Multilayered Heterogeneity of Glioblastoma Stem Cells: Biological and Clinical Significance
Glioblastoma is a primary tumor of the brain with a poor prognosis. Pathological examination shows that this disease is characterized by intra-tumor morphological heterogeneity, while numerous and ongoing genomic analysis reveals multiple layers of hetero
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Multilayered Heterogeneity of Glioblastoma Stem Cells: Biological and Clinical Significance Daniel V. Brown, Stanley S. Stylli, Andrew H. Kaye, and Theo Mantamadiotis
Abstract Glioblastoma is a primary tumor of the brain with a poor prognosis. Pathological examination shows that this disease is characterized by intra-tumor morphological heterogeneity, while numerous and ongoing genomic analysis reveals multiple layers of heterogeneity. Intra-tumor and patient-to-patient heterogeneity is underpinned by cellular, genetic, and molecular heterogeneity, which is thought to be key determinants of time to tumor recurrence and resistance to therapy. The key cell type believed to contribute to the establishment and ongoing evolution of tumor heterogeneity is a glioma stem cell (GSC) subpopulation. In this chapter, we review, highlight, and discuss controversies and clinical relevance of glioblastoma heterogeneity and its cellular basis. Characterization of how cancer stem cells (CSCs) behave is important in understanding how tumors are initiated and how they recur following initial treatment. Keywords Glioblastoma · GBM · Glioma · Brain cancer · Astrocytoma · Stem cells · GSC · Heterogeneity · Plasticity · Clonal · Subclonal
D. V. Brown Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia S. S. Stylli · A. H. Kaye Department of Surgery, The University of Melbourne, Parkville, VIC, Australia Department of Neurosurgery, The Royal Melbourne Hospital, Parkville, VIC, Australia T. Mantamadiotis (*) Department of Surgery, The University of Melbourne, Parkville, VIC, Australia Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC, Australia e-mail: [email protected]
© Springer Nature Switzerland AG 2019 A. Birbrair (ed.), Stem Cells Heterogeneity in Cancer, Advances in Experimental Medicine and Biology 1139, https://doi.org/10.1007/978-3-030-14366-4_1
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1.1 Introduction The original name of the major grade IV astrocytoma, glioblastoma multiforme (GBM), describes the morphological diversity of tumor cells in histological specimens. Glioblastoma is a primary cancer of the central nervous system with limited therapeutic choices available and continues to be one of the most lethal types of tumors (Kirkpatrick et al. 2017). The diagnosis of GBM is made difficult by this heterogeneity in biopsied material (Jung et al. 2011). In addition to this gross intra-tumoral heterogeneity, genome-wide analysis of spatially distinct tumor pieces and single cells has uncovered extensive genetic diversity (Gerlinger et al. 2012; McGranahan and Swanton 2012; Sottoriva et al. 2013). Understanding the extent and source of this heterogeneity is the key to understanding why resistant subclones emerge and therapy fails for the cancer patient. The current standard of post-surgery care is radiotherapy, in combination with the oral chemotherapeutic, temozolomide (TMZ). Due to the anatomical location and the diffuse nature of GBM, complete re
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