Recent in vitro models and tissue engineering strategies to study glioblastoma

Year 2024, , 52 - 66, 30.06.2024

Melike Karakaya Pınar Obakan Yerlikaya

https://doi.org/10.38042/biotechstudies.1463814

Abstract

Glioblastoma is a highly malignant brain tumor classified as grade IV with a poor prognosis and approximately a year of survival rate. The molecular changes that trigger primary glioblastoma are usually epidermal growth factor receptor mutations and amplifications, Mouse Double Minute and TP53 mutations, p16 deletion, phosphatase and tensin homolog and telomerase promoter mutations. In the vast majority of glioblastomas, altered signaling pathways were identified as receptor tyrosine kinase/Ras/PI3K, p53. Isocitrate dehydrogenase 1/2 mutations have also been associated with poor prognosis in glioblastoma The treatment options are very limited and complicated because of the diverse composition and heterogeneity of the tumors and unresponsiveness to the treatments with the existence of barriers reaching the brain tissue. Despite new trials, drug candidates that appeared effective in cell culture or mouse models failed in the clinic. Recently, new sophisticated experimental systems, including the those that mimic the tumor microenvironment, have started being used by several research groups, which will allow accurate prediction of drug efficacy. Tissue engineering strategies are also being combined with innovative cancer models, including spheroids, tumorspheres, organotypic slices, explants, tumoroids, and organoids. Such 3D systems provide powerful tools for studying glioblastoma biology by representing the dynamic evolution of the disease from the early to the metastatic stages and enabling interaction with the microenvironment. In this review, we both enlighten the molecular mechanisms that lead to glioblastoma development and detailed information on the tissue engineering approaches that have been used to model glioblastoma and the tumor microenvironment with the advantages and disadvantages. We anticipate that these novel approaches could improve the reliability of preclinical data by reducing the need for animal models.

Keywords

Glioblastoma, Molecular mechanisms, Tissue engineering

References

• Aldape, K., Zadeh, G., Mansouri, S., Reifenberger, G., & von Deimling, A. (2015). Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathologica, 129(6), 829–848. https://doi.org/10.1007/S00401-015-1432-1
• Ali, M. Y., Oliva, C. R., Noman, A. S. M., Allen, B. G., Goswami, P. C., Zakharia, Y., Monga, V., Spitz, D. R., Buatti, J. M., & Griguer, C. E. (2020). Radioresistance in Glioblastoma and the Development of Radiosensitizers. Cancers, 12(9), 1–29. https://doi.org/10.3390/CANCERS12092511
• Alifieris, C., & Trafalis, D. T. (2015a). Glioblastoma multiforme: Pathogenesis and treatment. Pharmacology & Therapeutics, 152, 63–82. https://doi.org/10.1016/J.PHARMTHERA.2015.05.005
• Alifieris, C., & Trafalis, D. T. (2015b). Glioblastoma multiforme: Pathogenesis and treatment. Pharmacology & Therapeutics, 152, 63–82. https://doi.org/10.1016/J.PHARMTHERA.2015.05.005
• Angeles, M., Torrejon, M., Gangoso, E., & Pollard, S. M. (2018). Modelling glioblastoma tumour-host cell interactions using adult brain organotypic slice co-culture. Disease Models & Mechanisms, 11(2). https://doi.org/10.1242/DMM.031435
• Batash, R., Asna, N., Schaffer, P., Francis, N., & Schaffer, M. (2017). Glioblastoma Multiforme, Diagnosis and Treatment; Recent Literature Review. Current Medicinal Chemistry, 24(27). https://doi.org/10.2174/0929867324666170516123206
• Batchelor, T. T., Mulholland, P., Neyns, B., Nabors, L. B., Campone, M., Wick, A., Mason, W., Mikkelsen, T., Phuphanich, S., Ashby, L. S., DeGroot, J., Gattamaneni, R., Cher, L., Rosenthal, M., Payer, F., Jürgensmeier, J. M., Jain, R. K., Sorensen, A. G., Xu, J., van den Bent, M. (2013). Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 31(26), 3212–3218. https://doi.org/10.1200/JCO.2012.47.2464
• Benitez, J. A., Finlay, D., Castanza, A., Parisian, A. D., Ma, J., Longobardi, C., Campos, A., Vadla, R., Izurieta, A., Scerra, G., Koga, T., Long, T., Chavez, L., Mesirov, J. P., Vuori, K., & Furnari, F. (2021). PTEN deficiency leads to proteasome addiction: A novel vulnerability in glioblastoma. Neuro-Oncology, 23(7), 1072–1086. https://doi.org/10.1093/NEUONC/NOAB001
• Brennan, C. W., Verhaak, R. G. W., McKenna, A., Campos, B., Noushmehr, H., Salama, S. R., Zheng, S., Chakravarty, D., Sanborn, J. Z., Berman, S. H., Beroukhim, R., Bernard, B., Wu, C. J., Genovese, G., Shmulevich, I., Barnholtz-Sloan, J., Zou, L., Vegesna, R., Shukla, S. A., McLendon, R. (2013). The somatic genomic landscape of glioblastoma. Cell, 155(2), 462. https://doi.org/10.1016/J.CELL.2013.09.034
• Bruns, J., Silviya, &, & Zustiak, P. (2021). Hydrogel-Based Spheroid Models of Glioblastoma for Drug Screening Applications. Missouri Medicine, 118(4), 346. /pmc/articles/PMC8343644/ Burdett, E., Kasper, F. K., Mikos, A. G., & Ludwig, J. A. (2010). Engineering tumors: a tissue engineering perspective in cancer biology. Tissue Engineering. Part B, Reviews, 16(3), 351–359. https://doi.org/10.1089/TEN.TEB.2009.0676
• Carlsson, S. K., Brothers, S. P., & Wahlestedt, C. (2014). Emerging treatment strategies for glioblastoma multiforme. EMBO Molecular Medicine, 6(11), 1359–1370. https://doi.org/10.15252/EMMM.201302627
• Chandra, P. K., Soker, S., & Atala, A. (2020). Tissue engineering: current status and future perspectives. Principles of Tissue Engineering, 1–35. https://doi.org/10.1016/B978-0-12-818422-6.00004-6
• Chi, A. S., Batchelor, T. T., Kwak, E. L., Clark, J. W., Wang, D. L., Wilner, K. D., Louis, D. N., & Iafrate, A. J. (2012). Rapid radiographic and clinical improvement after treatment of a MET-amplified recurrent glioblastoma with a mesenchymal-epithelial transition inhibitor. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 30(3). https://doi.org/10.1200/JCO.2011.38.4586
• Chua, J., Nafziger, E., & Leung, D. (2019). Evidence-Based Practice: Temozolomide Beyond Glioblastoma. Current Oncology Reports, 21(4). https://doi.org/10.1007/S11912-019-0783-5
• Denny, B. J., Tsang, L. L. H., Slack, J. A., Wheelhouse, R. T., & Stevens, M. F. G. (1994). NMR and molecular modeling investigation of the mechanism of activation of the antitumor drug temozolomide and its interaction with DNA. Biochemistry, 33(31), 9045–9051. https://doi.org/10.1021/BI00197A003
• Duvall, C. L., Prokop, A., Gersbach, C. A., & Davidson, J. M. (2013a). Gene Delivery into Cells and Tissues. In Principles of Tissue Engineering: Fourth Edition. Elsevier Inc. https://doi.org/10.1016/B978-0-12-398358-9.00035-5
• Duvall, C. L., Prokop, A., Gersbach, C. A., & Davidson, J. M. (2013b). Gene Delivery into Cells and Tissues. In Principles of Tissue Engineering: Fourth Edition. Elsevier Inc. https://doi.org/10.1016/B978-0-12-398358-9.00035-5
• Enderle, J. D., & Bronzino, J. D. (2011). Introduction to Biomedical Engineering. Introduction to Biomedical Engineering, 1–1253. https://doi.org/10.1016/C2009-0-19716-7
• Ermoian, R. P., Furniss, C. S., Lamborn, K. R., Basila, D., Berger, M. S., Gottschalk, A. R., Nicholas, M. K., Stokoe, D., & Haas-Kogan, D. A. (2002). Dysregulation of PTEN and protein kinase B is associated with glioma histology and patient survival. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 8(5), 1100–1106.
• Fisher, J. P., & Adamson, D. C. (2021). Current FDA-Approved Therapies for High-Grade Malignant Gliomas. Biomedicines, 9(3). https://doi.org/10.3390/BIOMEDICINES9030324
• Frei, K., Gramatzki, D., Tritschler, I., Schroeder, J. J., Espinoza, L., Rushing, E. J., & Weller, M. (2015). Transforming growth factor-β pathway activity in glioblastoma. Oncotarget, 6(8), 5963. https://doi.org/10.18632/ONCOTARGET.3467
• Froehlich, K., Haeger, J.-D., Heger, J., Pastuschek, J., Photini, S. M., Yan, Y., Lupp, A., Pfarrer, C., Mrowka, R., Schleußner, E., Markert, U. R., & Schmidt, A. (n.d.). Generation of Multicellular Breast Cancer Tumor Spheroids: Comparison of Different Protocols. Journal of Mammary Gland Biology and Neoplasia. https://doi.org/10.1007/s10911-016-9359-2
• Gedeon, P. C., Schaller, T. H., Chitneni, S. K., Choi, B. D., Kuan, C. T., Suryadevara, C. M., Snyder, D. J., Schmittling, R. J., Szafranski, S. E., Cui, X., Healy, P. N., Herndon, J. E., McLendon, R. E., Keir, S. T., Archer, G. E., Reap, E. A., Sanchez-Perez, L., Bigner, D. D., & Sampson, J. H. (2018). A Rationally Designed Fully Human EGFRvIII:CD3-Targeted Bispecific Antibody Redirects Human T Cells to Treat Patient-derived Intracerebral Malignant Glioma. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 24(15), 3611–3631. https://doi.org/10.1158/1078-0432.CCR-17-0126
• Gilard, V., Tebani, A., Dabaj, I., Laquerrière, A., Fontanilles, M., Derrey, S., Marret, S., & Bekri, S. (2021). Diagnosis and Management of Glioblastoma: A Comprehensive Perspective. Journal of Personalized Medicine 2021, Vol. 11, Page 258, 11(4), 258. https://doi.org/10.3390/JPM11040258
• Groszer, M., Erickson, R., Scripture-Adams, D. D., Dougherty, J. D., Le Belle, J., Zack, J. A., Geschwind, D. H., Liu, X., Kornblum, H. I., & Wu, H. (2006). PTEN negatively regulates neural stem cell self-renewal by modulating G0-G1 cell cycle entry. Proceedings of the National Academy of Sciences of the United States of America, 103(1), 111–116. https://doi.org/10.1073/PNAS.0509939103
• Horn, S., Figl, A., Rachakonda, P. S., Fischer, C., Sucker, A., Gast, A., Kadel, S., Moll, I., Nagore, E., Hemminki, K., Schadendorf, D., & Kumar, R. (2013). TERT promoter mutations in familial and sporadic melanoma. Science, 339(6122), 959–961. https://doi.org/10.1126/science.1230062
• Iacob, G., & Dinca, E. B. (2009). Current data and strategy in glioblastoma multiforme. Journal of Medicine and Life, 2(4), 386.
• Jacob, F., Salinas, R. D., Zhang, D. Y., Nguyen, P. T. T., Schnoll, J. G., Wong, S. Z. H., Thokala, R., Sheikh, S., Saxena, D., Prokop, S., Liu, D. ao, Qian, X., Petrov, D., Lucas, T., Chen, H. I., Dorsey, J. F., Christian, K. M., Binder, Z. A., Nasrallah, M., … Song, H. (2020). A Patient-Derived Glioblastoma Organoid Model and Biobank Recapitulates Inter- and Intra-tumoral Heterogeneity. Cell, 180(1), 188. https://doi.org/10.1016/J.CELL.2019.11.036
• Jin, G., Reitman, Z. J., Duncan, C. G., Spasojevic, I., Gooden, D. M., Rasheed, B. A., Yang, R., Lopez, G. Y., He, Y., McLendon, R. E., Bigner, D. D., & Yan, H. (2013). Disruption of wild type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas. Cancer Research, 73(2), 496. https://doi.org/10.1158/0008-5472.CAN-12-2852
• Karachi, A., Dastmalchi, F., Mitchell, D. A., & Rahman, M. (2018). Temozolomide for immunomodulation in the treatment of glioblastoma. Neuro-Oncology, 20(12), 1566. https://doi.org/10.1093/NEUONC/NOY072
• Kardan, A., & Satter, M. (2016). Advanced Methionine Positron-Emission Tomography Imaging for Brain Tumor Diagnosis, Surgical Planning, and Treatment. Handbook of Neuro-Oncology Neuroimaging: Second Edition, 371–384. https://doi.org/10.1016/B978-0-12-800945-1.00034-3
• Kim, J., Lee, Y., Cho, H. J., Lee, Y. E., An, J., Cho, G. H., Ko, Y. H., Joo, K. M., & Nam, D. H. (2014). NTRK1 Fusion in Glioblastoma Multiforme. PLOS ONE, 9(3), e91940. https://doi.org/10.1371/JOURNAL.PONE.0091940
• Kim, M. M., Umemura, Y., & Leung, D. (2018). Bevacizumab and Glioblastoma: Past, Present, and Future Directions. Cancer Journal (Sudbury, Mass.), 24(4), 180–186. https://doi.org/10.1097/PPO.0000000000000326
• Kleihues, P., & Ohgaki, H. (1999). Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro-Oncology, 1(1), 44–51. https://doi.org/10.1093/NEUONC/1.1.44
• le Rhun, E., Preusser, M., Roth, P., Reardon, D. A., van den Bent, M., Wen, P., Reifenberger, G., & Weller, M. (2019). Molecular targeted therapy of glioblastoma. Cancer Treatment Reviews, 80. https://doi.org/10.1016/J.CTRV.2019.101896
• Li, Y., Li, A., Glas, M., Lal, B., Ying, M., Sang, Y., Xia, S., Trageser, D., Guerrero-Cázares, H., Eberhart, C. G., Quiñones-Hinojosa, A., Scheffler, B., & Laterra, J. (2011). c-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype. Proceedings of the National Academy of Sciences of the United States of America, 108(24), 9951–9956. https://doi.org/10.1073/pnas.1016912108
• Ma, D. J., Galanis, E., Anderson, S. K., Schiff, D., Kaufmann, T. J., Peller, P. J., Giannini, C., Brown, P. D., Uhm, J. H., McGraw, S., Jaeckle, K. A., Flynn, P. J., Ligon, K. L., Buckner, J. C., & Sarkaria, J. N. (2015). A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K. Neuro-Oncology, 17(9), 1261–1269. https://doi.org/10.1093/NEUONC/NOU328
• Mao, H., Lebrun, D. G., Yang, J., Zhu, V. F., & Li, M. (2012). Deregulated signaling pathways in glioblastoma multiforme: molecular mechanisms and therapeutic targets. Cancer Investigation, 30(1), 48–56. https://doi.org/10.3109/07357907.2011.630050
• Masui, K., Mischel, P. S., & Reifenberger, G. (2016). Molecular classification of gliomas. Handbook of Clinical Neurology, 134, 97–120. https://doi.org/10.1016/B978-0-12-802997-8.00006-2
• Montemurro, N. (2020). Glioblastoma Multiforme and Genetic Mutations: The Issue Is Not Over Yet. An Overview of the Current Literature. Journal of Neurological Surgery. Part A, Central European Neurosurgery, 81(1), 64–70. https://doi.org/10.1055/S-0039-1688911
• Nam, J. Y., & De Groot, J. F. (2017). Treatment of Glioblastoma. Journal of Oncology Practice, 13(10), 629–638. https://doi.org/10.1200/JOP.2017.025536
• Nejo, T., Mende, A., & Okada, H. (2020). The current state of immunotherapy for primary and secondary brain tumors: similarities and differences. Japanese Journal of Clinical Oncology, 50(11), 1331–1345. https://doi.org/10.1093/JJCO/HYAA164
• Norden, A. D., & Wen, P. Y. (2006). Glioma therapy in adults. The Neurologist, 12(6), 279–292. https://doi.org/10.1097/01.NRL.0000250928.26044.47
• Ohgaki, H., Dessen, P., Jourde, B., Horstmann, S., Nishikawa, T., Di Patre, P. L., Burkhard, C., Schüler, D., Probst-Hensch, N. M., Maiorka, P. C., Baeza, N., Pisani, P., Yonekawa, Y., Yasargil, M. G., Lütolf, U. M., & Kleihues, P. (2004). Genetic pathways to glioblastoma: a population-based study. Cancer Research, 64(19), 6892–6899. https://doi.org/10.1158/0008-5472.CAN-04-1337
• O’Rourke, D. M., Nasrallah, M. P., Desai, A., Melenhorst, J. J., Mansfield, K., Morrissette, J. J. D., Martinez-Lage, M., Brem, S., Maloney, E., Shen, A., Isaacs, R., Mohan, S., Plesa, G., Lacey, S. F., Navenot, J. M., Zheng, Z., Levine, B. L., Okada, H., June, C. H., … Maus, M. V. (2017). A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Science Translational Medicine, 9(399). https://doi.org/10.1126/SCITRANSLMED.AAA0984
• Ou, A., Alfred Yung, W. K., & Majd, N. (2021). Molecular Mechanisms of Treatment Resistance in Glioblastoma. International Journal of Molecular Sciences, 22(1), 1–24. https://doi.org/10.3390/IJMS22010351
• Parker, J. J., Lizarraga, M., Waziri, A., & Foshay, K. M. (2017). A Human Glioblastoma Organotypic Slice Culture Model for Study of Tumor Cell Migration and Patient-specific Effects of Anti-Invasive Drugs. Journal of Visualized Experiments : JoVE, 2017(125), 53557. https://doi.org/10.3791/53557
• Peralta-Arrieta, I., Trejo-Villegas, O. A., Armas-López, L., Ceja-Rangel, H. A., Ordóñez-Luna, M. del C., Pineda-Villegas, P., González-López, M. A., Ortiz-Quintero, B., Mendoza-Milla, C., Zatarain-Barrón, Z. L., Arrieta, O., Zúñiga, J., & Ávila-Moreno, F. (2022). Failure to EGFR-TKI-based therapy and tumoural progression are promoted by MEOX2/GLI1-mediated epigenetic regulation of EGFR in the human lung cancer. European Journal of Cancer (Oxford, England : 1990), 160, 189–205. https://doi.org/10.1016/J.EJCA.2021.10.032
• Perry, A., & Wesseling, P. (2016). Histologic classification of gliomas. Handbook of Clinical Neurology, 134, 71–95. https://doi.org/10.1016/B978-0-12-802997-8.00005-0
• Reardon, D. A., & Wen, P. Y. (2006). Therapeutic advances in the treatment of glioblastoma: rationale and potential role of targeted agents. The Oncologist, 11(2), 152–164. https://doi.org/10.1634/THEONCOLOGIST.11-2-152
• Rock, K., McArdle, O., Forde, P., Dunne, M., Fitzpatrick, D., O’Neill, B., & Faul, C. (2012). A clinical review of treatment outcomes in glioblastoma multiforme--the validation in a non-trial population of the results of a randomised Phase III clinical trial: has a more radical approach improved survival? The British Journal of Radiology, 85(1017). https://doi.org/10.1259/BJR/83796755
• Rybin, M. J., Ivan, M. E., Ayad, N. G., & Zeier, Z. (2021). Organoid Models of Glioblastoma and Their Role in Drug Discovery. Frontiers in Cellular Neuroscience, 15, 605255. https://doi.org/10.3389/FNCEL.2021.605255
• Salmaggi, A., Boiardi, A., Gelati, M., Russo, A., Calatozzolo, C., Ciusani, E., Sciacca, F. L., Ottolina, A., Parati, E. A., la Porta, C., Alessandri, G., Marras, C., Croci, D., & de Rossi, M. (2006). Glioblastoma-derived tumorospheres identify a population of tumor stem-like cells with angiogenic potential and enhanced multidrug resistance phenotype. Glia, 54(8), 850–860. https://doi.org/10.1002/GLIA.20414
• Sasmita, A. O., Wong, Y. P., & Ling, A. P. K. (2018). Biomarkers and therapeutic advances in glioblastoma multiforme. Asia-Pacific Journal of Clinical Oncology, 14(1), 40–51. https://doi.org/10.1111/AJCO.12756
• Scott, J., Tsai, Y. Y., Chinnaiyan, P., & Yu, H. H. M. (2011). Effectiveness of radiotherapy for elderly patients with glioblastoma. International Journal of Radiation Oncology, Biology, Physics, 81(1), 206–210. https://doi.org/10.1016/J.IJROBP.2010.04.033
• Shah, J. L., Li, G. H., & Soltys, S. G. (2021). Glioblastoma Multiforme. CyberKnife Stereotactic Radiosurgery: Brain, 1, 85–98. https://doi.org/10.22290/jbnc.v24i1.1481
• Shimizu, F., Hovinga, K. E., Metzner, M., Soulet, D., & Tabar, V. (2011). Organotypic explant culture of glioblastoma multiforme and subsequent single-cell suspension. Current Protocols in Stem Cell Biology, Chapter 3(SUPPL.19). https://doi.org/10.1002/9780470151808.SC0305S19
• Sidorcenco, V., Krahnen, L., Schulz, M., Remy, J., Kögel, D., Temme, A., Krügel, U., Franke, H., & Aigner, A. (2020). Glioblastoma Tissue Slice Tandem-Cultures for Quantitative Evaluation of Inhibitory Effects on Invasion and Growth. Cancers, 12(9), 1–15. https://doi.org/10.3390/CANCERS12092707
• Smith, J. S., Tachibana, I., Passe, S. M., Huntley, B. K., Borell, T. J., Iturria, N., O’Fallon, J. R., Schaefer, P. L., Scheithauer, B. W., James, C. D., Buckner, J. C., & Jenkins, R. B. (2001). PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. Journal of the National Cancer Institute, 93(16), 1246–1256. https://doi.org/10.1093/jnci/93.16.1246
• Soubéran, A., & Tchoghandjian, A. (2020). Practical Review on Preclinical Human 3D Glioblastoma Models: Advances and Challenges for Clinical Translation. Cancers, 12(9), 1–21. https://doi.org/10.3390/CANCERS12092347
• Srividya, M. R., Thota, B., Shailaja, B. C., Arivazhagan, A., Thennarasu, K., Chandramouli, B. A., Hegde, A. S., & Santosh, V. (2011). Homozygous 10q23/PTEN deletion and its impact on outcome in glioblastoma: a prospective translational study on a uniformly treated cohort of adult patients. Neuropathology : Official Journal of the Japanese Society of Neuropathology, 31(4), 376–383. https://doi.org/10.1111/J.1440-1789.2010.01178.X
• Stoyanov, G. S., Dzhenkov, D., Ghenev, P., Iliev, B., Enchev, Y., & Tonchev, A. B. (2018a). Cell biology of glioblastoma multiforme: from basic science to diagnosis and treatment. Medical Oncology (Northwood, London, England), 35(3). https://doi.org/10.1007/S12032-018-1083-X
• Stoyanov, G. S., Dzhenkov, D., Ghenev, P., Iliev, B., Enchev, Y., & Tonchev, A. B. (2018b). Cell biology of glioblastoma multiforme: from basic science to diagnosis and treatment. Medical Oncology (Northwood, London, England), 35(3). https://doi.org/10.1007/S12032-018-1083-X
• Sun, N., Meng, X., Liu, Y., Song, D., Jiang, C., & Cai, J. (2021). Applications of brain organoids in neurodevelopment and neurological diseases. Journal of Biomedical Science 2021 28:1, 28(1), 1–16. https://doi.org/10.1186/S12929-021-00728-4
• Takahashi, M., Miki, S., Fujimoto, K., Fukuoka, K., Matsushita, Y., Maida, Y., Yasukawa, M., Hayashi, M., Shinkyo, R., Kikuchi, K., Mukasa, A., Nishikawa, R., Tamura, K., Narita, Y., Hamada, A., Masutomi, K., & Ichimura, K. (2019). Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts. Cancer Science, 110(7), 2247. https://doi.org/10.1111/CAS.14067
• Tan, A. C., Ashley, D. M., López, G. Y., Malinzak, M., Friedman, H. S., & Khasraw, M. (2020a). Management of glioblastoma: State of the art and future directions. CA: A Cancer Journal for Clinicians, 70(4), 299–312. https://doi.org/10.3322/CAAC.21613
• Tan, A. C., Ashley, D. M., López, G. Y., Malinzak, M., Friedman, H. S., & Khasraw, M. (2020b). Management of glioblastoma: State of the art and future directions. CA: A Cancer Journal for Clinicians, 70(4), 299–312. https://doi.org/10.3322/CAAC.21613
• Tatla, A. S., Justin, A. W., Watts, C., & Markaki, A. E. (2021). A vascularized tumoroid model for human glioblastoma angiogenesis. Scientific Reports, 11(1), 19550. https://doi.org/10.1038/S41598-021-98911-Y
• Tsang, L. L. H., Farmer, P. B., Gescher, A., & Slack, J. A. (1990). Characterisation of urinary metabolites of temozolomide in humans and mice and evaluation of their cytotoxicity. Cancer Chemotherapy and Pharmacology, 26(6), 429–436. https://doi.org/10.1007/BF02994094
• Uddin, M. S., Mamun, A. Al, Alghamdi, B. S., Tewari, D., Jeandet, P., Sarwar, M. S., & Ashraf, G. M. (2020). Epigenetics of glioblastoma multiforme: From molecular mechanisms to therapeutic approaches. Seminars in Cancer Biology. https://doi.org/10.1016/J.SEMCANCER.2020.12.015
• Van Den Bent, M. J., Gao, Y., Kerkhof, M., Kros, J. M., Gorlia, T., Van Zwieten, K., Prince, J., Van Duinen, S., Sillevis Smitt, P. A., Taphoorn, M., & French, P. J. (2015). Changes in the EGFR amplification and EGFRvIII expression between paired primary and recurrent glioblastomas. Neuro-Oncology, 17(7), 935–941. https://doi.org/10.1093/NEUONC/NOV013
• Weiswald, L. B., Bellet, D., & Dangles-Marie, V. (2015). Spherical Cancer Models in Tumor Biology. Neoplasia (New York, N.Y.), 17(1), 1. https://doi.org/10.1016/J.NEO.2014.12.004
• 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., Nag, S. (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
• Wen, P. Y., Schiff, D., Cloughesy, T. F., Raizer, J. J., Laterra, J., Smitt, M., Wolf, M., Oliner, K. S., Anderson, A., Zhu, M., Loh, E., & Reardon, D. A. (2011). A phase II study evaluating the efficacy and safety of AMG 102 (rilotumumab) in patients with recurrent glioblastoma. Neuro-Oncology, 13(4), 437–446. https://doi.org/10.1093/NEUONC/NOQ198
• Wick, W., Gorlia, T., Bady, P., Platten, M., Van Den Bent, M. J., Taphoorn, M. J. B., Steuve, J., Brandes, A. A., Hamou, M. F., Wick, A., Kosch, M., Weller, M., Stupp, R., Roth, P., Golfinopoulos, V., Frene, J. S., Campone, M., Ricard, D., Marosi, C., Hegi, M. E. (2016). Phase II Study of Radiotherapy and Temsirolimus versus Radiochemotherapy with Temozolomide in Patients with Newly Diagnosed Glioblastoma without MGMT Promoter Hypermethylation (EORTC 26082). Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 22(19), 4797–4806. https://doi.org/10.1158/1078-0432.CCR-15-3153
• Wong, C. W., Han, H. W., Tien, Y. W., & Hsu, S. hui. (2019). Biomaterial substrate-derived compact cellular spheroids mimicking the behavior of pancreatic cancer and microenvironment. Biomaterials, 213. https://doi.org/10.1016/J.BIOMATERIALS.2019.05.013
• Xu, C., Wu, X., & Zhu, J. (2013). VEGF promotes proliferation of human glioblastoma multiforme stem-like cells through VEGF receptor 2. TheScientificWorldJournal, 2013. https://doi.org/10.1155/2013/417413
• Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G. J., Friedman, H., Friedman, A., Reardon, D., Herndon, J., Kinzler, K. W., Velculescu, V. E., Vogelstein, B., & Bigner, D. D. (2009). IDH1 and IDH2 Mutations in Gliomas. The New England Journal of Medicine, 360(8), 765. https://doi.org/10.1056/NEJMOA0808710
• Zeng, A., Hu, Q., Liu, Y., Wang, Z., Cui, X., Li, R., Yan, W., & You, Y. (2015). IDH1/2 mutation status combined with Ki-67 labeling index defines distinct prognostic groups in glioma. Oncotarget, 6(30), 30232. https://doi.org/10.18632/ONCOTARGET.4920
• Zhang, C., Jin, M., Zhao, J., Chen, J., & Jin, W. (2020). Organoid models of glioblastoma: advances, applications and challenges. American Journal of Cancer Research, 10(8), 2242. /pmc/articles/PMC7471358/
• Zhao, Q., Shi, X., Xie, Y., Huang, J., BenShia, C., & Ma, S. (2015). Combining multidimensional genomic measurements for predicting cancer prognosis: observations from TCGA. Briefings in Bioinformatics, 16(2), 291–303. https://doi.org/10.1093/BIB/BBU003
• Zhao, W., Luo, Y., Li, B., & Zhang, T. (2016). Tumorigenic lung tumorospheres exhibit stem-like features with significantly increased expression of CD133 and ABCG2. Molecular Medicine Reports, 14(3), 2598–2606. https://doi.org/10.3892/MMR.2016.5524
• Zheng, H., Ying, H., Yan, H., Kimmelman, A. C., Hiller, D. J., Chen, A. J., Perry, S. R., Tonon, G., Chu, G. C., Ding, Z., Stommel, J. M., Dunn, K. L., Wiedemeyer, R., You, M. J., Brennan, C., Wang, Y. A., Ligon, K. L., Wong, W. H., Chin, L., & DePinho, R. A. (2008). p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature, 455(7216), 1129–1133. https://doi.org/10.1038/NATURE07443
• Zhu, H., Wang, H., Huang, Q., Liu, Q., Guo, Y., Lu, J., Li, X., Xue, C., & Han, Q. (2018). Transcriptional Repression of p53 by PAX3 Contributes to Gliomagenesis and Differentiation of Glioma Stem Cells. Frontiers in Molecular Neuroscience, 11. https://doi.org/10.3389/FNMOL.2018.00187