Article | Published:

IGFBP2 promotes vasculogenic mimicry formation via regulating CD144 and MMP2 expression in glioma


Vasculogenic mimicry (VM) refers to the fluid-conducting channels formed by aggressive tumor cells rather than endothelial cells (EC) with elevated expression of genes associated with vascularization. VM has been considered as one of the reasons that glioblastoma becomes resistant to anti-VEGF therapy. However, the molecular basis underlying VM formation remains unclear. Here we report that the insulin-like growth factor–binding protein 2 (IGFBP2) acts as a potent factor to enhance VM formation in glioma. Evidence showed that elevated IGFBP2 expression was positively related with VM formation in patients with glioma. Enforced expression of IGFBP2 increased network formation of glioma cells in vitro by activating CD144 and MMP2 (Matrix Metalloproteinase 2). U251 cells with stable knockdown of IGFBP2 led to decreased VM formation and tumor progression in orthotopic mouse model. Mechanistically, IGFBP2 interacts with integrin α5 and β1 subunits and augments CD144 expression in a FAK/ERK pathway-dependent manner. Luciferase reporter and ChIP assay suggested that IGFBP2 activated the transcription factor SP1, which could bind to CD144 promoter. Thus, IGFBP2 acts as a stimulator of VM formation in glioma cells via enhancing CD144 and MMP2 expression.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Ohgaki H, Kleihues P. Epidemiology and etiology of gliomas. Acta Neuropathol. 2005;109:93–108.

  2. 2.

    Harold F. Tumor stroma, tumor blood vessels, and antiangiogenesis therapy. Cancer J. 2015;21:237–43.

  3. 3.

    Braghiroli MI, Sabbaga J, Hoff PM, Ignez M, Sabbaga J. Expert review of anticancer therapy. Bevacizumab: overview of the literature. Expert Rev Anticancer Ther. 2017;12:567–80.

  4. 4.

    Norden AD, Drappatz ÆJ, Muzikansky ÆA, David ÆK, Gerard M, Mcnamara ÆMB. et al. An exploratory survival analysis of anti-angiogenic therapy for recurrent malignant glioma. J Neurooncol. 2009;92:149–55.

  5. 5.

    Lai A, Tran A, Nghiemphu PL, Pope WB, Solis OE, Selch M. et al. Phase II study of Bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. diagnosed glioblastoma multiforme. J Clin Oncol.2010;29:142–148.

  6. 6.

    Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LMG, Pe J, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol. 1999;155:739–52.

  7. 7.

    Kirschmann Da, Seftor Ea, Hardy KM, Seftor REB, Hendrix MJC. Molecular pathways: vasculogenic mimicry in tumor cells: diagnostic and therapeutic implications. Clin Cancer Res. 2012;18:2726–32.

  8. 8.

    Liu X, Zhang Q, Mu Y, Zhang X, Sai K, Pang JC-S, et al. Clinical significance of vasculogenic mimicry in human gliomas. J Neurooncol. 2011;105:173–9.

  9. 9.

    Yue W-Y, Chen Z-P. Does vasculogenic mimicry exist in astrocytoma? J Histochem Cytochem. 2005;53:997–1002.

  10. 10.

    Hendrix MJ, Seftor Ea, Meltzer PS, Gardner LM, Hess aR, Kirschmann Da, et al. Expression and functional significance of VE-cadherin in aggressive human melanoma cells: role in vasculogenic mimicry. Proc Natl Acad Sci USA. 2001;98:8018–23.

  11. 11.

    Hendrix MJC, Seftor Ea, Hess AR, Seftor REB. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer. 2003;3:411–21.

  12. 12.

    Seftor REB, Seftor EA, Koshikawa N, Meltzer PS, Gardner LMG, Bilban M, et al. Cooperative interactions of laminin 5 γ 2 chain, matrix metalloproteinase-2, and membrane type-1-matrix / metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma 1. Cancer Res. 2001;61:6322–7.

  13. 13.

    Guo P, Imanishi Y, Cackowski FC, Jarzynka MJ, Tao H-Q, Nishikawa R, et al. Up-regulation of angiopoietin-2, matrix metalloprotease-2, membrane type 1 metalloprotease, and laminin 5 gamma 2 correlates with the invasiveness of human glioma. Am J Pathol. 2005;166:877–90.

  14. 14.

    Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A, et al. Glioblastoma stem-like cells give rise to tumour endothelium. Nature. 2010;468:829–33.

  15. 15.

    Scully S, Francescone R, Faibish M, Bentley B, Taylor SL, Oh D, et al. Transdifferentiation of glioblastoma stem-like cells into mural cells drives vasculogenic mimicry in glioblastomas. J Neurosci. 2012;32:12950–60.

  16. 16.

    Ping Y, Bian X. Cancer stem cells switch on tumor neovascularization. Curr Mol Med. 2011;11:69–75.

  17. 17.

    Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev. 2002;23:824–54.

  18. 18.

    Kühnl A, Kaiser M, Neumann M, Fransecky L, Heesch S, Radmacher M, et al. High expression of IGFBP2 is associated with chemoresistance in adult acute myeloid leukemia. Leuk Res. 2011;35:1585–90.

  19. 19.

    So AI, Levitt R, Eigl B, Fazli L, Muramaki M, Leung S. et al. Cancer therapy: preclinical insulin-like growth factor binding protein-2 is a novel therapeutic target associated with breast cancer. Clin Cancer Res. 2008;14:6944–54.

  20. 20.

    Huang Y, Cheng W, Wu Y, Cheng Y, Hsu K. Circulating IGF system and treatment outcome in epithelial ovarian cancer. Endocr Relat Cancer. 2014;21:217–29.

  21. 21.

    Biernacka KM, Uzoh CC, Zeng L, Persad RA, Bahl A, Gillatt D, et al. Hyperglycaemia-induced chemoresistance of prostate cancer cells due to IGFBP2. Endocr Relat Cancer. 2013;20:741–51.

  22. 22.

    Renehan AG, Jones J, Potten CS, Shalet SM, Dwyer STO. Elevated serum insulin-like growth factor (IGF) -II and IGF binding protein-2 in patients with colorectal cancer. Br J Cancer. 2000;83:1344–50.

  23. 23.

    Dunlap SM, Celestino J, Wang H, Jiang R, Holland EC, Fuller GN. Insulin-like growth factor binding protein 2 promotes glioma development and progression. Proc Natl Acad Sci USA. 2007;104:11736–41.

  24. 24.

    Pereira J, Meyer T, Docherty S, Reid H, Marshall J, Thompson E, et al. Bimolecular interaction of insulin-like growth factor (IGF) binding protein-2 with alphavbeta3 negatively modulates IGF- I-mediated migration and tumor growth. Cancer Res. 2004;64:977–84.

  25. 25.

    Schutt BS, Langkamp M, Rauschnabel U, Ranke MB, Elmlinger MW. Integrin-mediated action of insulin-like growth factor binding protein-2 in tumor cells. J Mol Endocrinol. 2004;32:859–68.

  26. 26.

    Luque A, Gomez M, Puzon W, Takada Y, Sanchez-Madrid F, Cabanas C. Activated conformations of very late activation integrins detected by a group of antibodies (HUTS) specific for a novel regulatory region (355-425) of the common beta 1 chain. J Biol Chem. 1996;271:11067–75.

  27. 27.

    Moore MG, Wetterau LA, Francis MJ, Peehl DM, Cohen P. Novel stimulatory role for insulin-like growth factor binding protein-2 in prostate cancer cells. Int J Cancer. 2003;105:14–19.

  28. 28.

    Chen X, Zheng J, Zou Y, Song C, Hu X, Zhang CC. IGF binding protein 2 is a cell-autonomous factor supporting survival and migration of acute leukemia cells. J Hematol Oncol. 2013;6:72.

  29. 29.

    Wang H, Wang H, Shen W, Huang H, Hu L, Ramdas L, et al. Insulin-like growth factor binding protein 2 enhances glioblastoma invasion by activating invasion-enhancing genes. Cancer Res. 2003;63:4315–21.

  30. 30.

    Sallinen SL, Sallinen PK, Haapasalo HK, Helin HJ, Helen PT, Schraml P, et al. Identification of differentially expressed genes in human gliomas by DNA microarray and tissue chip techniques. Cancer Res. 2000;60:6617–22.

  31. 31.

    Fuller GN, Rhee CH, Hess KR, Caskey LS, Wang R, Bruner JM, et al. Reactivation of insulin-like growth factor binding protein 2 expression in glioblastoma multiforme: a revelation by parallel gene expression profiling. Cancer Res. 1999;59:4228–32.

  32. 32.

    Godard S, Getz G, Delorenzi M, Farmer P, Kobayashi H, Desbaillets I, et al. Classification of human astrocytic gliomas on the basis of gene expression: a correlated group of genes with angiogenic activity emerges as a strong predictor of subtypes. Cancer Res. 2003;63:6613–25.

  33. 33.

    Frommer KW, Reichenmiller K, Schutt BS, Hoeflich A, Ranke MB, Dodt G, et al. IGF-independent effects of IGFBP-2 on the human breast cancer cell line Hs578T. J Mol Endocrinol. 2006;37:13–23.

  34. 34.

    Uzoh CC, Holly JMP, Biernacka KM, Persad RA, Bahl A, Gillatt D, et al. Insulin-like growth factor-binding protein-2 promotes prostate cancer cell growth via IGF-dependent or independent mechanisms and reduces the efficacy of docetaxel. Br J Cancer. 2011;104:1587–93.

  35. 35.

    Gao S, Sun Y, Zhang X, Hu L, Liu Y, Chua CY, et al. IGFBP2 activates the NF-kB pathway to drive epithelial-mesenchymal transition and invasive character in pancreatic ductal adenocarcinoma. Cancer Res. 2016;76:6543–54.

  36. 36.

    Russo VC, Azar WJ, Yau SW, Sabin Ma, Werther Ga. IGFBP-2: The dark horse in metabolism and cancer. Cytokine Growth Factor Rev. 2015;26:329–46.

  37. 37.

    Schütt BS, Langkamp M, Rauschnabel U, Ranke MB, Elmlinger MW. Integrin-mediated action of insulin-like factor binding protein-2 in tumor cells. J Mol Endocrinol. 2004;32:859–68.

  38. 38.

    Russo VC, Schutt BS, Andaloro E, Ymer SI, Hoeflich A, Ranke MB, et al. Insulin-like growth factor binding protein-2 binding to extracellular matrix plays a critical role in neuroblastoma cell proliferation, migration, and invasion. Endocrinology. 2005;146:4445–55.

  39. 39.

    Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Biochem J. 2011;437:169–83.

  40. 40.

    Mendes KN, Wang GK, Fuller GN, Zhang W. JNK mediates insulin-like growth factor binding protein 2/integrin alpha5-dependent glioma cell migration. Int J Oncol. 2010;37:143–53.

  41. 41.

    Chiao M-T, Yang Y-C, Cheng W-Y, Shen C-C, Ko J-L. CD133 + glioblastoma stem-like cells induce vascular mimicry in vivo. Curr Neurovasc Res. 2011;8:210–9.

  42. 42.

    Mei X, Chen Y-S, Chen F-R, Xi S-Y, Chen Z-P. Glioblastoma stem cell differentiation into endothelial cells evidenced through live-cell imaging. Neuro Oncol. 2017;42:1–10.

  43. 43.

    Lai CY, Schwartz BE, Hsu MY. CD133 + melanoma subpopulations contribute to perivascular niche morphogenesis and tumorigenicity through vasculogenic mimicry. Cancer Res. 2012;72:5111–8.

  44. 44.

    Liu TJ, Sun BC, Zhao XL, Zhao XM, Sun T, Gu Q, et al. CD133 + cells with cancer stem cell characteristics associates with vasculogenic mimicry in triple-negative breast cancer. Oncogene. 2013;32:544–53.

  45. 45.

    El Hallani S, Boisselier B, Peglion F, Rousseau A, Colin C, Idbaih A, et al. A new alternative mechanism in glioblastoma vascularization: tubular vasculogenic mimicry. Brain. 2010;133:973–82.

  46. 46.

    Wagenblast E, Soto M, Gutie S, Erard N, Williams AM, Kim SY, et al. A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis. Nature. 2015;520:358–62.

  47. 47.

    V elez DO, Tsui B, Goshia T, Chute CL, Han A, Carter H. et al. 3D collagen architecture induces a conserved migratory and transcriptional response linked to vasculogenic mimicry. Nat Commun.2017;8:142–148.

  48. 48.

    Hsieh D, Hsieh A, Stea B, Ellsworth R. IGFBP2 promotes glioma tumor stem cell expansion and survival. Biochem Biophys Res Commun. 2010;397:367–72.

  49. 49.

    Climate B, Dyck V, Phylogenies TF, Compare EP, Singh SK, Hawkins C, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396–401.

  50. 50.

    Liu X, Wang JH, Li S, Li LL, Huang M, Zhang YH, et al. Histone deacetylase 3 expression correlates with vasculogenic mimicry through the phosphoinositide3-kinase / ERK-MMP-laminin5γ2 signaling pathway. Cancer Sci. 2015;106:857–66.

  51. 51.

    Zhu S, Soutto M, Chen Z, Peng D, Romero-Gallo J, Krishna US, et al. Helicobacter pylori-induced cell death is counteracted by NF-kappaB-mediated transcription of DARPP-32. Gut. 2017;66:761–2.

  52. 52.

    Francescone R, Scully S, Bentley B, Yan W, Taylor SL, Oh D, et al. Glioblastoma-derived tumor cells induce vasculogenic mimicry through Flk-1 protein activation. J Biol Chem. 2012;287:24821–31.

Download references


This work was supported by the National Natural Science Foundation of China (No. 81772651 and No. 81772652)

Author contributions

XLS and YQK completed conception and design of the research, YL drafted the manuscript; YL, FL, YTY prepared the figures, YL, XDX, JSC, TLC, HJC, YBZ, JYL conducted the experiments, YQK, YL, and XMX edited the manuscript, YQK approved final version of the manuscript.

Author information

Conflict of interest

The authors declare that they have no conflict of interest.

Correspondence to X. L. Sun or Y. Q. Ke.

Electronic supplementary material

  1. Supplementary Figures

  2. Supplementary data

Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.

About this article

Publication history

  • Received

  • Revised

  • Accepted

  • Published

  • Issue Date


Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7