Skip to main content

Advertisement

SpringerLink
Log in

The role of extracellular-5′-nucleotidase/CD73 in glioma peritumoural brain edema

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

During pathological conditions, extracellular-5′-nucleotidase/CD73 can protect neurons by reducing the permeability of the blood brain barrier. In recent years, it has been demonstrated that CD73 can negatively contribute to the growth of gliomas; however, the function of CD73 in glioma blood vessels is not clear. We analysed the expression of CD73 in 72 glioma patients using immunohistochemistry and correspondingly compared the results with the Edema index (EI). We established an in vitro model of the blood-tumour barrier and analysed the expression of CD73 in vascular endothelial cells. Lastly, CD73 expression was inhibited in endothelial cells, and the effects of this inhibition on tight junction structure and transendothelial resistance were observed. Compared to normal brains, the expression of CD73 in blood vessels of glioma patients was significantly decreased, and the amount was lower in the centre of the tumour than the periphery. The proportion of CD73-positive blood vessels had a positive correlation with the EI. The expression of CD73 in the in vitro endothelial cell blood-tumour barrier model was decreased. Lastly, inhibiting CD73 was found to decrease the expression of tight junction related proteins in endothelial cells and to decrease the value of transendothelial electric resistance. The expression of CD73 in glioma blood vessels was significantly decreased, which may play a multi-functional role in decreasing the expression of tight junction related proteins of brain microvascular endothelial cells and may also increase blood-tumour barrier permeability and accelerate the formation of PTBE.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Dubois LG, Campanati L, Righy C, D’Andrea-Meira I, Spohr TC, Porto-Carreiro I, Pereira CM, Balca-Silva J, Kahn SA, DosSantos MF, Oliveira Mde A, Ximenes-da-Silva A, Lopes MC, Faveret E, Gasparetto EL, Moura-Neto V (2014) Gliomas and the vascular fragility of the blood brain barrier. Front Cell Neurosci 8:418. doi:10.3389/fncel.2014.00418

    Article  PubMed  PubMed Central  Google Scholar 

  2. Wang XF, Lin GS, Lin ZX, Chen YP, Chen Y, Zhang JD, Tan WL (2014) Association of pSTAT3-VEGF signaling pathway with peritumoral edema in newly diagnosed glioblastoma: an immunohistochemical study. Int J Clin Exp Pathol 7(9):6133–6140

    PubMed  PubMed Central  Google Scholar 

  3. Lee J, Lund-Smith C, Borboa A, Gonzalez AM, Baird A, Eliceiri BP (2009) Glioma-induced remodeling of the neurovascular unit. Brain Res 1288:125–134. doi:10.1016/j.brainres.2009.06.095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang M, Olsson Y (1997) Hematogenous metastases of the human brain—characteristics of peritumoral brain changes: a review. J Neurooncol 35(1):81–89

    Article  CAS  PubMed  Google Scholar 

  5. Badaut J, Fukuda AM, Jullienne A, Petry KG (2014) Aquaporin and brain diseases. Biochim Biophys Acta 1840(5):1554–1565. doi:10.1016/j.bbagen.2013.10.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Walcott BP, Kahle KT, Simard JM (2012) Novel treatment targets for cerebral edema. Neurotherapeutics 9(1):65–72. doi:10.1007/s13311-011-0087-4

    Article  PubMed  PubMed Central  Google Scholar 

  7. Zhang B (2010) CD73: a novel target for cancer immunotherapy. Cancer Res 70(16):6407–6411. doi:10.1158/0008-5472.can-10-1544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Grunewald JK, Ridley AJ (2010) CD73 represses pro-inflammatory responses in human endothelial cells. J Inflamm (Lond) 7(1):10. doi:10.1186/1476-9255-7-10

    Article  Google Scholar 

  9. Wang L, Tang S, Wang Y, Xu S, Yu J, Zhi X, Ou Z, Yang J, Zhou P, Shao Z (2013) Ecto-5′-nucleotidase (CD73) promotes tumor angiogenesis. Clin Exp Metastasis 30(5):671–680. doi:10.1007/s10585-013-9571-z

    Article  CAS  PubMed  Google Scholar 

  10. Yoshioka H, Hama S, Taniguchi E, Sugiyama K, Arita K, Kurisu K (1999) Peritumoral brain edema associated with meningioma: influence of vascular endothelial growth factor expression and vascular blood supply. Cancer 85(4):936–944

    Article  CAS  PubMed  Google Scholar 

  11. Sica G (2010) Assessment of angiogenesis by CD105 and nestin expression in peritumor tissue of glioblastoma. Int J Oncol. doi:10.3892/ijo_00000822

    Google Scholar 

  12. Hatherell K, Couraud PO, Romero IA, Weksler B, Pilkington GJ (2011) Development of a three-dimensional, all-human in vitro model of the blood-brain barrier using mono-, co-, and tri-cultivation Transwell models. J Neurosci Methods 199(2):223–229. doi:10.1016/j.jneumeth.2011.05.012

    Article  PubMed  Google Scholar 

  13. Antonioli L, Pacher P, Vizi ES, Hasko G (2013) CD39 and CD73 in immunity and inflammation. Trends Mol Med 19(6):355–367. doi:10.1016/j.molmed.2013.03.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schaddelee MP, Voorwinden HL, van Tilburg EW, Pateman TJ, Ijzerman AP, Danhof M, de Boer AG (2003) Functional role of adenosine receptor subtypes in the regulation of blood–brain barrier permeability: possible implications for the design of synthetic adenosine derivatives. Eur J Pharm Sci Off J Eur Fed Pharm Sci 19(1):13–22

    CAS  Google Scholar 

  15. Lu XX, Chen YT, Feng B, Mao XB, Yu B, Chu XY (2013) Expression and clinical significance of CD73 and hypoxia-inducible factor-1alpha in gastric carcinoma. World J Gastroenterol 19(12):1912–1918. doi:10.3748/wjg.v19.i12.1912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yu YI, Wang W, Song L, Hu W, Dong C, Pei H, Zhou G, Yue Z (2015) Ecto-5′-nucleotidase expression is associated with the progression of renal cell carcinoma. Oncol Lett 9(6):2485–2494. doi:10.3892/ol.2015.3138

    PubMed  PubMed Central  Google Scholar 

  17. Zhang B, Song B, Wang X, Chang XS, Pang T, Zhang X, Yin K, Fang GE (2015) The expression and clinical significance of CD73 molecule in human rectal adenocarcinoma. Tumour Biol J Int Soc Oncodev Biol Med 36(7):5459–5466. doi:10.1007/s13277-015-3212-x

    Article  CAS  Google Scholar 

  18. Burghoff S, Gong X, Viethen C, Jacoby C, Flogel U, Bongardt S, Schorr A, Hippe A, Homey B, Schrader J (2014) Growth and metastasis of B16-F10 melanoma cells is not critically dependent on host CD73 expression in mice. BMC Cancer 14:898. doi:10.1186/1471-2407-14-898

    Article  PubMed  PubMed Central  Google Scholar 

  19. Ludwig HC, Rausch S, Schallock K, Markakis E (1999) Expression of CD 73 (ecto-5′-nucleotidase) in 165 glioblastomas by immunohistochemistry and electronmicroscopic histochemistry. Anticancer Res 19(3A):1747–1752

    CAS  PubMed  Google Scholar 

  20. Bavaresco L, Bernardi A, Braganhol E, Cappellari AR, Rockenbach L, Farias PF, Wink MR, Delgado-Canedo A, Battastini AM (2008) The role of ecto-5′-nucleotidase/CD73 in glioma cell line proliferation. Mol Cell Biochem 319(1–2):61–68. doi:10.1007/s11010-008-9877-3

    Article  CAS  PubMed  Google Scholar 

  21. Cappellari AR, Vasques GJ, Bavaresco L, Braganhol E, Battastini AM (2012) Involvement of ecto-5′-nucleotidase/CD73 in U138MG glioma cell adhesion. Mol Cell Biochem 359(1–2):315–322. doi:10.1007/s11010-011-1025-9

    Article  CAS  PubMed  Google Scholar 

  22. Heldin CH, Rubin K, Pietras K, Ostman A (2004) High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer 4(10):806–813. doi:10.1038/nrc1456

    Article  CAS  PubMed  Google Scholar 

  23. Weidle UH, Niewohner J, Tiefenthaler G (2015) The blood–brain barrier challenge for the treatment of brain cancer, secondary brain metastases, and neurological diseases. Cancer Genom Proteom 12(4):167–177

    CAS  Google Scholar 

  24. Wang W, Kim MT, Sedykh A, Zhu H (2015) Developing enhanced blood–brain barrier permeability models: integrating external bio-assay data in QSAR modeling. Pharm Res. doi:10.1007/s11095-015-1687-1

    Google Scholar 

  25. Shityakov S, Salvador E, Pastorin G, Forster C (2015) Blood–brain barrier transport studies, aggregation, and molecular dynamics simulation of multiwalled carbon nanotube functionalized with fluorescein isothiocyanate. Int J Nanomed 10:1703–1713. doi:10.2147/IJN.S68429

    Article  CAS  Google Scholar 

  26. Carman AJ, Mills JH, Krenz A, Kim DG, Bynoe MS (2011) Adenosine receptor signaling modulates permeability of the blood–brain barrier. J Neurosci Off J Soc Neurosci 31(37):13272–13280. doi:10.1523/jneurosci.3337-11.2011

    Article  CAS  Google Scholar 

  27. Ma J, Wang P, Liu Y, Zhao L, Li Z, Xue Y (2014) Kruppel-like factor 4 regulates blood-tumor barrier permeability via ZO-1, occludin and claudin-5. J Cell Physiol 229(7):916–926. doi:10.1002/jcp.24523

    Article  CAS  PubMed  Google Scholar 

  28. Miao YS, Zhao YY, Zhao LN, Wang P, Liu YH, Ma J, Xue YX (2015) MiR-18a increased the permeability of BTB via RUNX1 mediated down-regulation of ZO-1, occludin and claudin-5. Cell Signal 27(1):156–167. doi:10.1016/j.cellsig.2014.10.008

    Article  CAS  PubMed  Google Scholar 

  29. Liu W, Wang P, Shang C, Chen L, Cai H, Ma J, Yao Y, Shang X, Xue Y (2014) Endophilin-1 regulates blood-brain barrier permeability by controlling ZO-1 and occludin expression via the EGFR-ERK1/2 pathway. Brain Res 1573:17–26. doi:10.1016/j.brainres.2014.05.022

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank all the surgeons from the Neurosurgery Department of the Tianjin HuanHu Hospital for their help in gathering the tumour biopsies; Yi Zhang, Fang Lan, and Xin He for the critical reading of the manuscript and for helpful suggestions. The work is supported by the Science and Technology Foundation of the Tianjin Health Bureau (2014KY19).

Author information

Author notes

    Authors and Affiliations

    1. Department of Neurosurgery, Tianjin HuanHu Hospital, 122 QiXiangTai Road, Tianjin, China

      Bo Wang, Wei Wang, Yu Zhou, HongGuang Wang & Xin Yao

    2. Tianjin Key Laboratory of Cerebrovascular Disease and Neurodegenerative Disease, 122 QiXiangTai Road, Tianjin, China

      Bo Wang, Wei Wang, Yu Zhou, HongGuang Wang & Xin Yao

    3. Tianjin Neurosurgical Institute, 122 QiXiangTai Road, Tianjin, China

      Bo Wang, Wei Wang, Yu Zhou, HongGuang Wang, MengYuan Liu & Xin Yao

    4. Department of Neurosurgery, Tianjin Medical University, General Hospital, 154 Anshan Road, Tianjin, China

      Dong Wang

    5. Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, 154 Anshan Road, Tianjin, China

      Dong Wang

    6. Tianjin Neurological Institute, 154 Anshan Road, Tianjin, China

      Dong Wang

    7. Department of Rehabilitation, Tianjin HuanHu Hospital, 122 QiXiangTai Road, Tianjin, China

      ZhiZhong Zhu

    8. Department of Pathology, Tianjin HuanHu Hospital, 122 QiXiangTai Road, Tianjin, China

      XueBin Zhang, Fan Tang & XiaoLing Yan

    Authors
    1. Bo Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Dong Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. ZhiZhong Zhu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Wei Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. XueBin Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Fan Tang
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Yu Zhou
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. HongGuang Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. MengYuan Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Xin Yao
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. XiaoLing Yan
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to XiaoLing Yan.

    Ethics declarations

    Conflict of interest

    The authors disclose no potential conflicts of interest.

    Additional information

    B. Wang and D. Wang contributed to the paper equally.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Wang, B., Wang, D., Zhu, Z. et al. The role of extracellular-5′-nucleotidase/CD73 in glioma peritumoural brain edema. Neurol Sci 37, 603–611 (2016). https://doi.org/10.1007/s10072-016-2510-4

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10072-016-2510-4

    Keywords

    Search

    Navigation