Current Advances in The Molecular and Histopathological Aspects of Glioblastoma Multiforme: A Review

Abstract

Glioblastoma multiforme represents the most aggressive of all primary brain neoplasms in adults, characterized by extremely poor prognosis and limited therapeutic interventions. This paper reviews current knowledge regarding molecular and histopathological insights into GBM. Besides demonstrating necrosis and microvascular proliferation with high cellularity- which have made it a diagnosis of classification and clinical behavior- at the molecular level this tumor is unleashed by diverse genetic and epigenetic changes. This includes alterations in IDH mutation, PTEN loss, EGFR amplification as well as MGMT promoter methylation controlling tumor progression as well as treatment response to therapies. Further, therapeutic resistance arising due to the heterogeneity of cells within tumors plus associated recurrence has emphasized another dimension requiring focus in research studies regarding treatment options for cancer anywhere between baseline laboratory benches up through human patient applications. Additionally included are immune cell components among others such as extracellular matrix elements plus signaling pathways promoting invasion/survival processes inside mass development regions resulting finally to Spatial Transcriptomics-based single-cell sequencing mapping out spatial complexity yet providing directions towards potential biomarkers along with precise therapy choices. Progress does not dissuade the fact that GBM carries such a forlorn prognosis, hence the need for integrated research approaches that would incorporate histological, molecular, and microenvironmental information. It is, therefore, imperative to underscore comprehensive tumor profiling in guiding future therapeutic strategies toward clinical outcome improvement.

Keywords:

glioblastoma multiforme, IDH mutation, PTEN loss, EGFR amplification, MGMT

References

Brat, D. J., Verhaak, R. G., Aldape, K. D., Yung, W. K. A., Salama, S. R., Cooper, L. A. D., ... & Cancer Genome Atlas Research Network. (2015). Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. New England Journal of Medicine, 372(26), 2481–2498. https://doi.org/10.1056/NEJMoa1402121

Brennan, C. W., Verhaak, R. G. W., McKenna, A., Campos, B., Noushmehr, H., Salama, S. R., ... & Cancer Genome Atlas Research Network. (2013). The somatic genomic landscape of glioblastoma. Cell, 155(2), 462–477. https://doi.org/10.1016/j.cell.2013.09.034

Cancer Genome Atlas Research Network. (2008). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature, 455(7216), 1061–1068. https://doi.org/10.1038/nature07385

Chakravarti, A., Zhai, G., Suzuki, Y., Sarkesh, S., Black, P. M., Muzikansky, A., & Loeffler, J. S. (2002). The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. Journal of Clinical Oncology, 20(13), 3021–3027. https://doi.org/10.1200/JCO.2002.10.072

Combs, S. E., Debus, J., & Schulz-Ertner, D. (2014). Hypofractionated radiotherapy and stereotactic radiotherapy for glioblastomas. Journal of Neuro-Oncology, 113(2), 185–192. https://doi.org/10.1007/s11060-013-1091-9

Eckel-Passow, J. E., Lachance, D. H., Molinaro, A. M., Walsh, K. M., Decker, P. A., Sicotte, H., ... & Jenkins, R. B. (2015). Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. New England Journal of Medicine, 372(26), 2499–2508. https://doi.org/10.1056/NEJMoa1407279

Giese, A., Bjerkvig, R., Berens, M. E., & Westphal, M. (2003). Cost of migration: Invasion of malignant gliomas and implications for treatment. Journal of Clinical Oncology, 21(8), 1624–1636. https://doi.org/10.1200/JCO.2003.05.063

Hambardzumyan, D., Gutmann, D. H., & Kettenmann, H. (2016). The role of microglia and macrophages in glioma maintenance and progression. Nature Neuroscience, 19(1), 20–27. https://doi.org/10.1038/nn.4185

Hardee, M. E., & Zagzag, D. (2012). Mechanisms of glioma-associated neovascularization. The American Journal of Pathology, 181(4), 1126–1141. https://doi.org/10.1016/j.ajpath.2012.06.030

Hegi, M. E., Diserens, A. C., Gorlia, T., Hamou, M. F., de Tribolet, N., Weller, M., ... & 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/NEJMoa043331

Jackson, C. M., Lim, M., & Drake, C. G. (2019). Immunotherapy for brain cancer: recent progress and future promise. Clinical Cancer Research, 20(14), 3651–3659. https://doi.org/10.1158/1078-0432.CCR-13-1059

Kaur, H., Arora, M., Yarlagadda, M. S., & Singh, J. (2020). Role of microRNAs in the regulation of glioblastoma multiforme: new insights into therapeutic perspectives. Gene, 740, 144518. https://doi.org/10.1016/j.gene.2020.144518

Lathia, J. D., Mack, S. C., Mulkearns-Hubert, E. E., Valentim, C. L., & Rich, J. N. (2015). Cancer stem cells in glioblastoma. Genes & Development, 29(12), 1203–1217. https://doi.org/10.1101/gad.261982.115

Lim, M., Xia, Y., Bettegowda, C., & Weller, M. (2018). Current state of immunotherapy for glioblastoma. Nature Reviews Clinical Oncology, 15(7), 422–442. https://doi.org/10.1038/s41571-018-0003-5

Louis, D. N., Perry, A., Wesseling, P., Brat, D. J., Cree, I. A., Figarella-Branger, D., ... & Ellison, D. W. (2021). The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro-Oncology, 23(8), 1231–1251. https://doi.org/10.1093/neuonc/noab106

Mellai, M., Piazzi, A., Caldera, V., Annovazzi, L., Monzeglio, O., Cassoni, P., & Schiffer, D. (2018). A review of epithelioid glioblastoma: Molecular and histopathological features. Pathology - Research and Practice, 214(11), 1595–1601. https://doi.org/10.1016/j.prp.2018.07.030

Neftel, C., Laffy, J., Filbin, M. G., Hara, T., Shore, M. E., Rahme, G. J., ... & Suvà, M. L. (2019). An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell, 178(4), 835–849.e21. https://doi.org/10.1016/j.cell.2019.06.024

Noushmehr, H., Weisenberger, D. J., Diefes, K., Phillips, H. S., Pujara, K., Berman, B. P., ... & Laird, P. W. (2010). Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell, 17(5), 510–522. https://doi.org/10.1016/j.ccr.2010.03.017

Ostrom, Q. T., Cioffi, G., Gittleman, H., Patil, N., Waite, K., Kruchko, C., & Barnholtz-Sloan, J. S. (2020). CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2013–2017. Neuro-Oncology, 22(12_suppl_2), iv1–iv96. https://doi.org/10.1093/neuonc/noaa200

Patel, A. P., Tirosh, I., Trombetta, J. J., Shalek, A. K., Gillespie, S. M., Wakimoto, H., ... & Regev, A. (2014). Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science, 344(6190), 1396–1401. https://doi.org/10.1126/science.1254257

Poon, C. C., Sarkar, S., Yong, V. W., & Kelly, J. J. P. (2017). Glioblastoma-associated microglia and macrophages: targets for therapies to improve prognosis. Brain, 140(6), 1548–1560. https://doi.org/10.1093/brain/awx046

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.2017.02.009

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.2017.02.009

Ravi, V. M., Will, P., Kueckelhaus, J., Joseph, K., & Neidert, N. (2022). Spatial biology of glioblastoma: Emerging insights into tumor heterogeneity and therapy resistance. Frontiers in Oncology, 12, 835206. https://doi.org/10.3389/fonc.2022.835206

Sottoriva, A., Spiteri, I., Piccirillo, S. G., Touloumis, A., Collins, V. P., Marioni, J. C., ... & Tavaré, S. (2013). Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proceedings of the National Academy of Sciences, 110(10), 4009–4014. https://doi.org/10.1073/pnas.1219747110

Strobl, M. A. R., Dhruv, H. D., Mason, D. M., Koschmann, C., & Berens, M. E. (2022). Spatial biology and immuno-oncology of brain tumors. Frontiers in Oncology, 12, 826587. https://doi.org/10.3389/fonc.2022.826587

Stupp, R., Mason, W. P., van den Bent, M. J., Weller, M., Fisher, B., Taphoorn, M. J. B., ... & Mirimanoff, R. O. (2009). Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England Journal of Medicine, 352(10), 987–996. https://doi.org/10.1056/NEJMoa043330

Tan, A. C., Ashley, D. M., López, G. Y., Malinzak, M., Friedman, H. S., & Khasraw, M. (2020). 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

Tanaka, S., Louis, D. N., Curry, W. T., Batchelor, T. T., & Dietrich, J. (2013). Diagnostic and therapeutic avenues for glioblastoma: No longer a dead end? Nature Reviews Clinical Oncology, 10(1), 14–26. https://doi.org/10.1038/nrclinonc.2012.204

Verhaak, R. G. W., Hoadley, K. A., Purdom, E., Wang, V., Qi, Y., Wilkerson, M. D., ... & Hayes, D. N. (2010). Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell, 17(1), 98–110. https://doi.org/10.1016/j.ccr.2009.12.020

Wesseling, P., & Capper, D. (2018). WHO 2016 Classification of gliomas. Neuropathology and Applied Neurobiology, 44(2), 139–150. https://doi.org/10.1111/nan.12432

Xie, Y., Bergström, T., Jiang, Y., Johansson, P., Marinescu, V. D., Lindberg, N., ... & Smits, A. (2022). The human glioblastoma cell culture resource: Validated cell models representing all molecular subtypes. EBioMedicine, 83, 104229. https://doi.org/10.1016/j.ebiom.2022.104229

Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., ... & Kinzler, K. W. (2009). IDH1 and IDH2 mutations in gliomas. New England Journal of Medicine, 360(8), 765–773. https://doi.org/10.1056/NEJMoa0808710

Zhou, M., Wang, H., Zhu, L., & Fang, Y. (2017). Ki-67 and PCNA expression and their correlation with grading and prognosis in glioma. Journal of Clinical Neuroscience, 38, 101–105. https://doi.org/10.1016/j.jocn.2016.11.029