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Brevican knockdown reduces late-stage glioma tumor aggressiveness

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Growing evidence supports the important role of the tumor microenvironment (TME) in cancer biology. A defining aspect of the glioma TME is the unique composition and structure of its extracellular matrix (ECM), which enables tumor cells to overcome the inhibitory barriers of the adult central nervous system (CNS). In this way, the TME plays a role in glioma invasion and the cellular heterogeneity that distinguishes these tumors. Brain Enriched Hyaluronan Binding (BEHAB)/brevican (B/b), is a CNS-specific ECM constituent and is upregulated in the glioma TME. Previous studies have shown B/b exerts a pro-invasive function, suggesting it may represent a target to reduce glioma pathogenesis. Herein, we also provide evidence that B/b expression is enriched in the glioma initiating cell (GIC) niche. We demonstrate that B/b plays roles in the pathological progression, aggressiveness, and lethality of tumors derived from human GICs and traditional glioma cell lines. Interestingly, we found that B/b is not required to maintain the defining phenotypic properties of GICs and thereby acts primarily in late stages of glioma progression. This study suggests that the increased expression of B/b in the TME is a valuable therapeutic target for glioma.

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Abbreviations

B/b:

Brain enriched hyaluronan binding/brevican

CNS:

Central nervous system

DIV:

Days in vitro

DPI:

Days post injection

ECM:

Extracellular matrix

GIC:

Glioma initiating cell

HGGs:

High-grade gliomas

TME:

Tumor microenvironment

References

  1. Swartz MA, Iida N, Roberts EW, Sangaletti S, Wong MH et al (2012) Tumor microenvironment complexity: emerging roles in cancer therapy. Cancer Res 72:2473–2480

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Tanaka S, Louis DN, Curry WT, Batchelor TT, Dietrich J (2013) Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end? Nat Rev Clin Oncol 10:14–26

    Article  PubMed  CAS  Google Scholar 

  3. Chen J, McKay RM, Parada LF (2012) Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell 149:36–47

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Bellail AC, Hunter SB, Brat DJ, Tan C, Van Meir EG (2004) Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. Int J Biochem Cell Biol 36:1046–1069

    Article  PubMed  CAS  Google Scholar 

  5. Filatova AAT, Garvalov BK (2013) The cancer stem cell niche(s): the crosstalk between glioma stem cells and their microenvironment. Biochim Biophys Acta 1830:2496–2508

    Article  PubMed  CAS  Google Scholar 

  6. Lathia JD, Gallagher J, Heddleston JM, Wang J, Eyler CE et al (2010) Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 6:421–432

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Lathia JD, Li M, Hall PE, Gallagher J, Hale JS et al (2012) Laminin alpha 2 enables glioblastoma stem cell growth. Ann Neurol 72:766–778

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H (2012) The brain tumor microenvironment. Glia 60:502–514

    Article  PubMed  Google Scholar 

  9. Jaworski DM, Kelly GM, Hockfield S (1994) BEHAB, a new member of the proteoglycan tandem repeat family of hyaluronan-binding proteins that is restricted to the brain. J Cell Biol 125:495–509

    Article  PubMed  CAS  Google Scholar 

  10. Jaworski DM, Kelly GM, Hockfield S (1995) The CNS-specific hyaluronan-binding protein BEHAB is expressed in ventricular zones coincident with gliogenesis. J Neurosci 15:1352–1362

    PubMed  CAS  Google Scholar 

  11. Yamada H, Watanabe K, Shimonaka M, Yamaguchi Y (1994) Molecular cloning of brevican, a novel brain proteoglycan of the aggrecan/versican family. J Biol Chem 269:10119–10126

    PubMed  CAS  Google Scholar 

  12. Jaworski DM, Kelly GM, Piepmeier JM, Hockfield S (1996) BEHAB (brain enriched hyaluronan binding) is expressed in surgical samples of glioma and in intracranial grafts of invasive glioma cell lines. Cancer Res 56:2293–2298

    PubMed  CAS  Google Scholar 

  13. Gunther HS, Schmidt NO, Phillips HS, Kemming D, Kharbanda S et al (2008) Glioblastoma-derived stem cell-enriched cultures form distinct subgroups according to molecular and phenotypic criteria. Oncogene 27:2897–2909

    Article  PubMed  CAS  Google Scholar 

  14. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH et al (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9:157–173

    Article  PubMed  CAS  Google Scholar 

  15. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Gary SC, Zerillo CA, Chiang VL, Gaw JU, Gray G et al (2000) cDNA Cloning, chromosomal localization, and expression analysis of human BEHAB/brevican, a brain specific proteoglycan regulated during cortical development and in glioma. Gene 256:139–147

    Article  PubMed  CAS  Google Scholar 

  17. Matthews RT, Gary SC, Zerillo C, Pratta M, Solomon K et al (2000) Brain-enriched hyaluronan binding (BEHAB)/brevican cleavage in a glioma cell line is mediated by a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family member. J Biol Chem 275:22695–22703

    Article  PubMed  CAS  Google Scholar 

  18. Nutt CL, Zerillo CA, Kelly GM, Hockfield S (2001) Brain enriched hyaluronan binding (BEHAB)/brevican increases aggressiveness of CNS-1 gliomas in Lewis rats. Cancer Res 61:7056–7059

    PubMed  CAS  Google Scholar 

  19. Viapiano MS, Bi WL, Piepmeier J, Hockfield S, Matthews RT (2005) Novel tumor-specific isoforms of BEHAB/brevican identified in human malignant gliomas. Cancer Res 65:6726–6733

    Article  PubMed  CAS  Google Scholar 

  20. Viapiano MS, Hockfield S, Matthews RT (2008) BEHAB/brevican requires ADAMTS-mediated proteolytic cleavage to promote glioma invasion. J Neurooncol 88:261–272

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Viapiano MS, Matthews RT, Hockfield S (2003) A novel membrane-associated glycovariant of BEHAB/brevican is up-regulated during rat brain development and in a rat model of invasive glioma. J Biol Chem 278:33239–33247

    Article  PubMed  CAS  Google Scholar 

  22. Zhang H, Kelly G, Zerillo C, Jaworski DM, Hockfield S (1998) Expression of a cleaved brain-specific extracellular matrix protein mediates glioma cell invasion in vivo. J Neurosci 18:2370–2376

    PubMed  CAS  Google Scholar 

  23. Hu B, Kong LL, Matthews RT, Viapiano MS (2008) The proteoglycan brevican binds to fibronectin after proteolytic cleavage and promotes glioma cell motility. J Biol Chem 283:24848–24859

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Lu R, Wu C, Guo L, Liu Y, Mo W et al (2012) The role of brevican in glioma: promoting tumor cell motility in vitro and in vivo. BMC Cancer 12:607

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A et al (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64:7011–7021

    Article  PubMed  CAS  Google Scholar 

  26. Bottenstein JE, Sato GH (1979) Growth of a rat neuroblastoma cell line in serum-free supplemented medium. Proc Natl Acad Sci USA 76:514–517

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Rubinson DA, Dillon CP, Kwiatkowski AV, Sievers C, Yang L et al (2003) A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat Genet 33:401–406

    Article  PubMed  CAS  Google Scholar 

  28. Matsuki T, Matthews RT, Cooper JA, van der Brug MP, Cookson MR et al (2010) Reelin and stk25 have opposing roles in neuronal polarization and dendritic Golgi deployment. Cell 143:826–836

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Dwyer CA, Baker E, Hu H, Matthews RT (2012) RPTPzeta/phosphacan is abnormally glycosylated in a model of muscle-eye-brain disease lacking functional POMGnT1. Neuroscience 220:47–61

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Rosen GD, Harry JD (1990) Brain volume estimation from serial section measurements: a comparison of methodologies. J Neurosci Methods 35:115–124

    Article  PubMed  CAS  Google Scholar 

  31. Kruse CA, Molleston MC, Parks EP, Schiltz PM, Kleinschmidt-DeMasters BK et al (1994) A rat glioma model, CNS-1, with invasive characteristics similar to those of human gliomas: a comparison to 9L gliosarcoma. J Neurooncol 22:191–200

    Article  PubMed  CAS  Google Scholar 

  32. Rheinbay E, Suva ML, Gillespie SM, Wakimoto H, Patel AP et al (2013) An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma. Cell Rep 3:1567–1579

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Ligon KL, Huillard E, Mehta S, Kesari S, Liu H et al (2007) Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma. Neuron 53:503–517

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828

    PubMed  CAS  Google Scholar 

  35. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J et al (2004) Identification of human brain tumour initiating cells. Nature 432:396–401

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to acknowledge Wendi Burnette for technical assistance with histology and Shieldy Jean-Louis for blinded tumor volume quantification. This work was funded by R01NS035228 (NINDS) and the Joseph C. Georg Fund.

Conflict of interest

The authors declare they have no conflict of interest.

Ethical statements

These experiments comply with the ethical standards and current laws of the country in which the research was performed.

Author information

Authors and Affiliations

  1. SUNY Upstate Medical University, Syracuse, NY, USA

    Chrissa A. Dwyer & Russell T. Matthews

  2. Yale University, New Haven, CT, USA

    Wenya Linda Bi & Mariano S. Viapiano

  3. Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Wenya Linda Bi & Mariano S. Viapiano

  4. Department of Neuroscience and Physiology, SUNY Upstate Medical University, 3238 Weiskotten Hall 750 East Adams St., Syracuse, NY, 13210, USA

    Russell T. Matthews

Authors
  1. Chrissa A. Dwyer
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  2. Wenya Linda Bi
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  3. Mariano S. Viapiano
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  4. Russell T. Matthews
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Corresponding author

Correspondence to Russell T. Matthews.

Additional information

Chrissa A. Dwyer and Wenya Linda Bi contributed equally to this work. Wenya Linda Bi contributed studies done in rodent models while Chrissa A. Dwyer contributed studies done in glioma initiating cells.

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Dwyer, C.A., Bi, W.L., Viapiano, M.S. et al. Brevican knockdown reduces late-stage glioma tumor aggressiveness. J Neurooncol 120, 63–72 (2014). https://doi.org/10.1007/s11060-014-1541-z

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  • DOI: https://doi.org/10.1007/s11060-014-1541-z

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