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Tumor Discovery Understanding glioblastoma invasion and therapy

cells likely contributes to the observed survival advantage, The selectivity of the BBB significantly limits the
as radiotherapy-induced cellular toxicity requires increases number and diversity of therapeutic agents that can be
in intracellular calcium levels. TM-connected cells extend used to treat CNS pathology, including GBM. While the
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new TMs toward the surgical resection lesions and into the GBM disease process notoriously disrupts the BBB, this
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resection bed within 3 days of tumor debulking surgery. breakdown is far from being homogenous or complete.
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Following resection, the increase in tumor cell density Imaging is regularly used in GBM care to identify areas
within the lesion significantly outpaced the increase in of BBB breakdown, which enhances upon administration
tumor cell density in perilesional and distant brain tissue, of a gadolinium contrast agent. However, many studies
and the invasive velocity was significantly directed toward demonstrate that the GBM tumor burden extends far
the lesion. GAP-43 deficient tumors did not robustly beyond this arbitrary imaging margin and into areas that
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polymerize TMs toward the resection cavity and exhibited remain sheltered by an intact BBB. In addition, GBM
similar lesional density increases, suggesting that TMs may causes BBB to be permeable by destroying the integrity
facilitate the coordinated repopulation of surgical lesions. of the neuro vasculature, not by enhancing controlled
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This may explain why GBMs so commonly recur within diffusion mechanisms. The resultant indiscriminate
2 cm of the resection cavity margin despite aggressive leakage of fluid and ions through compromised vessels
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regional radiation targeting. Genetic targeting of TM elevates the tissue oncotic pressure and causes edema that
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networks in GBM PDX models decreased tumor burden, physically resists intratumoral drug penetration. The
tumor invasion, and repopulation of surgical resection BBB remains a significant hindrance to effective GBM
cavities while significantly increasing overall survival. 136,147 treatment. Hence, developing strategies to circumvent this
TMs serve as an excellent example of the ways in which the barrier is an area of concentrated research effort.
characterization of GBM pathophysiology is increasingly 9.2. The immune-cold GBM microenvironment
intersecting with developmental neuroscience.
The physical confines of the cranial vault significantly limit
9. Additional mechanisms of GBM therapy the amount of inflammation (and associated swelling)
resistance that the CNS can accommodate while still maintaining
physiologic ICP. This mechanism underlies the evolution
9.1. The BBB of existing anatomic and cellular mechanisms that tightly
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The BBB is a physical and molecular feature of the CNS control immune access and function within the CNS.
microvasculature that significantly prevents circulating Anatomically, the BBB significantly restricts circulating
ions, molecules, and cells from entering CNS tissue. immune cells from entering the CNS tissue. While a limited
Physically, CNS capillary beds are non-fenestrated, with number of peripheral immune cells are capable of entering
endothelial cells that form continuous tight junctions. the CNS under healthy conditions, baseline immune
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This blocks paracellular solute diffusion and forces all surveillance within the CNS is predominantly executed
agents to cross through endothelial cells to gain access to by resident microglia, which account for approximately
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the CNS. However, passage through CNS endothelial 10% of CNS cells. This reality notably limits not only
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cells is also biochemically limited. CNS endothelial cells do inherent anti-GBM immune activity but also anti-GBM
not readily pinocytose molecules, and transcellular solute immunotherapeutics. 158
movement is, therefore, very difficult. CNS endothelial CNS cells also use molecular mechanisms to
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cells additionally express luminal efflux pumps that limit intra-axial inflammation. The normal brain
actively export the majority of molecules that successfully basally expresses and secretes high levels of the anti-
pass through the endothelial membrane. The barrier inflammatory cytokines transforming growth factor-β
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functions of CNS endothelial cells are further reinforced and interleukin-10, which are further upregulated in the
by (i) the inner vascular basement membrane and the context of intracranial tumor development. Microglia
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outer parenchymal basement membrane (glial limitans), and infiltrating macrophages make up the majority of
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(ii) pericytes, which are embedded in the vascular brain tumor-associated immune cells. In GBM, tumor-
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basement membrane and control the diameter of capillary associated macrophages predominantly exhibit an M1/
vessels, regulate angiogenesis, deposit ECM, and control pro-tumor phenotype that poorly activates the T-cell
CNS immune cell trafficking, 153,154 and (iii) astrocytic end response. 162,163 Glioma cells also actively recruit regulatory
feet that link neuronal activity with blood vessel diameter T-cells and suppress T-cell activity by secreting indolamine
and flow. In the normal brain, these features collectively 2,3-dioxygenase. 164,165 Thus, the population of tumor-
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make up the neurovascular unit and block approximately infiltrating lymphocytes that do successfully infiltrate
98% of blood-soluble molecules from accessing the CNS. 156 the tumor commonly exhibit an exhausted phenotype.
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Volume 4 Issue 2 (2025) 31 doi: 10.36922/td.8578