patients. It is possible that hypoxia via induction of expression of HIF-1alpha, MMP-2, and MMP-9 may enhance VM formation in HCC.


Vasculogenic mimicry Hepatocellular carcinoma Hypoxic-inducible factor-1α Matrix metalloproteinase Extracellular matrix 



This study was supported by the National Natural Science Foundation of China (30972892), the Science and Technology Key Project of Anhui Province (07010302193), Anhui Provincial Natural Science Foundation (090413107), Anhui Provincial College Natural Science Key Project (KJ2009A178), the Science and Technological Fund of Anhui Province for Outstanding Youth (08040106818), and the Anhui Provincial ‘‘115’’ Industrial Innovation Program.


  1. 1.
    Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003;9(6):653–60.PubMedCrossRefGoogle Scholar
  2. 2.
    Chang YS, et al. Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc Natl Acad Sci USA. 2000;97(26):14608–13.PubMedCrossRefGoogle Scholar
  3. 3.
    Semela D, Dufour JF. Angiogenesis and hepatocellular carcinoma. J Hepatol. 2004;41(5):864–80.PubMedCrossRefGoogle Scholar
  4. 4.
    Maniotis AJ, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol. 1999;155(3):739–52.PubMedCrossRefGoogle Scholar
  5. 5.
    Folberg R, Maniotis AJ. Vasculogenic mimicry. APMIS. 2004;112(7–8):508–25.PubMedCrossRefGoogle Scholar
  6. 6.
    Guzman G, Cotler SJ, Lin AY, Maniotis AJ, Folberg R. A pilot study of vasculogenic mimicry immunohistochemical expression in hepatocellular carcinoma. Arch Pathol Lab Med. 2007;131(12):1776–81.PubMedGoogle Scholar
  7. 7.
    Hendrix MJ, Seftor EA, Hess AR, Seftor RE. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer. 2003;3(6):411–21.PubMedCrossRefGoogle Scholar
  8. 8.
    Lissitzky JC, et al. Cyclic AMP signaling as a mediator of vasculogenic mimicry in aggressive human melanoma cells in vitro. Cancer Res. 2009;69(3):802–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Basu GD, et al. A novel role for cyclooxygenase-2 in regulating vascular channel formation by human breast cancer cells. Breast Cancer Res. 2006;8(6):R69.PubMedCrossRefGoogle Scholar
  10. 10.
    Robertson FM, et al. Differential regulation of the aggressive phenotype of inflammatory breast cancer cells by prostanoid receptors EP3 and EP4. Cancer. 2010;116(11 Suppl):2806–14.PubMedCrossRefGoogle Scholar
  11. 11.
    Sharma N, et al. Prostatic tumor cell plasticity involves cooperative interactions of distinct phenotypic subpopulations: role in vasculogenic mimicry. Prostate. 2002;50(3):189–201.PubMedCrossRefGoogle Scholar
  12. 12.
    Sood AK, et al. Functional role of matrix metalloproteinases in ovarian tumor cell plasticity. Am J Obstet Gynecol. 2004;190(4):899–909.PubMedCrossRefGoogle Scholar
  13. 13.
    Scavelli C, et al. Vasculogenic mimicry by bone marrow macrophages in patients with multiple myeloma. Oncogene. 2008;27(5):663–74.PubMedCrossRefGoogle Scholar
  14. 14.
    van der Schaft DW, et al. Tumor cell plasticity in Ewing sarcoma, an alternative circulatory system stimulated by hypoxia. Cancer Res. 2005;65(24):11520–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Zhang LZ, et al. The role of VE-cadherin in osteosarcoma cells. Pathol Oncol Res. 2010;16(1):111–7.PubMedCrossRefGoogle Scholar
  16. 16.
    El Hallani S, et al. A new alternative mechanism in glioblastoma vascularization: tubular vasculogenic mimicry. Brain. 2010;133(Pt 4):973–82.PubMedCrossRefGoogle Scholar
  17. 17.
    Li M, et al. Vasculogenic mimicry: a new prognostic sign of gastric adenocarcinoma. Pathol Oncol Res. 2010;16(2):259–66.PubMedCrossRefGoogle Scholar
  18. 18.
    Baeten CI, Hillen F, Pauwels P, de Bruine AP, Baeten CG. Prognostic role of vasculogenic mimicry in colorectal cancer. Dis Colon Rectum. 2009;52(12):2028–35.PubMedCrossRefGoogle Scholar
  19. 19.
    Vartanian AA, et al. Prognostic significance of periodic acid-Schiff-positive patterns in clear cell renal cell carcinoma. Can J Urol. 2009;16(4):4726–32.PubMedGoogle Scholar
  20. 20.
    Mirshahi P, et al. Vasculogenic mimicry of acute leukemic bone marrow stromal cells. Leukemia. 2009;23(6):1039–48.PubMedCrossRefGoogle Scholar
  21. 21.
    Sun B, et al. Vasculogenic mimicry is associated with high tumor grade, invasion and metastasis, and short survival in patients with hepatocellular carcinoma. Oncol Rep. 2006;16(4):693–8.PubMedGoogle Scholar
  22. 22.
    Dupuy E, et al. Tumoral angiogenesis and tissue factor expression during hepatocellular carcinoma progression in a transgenic mouse model. J Hepatol. 2003;38(6):793–802.PubMedCrossRefGoogle Scholar
  23. 23.
    Sun T, et al. Expression and functional significance of Twist1 in hepatocellular carcinoma: its role in vasculogenic mimicry. Hepatology. 2010;51(2):545–56.PubMedCrossRefGoogle Scholar
  24. 24.
    Crowther M, Brown NJ, Bishop ET, Lewis CE. Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors. J Leukoc Biol. 2001;70(4):478–90.PubMedGoogle Scholar
  25. 25.
    Liu SY, et al. Clinicopathologic significance of tumor cell-lined vessel and microenvironment in oral squamous cell carcinoma. Oral Oncol. 2008;44(3):277–85.PubMedCrossRefGoogle Scholar
  26. 26.
    Sun B, et al. Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma. Cancer Lett. 2007;249(2):188–97.PubMedCrossRefGoogle Scholar
  27. 27.
    Mattern J, Koomagi R, Volm M. Association of vascular endothelial growth factor expression with intratumoral microvessel density and tumour cell proliferation in human epidermoid lung carcinoma. Br J Cancer. 1996;73(7):931–4.PubMedCrossRefGoogle Scholar
  28. 28.
    Yamamoto K, et al. Proliferation, differentiation, and tube formation by endothelial progenitor cells in response to shear stress. J Appl Physiol. 2003;95(5):2081–8.PubMedGoogle Scholar
  29. 29.
    Sood AK, et al. Molecular determinants of ovarian cancer plasticity. Am J Pathol. 2001;158(4):1279–88.PubMedCrossRefGoogle Scholar
  30. 30.
    Folkman J. Can mosaic tumor vessels facilitate molecular diagnosis of cancer? Proc Natl Acad Sci USA. 2001;98(2):398–400.PubMedCrossRefGoogle Scholar
  31. 31.
    Massi D, et al. Vasculogenic mimicry has no prognostic significance in pT3 and pT4 cutaneous melanoma. Hum Pathol. 2004;35(4):496–502.PubMedCrossRefGoogle Scholar
  32. 32.
    Vengellur A, Phillips JM, Hogenesch JB, LaPres JJ. Gene expression profiling of hypoxia signaling in human hepatocellular carcinoma cells. Physiol Genomics. 2005;22(3):308–18.PubMedCrossRefGoogle Scholar
  33. 33.
    Wu XZ, Xie GR, Chen D. Hypoxia and hepatocellular carcinoma: The therapeutic target for hepatocellular carcinoma. J Gastroenterol Hepatol. 2007;22(8):1178–82.PubMedCrossRefGoogle Scholar
  34. 34.
    Dai CX, et al. Hypoxia-inducible factor-1 alpha, in association with inflammation, angiogenesis and MYC, is a critical prognostic factor in patients with HCC after surgery. BMC Cancer. 2009;9:418.PubMedCrossRefGoogle Scholar
  35. 35.
    Bertout JA, Patel SA, Simon MC. The impact of O2 availability on human cancer. Nat Rev Cancer. 2008;8(12):967–75.PubMedCrossRefGoogle Scholar
  36. 36.
    Zhang S, Zhang D, Sun B. Vasculogenic mimicry: current status and future prospects. Cancer Lett. 2007;254(2):157–64.PubMedCrossRefGoogle Scholar
  37. 37.
    Seftor RE, et al. Cooperative interactions of laminin 5 gamma2 chain, matrix metalloproteinase-2, and membrane type-1-matrix/metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma. Cancer Res. 2001;61(17):6322–7.PubMedGoogle Scholar
  38. 38.
    Annabi B, et al. Hypoxia promotes murine bone-marrow-derived stromal cell migration and tube formation. Stem Cells. 2003;21(3):337–47.PubMedCrossRefGoogle Scholar
  39. 39.
    Ottino P, et al. Hypoxia activates matrix metalloproteinase expression and the VEGF system in monkey choroid-retinal endothelial cells: Involvement of cytosolic phospholipase A2 activity. Mol Vis. 2004;10:341–50.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Wen-bin Liu
    • 1
    • 2
  • Ge-liang Xu
    • 2
    Email author
  • Wei-dong Jia
    • 2
  • Jian-sheng Li
    • 2
  • Jin-liang Ma
    • 2
  • Ke Chen
    • 3
  • Zhi-hua Wang
    • 3
  • Yong-sheng Ge
    • 2
  • Wei-hua Ren
    • 2
  • Ji-hai Yu
    • 2
  • Wei Wang
    • 2
  • Xiu-jun Wang
    • 2
  1. 1.Graduate School of Tianjin Medical UniversityTianjinPeople’s Republic of China
  2. 2.Centre for the Study of Liver Cancer and Department of Hepatic Surgery, Anhui Provincial HospitalAnhui Medical UniversityHefeiPeople’s Republic of China
  3. 3.Department of Pathology, Anhui Provincial HospitalAnhui Medical UniversityHefeiPeople’s Republic of China

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