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Chondroitin sulfate content and decorin expression in glioblastoma are associated with proliferative activity of glioma cells and disease prognosis

  • Alexandra Y. Tsidulko
  • Galina M. Kazanskaya
  • Alexander M. Volkov
  • Anastasia V. Suhovskih
  • Roman S. Kiselev
  • Vyacheslav V. Kobozev
  • Alexei S. Gaytan
  • Alexei L. Krivoshapkin
  • Svetlana V. Aidagulova
  • Elvira V. GrigorievaEmail author
Regular Article
  • 53 Downloads

Abstract

Chondroitin sulfate proteoglycans (CSPGs) are important components of brain extracellular matrix (ECM), although their contribution in gliomagenesis remains underinvestigated. Here, both chondroitin sulfate (CS) content/distribution and expression of a number of CSPG core proteins were studied in glioblastoma multiforme (GBM) tumours with different prognosis (n = 40) using immunohistochemistry and RT-PCR analysis. Survival rates for clinically different patient groups were compared using the Kaplan-Meier analysis and univariate Cox model. CS content was increased in 60–65% of studied GBM tumours and distributed heterogeneously, mainly at perinecrotic and perivascular zones rather than tumour cells with specific morphology. CS accumulation, especially in the tumour extracellular matrix, was positively associated with the proliferative activity of GBM cells according to theKi67 index (p < 0.01) but revealed no significant association with age or sex of the patients, tumour localisation, relapse or disease outcome. The increase in CS content in GBM tumours was accompanied by upregulation of decorin (1.5-fold), biglycan (3-fold) and serglycin (2-fold) expression (p < 0.05), while only decorin expression level was negatively associated with the overall survival rate of the GBM patients (p < 0.05). These results demonstrate a contribution of CS to high intratumoural heterogeneity of GBM and suggest CS content and decorin expression for further investigation as potential microenvironmental glycomarkers/targets for GBM diagnostics and treatment.

Keywords

Chondroitin sulfate proteoglycan Decorin Extracellular matrix Tumour microenvironment Glioblastoma multiforme 

Notes

Acknowledgements

The authors would like to thank the ‘Proteomic analysis’ Center of the Institute of Molecular Biology and Biophysics (IMBB FRC FTM) for granting access to the equipment.

Funding information

This study was funded by the Russian Science Foundation, grant number 16-15-10243. AYT was supported by a scholarship of Russian Federation President for young scientists (SP-5435.2018.4). AVS was supported by a scholarship of Russian Federation President for young scientists (SP-1816.2019.4).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

References

  1. Abaskharoun M, Bellemare M, Lau E, Margolis RU (2010) Expression of hyaluronan and the hyaluronan-binding proteoglycans neurocan, aggrecan, and versican by neural stem cells and neural cells derived from embryonic stem cells. Brain Res 1327:6–15CrossRefGoogle Scholar
  2. Agerbaek MO, Pereira MA, Clausen TM, Pehrson C, Oo HZ, Spliid C, Rich JR, Fung V, Nkrumah F, Neequaye J, Biggar RJ, Reynolds SJ, Tosato G, Pullarkat ST, Ayers LW, Theander TG, Daugaard M, Bhatia K, Nielsen MA, Mbulaiteye SM, Salanti A (2017) Burkitt lymphoma expresses oncofetal chondroitin sulfate without being a reservoir for placental malaria sequestration. Int J Cancer 140:1597–1608CrossRefGoogle Scholar
  3. Asher RA, Morgenstern DA, Shearer MC, Adcock KH, Pesheva P, Fawcett JW (2002) Versican is upregulated in CNS injury and is a product of oligodendrocyte lineage cells. J Neurosci 22:2225–2236CrossRefGoogle Scholar
  4. Bandtlow CE, Zimmermann DR (2000) Proteoglycans in the developing brain: new conceptual insights for old proteins. Physiol Rev 80:1267–1290CrossRefGoogle Scholar
  5. Bertolotto A, Goia L, Schiffer D (1986) Immunohistochemical study of chondroitin sulfate in human gliomas. Acta Neuropathol 72:189–196CrossRefGoogle Scholar
  6. Clausen TM, Pereira MA, Al Nakouzi N, Oo HZ, Agerbæk MØ, Lee S, Ørum-Madsen MS, Kristensen AR, El-Naggar A, Grandgenett PM, Grem JL, Hollingsworth MA, Holst PJ, Theander T, Sorensen PH, Daugaard M, Salanti A (2016) Oncofetal chondroitin sulfate glycosaminoglycans are key players in integrin signaling and tumor cell motility. Mol Cancer Res 14:1288–1299CrossRefGoogle Scholar
  7. Dwyer CA, Bi WL, Viapiano MS, Mattheus RT (2014) Brevican knockdown reduces late-stage glioma tumor aggressiveness. J Neurooncol 120:63–72CrossRefGoogle Scholar
  8. Faissner A, Heck N, Dobbertin A, Garwood J (2006) DSD-1-proteoglycan/phosphacan and receptor protein tyrosine phosphatase-beta isoforms during development and regeneration of neural tissues. Adv Exp Med Biol 557:25–53CrossRefGoogle Scholar
  9. Farace C, Oliver JA, Melguizo C, Alvarez P, Bandiera P, Rama AR, Malaguarnera G, Ortiz R, Madeddu R, Prados J (2015) Microenvironmental modulation of decorin and lumican in temozolomide-resistant glioblastoma and neuroblastoma cancer stem-like cells. PLoS One 10:e0134111.  https://doi.org/10.1371/journal.pone.0134111 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, Chin L, DePinho RA, Cavenee WK (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21:2683–2710CrossRefGoogle Scholar
  11. Hernandez D, Miquel-Serra L, Docampo MJ, Marco-Ramell A, Cabrera J, Fabra A, Bassols A (2011) V3 versican isoform alters the behavior of human melanoma cells by interfering with CD44/ErbB-dependent signaling. J Biol Chem 286:1475–1485CrossRefGoogle Scholar
  12. 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 283:24848–24859CrossRefGoogle Scholar
  13. Kazanskaya GM, Tsidulko AY, Volkov AM, Kiselev RS, Suhovskih AV, Kobozev VV, Gaytan AS, Aidagulova SV, Krivoshapkin AL, Grigorieva EV (2018) Heparan sulfate accumulation and perlecan/HSPG2 up-regulation in tumour tissue predict low relapse-free survival for patients with glioblastoma. Histochem Cell Biol 149:235–244CrossRefGoogle Scholar
  14. Lau LW, Keough MB, Haylock-Jacobs S, Cua R, Doring A, Sloka S, Stirling DP, Rivest S, Yong VW (2012) Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination. Ann Neurol 72:419–432CrossRefGoogle Scholar
  15. Maeda N (2015) Proteoglycans and neuronal migration in the cerebral cortex during development and disease. Front Neurosci 9:98CrossRefGoogle Scholar
  16. Nicholson C, Hrabetova S (2017) Brain extracellular space: the final frontier of neuroscience. Biophys J 113:2133–2142CrossRefGoogle Scholar
  17. Nioka H, Matsumura K, Nakasu S, Handa J (1994) Immunohistochemical localization of glycosaminoglycans in experimental rat glioma models. J Neurooncol 21:233–242CrossRefGoogle Scholar
  18. Novak U, Kaye AH (2000) Extracellular matrix and the brain: components and function. J Clin Neurosci 7:280–290CrossRefGoogle Scholar
  19. Onishi M, Ichikawa T, Kurozumi K, Date I (2011) Angiogenesis and invasion in glioma. Brain Tumor Pathol 28:13–24CrossRefGoogle Scholar
  20. Phillips JJ (2012) Novel therapeutic targets in the brain tumor microenvironment. Oncotarget 3:568–575CrossRefGoogle Scholar
  21. Poli A, Wang J, Domingues O, Planagumà J, Yan T, Rygh CB, Skaftnesmo KO, Thorsen F, McCormack E, Hentges F, Pedersen PH, Zimmer J, Enger PØ, Chekenya M (2013) Targeting glioblastoma with NK cells and mAb against NG2/CSPG4 prolongs animal survival. Oncotarget 4:1527–1546CrossRefGoogle Scholar
  22. Quirico-Santos T, Fonseca CO, Lagrota-Candido J (2010) Brain sweet brain: importance of sugars for the cerebral microenvironment and tumor development. Arq Neuropsiquiatr 68:799–803CrossRefGoogle Scholar
  23. Rape A, Ananthanarayanan B, Kumar S (2014) Engineering strategies to mimic the glioblastoma microenvironment. Adv Drug Deliv Rev 79-80:172–183CrossRefGoogle Scholar
  24. Reinhard J, Brosicke N, Theocharidis U, Faissner A (2016) The extracellular matrix niche microenvironment of neural and cancer stem cells in the brain. Int J Biochem Cell Biol 81:174–183CrossRefGoogle Scholar
  25. Ricciardelli C, Mayne K, Sykes PJ, Raymond WA, McCaul K, Marshall VR, Tilley WD, Skinner JM, Horsfall DJ (1997) Elevated stromal chondroitin sulfate glycosaminoglycan predicts progression in early-stage prostate cancer. Clin Cancer Res 3:983–992PubMedGoogle Scholar
  26. Roy A, Attarha S, Weishaupt H, Edqvist PH, Swartling FJ, Bergqvist M, Siebzehnrubl FA, Smits A, Pontén F, Tchougounova E (2017) Serglycin as a potential biomarker for glioma: association of serglycin expression, extent of mast cell recruitment and glioblastoma progression. Oncotarget 8:24815–24827PubMedPubMedCentralGoogle Scholar
  27. Silver DJ, Siebzehnrubl FA, Schildts MJ, Yachnis AT, Smith GM, Smith AA, Scheffler B, Reynolds BA, Silver J, Steindler DA (2013) Chondroitin sulfate proteoglycans potently inhibit invasion and serve as a central organizer of the brain tumor microenvironment. J Neurosci 33:15603–15617CrossRefGoogle Scholar
  28. Sugahara K, Mikami T (2007) Chondroitin/dermatan sulfate in the central nervous system. Curr Opin Struct Biol 17:536–545CrossRefGoogle Scholar
  29. Svensson KJ, Christianson HC, Kucharzewska P, Fagerström V, Lundstedt L, Borgquist S, Jirström K, Belting M (2011) Chondroitin sulfate expression predicts poor outcome in breast cancer. Int J Oncol 39:1421–1428PubMedGoogle Scholar
  30. ten Dam GB, van de Westerlo EM, Purushothaman A, Stan RV, Bulten J, Sweep FC, Massuger LF, Sugahara K, van Kuppevelt TH (2007) Antibody GD3G7 selected against embryonic glycosaminoglycans defines chondroitin sulfate-E domains highly up-regulated in ovarian cancer and involved in vascular endothelial growth factor binding. Am J Pathol 171:1324–1333CrossRefGoogle Scholar
  31. Theocharis AD, Tsara ME, Papageorgacopoulou N, Karavias DD, Theocharis DA (2000) Pancreatic carcinoma is characterized by elevated content of hyaluronan and chondroitin sulfate with altered disaccharide composition. Biochim Biophys Acta 1502:201–206CrossRefGoogle Scholar
  32. Theocharis AD, Vynios DH, Papageorgacopoulou N, Skandalis SS, Theocharis DA (2003) Altered content composition and structure of glycosaminoglycans and proteoglycans in gastric carcinoma. Int J Biochem Cell Biol 35:376–390CrossRefGoogle Scholar
  33. Tran VM, Wade A, McKinney A, Chen K, Lindberg OR, Engler JR, Persson AI, Phillips J (2017) Heparan sulfate glycosaminoglycans in glioblastoma promote tumor invasion. Mol Cancer Res 15:1623–1633CrossRefGoogle Scholar
  34. Trotter J, Karram K, Nishiyama A (2010) NG2 cells: Properties, progeny and origin. Brain Res Rev 63:72–82CrossRefGoogle Scholar
  35. Tsidulko AY, Kazanskaya GM, Kostromskaya DV, Aidagulova SV, Kiselev RS, Volkov AM, Kobozev VV, Gaitan AS, Krivoshapkin AL, Grigorieva EV (2017) Prognostic relevance of NG2/CSPG4, CD44 and Ki-67 in patients with glioblastoma. Tumor Biol 39:10.1177/1010428317724282CrossRefGoogle Scholar
  36. Ushakov VS, Tsidulko AY, de La Bourdonnaye G, Kazanskaya GM, Volkov AM, Kiselev RS, Kobozev VV, Kostromskaya DV, Gaytan AS, Krivoshapkin AL, Aidagulova SV, Grigorieva EV (2017) Heparan sulfate biosynthetic system is inhibited in human glioma due to EXT1/2 and HS6ST1/2 down-regulation. Int J Mol Sci 18.  https://doi.org/10.3390/ijms18112301 CrossRefGoogle Scholar
  37. Vallen MJ, Massuger LF, ten Dam GB, Bulten J, van Kuppevelt TH (2012) Highly sulfated chondroitin sulfates, a novel class of prognostic biomarkers in ovarian cancer tissue. Gynecol Oncol 127:202–209CrossRefGoogle Scholar
  38. Wade A, Robinson AE, Engler JR, Petritsch C, James CD, Phillips JJ (2013) Proteoglycans and their roles in brain cancer. FEBS J 280:2399–2417CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Alexandra Y. Tsidulko
    • 1
  • Galina M. Kazanskaya
    • 1
    • 2
  • Alexander M. Volkov
    • 2
  • Anastasia V. Suhovskih
    • 1
    • 2
    • 3
  • Roman S. Kiselev
    • 2
    • 4
  • Vyacheslav V. Kobozev
    • 2
  • Alexei S. Gaytan
    • 5
  • Alexei L. Krivoshapkin
    • 2
    • 4
    • 5
  • Svetlana V. Aidagulova
    • 4
  • Elvira V. Grigorieva
    • 1
    • 3
    Email author
  1. 1.Institute of Molecular Biology and Biophysics FRC FTMNovosibirskRussia
  2. 2.Meshalkin National Medical Research CentreNovosibirskRussia
  3. 3.Novosibirsk State UniversityNovosibirskRussia
  4. 4.Novosibirsk State Medical UniversityNovosibirskRussia
  5. 5.European Medical CentreMoscowRussia

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