12/17/2020 12:24:32 PM
Is Neural Stem Cell therapy The End of Glioblastoma Multiform Life Story?
Glioma is the most common form of central nervous system (CNS) neoplasm that originates from glial cells (astrocytes, oligodendrocyte cells). Grade IV astrocytoma termed glioblastoma multiform (GBM), is one of the most common, severe, and aggressive forms of malignant glioma known to man. Despite intensive therapies, the median survival has remained approximately 15 months. (1-4)
One of the major challenges to the treatment of GBM is the blood-brain barrier (BBB). This barrier is a highly specialized structure in the brain. It acts as a selective physical barrier for maintaining the homeostasis of the brain by regulating immune cell transport, passive diffusion of chemicals, and etc. physiologically, the BBB selectively allows only certain substance to pass between brain tissue and blood; therefore the BBB protects the brain from possible toxic elements and also prevents drugs from getting into the tumor site, so few amounts of the drugs can get to the site of malignancy. (4–10)
Importantly, as glioblastoma has an aggressive nature through infiltration and invasion, surgical resection is frequently unable to remove all of the glioblastoma foci. This is supported by the fact that most patients die within a year from a reoccurring secondary tumor foci near the resected area. (11)
Fortunately, research has shown stem cells can cross the blood-brain barrier(12). Some other studies found that neural stem cells (NSCs) can reach tumor foci, meaning they have tumor tropism. (13)
It seems that tumor tropism ability of NSC is based on tissue hypoxia caused by tumor cells activity, During hypoxia, glioblastoma cells up-regulate the expression of several chemo attractants and pro-angiogenic factors, such as hypoxia-inducible factor-1 alpha and its downstream targets stromal-cell-derived factor-1 and vascular endothelial growth factor, that attract stem cells to migrate towards the tumor foci.(14,15) Also, Chemokines expressed by glioma stem cells, such as vascular endothelial growth factor, epidermal growth factor, and basic fibroblast growth factor, contributed to the hypoxia-enhanced NSC-tropic migration. (16)
According to the explanations, it can be concluded that stem cells (especially NSC) can be used to treat GBM patients.
The route of delivery of NSC is so essential because the number of NSCs that can reach the tumor foci is dependent on the tumor delivery routes; now, what are the routes of delivery of stem cells to the patient’s body?
In murine models, GBM injection of NSCs, contralateral to the tumor site, leads to migration and efficient delivery of therapy(20), but the problem of this route of delivery to human patients is its invasive nature and the trouble repeating injections;. At the same time, intravenous administration of NSCs can still cause migration to the tumor site, the efficacy of this route remains controversial. Recently, as a way to curtail these limitations, it has been demonstrated that NSC can be delivered intra-nasally and efficiently migrate to the tumor foci. The intranasal route allows to repeat administration and has higher amounts of NSC migration(21)
In the end, it must be expressed that Stem cell vectors may, by their capacity to target infiltrative tumor cells, provide a powerful treatment modality for GBM. However, many issues, including the choice of cell vector and the therapeutic transgene, the optimal route of administration, and biosafety, need to be addressed. (22)
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