Top

Published in:

Open Access 01-03-2022 | Glioblastoma | Review

Glioma: molecular signature and crossroads with tumor microenvironment

Authors: Lennart Barthel, Martin Hadamitzky, Philipp Dammann, Manfred Schedlowski, Ulrich Sure, Basant Kumar Thakur, Susann Hetze

Published in: Cancer and Metastasis Reviews | Issue 1/2022

Abstract

In patients with glioblastoma, the average survival time with current treatments is short, mainly due to recurrences and resistance to therapy. This insufficient treatment success is, in large parts, due to the tremendous molecular heterogeneity of gliomas, which affects the overall prognosis and response to therapies and plays a vital role in gliomas’ grading. In addition, the tumor microenvironment is a major player for glioma development and resistance to therapy. Active communication between glioma cells and local or neighboring healthy cells and the immune environment promotes the cancerogenic processes and contributes to establishing glioma stem cells, which drives therapy resistance. Besides genetic alterations in the primary tumor, tumor-released factors, cytokines, proteins, extracellular vesicles, and environmental influences like hypoxia provide tumor cells the ability to evade host tumor surveillance machinery and promote disease progression. Moreover, there is increasing evidence that these players affect the molecular biological properties of gliomas and enable inter-cell communication that supports pro-cancerogenic cell properties. Identifying and characterizing these complex mechanisms are inevitably necessary to adapt therapeutic strategies and to develop novel measures. Here we provide an update about these junctions where constant traffic of biomolecules adds complexity in the management of glioblastoma.

Graphical abstract

Hadjipanayis, C. G., & Van Meir, E. G. (2009). Tumor initiating cells in malignant gliomas: Biology and implications for therapy. Journal of Molecular Medicine, 87, 363–374. https://doi.org/10.1007/s00109-009-0440-9CrossRefPubMed

Lathia, J. D., Mack, S. C., Mulkearns-hubert, E. E., Valentim, C. L. L., & Rich, J. N. (2015). Cancer stem cells in glioblastoma. Genes and Development, 29, 1203–1217. https://doi.org/10.1101/gad.261982.115.tumorsCrossRefPubMedPubMedCentral

Prager, B. C., Bhargava, S., Mahadev, V., Hubert, C. G., & Rich, J. N. (2020). Glioblastoma stem cells: Driving resilience through chaos. Trends in Cancer, 6(3), 223–235. https://doi.org/10.1016/j.trecan.2020.01.009CrossRefPubMedPubMedCentral

Osuka, S., & Van Meir, E. G. (2017). Overcoming therapeutic resistance in glioblastoma: The way forward. The Journal of Clinical Investigation, 127(2), 415. https://doi.org/10.1172/JCI89587CrossRefPubMedPubMedCentral

Cole, A. P., Hoffmeyer, E., Chetty, S. L., Cruz-Cruz, J., & C.-, Hamrick, F. H., Youssef, O., Cheshier, S., & Mitra, S. S. . (2020). Microglia in the brain tumor microenvironment. Advances in experimental medicine and biology, 1273, 197–208. https://doi.org/10.1007/978-3-030-49270-0_11CrossRefPubMed

Goenka, A., Tiek, D., Song, X., Huang, T., Hu, B., & Cheng, S. Y. (2021). The many facets of therapy resistance and tumor recurrence in glioblastoma. Cells, 10(3). https://doi.org/10.3390/cells10030484

Vitale, I., Manic, G., Coussens, L. M., Kroemer, G., & Galluzzi, L. (2019). Macrophages and metabolism in the tumor microenvironment. Cell Metabolism, 30(1), 36–50. https://doi.org/10.1016/j.cmet.2019.06.001CrossRefPubMed

Cheng, W., Ren, X., Zhang, C., Cai, J., Liu, Y., Han, S., & Wu, A. (2016). Bioinformatic profiling identifies an immune-related risk signature for glioblastoma. Neurology, 86(24), 2226–2234. https://doi.org/10.1212/WNL.0000000000002770CrossRefPubMed

Ko, E. A., Lee, H., Sanders, K. M., Koh, S. D., & Zhou, T. (2020). Expression of alpha-type platelet-derived growth factor receptor–influenced genes predicts clinical outcome in glioma. Translational Oncology, 13(2), 233–240. https://doi.org/10.1016/j.tranon.2019.10.002CrossRefPubMed

10.

Bazzoni, R., & Bentivegna, A. (2019). Role of notch signaling pathway in glioblastoma pathogenesis. Cancers, 11(3), 1–25. https://doi.org/10.3390/cancers11030292CrossRef

11.

Osterberg, N., Ferrara, N., Vacher, J., Gaedicke, S., Niedermann, G., Weyerbrock, A., Doostkam, S., Schaefer, H.-E., Plate, K. H., & Machein, M. R. (2016). Decrease of VEGF-A in myeloid cells attenuates glioma progression and prolongs survival in an experimental glioma model. Neuro-Oncology, 18(7), 939–949. https://doi.org/10.1093/neuonc/now005CrossRefPubMedPubMedCentral

12.

Suina, K., Tsuchihashi, K., Yamasaki, J., Kamenori, S., Shintani, S., Hirata, Y., Okazaki, S., Sampetrean, O., Baba, E., Akashi, K., Mitsuishi, Y., Takahashi, F., Takahashi, K., Saya, H., & Nagano, O. (2018). Epidermal growth factor receptor promotes glioma progression by regulating xCT and GluN2B-containing N-methyl-d-aspartate–sensitive glutamate receptor signaling. Cancer Science, 109(12), 3874–3882. https://doi.org/10.1111/cas.13826CrossRefPubMedPubMedCentral

13.

Su, C., Zhang, J., Yarden, Y., & Fu, L. (2021). The key roles of cancer stem cell-derived extracellular vesicles. Signal Transduction and Targeted Therapy, 6(1), 1–15. https://doi.org/10.1038/s41392-021-00499-2CrossRef

14.

Fuchs, Q., Pierrevelcin, M., Messe, M., Lhermitte, B., Blandin, A.-F., Papin, C., Coca, A., Dontenwill, M., & Entz-Werlé, N. (2020). Hypoxia inducible factors’ signaling in pediatric high-grade gliomas: Role, modelization and innovative targeted approaches. Cancers, 12(4). https://doi.org/10.3390/CANCERS12040979

15.

Molenaar, R. J. (2011). Ion channels in glioblastoma. ISRN Neurology, 1–7.https://doi.org/10.5402/2011/590249

16.

Louis, D. N., Perry, A., Reifenberger, G., von Deimling, A., Figarella-Branger, D., Cavenee, W. K., Ohgaki, H., Wiestler, O. D., Kleihues, P., & Ellison, D. W. (2016). The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathologica, 131(6), 803–820. https://doi.org/10.1007/s00401-016-1545-1CrossRefPubMed

17.

Puchalski, R. B., Shah, N., Miller, J., Dalley, R., Nomura, S. R., Yoon, J. G., Smith, K. A., Lankerovich, M., Bertagnolli, D., Bickley, K., Boe, A. F., Brouner, K., Butler, S., Caldejon, S., Chapin, M., Datta, S., Dee, N., Desta, T., Dolbeare, T., Dotson, N., … Foltz, G. D. (2018). An anatomic transcriptional atlas of human glioblastoma. Science (New York, N.Y.), 360(6389), 660–663.https://doi.org/10.1126/science.aaf2666

18.

Yekula, A., Yekula, A., Muralidharan, K., Kang, K., Carter, B. S., & Balaj, L. (2020). Extracellular vesicles in glioblastoma tumor microenvironment. Frontiers in Immunology, 10(January), 1–12. https://doi.org/10.3389/fimmu.2019.03137CrossRef

19.

Behnan, J., Finocchiaro, G., & Hanna, G. (2019, April 1). The landscape of the mesenchymal signature in brain tumours. Brain. Oxford University Press. https://doi.org/10.1093/brain/awz044

20.

Perrin, S. L., Samuel, M. S., Koszyca, B., Brown, M. P., Ebert, L. M., Oksdath, M., & Gomez, G. A. (2019). Glioblastoma heterogeneity and the tumour microenvironment: Implications for preclinical research and development of new treatments. Biochemical Society transactions, 47(2), 625–638. https://doi.org/10.1042/BST20180444CrossRefPubMed

21.

Justus, C. R., Sanderlin, E. J., & Yang, L. V. (2015). Molecular connections between cancer cell metabolism and the tumor microenvironment. International Journal of Molecular Sciences, 16(5), 11055. https://doi.org/10.3390/IJMS160511055CrossRefPubMedPubMedCentral

22.

Boedtkjer, E., & Pedersen, S. F. (2020). The acidic tumor microenvironment as a driver of cancer. Annual Review of Physiology, 82(1), 103–126. https://doi.org/10.1146/annurev-physiol-021119-034627CrossRefPubMed

23.

Huang, H. W., Zuo, C., Chen, X., Peng, Y. P., & Qiu, Y. H. (2016). Effect of tyrosine hydroxylase overexpression in lymphocytes on the differentiation and function of T helper cells. International Journal of Molecular Medicine, 38(2), 635–642. https://doi.org/10.3892/ijmm.2016.2639CrossRefPubMed

24.

An, Z., Knobbe-Thomsen, C. B., Wan, X., Fan, Q. W., Reifenberger, G., & Weiss, W. A. (2018). EGFR cooperates with EGFRvIII to recruit macrophages in glioblastoma. Cancer Research, 78(24), 6785–6794. https://doi.org/10.1158/0008-5472.CAN-17-3551CrossRefPubMedPubMedCentral

25.

Carnero, A., & Lleonart, M. (2016). The hypoxic microenvironment : A determinant of cancer stem cell evolution. Inside The Cell, 96–105. https://doi.org/10.1002/icl3.1039

26.

Pearson, J. R. D., & Regad, T. (2017). Targeting cellular pathways in glioblastoma multiforme. Signal Transduction and Targeted Therapy, 2(May), 1–11. https://doi.org/10.1038/sigtrans.2017.40CrossRef

27.

Struve, N., Binder, Z. A., Stead, L. F., Brend, T., Bagley, S. J., Faulkner, C., Ott, L., Müller-Goebel, J., Weik, A-S., Hoffer, K., Krug, L., Rieckmann, T., Bubmann, L., Henze, M., Morrissette, J. J. D., Kurian, K. M., Schüller, U., Petersen, C., Rothkamm, K., … Kriegs, M. (2020). EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma. Oncogene, 3041–3055. https://doi.org/10.1038/s41388-020-1208-5

28.

Berghoff, A. S., Kiesel, B., Widhalm, G., Wilhelm, D., Rajky, O., Kurscheid, S., Kresl, P., Wöhrer, A., Marosi, C., Hegi, M. E., & Preusser, M. (2017). Correlation of immune phenotype with IDH mutation in diffuse glioma. Neuro-oncology, 19(11), 1460–1468. https://doi.org/10.1093/neuonc/nox054CrossRefPubMedPubMedCentral

29.

Richardson, L. G., Choi, B. D., & Curry, W. T. (2019). (R)-2-hydroxyglutarate drives immune quiescence in the tumor microenvironment of IDH-mutant gliomas. Translational cancer research, 8(Suppl 2), S167–S170. https://doi.org/10.21037/tcr.2019.01.08

30.

Nandakumar, P., Mansouri, A., & Das, S. (2017, September 29). The role of ATRX in glioma biology. Frontiers in Oncology. https://doi.org/10.3389/fonc.2017.00236

31.

Bowie, M., Hariharan, S., Hostettler, J., Roso, K., He, Y., Pirozzi, C., Roskoski, M., Keir, S., Brown, M., Zhang, G., Gromeier, M., Yan, H., & Ashley, D. (2019). IMMU-34. ATRX mutations predict response to innate based therapy in glioma. Neuro-Oncology, 21(Suppl 6), vi126. https://doi.org/10.1093/neuonc/noz175.526

32.

Behling, F., & Schittenhelm, J. (2019, June 1). Oncogenic BRAF alterations and their role in brain tumors. Cancers, 11(6), 794. https://doi.org/10.3390/cancers11060794

33.

Chen, R., Keoni, C., Waker, C. A., Lober, R. M., & Gutmann, D. H. (2019). KIAA1549-BRAF expression establishes a permissive tumor microenvironment through NFκB-mediated CCL2 production. Neoplasia (United States), 21(1), 52–60. https://doi.org/10.1016/j.neo.2018.11.007CrossRef

34.

Wang, Q., Hu, B., Hu, X., Kim, H., Squatrito, M., Scarpace, L., deCarvalho, A. C., Lyu, S., Li, P., Li, Y., Barthel, F., Cho, H. J., Lin, Y-H., Satani, N., Martinex-Ledesma, E., Zheng, S., Cheng, E., Sauve, C-E. G., Olar, … & Verhaak, R. G. W. (2017). Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. Cancer Cell, 32(1), 42-56.e6. https://doi.org/10.1016/j.ccell.2017.06.003

35.

Piro, G., Carbone, C., Carbognin, L., Pilotto, S., Ciccarese, C., Iacovelli, R., Milella, M., Bria E., & Tortora, G. (2019, October 1). Revising PTEN in the era of immunotherapy: New perspectives for an old story. Cancers, 11(10), 1525. https://doi.org/10.3390/cancers11101525

36.

Parsa, A. T., Waldron, J. S., Panner, A., Crane, C. A., Parney, I. F., Barry, J. J., Cachola, K. E., Murray, J. C., Tihan, T., Jensen, M. C., Mischel, P. S., Stokoe, D., & Pieper, R. O. (2007). Loss of tumor suppressor PTEN function increases B7–H1 expression and immunoresistance in glioma. Nature Medicine, 13(1), 84–88. https://doi.org/10.1038/nm1517CrossRefPubMed

37.

Waldron, J. S., Yang, I., Han, S., Tihan, T., Sughrue, M. E., Mills, S. A., Pieper, R. O., & Parsa, A. T. (2010). Implications for immunotherapy of tumor-mediated T-cell apoptosis associated with loss of the tumor suppressor PTEN in glioblastoma. Journal of clinical neuroscience : Official journal of the Neurosurgical Society of Australasia, 17(12), 1543–1547. https://doi.org/10.1016/j.jocn.2010.04.021CrossRef

38.

Chen, P., Zhao, D., Li, J., Liang, X., Li, J., Chang, A., Henry, V. K., Lan, Z., Spring, D. J., Rao, G., Wang, Y. A., & DePinho, R. A. (2019). Symbiotic macrophage-glioma cell interactions reveal synthetic lethality in PTEN-Null glioma. Cancer Cell, 35(6), 868-884.e6. https://doi.org/10.1016/j.ccell.2019.05.003CrossRefPubMedPubMedCentral

39.

Smith-Mungo, L. I., & Kagan, H. M. (1998). Lysyl oxidase: Properties, regulation and multiple functions in biology. Matrix Biology, 16(7), 387–398. https://doi.org/10.1016/S0945-053X(98)90012-9CrossRefPubMed

40.

Pore, N., Liu, S., Haas-Kogan, D. A., O’Rourke, D. M., & Maity, A. (2003). PTEN mutation and epidermal growth factor receptor activation regulate vascular endothelial growth factor (VEGF) mRNA expression in human glioblastoma cells by transactivating the proximal VEGF promoter. Cancer Research, 63(1), 236–241.PubMed

41.

Oldrini, B., Vaquero-Siguero, N., Mu, Q., Kroon, P., Zhang, Y., Galán-Ganga, M., Bao, Z., Wang, Z., Liu, H., Sa, J. K., Zhao, J., Kim, H., Rodriguez-Perales, S., Nam, D-H., Verhaak, R. G. W., Rabadan, R., Jiang, T., Wang, J., & Squatrito, M. (n.d.). MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas. Nature Communications, 11, 3883. https://doi.org/10.1038/s41467-020-17717-0

42.

Pistollato, F., Abbadi, S., Rampazzo, E., Persano, L., Della Puppa, A., Frasson, C., Sarto, E., Scienza, R., D’avella, D., & Basso, G. (2010). Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma. Stem Cells, 28(5), 851–862. https://doi.org/10.1002/stem.415CrossRefPubMed

43.

Wickström, M., Dyberg, C., Milosevic, J., Einvik, C., Calero, R., Sveinbjörnsson, B., Sandén, E., Darabi, A., Siesjö, P., Kool, M., Kogner, P., Baryawno, N., & Johnsen, J. I. (2015). Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance. Nature Communications, 6. https://doi.org/10.1038/ncomms9904

44.

Zhao, L., Zhang, J., Xuan, S., Liu, Z., Wang, Y., & Zhao, P. (2021). Molecular and clinicopathological characterization of a prognostic immune gene signature associated with MGMT methylation in glioblastoma. Frontiers in Cell and Developmental Biology, 9, 72. https://doi.org/10.3389/FCELL.2021.600506CrossRef

45.

Coppé, J. P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P-Y., & Campisi, J. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biology, 6(12). https://doi.org/10.1371/journal.pbio.0060301

46.

Kastenhuber, E. R., & Lowe, S. W. (2017, September 7). Putting p53 in Context. Cell, 170(6), 1062–1078. https://doi.org/10.1016/j.cell.2017.08.028

47.

Cooks, T., Harris, C. C., & Oren, M. (2014). Caught in the cross fire: P53 in inflammation. Carcinogenesis, 35(8), 1680–1690. https://doi.org/10.1093/carcin/bgu134CrossRefPubMedPubMedCentral

48.

Guo, G., Yu, M., Xiao, W., Celis, E., & Cui, Y. (2017). Local activation of p53 in the tumor microenvironment overcomes immune suppression and enhances antitumor immunity. Cancer Research, 77(9), 2292–2305. https://doi.org/10.1158/0008-5472.CAN-16-2832CrossRefPubMedPubMedCentral

49.

Schröder, L. B. W., & McDonald, K. L. (2015). CDK4/6 inhibitor PD0332991 in glioblastoma treatment: Does it have a future? Frontiers in Oncology, 5(NOV), 259. https://doi.org/10.3389/fonc.2015.00259

50.

Goldhoff, P., Clarke, J., Smirnov, I., Berger, M. S., Prados, M. D., James, C. D., Perry, A., & Phillips, J. J. (2012). Clinical stratification of glioblastoma based on alterations in retinoblastoma tumor suppressor protein (RB1) and association with the proneural subtype. Journal of neuropathology and experimental neurology, 71(1), 83–89. https://doi.org/10.1097/NEN.0b013e31823fe8f1CrossRefPubMed

51.

Ciznadija, D., Liu, Y., Pyonteck, S. M., Holland, E. C., & Koff, A. (2011). Cyclin D1 and Cdk4 mediate development of neurologically destructive oligodendroglioma. Cancer Research, 71(19), 6174–6183. https://doi.org/10.1158/0008-5472.CAN-11-1031CrossRefPubMedPubMedCentral

52.

Hambardzumyan, D., & Bergers, G. (2015). Glioblastoma: Defining tumor niches. TRENDS in CANCER, 1, 252–265. https://doi.org/10.1016/j.trecan.2015.10.009CrossRefPubMedPubMedCentral

53.

Griguer, C. E., Oliva, C. R., Gobin, E., Marcorelles, P., Benos, D. J., Jack, R., & Gillespie, G. Y. (2008). CD133 is a marker of bioenergetic stress in human glioma. PLoS ONE, 3(11), 1–11. https://doi.org/10.1371/journal.pone.0003655CrossRef

54.

Goodman, R., Slater, E., & Herschman, H. R. (1980). Epidermal growth factor induces tyrosine hydroxylase in a clonal pheochromocytoma cell line, PC-G2. Journal of Cell Biology, 84(3), 495–500. https://doi.org/10.1083/jcb.84.3.495CrossRefPubMed

55.

Shergalis, A., Bankhead, A., Luesakul, U., Muangsin, N., & Neamati, N. (2018). Current challenges and opportunities in treating glioblastomas. Pharmacological Reviews, 70(3), 412–445. https://doi.org/10.1124/pr.117.014944CrossRefPubMedPubMedCentral

56.

Tsuchihashi, K., Okazaki, S., Ohmura, M., Ishikawa, M., Sampetrean, O., Onishi, N., Wakimoto. H., Yoshikawa, M., Seishima, R., Iwasaki, Y., Morikawa, T., Abe, S., Takao, A., Shimizu, M., Masuko, T., Nagane, M., Furnari, F. B., Akiyama. T., Suematsu., M., …& Nagano, O. (2016). The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc(−) HHS Public Access. Cancer Res, 76(10), 2954–2963. https://doi.org/10.1158/0008-5472.CAN-15-2121

57.

Conrad, M., & Sato, H. (2012). The oxidative stress-inducible cystine/glutamate antiporter, system x c-: Cystine supplier and beyond. Amino Acids, 42, 231–246. https://doi.org/10.1007/s00726-011-0867-5CrossRefPubMed

58.

Corsi, L., Mescola, A., & Alessandrini, A. (2019). Glutamate receptors and glioblastoma multiforme: An old “route” for new perspectives. International journal of molecular sciences, 20(7), 1796. https://doi.org/10.3390/ijms20071796CrossRefPubMedCentral

59.

Al-Nedawi, K., Meehan, B., Micallef, J., Lhotak, V., May, L., Guha, A., & Rak, J. (2008). Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nature Cell Biology, 10(5), 619–624. https://doi.org/10.1038/NCB1725CrossRefPubMed

60.

Diksin, M., Smith, S. J., & Rahman, R. (2017). The molecular and phenotypic basis of the glioma invasive perivascular niche. International Journal of Molecular Sciences, 18(11), 2342. https://doi.org/10.3390/ijms18112342CrossRefPubMedCentral

61.

Hao, Q., Vadgama, J. V., & Wang, P. (2020). CCL2/CCR2 signaling in cancer pathogenesis. Cell Communication and Signaling, 18(1), 1–13. https://doi.org/10.1186/S12964-020-00589-8CrossRef

62.

Bonavia, R., Inda, M. M., Vandenberg, S., Cheng, S. Y., Nagane, M., Hadwiger, P., Tan, P., Sah, D. W. Y., Cavanee, W. K., & Furnari, F. B. (2012). EGFRvIII promotes glioma angiogenesis and growth through the NF-B, interleukin-8 pathway. Oncogene, 31(36), 4054–4066. https://doi.org/10.1038/onc.2011.563CrossRefPubMed

63.

Guequén, A., Zamorano, P., Córdova, F., Koning, T., Torres, A., Ehrenfeld, P., Boric, M. P., Salazar-Onfray, F., Gavard, J., Duran, W. N., Quezada, C., Sarmiento, J., & Sánchez, F. A. (2019). Interleukin-8 secreted by glioblastoma cells induces microvascular hyperpermeability through no signaling involving S-Nitrosylation of VE-cadherin and p120 in endothelial cells. Frontiers in Physiology, 0(JUL), 988. https://doi.org/10.3389/FPHYS.2019.00988

64.

Zanca, C., Villa, G. R., Benitez, J. A., Thorne, A. H., Koga, T., D’Antonio, M., Ikegami, S., Ma, J., Boyer, A. D., Banisadr, A., Jameson, N. M., Parisian, A. D., Eliseeva, O. V., Barnabe, G. F., Liu, F., Wu, S., Yang, H., Wykosky, J., Frazer, K. A., … Furnari, F. B. (2017). Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity. Genes and Development, 31(12), 1212–1227. https://doi.org/10.1101/gad.300079.117

65.

Lamano, J. B., Lamano, J. B., Li, Y. D., DiDomenico, J. D., Choy, W., Veliceasa, D., Oyon, D. E., Fakurnejad, S., Ampie, L., Kesavabholta, K., Kaur, R., Kaur, G., Biyashev, D., Unruh, D. J., Horbinski, C. M., James, D., Parsa, A. T., & Bloch, O. (2019). Glioblastoma-derived IL6 induces immunosuppressive peripheral myeloid cell PD-L1 and promotes tumor growth. Clinical Cancer Research, 25(12), 3643–3657. https://doi.org/10.1158/1078-0432.CCR-18-2402CrossRefPubMedPubMedCentral

66.

Litak, J., Mazurek, M., Grochowski, C., Kamieniak, P., & Roliński, J. (2019). PD-L1/PD-1 axis in glioblastoma multiforme. International Journal of Molecular Sciences, 20(21), 1–16. https://doi.org/10.3390/ijms20215347CrossRef

67.

Rius-Pérez, S., Pérez, S., Martí-Andrés, P., Monsalve, M., & Sastre, J. (2020). Nuclear factor Kappa B signaling complexes in acute inflammation. Antioxidants & Redox Signaling, ars.2019.7975. https://doi.org/10.1089/ars.2019.7975

68.

Cohen, A. L., Holmen, S. L., & Colman, H. (2013). IDH1 and IDH2 mutations in gliomas. Current Neurol Neurosci Rep, 13(345), 1–7. https://doi.org/10.1007/s11910-013-0345-4CrossRef

69.

Michelson, N., Rincon-Torroella, J., Quiñones-Hinojosa, A., & Greenfield, J. P. (2016). Exploring the role of inflammation in the malignant transformation of low-grade gliomas. Journal of neuroimmunology, 297, 132–140. https://doi.org/10.1016/j.jneuroim.2016.05.019CrossRefPubMed

70.

Batsios, G., Viswanath, P., Subramani, E., Najac, C., Gillespie, A. M., Santos, R. D., Molloy, A. R., Pieper, R. O., & Ronen, S. M. (2019). PI3K/mTOR inhibition of IDH1 mutant glioma leads to reduced 2HG production that is associated with increased survival. Scientific Reports, 9(1), 1–15. https://doi.org/10.1038/s41598-019-47021-xCrossRef

71.

Perus, L. J. M., Walsh, L. A., & Walsh, L. A. (2019). Microenvironmental heterogeneity in brain malignancies. Frontiers in Immunology, 10(October). https://doi.org/10.3389/fimmu.2019.02294

72.

Barthel, F. P., Wesseling, P., & Verhaak, R. G. W. (2018). Reconstructing the molecular life history of gliomas. Acta Neuropathologica, 135(5), 649–670. https://doi.org/10.1007/s00401-018-1842-yCrossRefPubMedPubMedCentral

73.

Kechagia, J. Z., Ivaska, J., & Roca-Cusachs, P. (2019). Integrins as biomechanical sensors of the microenvironment. Nature Reviews Molecular Cell Biology, 20(8), 457–473. https://doi.org/10.1038/s41580-019-0134-2CrossRefPubMed

74.

Previtali, S. C., Quattrini, A., Pardini, C. L., Nemni, R., Feltri, M. L., Boncinelli, E., Canal, N., & Wrabetz, L. (1999). Laminin receptor α6β4 integrin is highly expressed in ENU-induced glioma in rat. Glia, 26(1), 55–63. https://doi.org/10.1002/(SICI)1098-1136(199903)26:1%3c55::AID-GLIA6%3e3.0.CO;2-1CrossRefPubMed

75.

Stewart, R. L., Chen, M., Mulkearns-Hubert, E. E., Lathia, J., O’Connor, K. L., & Horbinski, C. (2019). Integrin α6β4 is downregulated in mutant IDH1 oligodendrogliomas, promotes glioma growth, and associates with a worse outcome in glioma patients. bioRxiv [preprint]. https://doi.org/10.1101/726489 .

76.

Killela, P. J., Reitman, Z. J., Jiao, Y., Bettegowda, C., Agrawal, N., Diaz, L. A., Friedman, A. H., Friedman, H., Gallia, G. L., Giovanella, B. C., Grollman, A. P., He, T-C., He, Y., Hruban, R. H., Jallo, G. I., Mandahl, N., Meeker, A. K., Mertens, F., Netto, G. J., … &Yan, H. (2013). TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proceedings of the National Academy of Sciences of the United States of America, 110(15), 6021–6026. https://doi.org/10.1073/pnas.1303607110

77.

Korshunov, A., Meyer, J., Capper, D., Christians, A., Remke, M., Witt, H., Pfister, S., von Deimling, A., & Hartmann, C. (2009). Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta neuropathologica, 118(3), 401–405. https://doi.org/10.1007/s00401-009-0550-zCrossRefPubMed

78.

Knobbe, C. B., Reifenberger, J., & Reifenberger, G. (2004). Mutation analysis of the Ras pathway genes NRAS, HRAS, KRAS and BRAF in glioblastomas. Acta neuropathologica, 108(6), 467–470. https://doi.org/10.1007/s00401-004-0929-9CrossRefPubMed

79.

Schindler, G., Capper, D., Meyer, J., Janzarik, W., Omran, H., Herold-Mende, C., Schmieder, K., Wesseling, P., Mawrin, C., Hasselblatt, M., Louis, D. N., Korshunov, A., Pfister, S., Hartmann, C., Paulus, W., Reifenberger, G., & Von Deimling, A. (2011). Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathologica, 121(3), 397–405. https://doi.org/10.1007/s00401-011-0802-6CrossRefPubMed

80.

D’Angelo, F., Ceccarelli, M., Tala, Garofano, L., Zhang, J., Frattini, V., Caruso, F. P., Lewis, G., Alfar, K. D., Bauschet, L., Berzero, G., Cachia, D., Cangiano, M., Capelle, L., de Groot, J., DiMeco, F., Ducray, F., Farah, W., Finocchiaro, G., …& Iavarone, A. (2019). The molecular landscape of glioma in patients with neurofibromatosis 1. Nature Medicine, 25(1), 176–187. https://doi.org/10.1038/s41591-018-0263-8

81.

Lobbous, M., Bernstock, J. D., Coffee, E., Friedman, G. K., Metrock, L. K., Chagoya, G., Elsayed, G., Nakano, I., Hackney, J. R., Korf, B. R., & Nabors, L. B. (2020). An update on neurofibromatosis type 1-associated gliomas. Cancers, 12(1), 1–15. https://doi.org/10.3390/cancers12010114CrossRef

82.

Pulido, R., Baker, S. J., Barata, J. T., Carracedo, A., Cid, V. J., Chin-Sang, I. D., Dave, V., Hertog, J. D., Devreotes, P., Eickholt, B. J., Eng, C., Furnari, F. B., Georgesco, M-M., Gericke, A., Hopkins, B., Jiang, X., Lee, S-R., Losche, M., Malaney, P., … & Leslie, N. R. (2015). A unified nomenclature and amino acid numbering for human PTEN. Sci Signal, 7(332), 15. https://doi.org/10.1126/scisignal.2005560

83.

Brito, C., Azevedo, A., Esteves, S., Marques, A. R., Martins, C., Costa, I., Mafra, M., Marques, J. M. N., Roque, L., & Pojo, M. (2019). Clinical insights gained by refining the 2016 WHO classification of diffuse gliomas with: EGFR amplification, TERT mutations, PTEN deletion and MGMT methylation. BMC Cancer, 19(1), 1–14. https://doi.org/10.1186/s12885-019-6177-0CrossRef

84.

Cetintas, V. B., & Batada, N. N. (2020, January 30). Is there a causal link between PTEN deficient tumors and immunosuppressive tumor microenvironment? Journal of Translational Medicine, 18, 45. https://doi.org/10.1186/s12967-020-02219-w

85.

Peng, W., Qing Chen, J., Liu, C., Malu, S., Creasy, C., Tetzlaff, M. T., Xu, C., McKenzie, J. A., Zhang, C., Liang, X., Williams, L. J., Deng, W., Chen, G., Mbofung, R., Lazar, A. J., Torres-Cabala, C. A., Cooper, Z. A. Chen, P-L., Tieu, … Roszik, J. (2016). Loss of PTEN promotes resistance to T cell-mediated immunotherapy Analysis and interpretation of data (statistical analysis and bioinformatic analysis): HHS Public Access. Cancer Discov, 6(2), 202–216. https://doi.org/10.1158/2159-8290.CD-15-0283

86.

Shao, H., Chung, J., Lee, K., Balaj, L., Min, C., Carter, B. S., Hochberg, F. H., Breakefield, X. O., Lee, H., & Weissleder, R. (2015). Chip-based analysis of exosomal mRNA mediating drug resistance in glioblastoma. Nature Communications, 6(May), 1–9. https://doi.org/10.1038/ncomms7999CrossRef

87.

Hegi, M. E., Diserens, A. C., Gorlia, T., Hamou, M. F., De Tribolet, N., Weller, M., Kros, J. M., Hainfellner, J. A., Mason, W., Mariani, L., Bromberg, J. E. C., Hau, P., Mirimanoff, R. O., Cairncross, J. G., Janzer, R. C., & Stupp, R. (2005). MGMT gene silencing and benefit from temozolomide in glioblastoma. New England Journal of Medicine, 352(10), 997–1003. https://doi.org/10.1056/NEJMoa043331CrossRefPubMed

88.

Ng, L., Kaur, P., Bunnag, N., Suresh, J., Sung, I., Tan, Q., Gruber, J., & Tolwinski, N. (2019). WNT Signaling in Disease. Cells, 8(8), 826. https://doi.org/10.3390/cells8080826

89.

Lujambio, A., Akkari, L., Simon, J., Grace, D., Tschaharganeh, D. F., Bolden, J. E., Zhao, Z., Thapar, V., Joyce, J. A., Krizhanovsky, V., & Lowe, S. W. (2013). Non-cell-autonomous tumor suppression by p53. Cell, 153(2), 449–460. https://doi.org/10.1016/j.cell.2013.03.020CrossRefPubMedPubMedCentral

90.

Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007). Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature, 445(7128), 656–660. https://doi.org/10.1038/nature05529CrossRefPubMedPubMedCentral

91.

Ham, S. W., Jeon, H. Y., Jin, X., Kim, E. J., Kim, J. K., Shin, Y. J., Lee, Y., Kim, S. H., Lee, S. Y., Seo, S., Park, M. G., Kim, H.-M., Nam, D.-H., & Kim, H. (2019). TP53 gain-of-function mutation promotes inflammation in glioblastoma. Cell Death and Differentiation, 26(3), 409–425. https://doi.org/10.1038/s41418-018-0126-3CrossRefPubMed

92.

Zhang, Y., Dube, C., Gibert, M., Cruickshanks, N., Wang, B., Coughlan, M., Yang, Y., Setiady, I., Deveau, C., Saoud, K., Grello, C., Oxford, M., Yuan, F., & Abounader, R. (2018, September 1). The p53 pathway in glioblastoma. Cancers, 10(9), 297. https://doi.org/10.3390/cancers10090297

93.

Saleh, T., Tyutynuk-Massey, L., Cudjoe, E. K., Jr., Idowu, M. O., Landry, J. W., & Gewirtz, D. A. (2018). Non-cell autonomous effects of the senescence-associated secretory phenotype in cancer therapy. Frontiers in oncology, 8, 164. https://doi.org/10.3389/fonc.2018.00164CrossRefPubMedPubMedCentral

94.

Fujita, K. (2019). P53 isoforms in cellular senescence-and ageing-associated biological and physiological functions. International Journal of Molecular Sciences, 20(23). https://doi.org/10.3390/ijms20236023

95.

Biasoli, D., Sobrinho, M. F., Da Fonseca, A. C. C., De Matos, D. G., Romão, L., De Moraes Maciel, R., Rehen, S. K., Moura-Neto, V., Borges, H. L., & Lima, F. R. S. (2014). Glioblastoma cells inhibit astrocytic p53-expression favoring cancer malignancy. Oncogenesis, 3(10), e123–e123. https://doi.org/10.1038/oncsis.2014.36CrossRefPubMedPubMedCentral

96.

Akhavan, A., Griffith, O. L., Soroceanu, L., Leonoudakis, D., Luciani-Torres, M. G., Daemen, A., Gray, J. W., & Muschler, J. L. (2012). Loss of cell-surface laminin anchoring promotes tumor growth and is associated with poor clinical outcomes. Cancer Research, 72(10), 2578–2588. https://doi.org/10.1158/0008-5472.CAN-11-3732CrossRefPubMedPubMedCentral

97.

Ohnishi, T., Arita, N., Hiraga, S., Higuchi, M., & Hayakawa, T. (1991). Human malignant glioma cells migrate to fibronectin and laminin: Role of extracellular matrix components in glioma cell invasion. Biological Aspects of Brain Tumors, Vol 1 (408–415. https://doi.org/10.1007/978-4-431-68150-2_57

98.

Murphree, A. L., & Benedict, W. F. (1984). Retinoblastoma: Clues to human oncogenesis. Science, 223(4640), 1028–1033. https://doi.org/10.1126/science.6320372CrossRefPubMed

99.

Bronner, S. M., Merrick, K. A., Murray, J., Salphati, L., Moffat, J. G., Pang, J., Sneeringer, C. J., Dompe, N., Cyr, P., Purkey, H., de Leon Boenig, G., Li, J., Kolesnikov, A., Larouche-Gauthier, R., Lai, K. W., Shen, X, Aubert-Nicol, S., Chen, Y-C., … Heffron, T. P. (2019). Design of a brain-penetrant CDK4/6 inhibitor for glioblastoma. Bioorganic and Medicinal Chemistry Letters, 29(16), 2294–2301. https://doi.org/10.1016/j.bmcl.2019.06.021

100.

Henson, J. W., Schnitker, B. L., Correa, K. M., von Deimling, A., Fassbender, F., Xu, H.-J., Benedict, W. F., Yandell, D. W., & Louis, D. N. (1994). The retinoblastoma gene is involved in malignant progression of astrocytomas. Annals of Neurology, 36(5), 714–721. https://doi.org/10.1002/ana.410360505CrossRefPubMed

101.

Kreis, N. N., Louwen, F., & Yuan, J. (2019). The multifaceted p21 (Cip1/Waf1/CDKN1A) in cell differentiation, migration and cancer therapy. Cancers, 11(9), 1220. https://doi.org/10.3390/cancers11091220CrossRefPubMedCentral

102.

Warfel, N. A., & El-Deiry, W. S. (2013). P21WAF1 and tumourigenesis: 20 years after. Current Opinion in Oncology, 25(1), 52–58. https://doi.org/10.1097/CCO.0b013e32835b639eCrossRefPubMed

103.

Zhang, D., Dai, D., Zhou, M., Li, Z., Wang, C., Lu, Y., & Wang, J. (2018). Inhibition of cyclin D1 expression in human glioblastoma cells is associated with increased temozolomide chemosensitivity. Cellular Physiology and Biochemistry, 51(6), 2496–2508. https://doi.org/10.1159/000495920CrossRefPubMed

104.

Schneider, S. W., Ludwig, T., Tatenhorst, L., Braune, S., Oberleithner, H., Senner, V., & Paulus, W. (2004). Glioblastoma cells release factors that disrupt blood-brain barrier features. Acta neuropathologica, 107(3), 272–276. https://doi.org/10.1007/S00401-003-0810-2CrossRefPubMed

105.

Pinton, L., Masetto, E., Vettore, M., Solito, S., Magri, S., D’Andolfi, M., Bianco, P. D., Lollo, G., Benoit, J.-P., Okada, H., Diaz, A., Puppa, A. D., & Mandruzzato, S. (2019). The immune suppressive microenvironment of human gliomas depends on the accumulation of bone marrow-derived macrophages in the center of the lesion. Journal for ImmunoTherapy of Cancer, 7(1), 1–14. https://doi.org/10.1186/s40425-019-0536-xCrossRef

106.

Dix, A. R., Brooks, W. H., Roszman, T. L., & Morford, L. A. (1999). Immune defects observed in patients with primary malignant brain tumors. Journal of Neuroimmunology, 100(1–2), 216–232. https://doi.org/10.1016/S0165-5728(99)00203-9CrossRefPubMed

107.

Chen, X., Fan, X., Zhao, C., Zhao, Z., Hu, L., Wang, D., Wang, R., & Fang, Z. (2020). Molecular subtyping of glioblastoma based on immune-related genes for prognosis. Scientific Reports, 10(1), 1–12. https://doi.org/10.1038/s41598-020-72488-4CrossRef

108.

Huang, S., Song, Z., Zhang, T., He, X., Huang, K., Zhang, Q., Shen, J., & Pan, J. (2020). Identification of immune cell infiltration and immune-related genes in the tumor microenvironment of glioblastomas. Frontiers in Immunology, 11, 2708. https://doi.org/10.3389/FIMMU.2020.585034CrossRef

109.

Mitchell, D. A., Xie, W., Schmittling, R., Learn, C., Friedman, A., McLendon, R. E., & Sampson, J. H. (2008). Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro-Oncology, 10(1), 10–18. https://doi.org/10.1215/15228517-2007-035CrossRefPubMedPubMedCentral

110.

Quail, D. F., & Joyce, J. A. (2017). The microenvironmental landscape of brain tumors. Cancer Cell, 31(3), 326–341. https://doi.org/10.1016/j.ccell.2017.02.009CrossRefPubMedPubMedCentral

111.

Chen, H., Li, M., Guo, Y., Zhong, Y., He, Z., Xu, Y., & Zou, J. (2020). Immune response in glioma’s microenvironment. Innovative Surgical Sciences, 5(3–4), 115–125. https://doi.org/10.1515/ISS-2019-0001CrossRef

112.

Xu, J., Zhang, J., Zhang, Z., Gao, Z., Qi, Y., Qiu, W., Pan, Z., Guo, Q., Li, B., Zhao, S., Guo, X., Qian, M., Chen, Z., Wang, S., Gao, X., Zhang, S., Wang, H., Guo, Z., Zhang, P., …& Li, G. (2021). Hypoxic glioma-derived exosomes promote M2-like macrophage polarization by enhancing autophagy induction. Cell Death & Disease, 12(4), 1–16. https://doi.org/10.1038/s41419-021-03664-1

113.

Wang, Q., Hu, X., Muller, F., Kim, H., Squatrito, M., Mikkelsen, T., Scarpace, L., Barthel, F., Lin, Y-H., Satani, S., Martinez-Ledesma, E., Chang, E., Olar, A., Hu, B., deCarvalho, A., Eskilsson, E., Zheng, S., Heimberger, A., Sulman, E., … & Verhaak, R. (2017). Tumor evolution of glioma intrinsic gene expression subtype associates with immunological changes in the microenvironment. Cancer Cell, 18(suppl_6), vi202–vi202. https://doi.org/10.1093/neuonc/now212.854

114.

Hao, Z., & Guo, D. (2019). EGFR mutation: Novel prognostic factor associated with immune infiltration in lower-grade glioma; an exploratory study. BMC Cancer, 19(1), 1–13. https://doi.org/10.1186/S12885-019-6384-8CrossRef

115.

Li, F., Zhang, W., Wang, M., & Jia, P. (2020). IL1RAP regulated by PRPRD promotes gliomas progression via inducing neuronal synapse development and neuron differentiation in vitro. Pathology Research and Practice, 216(11), 153141. https://doi.org/10.1016/j.prp.2020.153141CrossRefPubMed

116.

Scherer, H. J. (1938). Structural development in gliomas. American Journal of Cancer, 34(3), 333–351. https://doi.org/10.1158/ajc.1938.333CrossRef

117.

Singh, S. K., Clarke, I. D., Terasaki, M., Bonn, V. E., Hawkins, C., Squire, J., & Dirks, P. B. (2003). Identification of a cancer stem cell in human brain tumors. CANCER RESEARCH, 63, 5821–5828.PubMed

118.

Bao, S., Wu, Q., Sathornsumetee, S., Hao, Y., Li, Z., Hjelmeland, A. B., Shi, Q., McLendon, R. E., Bigner, D. D., & Rich, J. N. (2006). Stem cell – like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Research, 66(16), 7843–7849. https://doi.org/10.1158/0008-5472.CAN-06-1010CrossRefPubMed

119.

Calabrese, C., Poppleton, H., Kocak, M., Hogg, T. L., Fuller, C., Hamner, B., Oh, E. Y., Gaber, M. W., Finklestein, D., Allen, M., Frank, A., Bayazitove, I. T., Zakharenko, S. S., Gajjar, A., Davidoff, A., & Gilbertson, R. J. (2007). A perivascular niche for brain tumor stem cells. Cancer Cell, 11(1), 69–82. https://doi.org/10.1016/j.ccr.2006.11.020CrossRefPubMed

120.

Wen, L., Tan, Y., Dai, S., Zhu, Y., Meng, T., Yang, X., Liu, X., Yuan, H., & Hu, F. (2017). Vegf-mediated tight junctions pathological fenestration enhances doxorubicin-loaded glycolipid-like nanoparticles traversing bbb for glioblastoma-targeting therapy. Drug Delivery, 24(1), 1843–1855. https://doi.org/10.1080/10717544.2017.1386731CrossRefPubMedPubMedCentral

121.

Gruys, E., Toussaint, M. J. M., Niewold, T. A., & Koopmans, S. J. (2005). Acute phase reaction and acute phase proteins. Journal of Zhejiang University: Science, 6 B(11), 1045–1056. https://doi.org/10.1631/jzus.2005.B1045

122.

West, A. J., Tsui, V., Stylli, S. S., Nguyen, H. P. T., Morokoff, A. P., Kaye, A. H., & Luwor, R. B. (2018, October 1). The role of interleukin-6-STAT3 signalling in glioblastoma. Oncology Letters. Spandidos Publications. https://doi.org/10.3892/ol.2018.9227

123.

Hasan, T., Caragher, S. P., Shireman, J. M., Park, C. H., Atashi, F., Baisiwala, S., Lee, G., Guo, D., Wang, J. Y., Dey, M., Wu, M., Lesniak, M. S., Horbinski, C. M., James, D., & Ahmed, A. U. (2019). Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma. Cell Death and Disease, 10(4), 1–17. https://doi.org/10.1038/s41419-019-1387-6CrossRef

124.

Raychaudhuri, B., & Vogelbaum, M. A. (2011). IL-8 is a mediator of NF-κB induced invasion by gliomas. Journal of Neuro-Oncology, 101(2), 227–235. https://doi.org/10.1007/s11060-010-0261-2CrossRefPubMed

125.

Jögi, A., Øra, I., Nilsson, H., Lindeheim, Å., Makino, Y., Poellinger, L., Alexson, H., & Påhlman, S. (2002). Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. Proceedings of the National Academy of Sciences of the United States of America, 99(10), 7021–7026. https://doi.org/10.1073/pnas.102660199CrossRefPubMedPubMedCentral

126.

Kim, K. B., Choi, Y. H., Kim, I. K., Chung, C. W., Kim, B. J., Park, Y. M., & Jung, Y. K. (2002). Potentiation of Fas- and trail-mediated apoptosis by IFN-γ in A549 lung epithelial cells: Enhancement of caspase-8 expression through IFN-response element. Cytokine, 20(6), 283–288. https://doi.org/10.1006/cyto.2003.2008CrossRefPubMed

127.

Kominsky, S., Johnson, H. M., Bryan, G., Tanabe, T., Hobeika, A. C., Subramaniam, P. S., & Torres, B. (1998). IFNγ inhibition of cell growth in glioblastomas correlates with increased levels of the cyclin dependent kinase inhibitor p21(WAF1/CIP1). Oncogene, 17(23), 2973–2979. https://doi.org/10.1038/sj.onc.1202217CrossRefPubMed

128.

Corbet, C., & Feron, O. (2017). Tumour acidosis: From the passenger to the driver’s seat. Nature Reviews Cancer, 17(10), 577–593. https://doi.org/10.1038/nrc.2017.77CrossRefPubMed

129.

Watkins, S., Robel, S., Kimbrough, I. F., Robert, S. M., Ellis-Davies, G., & Sontheimer, H. (2014). Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells. Nature Communications, 5(May), 1–15. https://doi.org/10.1038/ncomms5196CrossRef

130.

Cheng, L., Huang, Z., Zhou, W., Wu, Q., Donnola, S., Liu, J. K., Fang, X., Sloan, A. E., Mao, Y., Lathia, J. D., Min, W., McLendon, R. E., Rich, J. N., & Bao, S. (2013). Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell, 153(1), 139–152. https://doi.org/10.1016/j.cell.2013.02.021CrossRefPubMedPubMedCentral

131.

Saba, R., Alsayed, A., Zacny, J. P., & Dudek, A. Z. (2016). The Role of Forkhead Box Protein M1 in breast cancer progression and resistance to therapy. International journal of breast cancer, 2016, 9768183. https://doi.org/10.1155/2016/9768183CrossRefPubMedPubMedCentral

132.

Wang, S., Chen, C., Li, J., Xu, X., Chen, W., & Li, F. (2020). The CXCL12 / CXCR4 axis confers temozolomide resistance to human glioblastoma cells via up-regulation of FOXM1. Journal of the Neurological Sciences, 414(April), 116837. https://doi.org/10.1016/j.jns.2020.116837CrossRefPubMed

133.

Thakur, B. K., Zhang, H., Becker, A., Matei, I., Huang, Y., Costa-Silva, B., Zheng, Y., Hoshino, A., Brazier, H., Xiang, J., Williams, C., Rodriguez-Barrueco, R., Silva, J. M., Zhang, W., Hearn, S., Elemento, O., Paknejad, N., Manova-Todorova, K., Welte, K., … Jacqueline Bromberg Lyden, D. (2014, April 8). Double-stranded DNA in exosomes: A novel biomarker in cancer detection. Cell Research, 24, 766–769. https://doi.org/10.1038/cr.2014.44

134.

Simon, T., Jackson, E., & Giamas, G. (2020). Breaking through the glioblastoma micro-environment via extracellular vesicles. Oncogene, 39(23), 4477–4490. https://doi.org/10.1038/s41388-020-1308-2CrossRefPubMedPubMedCentral

135.

Bronisz, A., Wang, Y., Nowicki, M. O., Peruzzi, P., Ansari, K. I. A., Ogawa, D., Balaj, L., De Rienzo, G., Mineo, M., Nakano, I., Ostrovski, M. C., Hochberg, F., Weissleder, R., Lawler, S. E., Chiocca, E. A., & Godlewski, J. (2014). Extracellular vesicles modulate the glioblastoma microenvironment via a tumor suppression signaling network directed by miR-1. Cancer research, 74(3), 738–750. https://doi.org/10.1158/0008-5472.CAN-13-2650CrossRefPubMed

136.

Hallal, S., Mallawaaratchy, D. M., Wei, H., Ebrahimkhani, S., Stringer, B. W., Day, B. W., Boyd, A. W., Guillemin, G. J., Buckland, M. E., & Kaufman, K. L. (2019). Extracellular vesicles released by glioblastoma cells stimulate normal astrocytes to acquire a tumor-supportive phenotype via p53 and MYC signaling pathways. Molecular Neurobiology, 56(6), 4566–4581. https://doi.org/10.1007/S12035-018-1385-1CrossRefPubMed

137.

Choi, D., Montermini, L., Kim, D. K., Meehan, B., Roth, F. P., & Rak, J. (2018). The impact of oncogenic egfrviii on the proteome of extracellular vesicles released from glioblastoma cells. Molecular and Cellular Proteomics, 17(10), 1948–1964. https://doi.org/10.1074/mcp.RA118.000644CrossRefPubMedPubMedCentral

138.

Skog, J., Wurdinger, T., van Rijn, S., Meijer, D., Gainche, L., Curry, W. T., Carter, B. S., Krichevsky, A. M., & Breakefield, X. O. (2008). Glioblastoma microvesicles transport RNA and protein that promote tumor growth and provide diagnostic biomarkers. Nature Cell Bbiology, 10(12), 1470. https://doi.org/10.1038/NCB1800CrossRef

139.

Figueroa, J. M., Skog, J., Akers, J., Li, H., Komotar, R., Jensen, R., Ringel, F., Yang, I., Kalkanis, S., Thompson, R., LoGuidice, L., Berghoff, E., Parsa, A., Liau, L., Curry, W., Cahill, D., Bettegowda, C., Lang, F. F., Chiocca, E. A., … Carter, B. S. (2017). Detection of wild-type EGFR amplification and EGFRvIII mutation in CSF-derived extracellular vesicles of glioblastoma patients. Neuro-oncology, 19(11), 1494–1502. https://doi.org/10.1093/NEUONC/NOX085

140.

Taraboletti, G., D’Ascenzo, S., Giusti, I., Marchetti, D., Borsotti, P., Millimaggi, D., Giavazzi, R., Pavan, A., & Dolo, V. (2006). Bioavailability of VEGF in tumor-shed vesicles depends on vesicle burst induced by acidic pH 1. Neoplasia, 8(2), 96–103. https://doi.org/10.1593/neo.05583CrossRefPubMedPubMedCentral

141.

McGranahan, T., Therkelsen, K. E., Ahmad, S., & Nagpal, S. (2019). Current state of immunotherapy for treatment of glioblastoma. Current treatment options in oncology, 20(3), 24. https://doi.org/10.1007/s11864-019-0619-4CrossRefPubMedPubMedCentral

142.

Huang, B., Li, X., Li, Y., Zhang, J., Zong, Z., & Zhang, H. (2021). Current immunotherapies for glioblastoma multiforme. Frontiers in immunology, 11, 603911. https://doi.org/10.3389/fimmu.2020.603911CrossRefPubMedPubMedCentral

143.

Brown, C. E., Badie, B., Barish, M. E., Weng, L., Ostberg, J. R., Chang, W. C., Naranjo, A., Starr, R., Wagner, J., Wright, C., Zhai, Y., Bading, J. R., Ressler, J. A., Portnow, J., D’Apuzzo, M., Forman, S. J., & Jensen, M. C. (2015). Bioactivity and safety of IL13Rα2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma. Clinical cancer research : An official journal of the American Association for Cancer Research, 21(18), 4062–4072. https://doi.org/10.1158/1078-0432.CCR-15-0428CrossRef

144.

Ahmed, N., Brawley, V., Hegde, M., Bielamowicz, K., Kalra, M., Landi, D., Robertson, C., Gray, T. L., Diouf, O., Wakefield, A., Ghazi, A., Gerken, C., Yi, Z., Ashoori, A., Wu, M. F., Liu, H., Rooney, C., Dotti, G., Gee, A., Su, J., … Gottschalk, S. (2017). HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: A phase 1 dose-escalation trial. JAMA Oncology, 3(8), 1094–1101. https://doi.org/10.1001/jamaoncol.2017.0184

145.

Schuessler, A., Smith, C., Beagley, L., Boyle, G. M., Rehan, S., Matthews, K., Jones, L., Crough, T., Dasari, V., Klein, K., Smalley, A., Alexander, H., Walker, D. G., & Khanna, R. (2014). Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma. Cancer research, 74(13), 3466–3476. https://doi.org/10.1158/0008-5472.CAN-14-0296CrossRefPubMed

146.

Kong, D. S., Nam, D. H., Kang, S. H., Lee, J. W., Chang, J. H., Kim, J. H., Lim, Y. J., Koh, Y. C., Chung, Y. G., Kim, J. M., & Kim, C. H. (2017). Phase III randomized trial of autologous cytokine-induced killer cell immunotherapy for newly diagnosed glioblastoma in Korea. Oncotarget, 8(4), 7003–7013. https://doi.org/10.18632/oncotarget.12273

147.

Margolin, K., Ernstoff, M. S., Hamid, O., Lawrence, D., McDermott, D., Puzanov, I., Wolchok, J. D., Clark, J. I., Sznol, M., Logan, T. F., Richards, J., Michener, T., Balogh, A., Heller, K. N., & Hodi, F. S. (2012). Ipilimumab in patients with melanoma and brain metastases: An open-label, phase 2 trial. The Lancet. Oncology, 13(5), 459–465. https://doi.org/10.1016/S1470-2045(12)70090-6CrossRefPubMed

148.

Reardon, D. A., Brandes, A. A., Omuro, A., Mulholland, P., Lim, M., Wick, A., Baehring, J., Ahluwalia, M. S., Roth, P., Bähr, O., Phuphanich, S., Sepulveda, J. M., De Souza, P., Sahebjam, S., Carleton, M., Tatsuoka, K., Taitt, C., Zwirtes, R., Sampson, J., & Weller, M. (2020). Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: The CheckMate 143 phase 3 randomized clinical trial. JAMA Oncology, 6(7), 1003–1010. https://doi.org/10.1001/jamaoncol.2020.1024CrossRefPubMed

149.

Rampling, R., Peoples, S., Mulholland, P. J., James, A., Al-Salihi, O., Twelves, C. J., McBain, C., Jefferies, S., Jackson, A., Stewart, W., Lindner, J., Kutscher, S., Hilf, N., McGuigan, L., Peters, J., Hill, K., Schoor, O., Singh-Jasuja, H., Halford, S. E., & Ritchie, J. W. (2016). A Cancer Research UK first time in human phase I trial of IMA950 (novel multipeptide therapeutic vaccine) in patients with newly diagnosed glioblastoma. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 22(19), 4776–4785. https://doi.org/10.1158/1078-0432.CCR-16-0506CrossRef

150.

Inogés, S., Tejada, S., de Cerio, A. L., Gállego Pérez-Larraya, J., Espinós, J., Idoate, M. A., Domínguez, P. D., de Eulate, R. G., Aristu, J., Bendandi, M., Pastor, F., Alonso, M., Andreu, E., Cardoso, F. P., & Valle, R. D. (2017). A phase II trial of autologous dendritic cell vaccination and radiochemotherapy following fluorescence-guided surgery in newly diagnosed glioblastoma patients. Journal of translational medicine, 15(1), 104. https://doi.org/10.1186/s12967-017-1202-zCrossRefPubMedPubMedCentral

151.

Weller, M., Butowski, N., Tran, D. D., Recht, L. D., Lim, M., Hirte, H., Ashby, L., Mechtler, L., Goldlust, S. A., Iwamoto, F., Drappatz, J., O’Rourke, D. M., Wong, M., Hamilton, M. G., Finocchiaro, G., Perry, J., Wick, W., Green, J., He, Y., Turner, C. D., … ACT IV trial investigators (2017). Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): A randomised, double-blind, international phase 3 trial. The Lancet. Oncology, 18(10), 1373–1385. https://doi.org/10.1016/S1470-2045(17)30517-X

152.

Schuster, J., Lai, R. K., Recht, L. D., Reardon, D. A., Paleologos, N. A., Groves, M. D., Mrugala, M. M., Jensen, R., Baehring, J. M., Sloan, A., Archer, G. E., Bigner, D. D., Cruickshank, S., Green, J. A., Keler, T., Davis, T. A., Heimberger, A. B., & Sampson, J. H. (2015). A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: The ACT III study. Neuro-oncology, 17(6), 854–861. https://doi.org/10.1093/neuonc/nou348CrossRefPubMedPubMedCentral

153.

Bloch, O., Crane, C. A., Fuks, Y., Kaur, R., Aghi, M. K., Berger, M. S., Butowski, N. A., Chang, S. M., Clarke, J. L., McDermott, M. W., Prados, M. D., Sloan, A. E., Bruce, J. N., & Parsa, A. T. (2014). Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: A phase II, single-arm trial. Neuro-oncology, 16(2), 274–279. https://doi.org/10.1093/neuonc/not203CrossRefPubMed

154.

Fenstermaker, R. A., Ciesielski, M. J., Qiu, J., Yang, N., Frank, C. L., Lee, K. P., Mechtler, L. R., Belal, A., Ahluwalia, M. S., & Hutson, A. D. (2016). Clinical study of a survivin long peptide vaccine (SurVaxM) in patients with recurrent malignant glioma. Cancer immunology, immunotherapy : CII, 65(11), 1339–1352. https://doi.org/10.1007/s00262-016-1890-xCrossRefPubMed

155.

Batich, K. A., Reap, E. A., Archer, G. E., Sanchez-Perez, L., Nair, S. K., Schmittling, R. J., Norberg, P., Xie, W., Herndon, J. E., 2nd., Healy, P., McLendon, R. E., Friedman, A. H., Friedman, H. S., Bigner, D., Vlahovic, G., Mitchell, D. A., & Sampson, J. H. (2017). Long-term survival in glioblastoma with cytomegalovirus pp65-targeted vaccination. Clinical Cancer Research : An official journal of the American Association for Cancer Research, 23(8), 1898–1909. https://doi.org/10.1158/1078-0432.CCR-16-2057CrossRef

156.

Curry, W. T., Jr., Gorrepati, R., Piesche, M., Sasada, T., Agarwalla, P., Jones, P. S., Gerstner, E. R., Golby, A. J., Batchelor, T. T., Wen, P. Y., Mihm, M. C., & Dranoff, G. (2016). Vaccination with irradiated autologous tumor cells mixed with irradiated GM-K562 cells stimulates antitumor immunity and T lymphocyte activation in patients with recurrent malignant glioma. Clinical Cancer Research : An official journal of the American Association for Cancer Research, 22(12), 2885–2896. https://doi.org/10.1158/1078-0432.CCR-15-2163CrossRef

157.

Liau, L. M., Ashkan, K., Tran, D. D., Campian, J. L., Trusheim, J. E., Cobbs, C. S., Heth, J. A., Salacz, M., Taylor, S., D’Andre, S. D., Iwamoto, F. M., Dropcho, E. J., Moshel, Y. A., Walter, K. A., Pillainayagam, C. P., Aiken, R., Chaudhary, R., Goldlust, S. A., Bota, D. A., Duic, P., … Bosch, M. L. (2018). First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. Journal of translational medicine, 16(1), 142. https://doi.org/10.1186/s12967-018-1507-6

158.

Platten, M., Bunse, L., Wick, A., Bunse, T., Le Cornet, L., Harting, I., Sahm, F., Sanghvi, K., Tan, C. L., Poschke, I., Green, E., Justesen, S., Behrens, G. A., Breckwoldt, M. O., Freitag, A., Rother, L. M., Schmitt, A., Schnell, O., Hense, J., Misch, M., … Wick, W. (2021). A vaccine targeting mutant IDH1 in newly diagnosed glioma. Nature, 592(7854), 463–468. https://doi.org/10.1038/s41586-021-03363-z

159.

Lang, F. F., Conrad, C., Gomez-Manzano, C., Yung, W., Sawaya, R., Weinberg, J. S., Prabhu, S. S., Rao, G., Fuller, G. N., Aldape, K. D., Gumin, J., Vence, L. M., Wistuba, I., Rodriguez-Canales, J., Villalobos, P. A., Dirven, C., Tejada, S., Valle, R. D., Alonso, M. M., Ewald, B., … Fueyo, J. (2018). Phase I study of DNX-2401 (delta-24-RGD) oncolytic adenovirus: Replication and immunotherapeutic effects in recurrent malignant glioma. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 36(14), 1419–1427. https://doi.org/10.1200/JCO.2017.75.8219

160.

Weller, M., van den Bent, M., Preusser, M., Le Rhun, E., Tonn, J. C., Minniti, G., Bendszus, M., Balana, C., Chinot, O., Dirven, L., French, P., Hegi, M. E., Jakola, A. S., Platten, M., Roth, P., Rudà, R., Short, S., Smits, M., Taphoorn, M., von Deimling, A., … Wick, W. (2021). EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nature reviews. Clinical oncology, 18(3), 170–186. https://doi.org/10.1038/s41571-020-00447-z

Title: Glioma: molecular signature and crossroads with tumor microenvironment
Authors: Lennart Barthel
Martin Hadamitzky
Philipp Dammann
Manfred Schedlowski
Ulrich Sure
Basant Kumar Thakur
Susann Hetze
Publication date: 01-03-2022
Publisher: Springer US
Keywords: Glioblastoma
Glioma
Glioma
Glioblastoma
Glioblastoma
Glioma
Published in: Cancer and Metastasis Reviews / Issue 1/2022
Print ISSN: 0167-7659
Electronic ISSN: 1573-7233
DOI: https://doi.org/10.1007/s10555-021-09997-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Graphical abstract

Please log in to get access to this content

Other articles of this Issue 1/2022

Anti-HER2 therapy in metastatic breast cancer: many choices and future directions

Lipid metabolism reprogramming in renal cell carcinoma

Of vascular defense, hemostasis, cancer, and platelet biology: an evolutionary perspective

The emerging roles of circular RNAs in vessel co-option and vasculogenic mimicry: clinical insights for anti-angiogenic therapy in cancers

Systematic review of the receptor tyrosine kinase superfamily in neuroblastoma pathophysiology

MicroRNAs as a clue to overcome breast cancer treatment resistance

Keynote webinar | Spotlight on antibody–drug conjugates in cancer