Immunohistochemical detection of stem cell markers, transcription factors and PD-L1 in malignant gliomas in adults patients


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

The prognosis of glioblastoma (GLB) is poor: the 5-year survival rate is less than 10%. Almost all patients relapse after surgery according to the standard of treatment: resection, radiation therapy, and temozolomide. T reatment options today for relapse are limited, and no amount of therapy prolongs patients' lives. The development of resistance to therapy is associated with the microenvironment and tumor stem cells. Objective: to study the expression of stem cell markers, transcription factors and PD-L1 in malignant gliomas. A retrospective study included 17 patients with high-grade gliomas who underwent surgery. All patients underwent traditional histological examination, immunohistochemical analysis with antibodies to IDH1R132H, BRAF V600E, Ki-67, GFAP, NANOG, Nestin, CD133, SALL4, OCT4, SOX2, CD38, PD-L1, FOXM1, morphometric analysis with calculation of the average ratio cells with antigen expression to the number of all tumor cells. Expression of NANOG was observed in 47% of cases, Nestin - in 88%, CD133 - in 71%, SOX2 - in 100%, CD38 and FOXM1 - in 65%. None of the tumors expressed SALL4, only one OCT4. PD-L1 expression was detected only in 2 cases. Correlation analysis established the presence of significant associations between the expression of Nestin and CD133; FOXM1 and NANOG; Nestin and CD38; Ki-67 and SOX2. The presence of expression of stem cell markers and transcription factors NANOG, Nestin, CD133, CD38, SOX2, FOXM1 in malignant gliomas, in our opinion, dictates further targeted study of these markers on a larger sample and opens up new potential targets for targeted therapy.

Full Text

Restricted Access

About the authors

K. A Sulin

Almazov National Medical Research Centre

Email: lubamitr@yandex.ru
St. Petersburg, Russia

B. E Galkovsky

Almazov National Medical Research Centre

Email: lubamitr@yandex.ru
St. Petersburg, Russia

A. A Petrov

Almazov National Medical Research Centre

Email: lubamitr@yandex.ru
St. Petersburg, Russia

D. V Ryzhkova

Almazov National Medical Research Centre

Email: lubamitr@yandex.ru
St. Petersburg, Russia

P. V Krasnoshlyk

Almazov National Medical Research Centre

Email: lubamitr@yandex.ru
St. Petersburg, Russia

D. A Gulyaev

Almazov National Medical Research Centre

Email: lubamitr@yandex.ru
St. Petersburg, Russia

I. A Makarov

Almazov National Medical Research Centre

Email: lubamitr@yandex.ru
St. Petersburg, Russia

O. N Gaycova

Almazov National Medical Research Centre

Email: lubamitr@yandex.ru
St. Petersburg, Russia

V. S Sidorin

Almazov National Medical Research Centre

Email: lubamitr@yandex.ru
St. Petersburg, Russia

L. B Mitrofanova

Almazov National Medical Research Centre

Email: lubamitr@yandex.ru
St. Petersburg, Russia

References

  1. Ostrom Q.T., Gittleman H., Fulop J. et al. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012. J. Neurooncol. 2015; 17(4): 1-62.
  2. Darlix A., Zouaoui S., Rigau V. et al. Epidemiology for primary brain tumors: a nationwide population-based study. J. Neurooncol. 2017; 131(3): 525-46.
  3. Stupp R., Hegi M.E., Mason W.P. et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009; 10(5): 459-66.
  4. Stupp R., Mason W.P., van den Bent M.J. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 2005; 352(10): 987-96.
  5. Reardon D.A., Brandes A.A., Omuro A. et al. Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma: The CheckMate 143 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020; 6(7): 1003-10.
  6. Nabors L.B., Portnow J., Ammirati M. et al. NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017. J. Natl.Compr. Canc.Netw. 2017; 15(11): 1331-45.
  7. Lathia J.D., Mack S.C., Mulkearns-Hubert E.E. et al. Cancer stem cells in glioblastoma. Genes Dev. 2015; 29(12): 1203-17.
  8. Lim M., Xia Y., Bettegowda C. et al. Current state of immunotherapy for glioblastoma. Nat. Rev. Clin. Oncol. 2018; 15(7): 422-42.
  9. Louis D.N., Perry A., Wesseling P. et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. J. Neurooncol. 2021; 23(8): 1231-51.
  10. Miraglia S., Godfrey W., Yin A.H. et al. A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning. Blood 1997; 90(12): 5013-21.
  11. Bryukhovetskiy I., Ponomarenko A., Lyakhova I. et al. Personalized regulation of glioblastoma cancer stem cells based on biomedical technologies: From theory to experiment (Review).Int. J. Mol. Med. 2018; 42(2): 691-702.
  12. Schmitz M., Temme A., Senner V. et al. Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy. Br.J. Cancer 2007; 96(8): 1293-301.
  13. Levy A., Blacher E., Vaknine H. et al. CD38 deficiency in the tumor microenvironment attenuates glioma progression and modulates features of tumor-associated microglia/macrophages. J. Neurooncol. 2012; 14(8): 1037-49.
  14. Aulakh S., Manna A., Schiapparelli P. et al. CD38-targeted therapy in glioblastoma: A step foreward. J. of Clinical Oncology 2018; 36: 15.
  15. Гальковский Б.Э., Митрофанова Л.Б., Лахина Ю.С. и соавт. Иммуногистохимическое исследование белков Prox1, CD133 и CD38 в глиобластомах вентрикулярно-субвентрикулярной зоны и их влияние на продолжительность жизни пациентов. Ученые записки Санкт-Петербургского государственного медицинского университета имени академика И.П. Павлова 2020; 27(1): 75-85.
  16. Zhang N., Wei P., Gong A. et al. FoxM1 promotes β-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigen-esis. Cancer Cell 2011; 20(4): 427-42.
  17. Chen L.P., Zhang N.N., Ren X.Q. et al. miR-103/miR-195/miR-15b Regulate SALL4 and Inhibit Proliferation and Migration in Glioma. Molecules 2018; 23(11): 2938.
  18. Wu Y., Sun B., Shi W. et al. OCT4 is up-regulated by DNA hypomethylation of promoter in recurrent gliomas. Neoplasma 2016; 63(3): 378-84.
  19. Hao C., Chen G., Zhao H. et al. PD-L1 Expression in Glioblastoma, the Clinical and Prognostic Significance: A Systematic Literature Review and Meta-Analysis. Front. Oncol. 2020; 10: 1015.
  20. Berghoff A.S., Kiesel B., Widhalm G. et al. Programmed death ligand 1 expression and tumour-infiltrating lymphocytes in glioblastoma. J. Neurooncol. 2015; 17(8): 1064-75.
  21. Zbinden M., Duquet A., Lorente-Trigos A. et al. 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.
  22. Kuciak M., Mas C., Borges I. et al. Chimeric NANOG repressors inhibit glioblastoma growth in vivo in a context-dependent manner. Sci. Rep. 2019; 9(1): 3891.
  23. Luo W., Gao F., Li S. et al. FoxM1 Promotes Cell Proliferation, Invasion, and Stem Cell Properties in Nasopharyngeal Carcinoma. Front. Oncol. 2018; 8: 483.
  24. Gong A., Huang S. FoxM1 and Wnt/-Catenin Signaling in Glioma Stem Cells. Cancer Research 2012; 72(22): 5658-62.
  25. Гальковский Б.Э., Митрофанова Л.Б., Гуляев Д.А. и соавт. Иммуногистохимическое исследование транскрипционных факторов NeuroD1, Prox1, FoxM1, соматостатиновых, а также CXCR4- и CD38-рецепторов в глиобластомах в целях разработки новых подходов для таргетной терапии. Молекулярная медицина 2020; 18(2): 44-50.
  26. Singh S.K., Hawkins C., Clarke I.D. et al. Identification of human brain tumour initiating cells. Nature 2004; 432(7015): 396-401.
  27. Liu G., Yuan X., Zeng Z. et al. Analysis of gene expression and chemore-sistance of CD133+ cancer stem cells in glioblastoma. Mol. Cancer 2006; 5: 67.
  28. Zhang Q., Xu B., Chen J. et al. Clinical significance of CD133 and Nestin in astrocytic tumor: The correlation with pathological grade and survival. J. Clin. Lab. Anal. 2020; 34(3): 23082.
  29. Zhang M., Song T., Yang L. et al. Nestin and CD133: valuable stem cell-specific markers for determining clinical outcome of glioma patients. J. Exp. Clin. Cancer Res. 2008; 27(1): 85.
  30. Ludwig K., Kornblum H.I. Molecular markers in glioma. J. Neurooncol. 2017; 134(3): 505-12.
  31. Dahlrot R.H., Hermansen S.K., Hansen S. et al. What is the clinical value of cancer stem cell markers in gliomas? Int. J. Clin. Exp. Pathol. 2013; 6(3): 334-48.
  32. Bradshaw A., Wickremsekera A., Tan S.T. et al. Cancer Stem Cell Hierarchy in Glioblastoma Multiforme. Front. Surg. 2016; 3: 21.
  33. Xie L., Zeng X., Hu J. et al. Characterization of Nestin, a Selective Marker for Bone Marrow Derived Mesenchymal Stem Cells.Int. J. Stem Cells 2015; 2015: 762098.
  34. Blacher E., Ben Baruch B., Levy A. et al. Inhibition of glioma progression by a newly discovered CD38 inhibitor.Int. J. Cancer 2015; 136(6): 1422-33.
  35. Alak M., Sonikpreet A., Asher C. et al. Therapeutic targeting of CD38 enhances temozolomide activity in glioblastoma cells and modulates their tumor microenvironment by eliciting an enhanced CD8+ T cell response. J. of Immunology 2020; 204(1): 91.
  36. Yang J., Gao C., Chai L. et al. A Novel SALL4/OCT4 Transcriptional Feedback Network for Pluripotency of Embryonic Stem Cells. PLoS ONE 2010; 5(5): 10766.
  37. Xue S., Hu M., Iyer V. et al. Blocking the PD-1/PD-L1 pathway in glioma: a potential new treatment strategy. J. Hematol. Oncol. 2017; 10(1): 81.
  38. Vora P., Venugopal C., Salim S.K. et al. The Rational Development of CD133-Targeting Immunotherapies for Glioblastoma.Int. J. Stem Cells 2020; 26(6): 832-44.

Copyright (c) 2021 Eco-Vector


СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ПИ № ФС 77 - 57156 от 11.03.2014.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies