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

Oncogene volume 38, pages 1815–1831 (2019)Cite this article

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Abstract

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.

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References

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

    Article  Google Scholar 

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

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Google Scholar 

  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.

    Article  CAS  Google Scholar 

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Acknowledgements

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.

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  1. Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China

    Y. Liu, F. Li, Y. T. Yang, X. D. Xu, J. S. Chen, T. L. Chen, H. J. Chen, Y. B. Zhu, J. Y. Lin, Y. Li, X. M. Xie, X. L. Sun & Y. Q. Ke

  2. The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangzhou, China

    Y. Liu, F. Li, Y. T. Yang, X. D. Xu, J. S. Chen, T. L. Chen, H. J. Chen, Y. B. Zhu, J. Y. Lin, Y. Li, X. M. Xie, X. L. Sun & Y. Q. Ke

  3. Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, China

    Y. Liu, F. Li, Y. T. Yang, X. D. Xu, J. S. Chen, T. L. Chen, H. J. Chen, Y. B. Zhu, J. Y. Lin, Y. Li, X. M. Xie, X. L. Sun & Y. Q. Ke

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Liu, Y., Li, F., Yang, Y.T. et al. IGFBP2 promotes vasculogenic mimicry formation via regulating CD144 and MMP2 expression in glioma. Oncogene 38, 1815–1831 (2019). https://doi.org/10.1038/s41388-018-0525-4

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