Glioblastoma Multiformе Tumour Stem Cells as Potential Therapeutic Targets

The original concept of tumour stem cells (TSC) has been questioned ten years after TSCs in glioblastoma (GBM) had been described for the first time. Our understanding of cell heterogeneity in malignant brain tumours has become more complex. The improvements in our knowledge of tumour stem cells also impact on pre-clinical research and clinical practice. Chemoresistance is one of the key obstacles to success in treating malignant tumours; it results in tumour recurrence and metastatic spread. GBM relapse is almost universal, and its prognosis remains uncertain despite significant advances in treatment over the last decade. Tumour stem cells, glioblastoma stem cells (GSC) in particular, are highly resistant to chemotherapy, radiation therapy and immune recognition. GBM shows significant intratumoural phenotypic and molecular heterogeneity containing a population of tumour stem cells that contributes to the division of tumour cells supporting the resistance to treatment. TSCs are defined functionally by their ability for self-renewal and differentiation; they present a most diverse hierarchy of cells making up the tumour. The critical role of TSCs in glioblastoma pathogenesis makes the research into their molecular and phenotypic characteristics is a therapeutic priority.

glioblastoma, central nervous system, stem cells, tumour stem cells, glioblastoma stem cells, therapeutic targets, tumour biomarkers, signalling pathway, alkylating antineoplastic agents

1. Yuan X., Curtin J., Xiong Y., Liu G., Waschsmann-Hogiu S., Farkas D.L., et al. Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene. 2004;23(58):9392–400. DOI: 10.1038/ sj.onc.1208311

2. Lathia J.D., Mack S.C., Mulkearns-Hubert E.E., Valentim C.L., Rich J.N. Cancer stem cells in glioblastoma. Genes Dev. 2015;29(12):1203–17. DOI: 10.1101/gad.261982.115

3. Ludwig K., Kornblum H.I. Molecular markers in glioma. J Neurooncol. 2017;134(3):505–12. DOI: 10.1007/s11060-017-2379-y

4. Chen R., Nishimura M.C., Bumbaca S.M., Kharbanda S., Forrest W.F., Kasman I.M., et al. A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell. 2010;17(4):362–75. DOI: 10.1016/j. ccr.2009.12.049

5. Calabrese C., Poppleton H., Kocak M., Hogg T.L., Fuller C., Hamner B., et al. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007;11:69–82.

6. Seidel S., Garvalov B.K., Wirta V., von Stechow L., Schänzer A., Meletis K., et al. A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. Brain. 2010;133:983–95. DOI: 10.1093/brain/awq042

7. Sottoriva A., Spiteri I., Piccirillo S.G., Touloumis A., Collins V.P., Marioni J.C., et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Nat Acad Sci USA. 2013;110(10):4009–14. DOI: 10.1073/pnas.1219747110

8. Sottoriva A., Spiteri I., Shibata D., Curtis C., Tavare S. Single-molecule genomic data delineate patient-specific tumor profiles and cancer stem cell organization. Cancer Res. 2013;73(1):41–9. DOI: 10.1158/0008- 5472.CAN-12-2273

9. Patel A.P., Tirosh I., Trombetta J.J., Shalek A.K., Gillespie S.M., Wakimoto H., et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344(6190):1396–401. DOI: 10.1126/science.1254257

10. Debruyne D.N., Turchi L., Burel-Vandenbos F., Fareh M., Almairac F., Virolle V., et al. DOCK4 promotes loss of proliferation in glioblastoma progenitor cells through nuclear beta-catenin accumulation and subsequent miR-302-367 cluster expression. Oncogene. 2018;37(2):241–54. DOI: 10.1038/onc.2017.323

11. Liebelt B.D., Shingu T., Zhou X., Ren J., Shin S.A., Hu J. Glioma stem cells: signaling, microenvironment, and therapy. Stem Cells Int. 2016;2016:7849890. DOI: 10.1155/2016/7849890

12. Sakakini N., Turchi L., Bergon A., Holota H., Rekima S., Lopez F., et al. A positive feed-forward loop associating EGR1 and PDGFA promotes proliferation and self-renewal in glioblastoma stem cells. J Biol Chem. 2016;291(20):10684–99. DOI: 10.1074/jbc.M116.720698

13. Turchi L., Debruyne D.N., Almairac F., Virolle V., Fareh M., Neirijnck Y., et al. Tumorigenic potential of miR-18A* in glioma initiating cells requires NOTCH-1 signaling. Stem Cells. 2013;31(7):1252–65. DOI: 10.1002/stem.1373

14. Patru C., Omao L., Varlet P., Coulombel L., Raponi E., Cadusseau J., et al. CD133, CD15/SSEA-1, CD34 or side populations do not resume tumorinitiating properties of long-term cultured cancer stem cells from human malignant glioneuronal tumors. BMC Cancer. 2010;10:66. DOI: 10.1186/1471-2407-10-66

15. Fareh M., Turchi L., Virolle V., Debruyne D., Almairac F., de-la-Forest Divonne S., et al. The miR 302-367 cluster drastically affects self-renewal and infiltration properties of glioma-initiating cells through CXCR4 repression and consequent disruption of the SHH-GLI-NANOG network. Cell Death Different. 2012;19(2):232–44. DOI: 10.1038/cdd.2011.89

16. Piccirillo S.G., Vescovi A.L. Bone morphogenetic proteins regulate tumorigenicity in human glioblastoma stem cells. Ernst Schering Found Symp Proc. 2006;(5):59–81. PMID: 17939295

17. El-Habr E.A., Dubois L.G., Burel-Vandenbos F., Bogeas A., Lipecka J., Turchi L., et al. A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma. Acta Neuropathol. 2017;133(4):645–60. DOI: 10.1007/s00401-016-1659-5

18. Fareh M., Almairac F., Turchi L., Burel-Vandenbos F., Paquis P., Fontaine D., et al. Cell-based therapy using miR-302-367 expressing cells represses glioblastoma growth. Cell Death Dis. 2017;8(3):e2713. DOI: 10.1038/cddis.2017.117

19. Yan H., Romero-López M., Benitez L.I., Di K., Frieboes H.B., Hughes C.C.W., et al. 3D Mathematical modeling of glioblastoma suggests that transdifferentiated vascular endothelial cells mediate resistance to current standard-of-care therapy. Cancer Res. 2017;77(15):4171–84. DOI: 10.1158/0008-5472.CAN-16-3094

20. Mei X., Chen Y.S., Chen F.R., Xi S.Y., Chen Z.P. Glioblastoma stem cell differentiation into endothelial cells evidenced through live-cell imaging. Neuro Oncol. 2017;19(8):1109–18. DOI: 10.1093/neuonc/nox016

21. Cheng L., Huang Z., Zhou W., Wu Q., Donnola S., Liu J.K., et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. 2013;153(1):139–52. DOI: 10.1016/j. cell.2013.02.021

22. Guichet P.O., Guelfi S., Teigell M., Hoppe L., Bakalara N., Bauchet L., et al. Notch1 stimulation induces a vascularization switch with pericyte-like cell differentiation of glioblastoma stem cells. Stem Cells. 2015;33(1):21–34. DOI: 10.1002/stem.1767

23. Dahan P., Martinez Gala J., Delmas C., Monferran S., Malric L., Zentkowski D., et al. Ionizing radiations sustain glioblastoma cell dedifferentiation to a stem-like phenotype through survivin: possible involvement in radioresistance. Cell Death Dis. 2014;5(11):e1543. DOI: 10.1038/cddis.2014.509

24. Hegi M.E., Murat A., Lambiv W.L., Stupp R. Brain tumors: molecular biology and targeted therapies. Ann Oncol. 2006;17(Suppl. 10):x191–7. DOI: 10.1093/annonc/mdl259

25. Stupp R., Mason W.P., van den Bent M.J., Weller M., Fisher B., Taphoorn M.J., et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96. DOI: 10.1056/NEJMoa043330

26. Lechapt-Zalcman E., Levallet G., Dugué A.E., Vital A., Diebold M.D., Menei P., et al. O(6) -methylguanine-DNA methyltransferase (MGMT) promoter methylation and low MGMT-encoded protein expression as prognostic markers in glioblastoma patients treated with biodegradable carmustine wafer implants after initial surgery followed by radiotherapy with concomitant and adjuvant temozolomide. Cancer. 2012;118(18):4545–54. DOI: 10.1002/cncr.27441

27. Bao S., Wu Q., McLendon R.E., Hao Y., Shi Q., Hjelmeland A.B., et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–60. DOI: 10.1038/nature05236

28. Bleau A.M., Hambardzumyan D., Ozawa T., Fomchenko E.I., Huse J.T., Brennan C.W., et al. PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell. 2009;4(3):226–35. DOI: 10.1016/j.stem.2009.01.007

29. Eramo A., Ricci-Vitiani L., Zeuner A., Pallini R., Lotti F., Sette G., et al. Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ. 2006;13(7):1238–41. DOI: 10.1038/sj.cdd.4401872

30. Shi L., Zhang S., Feng K., Wu F., Wan Y., Wang Z., et al. MicroRNA125b-2 confers human glioblastoma stem cells resistance to temozolomide through the mitochondrial pathway of apoptosis. Int J Oncol. 2012;40(1):119–29. DOI: 10.3892/ijo.2011.1179

31. Gareev I.F., Beylerli O.A., Pavlov V.N., Shiguang Zhao, Xin Chen, Zhixing Zheng, et al. Nanoparticles: a new approach to the diagnosis and treatment of cerebral glial tumours. Creative Surgery and Oncology. 2019;9(1):66–74 (In Russ.). DOI: 10.24060/2076-3093-2019-9-1-66-74

32. Platten M., Wick W., Weller M. Malignant glioma biology: role for TGF-beta in growth, motility, angiogenesis, and immune escape. Microsc Res Tech. 2001;52(4):401–10. DOI: 10.1002/1097-0029(20010215)52:43.0.CO;2-C

33. Khan H., Gucalp R., Shapira I. Evolving concepts: immunity in oncology from targets to treatments. J Oncol. 2015;8473:83. DOI:10.1155/2015/847383

34. Di Tomaso T., Mazzoleni S., Wang E., Sovena G., Clavenna D., Franzin A., et al. Immunobiological characterization of cancer stem cells isolated from glioblastoma patients. Clin Cancer Res. 2010;16(3):800– 13. DOI: 10.1158/1078-0432.CCR-09-2730

35. Wu A., Wei J., Kong L.Y., Wang Y., Priebe W., Qiao W., et al. Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro Oncol. 2010;12(11):1113–25. DOI: 10.1093/neuonc/noq082

36. Gardeck A.M., Sheehan J., Low W.C. Immune and viral therapies for malignant primary brain tumors. Expert Opin Biol Ther. 2017;17(4):457–74. DOI: 10.1080/14712598.2017.1296132