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

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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.

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References

  • 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 1327:6–15

    Article  CAS  Google Scholar 

  • 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 140:1597–1608

    Article  CAS  Google Scholar 

  • 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 22:2225–2236

    Article  CAS  Google Scholar 

  • Bandtlow CE, Zimmermann DR (2000) Proteoglycans in the developing brain: new conceptual insights for old proteins. Physiol Rev 80:1267–1290

    Article  CAS  Google Scholar 

  • Bertolotto A, Goia L, Schiffer D (1986) Immunohistochemical study of chondroitin sulfate in human gliomas. Acta Neuropathol 72:189–196

    Article  CAS  Google Scholar 

  • 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 14:1288–1299

    Article  CAS  Google Scholar 

  • Dwyer CA, Bi WL, Viapiano MS, Mattheus RT (2014) Brevican knockdown reduces late-stage glioma tumor aggressiveness. J Neurooncol 120:63–72

    Article  CAS  Google Scholar 

  • 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 557:25–53

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 21:2683–2710

    Article  CAS  Google Scholar 

  • 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 286:1475–1485

    Article  CAS  Google Scholar 

  • 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  CAS  Google Scholar 

  • 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 149:235–244

    Article  CAS  Google Scholar 

  • 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 72:419–432

    Article  CAS  Google Scholar 

  • Maeda N (2015) Proteoglycans and neuronal migration in the cerebral cortex during development and disease. Front Neurosci 9:98

    Article  Google Scholar 

  • Nicholson C, Hrabetova S (2017) Brain extracellular space: the final frontier of neuroscience. Biophys J 113:2133–2142

    Article  CAS  Google Scholar 

  • Nioka H, Matsumura K, Nakasu S, Handa J (1994) Immunohistochemical localization of glycosaminoglycans in experimental rat glioma models. J Neurooncol 21:233–242

    Article  CAS  Google Scholar 

  • Novak U, Kaye AH (2000) Extracellular matrix and the brain: components and function. J Clin Neurosci 7:280–290

    Article  CAS  Google Scholar 

  • Onishi M, Ichikawa T, Kurozumi K, Date I (2011) Angiogenesis and invasion in glioma. Brain Tumor Pathol 28:13–24

    Article  CAS  Google Scholar 

  • Phillips JJ (2012) Novel therapeutic targets in the brain tumor microenvironment. Oncotarget 3:568–575

    Article  Google Scholar 

  • 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 4:1527–1546

    Article  Google Scholar 

  • Quirico-Santos T, Fonseca CO, Lagrota-Candido J (2010) Brain sweet brain: importance of sugars for the cerebral microenvironment and tumor development. Arq Neuropsiquiatr 68:799–803

    Article  Google Scholar 

  • Rape A, Ananthanarayanan B, Kumar S (2014) Engineering strategies to mimic the glioblastoma microenvironment. Adv Drug Deliv Rev 79-80:172–183

    Article  CAS  Google Scholar 

  • 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 81:174–183

    Article  CAS  Google Scholar 

  • 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 3:983–992

    CAS  PubMed  Google Scholar 

  • 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 8:24815–24827

    PubMed  PubMed Central  Google Scholar 

  • 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 33:15603–15617

    Article  CAS  Google Scholar 

  • Sugahara K, Mikami T (2007) Chondroitin/dermatan sulfate in the central nervous system. Curr Opin Struct Biol 17:536–545

    Article  CAS  Google Scholar 

  • 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 39:1421–1428

    CAS  PubMed  Google Scholar 

  • 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 171:1324–1333

    Article  Google Scholar 

  • 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 1502:201–206

    Article  CAS  Google Scholar 

  • 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 35:376–390

    Article  CAS  Google Scholar 

  • 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 15:1623–1633

    Article  CAS  Google Scholar 

  • Trotter J, Karram K, Nishiyama A (2010) NG2 cells: Properties, progeny and origin. Brain Res Rev 63:72–82

    Article  CAS  Google Scholar 

  • 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 39:10.1177/1010428317724282

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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 127:202–209

    Article  CAS  Google Scholar 

  • Wade A, Robinson AE, Engler JR, Petritsch C, James CD, Phillips JJ (2013) Proteoglycans and their roles in brain cancer. FEBS J 280:2399–2417

    Article  CAS  Google Scholar 

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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

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).

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Authors and Affiliations

  1. Institute of Molecular Biology and Biophysics FRC FTM, Timakova 2/12, Novosibirsk, 630117, Russia

    Alexandra Y. Tsidulko, Galina M. Kazanskaya, Anastasia V. Suhovskih & Elvira V. Grigorieva

  2. Meshalkin National Medical Research Centre, Novosibirsk, Russia

    Galina M. Kazanskaya, Alexander M. Volkov, Anastasia V. Suhovskih, Roman S. Kiselev, Vyacheslav V. Kobozev & Alexei L. Krivoshapkin

  3. Novosibirsk State University, Novosibirsk, Russia

    Anastasia V. Suhovskih & Elvira V. Grigorieva

  4. Novosibirsk State Medical University, Novosibirsk, Russia

    Roman S. Kiselev, Alexei L. Krivoshapkin & Svetlana V. Aidagulova

  5. European Medical Centre, Moscow, Russia

    Alexei S. Gaytan & Alexei L. Krivoshapkin

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  1. Alexandra Y. Tsidulko
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  2. Galina M. Kazanskaya
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  8. Alexei L. Krivoshapkin
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  9. Svetlana V. Aidagulova
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  10. Elvira V. Grigorieva
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Correspondence to Elvira V. Grigorieva.

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Tsidulko, A.Y., Kazanskaya, G.M., Volkov, A.M. et al. Chondroitin sulfate content and decorin expression in glioblastoma are associated with proliferative activity of glioma cells and disease prognosis. Cell Tissue Res 379, 147–155 (2020). https://doi.org/10.1007/s00441-019-03127-2

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