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Tumor Discovery Understanding glioblastoma invasion and therapy

Furthermore, intracranial tumors can cause T-cells to mass but function as the cornerstone of tumorigenesis
be sequestered within the bone marrow, and significant and therapeutic resistance in GBM. 175-178 GBMSCs are
portions of GBM patients exhibit profound systemic fundamentally defined by the capacity to self-renew
baseline lymphopenia that can be further exacerbated by and the ability to differentiate into a heterogeneous
treatment. 167,168 Thus far, attempts to target GBM’s intrinsic complement of progeny cells. Thus, GBMSC clones
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immunosuppressive mechanisms therapeutically have been occupy the multipotent apex of the GBM cellular hierarchy
largely unsuccessful. Importantly, efforts to develop and exhibit substantial epigenetic and transcriptional
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new immunotherapies in GBM must carefully balance plasticity that allows them to evade apoptosis. 180,181 Notably,
increases in tumor-associated immune activity with the GBMSCs can robustly activate DNA damage response
need to maintain physiologic ICP. 158 pathways (178), autophagy, and high expression of drug
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efflux transporters. 183
9.3. Cellular heterogeneity
It remains unclear whether GBMSCs arise from
GBM also exhibits significant intratumoral heterogeneity acquired mutations in normal neural stem cells (NSCs)
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that is attributable to genetic, epigenetic, developmental, or develop through dedifferentiation of more terminally
and microenvironmental variation. Single-cell RNA differentiated mutant glia, but GBMSCs and NSCs
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sequencing analyses demonstrate that mixed populations share many biological features that underlie the clinical
of classical, mesenchymal, and pro-neural cells routinely difficulties posed by GBMSCs. For example, GBMSCs reside
co-exist within individual GBM tumors and that in specific oncogenic niches that closely mirror neurogenic
predominating TCGA subtype can vary significantly niches. Interestingly, adult gliomas predominantly
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between different regions of a single tumor. Each develop adjacent to or in direct contact with the lateral
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TCGA subtype is associated with a different tumor ventricular system, where the subventricular zone of adult
microenvironment immune signature. Individual neurogenesis also resides. GBMSCs and NSCs express
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GBMs also harbor at least four different highly plastic similar markers, such as CD133, Nestin, oligodendrocyte
neural-progenitor-like cellular states that interconvert in transcription factor 2 (OLIG2), and GFAP. They also rely
response to microenvironmental changes. Remarkably, on the activation of intersecting growth pathways such
10
xenografts exclusively seeded from any single progenitor as Notch, epidermal growth factor, and fibroblast growth
cell state consistently generate tumors comprised of all factor. The counterbalancing pathways that restrain
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four signatures. 10 growth in NSCs are notably absent or dysregulated in
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The clinical targetability of identified GBM diversity GBMSCs. Both GBMSCs and NSCs also form a three-
remains unrealized, but it is well-recognized that clonal dimensional neurosphere in vitro and give rise to fast-
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diversity and plasticity contribute significantly to GBM cycling and highly migratory progenitors. GBMSCs also
therapy resistance. Cancer therapies provide selective exhibit activity-dependent growth that includes significant
pressure that ultimately enhances the outgrowth of downregulation of inhibitory γ-aminobutyric acid
treatment-resistant clones. In addition, both TMZ and receptors and upregulation of glutamate signaling. 187,188
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RT are mutagenic treatments that can cause mutations Understanding normal NSC function may highlight
that further drive GBM clonal diversity. For example, targetable dysfunction of similar pathways in GBMSCs.
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hypermutation in GBM recurrence is only observed
after TMZ treatment. 171,172 Recurrent tumors can exhibit 10. Concluding remarks
both divergent evolution – in which the recurrent The glioma research community has increasingly
tumor is comprised of clones absent from the primary acknowledged that a lack of integration between cancer
mass – and linear evolution, in which the predominant biology and neuroscience investigations has hindered
clones at recurrence existed in the original mass. progress in understanding glioma pathobiology.
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The predominating TCGA bulk expression subtype Correspondingly, the glioma research framework is
also commonly differs between primary and recurrent steadily evolving toward a collective understanding that
tumors, with an observable predominance of the meaningful progress in treating diffuse glioma will require
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mesenchymal subtype at recurrence, suggesting that coordinated collaboration between cancer biologists and
therapy induces genetic changes that converge on common neuroscientists. These emerging collaborative efforts
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pathways. aim to understand how the unique physiologic properties
of the CNS fundamentally shape glioma development and
9.4. Stem-like cell enrichment aggression. Such studies now serve as the foundation for
GBM stem-like cells are a slow-cycling population of GBM the burgeoning field of cancer neuroscience that has rapidly
cells that represent a small percentage of the overall tumor expanded beyond gliomas to additionally ignite diverse

Volume 4 Issue 2 (2025) 32 doi: 10.36922/td.8578