Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

CD163, a novel therapeutic target, regulates the proliferation and stemness of glioma cells via casein kinase 2

Abstract

Glioma is a devastating cancer with a dismal prognosis and there is an urgent need to discover novel glioma-specific antigens for glioma therapy. Previous studies have identified CD163-positive tumour cells in certain solid tumours, but CD163 expression in glioma remains unknown. In this study, via an analysis of public datasets, we demonstrated that CD163 overexpression in glioma specimens correlated with an unfavourable patient prognosis. CD163 expression was increased in glioma cells, especially primary glioma cells. The loss of CD163 expression inhibited both cell cycle progression and the proliferation of glioblastoma multiforme (GBM) cell lines and primary glioma cells. CD163 interacted directly with casein kinase 2 (CK2) and CD163 silencing reduced AKT/GSK3β/β-catenin/cyclin D1 pathway activity via CK2. Moreover, CD163 was upregulated in CD133-positive glioma stem cells (GSCs), and CD163 downregulation decreased the expression of GSC markers, including CD133, ALDH1A1, NANOG and OCT4. The knockdown of CD163 impaired GSC stemness by inhibiting the CK2/AKT/GSK3β/β-catenin pathway. Finally, a CD163 antibody successfully induced complement-dependent cytotoxicity against glioma cells. Our findings indicate that CD163 contributes to gliomagenesis via CK2 and provides preclinical evidence that CD163 and the CD163 pathway might serve as a therapeutic target for glioma.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, et al. CBTRUS Statistical Report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol. 2017;19:v1–v88.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359:492–507.

    Article  CAS  PubMed  Google Scholar 

  3. Boussiotis VA, Charest A. Immunotherapies for malignant glioma. Oncogene. 2018;37:1121–41.

    Article  CAS  PubMed  Google Scholar 

  4. Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375:2561–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, et al. Glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model. Cancer Immunol Res. 2016;4:124–35.

    Article  CAS  PubMed  Google Scholar 

  6. Reardon DA, Omuro A, Brandes AA, Rieger J, Wick A, Sepulveda J, et al. OS10.3 Randomized phase 3 study evaluating the efficacy and safety of nivolumab vs bevacizumab in patients with recurrent glioblastoma: CheckMate 143. Neuro Oncol. 2017;19:iii21–iii21.

    Article  PubMed Central  Google Scholar 

  7. Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res. 2015;21:687–92.

    Article  CAS  PubMed  Google Scholar 

  8. Law SK, Micklem KJ, Shaw JM, Zhang XP, Dong Y, Willis AC, et al. A new macrophage differentiation antigen which is a member of the scavenger receptor superfamily. Eur J Immunol. 1993;23:2320–5.

    Article  CAS  PubMed  Google Scholar 

  9. Kristiansen M, Graversen JH, Jacobsen C, Sonne O, Hoffman HJ, Law SK, et al. Identification of the haemoglobin scavenger receptor. Nature. 2001;409:198–201.

    Article  CAS  PubMed  Google Scholar 

  10. Fabriek BO, van Bruggen R, Deng DM, Ligtenberg AJ, Nazmi K, Schornagel K, et al. The macrophage scavenger receptor CD163 functions as an innate immune sensor for bacteria. Blood. 2009;113:887–92.

    Article  CAS  PubMed  Google Scholar 

  11. Calvert JG, Slade DE, Shields SL, Jolie R, Mannan RM, Ankenbauer RG, et al. CD163 expression confers susceptibility to porcine reproductive and respiratory syndrome viruses. J Virol. 2007;81:7371–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sanchez-Torres C, Gomez-Puertas P, Gomez-del-Moral M, Alonso F, Escribano JM, Ezquerra A, et al. Expression of porcine CD163 on monocytes/macrophages correlates with permissiveness to African swine fever infection. Arch Virol. 2003;148:2307–23.

    Article  CAS  PubMed  Google Scholar 

  13. Ostuni R, Kratochvill F, Murray PJ, Natoli G. Macrophages and cancer: from mechanisms to therapeutic implications. Trends Immunol. 2015;36:229–39.

    Article  CAS  PubMed  Google Scholar 

  14. Qi L, Yu H, Zhang Y, Zhao D, Lv P, Zhong Y, et al. IL-10 secreted by M2 macrophage promoted tumorigenesis through interaction with JAK2 in glioma. Oncotarget. 2016;7:71673–85.

    PubMed  PubMed Central  Google Scholar 

  15. Ye XZ, Xu SL, Xin YH, Yu SC, Ping YF, Chen L, et al. Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-beta1 signaling pathway. J Immunol. 2012;189:444–53.

    Article  CAS  PubMed  Google Scholar 

  16. Chang AL, Miska J, Wainwright DA, Dey M, Rivetta CV, Yu D, et al. CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Cancer Res. 2016;76:5671–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shi Y, Ping YF, Zhou W, He ZC, Chen C, Bian BS, et al. Tumour-associated macrophages secrete pleiotrophin to promote PTPRZ1 signalling in glioblastoma stem cells for tumour growth. Nat Commun. 2017;8:15080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. Lisi L, Ciotti GM, Braun D, Kalinin S, Curro D, Dello RC, et al. Expression of iNOS, CD163 and ARG-1 taken as M1 and M2 markers of microglial polarization in human glioblastoma and the surrounding normal parenchyma. Neurosci Lett. 2017;645:106–12.

    Article  CAS  PubMed  Google Scholar 

  20. Prosniak M, Harshyne LA, Andrews DW, Kenyon LC, Bedelbaeva K, Apanasovich TV, et al. Glioma grade is associated with the accumulation and activity of cells bearing M2 monocyte markers. Clin Cancer Res. 2013;19:3776–86.

    Article  CAS  PubMed  Google Scholar 

  21. Ma C, Horlad H, Ohnishi K, Nakagawa T, Yamada S, Kitada S. CD163-positive cancer cells are potentially associated with high malignant potential in clear cell renal cell carcinoma. Med Mol Morphol. 2017;51:13–20.

    Article  PubMed  Google Scholar 

  22. Jensen TO, Schmidt H, Steiniche T, Hoyer M, Moller HJ, Jensen TO, et al. Melanoma cell expression of macrophage markers in AJCC stage I/II melanoma. J Clin Oncol. 2010;28:e19034–e19034.

    Article  Google Scholar 

  23. Shabo I, Olsson H, Sun XF, Svanvik J. Expression of the macrophage antigen CD163 in rectal cancer cells is associated with early local recurrence and reduced survival time. Int J Cancer. 2009;125:1826–31.

    Article  CAS  PubMed  Google Scholar 

  24. Shabo I, Stal O, Olsson H, Dore S, Svanvik J. Breast cancer expression of CD163, a macrophage scavenger receptor, is related to early distant recurrence and reduced patient survival. Int J Cancer. 2008;123:780–6.

    Article  CAS  PubMed  Google Scholar 

  25. Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell. 2006;9:391–403.

    Article  CAS  PubMed  Google Scholar 

  26. Shtutman M, Zhurinsky J, Simcha I, Albanese C, Amico MD, Pestell R, et al. The cyclin D1 gene is a target of the β-catenin/LEF-1 pathway. Proc Natl Acad Sci USA. 1998;96:5522–7.

    Article  Google Scholar 

  27. Lai SS, Zhao DD, Cao P, Lu K, Luo OY, Chen WB, et al. PP2Acalpha positively regulates the termination of liver regeneration in mice through the AKT/GSK3beta/Cyclin D1 pathway. J Hepatol. 2016;64:352–60.

    Article  CAS  PubMed  Google Scholar 

  28. Litchfield DW. Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem J. 2003;369:1–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ritter M, Buechler C, Kapinsky M, Schmitz G. Interaction of CD163 with the regulatory subunit of casein kinase II (CKII) and dependence of CD163 signaling on CKII and protein kinase C. Eur J Immunol. 2001;31:999–1009.

    Article  CAS  PubMed  Google Scholar 

  30. Di Maira G, Salvi M, Arrigoni G, Marin O, Sarno S, Brustolon F, et al. Protein kinase CK2 phosphorylates and upregulates Akt/PKB. Cell Death Differ. 2005;12:668–77.

    Article  PubMed  Google Scholar 

  31. Ponce DP, Maturana JL, Cabello P, Yefi R, Niechi I, Silva E, et al. Phosphorylation of AKT/PKB by CK2 is necessary for the AKT-dependent up-regulation of beta-catenin transcriptional activity. J Cell Physiol. 2011;226:1953–9.

    Article  CAS  PubMed  Google Scholar 

  32. Kaminska B, Ellert-Miklaszewska A, Oberbek A, Wisniewski P, Kaza B, Makowska M, et al. Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells. Int J Oncol. 2009;35:1091–100.

    Article  CAS  PubMed  Google Scholar 

  33. Xi G, Hayes E, Lewis R, Ichi S, Mania-Farnell B, Shim K, et al. CD133 and DNA-PK regulate MDR1 via the PI3K- or Akt-NF-kappaB pathway in multidrug-resistant glioblastoma cells in vitro. Oncogene. 2016;35:241–50.

    Article  CAS  PubMed  Google Scholar 

  34. Rasper M, Schafer A, Piontek G, Teufel J, Brockhoff G, Ringel F, et al. Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity. Neuro Oncol. 2010;12:1024–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zbinden M, Duquet A, Lorente-Trigos A, Ngwabyt SN, Borges I, Ruiz IAA. NANOG regulates glioma stem cells and is essential in vivo acting in a cross-functional network with GLI1 and p53. EMBO J. 2010;29:2659–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ikushima H, Todo T, Ino Y, Takahashi M, Saito N, Miyazawa K, et al. Glioma-initiating cells retain their tumorigenicity through integration of the Sox axis and Oct4 protein. J Biol Chem. 2011;286:41434–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Condello S, Morgan CA, Nagdas S, Cao L, Turek J, Hurley TD, et al. β-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids. Oncogene. 2015;34:2297–308.

    Article  CAS  PubMed  Google Scholar 

  38. Tang Y, Berlind J, Mavila N. Inhibition of CREB binding protein-beta-catenin signaling down regulates CD133 expression and activates PP2A-PTEN signaling in tumor initiating liver cancer cells. Cell Commun Signal. 2018;16:9.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Cole MF, Johnstone SE, Newman JJ, Kagey MH, Young RA. Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. Genes Dev. 2008;22:746–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Natsume A, Niwa R, Satoh M. Improving effector functions of antibodies for cancer treatment: Enhancing ADCC and CDC. Drug Des Devel Ther. 2009;3:7–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Prinz M, Priller J, Sisodia SS, Ransohoff RM. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci. 2011;14:1227–35.

    Article  CAS  PubMed  Google Scholar 

  42. Kim WK, Alvarez X, Fisher J, Bronfin B, Westmoreland S, McLaurin J, et al. CD163 identifies perivascular macrophages in normal and viral encephalitic brains and potential precursors to perivascular macrophages in blood. Am J Pathol. 2006;168:822–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang Z, Zhang ZY, Wu Y, Schluesener HJ. Lesional accumulation of CD163+macrophages/microglia in rat traumatic brain injury. Brain Res. 2012;1461:102–10.

    Article  CAS  PubMed  Google Scholar 

  44. Noubissi FK, Ogle BM. Cancer cell fusion: mechanisms slowly unravel. Int J Mol Sci. 2016;17:1587–1596.

    Article  PubMed Central  Google Scholar 

  45. Shabo I, Svanvik J. Expression of macrophage antigens by tumor cells. Adv Exp Med Biol. 2011;714:141–50.

    Article  CAS  PubMed  Google Scholar 

  46. Lu X, Kang Y. Cell fusion hypothesis of the cancer stem cell. Adv Exp Med Biol. 2011;714:129–40.

    Article  CAS  PubMed  Google Scholar 

  47. Bigner SH, Bjerkvig R, Laerum OD. DNA content and chromosomal composition of malignant human gliomas. Neurol Clin. 1985;3:769–84.

    Article  CAS  PubMed  Google Scholar 

  48. He C, Zheng S, Luo Y, Wang B. Exosome theranostics: biology and translational medicine. Theranostics. 2018;8:237–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Olsen BB, Issinger OG, Guerra B. Regulation of DNA-dependent protein kinase by protein kinase CK2 in human glioblastoma cells. Oncogene. 2010;29:6016–26.

    Article  CAS  PubMed  Google Scholar 

  50. Dixit D, Sharma V, Ghosh S, Mehta VS, Sen E. Inhibition of casein kinase-2 induces p53-dependent cell cycle arrest and sensitizes glioblastoma cells to tumor necrosis factor (TNFalpha)-induced apoptosis through SIRT1 inhibition. Cell Death Dis. 2012;3:e271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Nitta RT, Gholamin S, Feroze AH, Agarwal M, Cheshier SH, Mitra SS, et al. Casein kinase 2alpha regulates glioblastoma brain tumor-initiating cell growth through the beta-catenin pathway. Oncogene. 2015;34:3688–99.

    Article  CAS  PubMed  Google Scholar 

  52. Lin KY, Fang CL, Chen Y, Li CF, Chen SH, Kuo CY, et al. Overexpression of nuclear protein kinase CK2 Beta subunit and prognosis in human gastric carcinoma. Ann Surg Oncol. 2010;17:1695–702.

    Article  PubMed  Google Scholar 

  53. Pallares J, Llobet D, Santacana M, Eritja N, Velasco A, Cuevas D, et al. CK2beta is expressed in endometrial carcinoma and has a role in apoptosis resistance and cell proliferation. Am J Pathol. 2009;174:287–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kemper K, Sprick MR, de Bree M, Scopelliti A, Vermeulen L, Hoek M, et al. The AC133 epitope, but not the CD133 protein, is lost upon cancer stem cell differentiation. Cancer Res. 2010;70:719–29.

    Article  CAS  PubMed  Google Scholar 

  55. Ying M, Wang S, Sang Y, Sun P, Lal B, Goodwin CR, et al. Regulation of glioblastoma stem cells by retinoic acid: role for Notch pathway inhibition. Oncogene. 2011;30:3454–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Binnemars-Postma K, Storm G, Prakash J. Nanomedicine strategies to target tumor-associated macrophages. Int J Mol Sci. 2017;18:979–1005.

    Article  PubMed Central  Google Scholar 

  57. Quail DF, Joyce JA. The microenvironmental landscape of brain tumors. Cancer Cell. 2017;31:326–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Natural Science Foundation of China (nos. 81772651 and 81772652).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Xinlin Sun or Yiquan Ke.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

These authors contributed equally: Taoliang Chen, Jiansheng Chen

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, T., Chen, J., Zhu, Y. et al. CD163, a novel therapeutic target, regulates the proliferation and stemness of glioma cells via casein kinase 2. Oncogene 38, 1183–1199 (2019). https://doi.org/10.1038/s41388-018-0515-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-018-0515-6

This article is cited by

Search

Quick links