Gliomagenesis and the use of neural stem cells in brain tumor treatment

Abstract

The role of neural stem cells (NSCs) in both the physiological and pathological processes in the brain has been refined through recent studies within the neuro-oncological field. Alterations in NSC regulatory mechanisms may be fundamental for the development and progression of malignant gliomas. A subpopulation of cells within the tumor known as brain tumor stem cells (BTSCs) have been shown to share key properties with NSCs. The BTSC hypothesis has significantly contributed to a potential understanding as to why brain tumors hold such dismal prognosis. On the other hand, the normal NSCs possess the capacity to migrate extensively towards the tumor bulk as well as to lingering neoplastic regions of the brain. The tropism of NSCs towards brain tumors may provide an additional tool for the treatment of brain cancer. The creation of potential therapies through the use of NSCs has been studied and includes the delivery of gene products to specific locations of the central nervous system selectively targeting malignant brain tumor cells and maximizing the efficiency of their delivery. Here, the proposed mechanisms of how brain tumors emerge, the molecular pathways interrupted in NSC pathogenesis and the most recent preclinical results in the use of NSCs for glioma treatment are reviewed.

Fig. (1)

Normal NSCs self-renew and give rise to neural progenitor cells which differentiate into three neuronal lineages of the brain – neurons, astrocytes and oligodendrocytes (shown by black arrows). Epigenetic and/or genetic alterations in NSCs, progenitor cells, or mature cells through a dedifferentiation process may lead to transformation into BTSCs that are capable of self-renewing and of giving rise to brain tumors (shown by red arrows).

Fig. (2)

Systemic injections of genetically engineered NSCs migrate to the tumor site and secrete anti-neoplastic compounds such as pro-drug activating enzymes, viral vectors and immune response modulators. These compounds may target brain tumors by blocking DNA replication, by boosting an immune response or by inducing apoptosis of tumor cells.

Fig. (3)

Intravascular injection in glioma patients of NSCs labeled with nanoparticles in glioma patients are capable of migrating to the site of tumor. These cells can be visualized by MRI and may potentially be used to demarcate the periphery of the tumor. This allows not only for better distinction of the tumor margins but also provides surveillance of the engineered NSCs that are being used to deliver a given therapeutic agent.