Malignant Cells Beyond the Tumor Core: The Non-Negligible Factor to Overcome the Refractory of Glioblastoma

Abstract

Background: Glioblastoma (GBM) is one of the most aggressive primary brain tumors in adults. Over 95% of GBM patients experience recurrence in the peritumoral brain tissue or distant regions, indicating the presence of critical factors in these areas that drive tumor recurrence. Current clinical treatments primarily focus on tumor cells from the tumor core (TC), while the role of neoplastic cells beyond the TC has been largely neglected.

Methods: We conducted a comprehensive review of existing literature and studies on GBM, focusing on the identification and characterization of questionable cells (Q cells). Advanced imaging techniques, such as diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET), were utilized to identify Q cells beyond the tumor core. We also analyzed the functional properties, cellular microenvironment, and physical characteristics of Q cells, as well as their implications for surgical resection.

Results: Our review revealed that Q cells exhibit unique functional attributes, including enhanced invasiveness, metabolic adaptations, and resistance mechanisms. These cells reside in a distinct cellular microenvironment and are influenced by physical properties such as solid stress and stiffness. Advanced imaging techniques have improved the identification of Q cells, enabling more precise surgical resection. Targeting Q cells in therapeutic strategies could significantly reduce the risk of GBM recurrence.

Conclusion: The presence of Q cells in the peritumoral brain zone (PBZ) and beyond is a critical factor in GBM recurrence. Current treatments, which primarily target tumor cells in the TC, are insufficient to prevent recurrence due to the neglect of Q cells. Future research should focus on understanding the mechanisms influencing Q cells and developing targeted therapies to improve patient outcomes.

Keywords: GBM; PBZ; SMR; imaging; microenvironment; physics.

FIGURE 1

Functional characterization of Q cells beyond the tumor core. Q cells that are situated beyond the CE zone possess particular functional attributes. PMT is capable of converting Q cells into more invasive subtypes of MES; furthermore, their invasive capability is enhanced by the overexpression of miR‐940, miR‐126, miR‐369‐5p, miR‐487b, PEA‐15, and BCL XL. In comparison to the TC microenvironment, the Q cell microenvironment is richer in a variety of fatty acids (including arachidonic acid, Adrenic acid, oleic acid, VLCFA, and PUFA). Glutamate release by Q cells can further stimulate GSH synthesis. Down‐regulation of glycolysis‐related genes in the PN subtype of Q cells results in weaker glycolysis than in TC tumor cells. Galectin‐1, GJB1, FGF1, and the CCL28/CCR10 axis, which are all upregulated, promote angiogenesis in the region containing Q cells. In the interim, Q cells facilitate the formation of tubular blood vessels through the promotion of proliferation of endothelial cells. By increasing Q cell self‐renewal capacity, high expression of MGMT and FADS2 can confer TMZ resistance; conversely, high expression of BCRP and P‐glycoprotein promotes drug efflux and TMZ resistance.

FIGURE 2

Influence of cellular microenvironment and physical properties on Q cells. The co‐localization of oligodendrocyte lineage cells, macrophages, and microglial cells in the PBZ is induced by the high expression of three microRNAs (miR‐219‐5p, miR‐219‐3p, and miR‐338‐3p); meanwhile, this co‐localization subsequently stimulates the expression of stemness genes in Q cells. Q cells' proliferation and migration are concurrently stimulated by interactions with microglia and astrocytes. High expression of CCL20, CSF3, and IL1b by Q cells induces lymphopenia as well as differentiation of the monocyte phenotype into a myelosuppressive phenotype, further contributing to the formation of an immunosuppressive microenvironment around Q cells. The mobility and migration of Q cells are facilitated by environmental attributes such as low solid stress and stiffness.