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Journal of Neuro-Oncology

, Volume 120, Issue 1, pp 63–72 | Cite as

Brevican knockdown reduces late-stage glioma tumor aggressiveness

  • Chrissa A. Dwyer
  • Wenya Linda Bi
  • Mariano S. Viapiano
  • Russell T. Matthews
Laboratory Investigation

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.

Keywords

Brevican Glioma Neural extracellular matrix Proteoglycan Central nervous system 

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

Notes

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.

Supplementary material

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References

  1. 1.
    Swartz MA, Iida N, Roberts EW, Sangaletti S, Wong MH et al (2012) Tumor microenvironment complexity: emerging roles in cancer therapy. Cancer Res 72:2473–2480PubMedCrossRefPubMedCentralGoogle Scholar
  2. 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 10:14–26PubMedCrossRefGoogle Scholar
  3. 3.
    Chen J, McKay RM, Parada LF (2012) Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell 149:36–47PubMedCrossRefPubMedCentralGoogle Scholar
  4. 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 36:1046–1069PubMedCrossRefGoogle Scholar
  5. 5.
    Filatova AAT, Garvalov BK (2013) The cancer stem cell niche(s): the crosstalk between glioma stem cells and their microenvironment. Biochim Biophys Acta 1830:2496–2508PubMedCrossRefGoogle Scholar
  6. 6.
    Lathia JD, Gallagher J, Heddleston JM, Wang J, Eyler CE et al (2010) Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 6:421–432PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Lathia JD, Li M, Hall PE, Gallagher J, Hale JS et al (2012) Laminin alpha 2 enables glioblastoma stem cell growth. Ann Neurol 72:766–778PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H (2012) The brain tumor microenvironment. Glia 60:502–514PubMedCrossRefGoogle Scholar
  9. 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 125:495–509PubMedCrossRefGoogle Scholar
  10. 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 15:1352–1362PubMedGoogle Scholar
  11. 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 269:10119–10126PubMedGoogle Scholar
  12. 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 56:2293–2298PubMedGoogle Scholar
  13. 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 27:2897–2909PubMedCrossRefGoogle Scholar
  14. 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 9:157–173PubMedCrossRefGoogle Scholar
  15. 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 17:98–110PubMedCrossRefPubMedCentralGoogle Scholar
  16. 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 256:139–147PubMedCrossRefGoogle Scholar
  17. 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 275:22695–22703PubMedCrossRefGoogle Scholar
  18. 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 61:7056–7059PubMedGoogle Scholar
  19. 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 65:6726–6733PubMedCrossRefGoogle Scholar
  20. 20.
    Viapiano MS, Hockfield S, Matthews RT (2008) BEHAB/brevican requires ADAMTS-mediated proteolytic cleavage to promote glioma invasion. J Neurooncol 88:261–272PubMedCrossRefPubMedCentralGoogle Scholar
  21. 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 278:33239–33247PubMedCrossRefGoogle Scholar
  22. 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 18:2370–2376PubMedGoogle Scholar
  23. 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 283:24848–24859PubMedCrossRefPubMedCentralGoogle Scholar
  24. 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 12:607PubMedCrossRefPubMedCentralGoogle Scholar
  25. 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 64:7011–7021PubMedCrossRefGoogle Scholar
  26. 26.
    Bottenstein JE, Sato GH (1979) Growth of a rat neuroblastoma cell line in serum-free supplemented medium. Proc Natl Acad Sci USA 76:514–517PubMedCrossRefPubMedCentralGoogle Scholar
  27. 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 33:401–406PubMedCrossRefGoogle Scholar
  28. 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 143:826–836PubMedCrossRefPubMedCentralGoogle Scholar
  29. 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 220:47–61PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Rosen GD, Harry JD (1990) Brain volume estimation from serial section measurements: a comparison of methodologies. J Neurosci Methods 35:115–124PubMedCrossRefGoogle Scholar
  31. 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 22:191–200PubMedCrossRefGoogle Scholar
  32. 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 3:1567–1579PubMedCrossRefPubMedCentralGoogle Scholar
  33. 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 53:503–517PubMedCrossRefPubMedCentralGoogle Scholar
  34. 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 63:5821–5828PubMedGoogle Scholar
  35. 35.
    Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J et al (2004) Identification of human brain tumour initiating cells. Nature 432:396–401PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Chrissa A. Dwyer
    • 1
  • Wenya Linda Bi
    • 2
    • 3
  • Mariano S. Viapiano
    • 2
    • 3
  • Russell T. Matthews
    • 1
    • 4
  1. 1.SUNY Upstate Medical UniversitySyracuseUSA
  2. 2.Yale UniversityNew HavenUSA
  3. 3.Brigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  4. 4.Department of Neuroscience and PhysiologySUNY Upstate Medical UniversitySyracuseUSA

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