Implications of irradiating the subventricular zone stem cell niche

Abstract

Radiation therapy is a standard treatment for brain tumor patients. However, it comes with side effects, such as neurological deficits. While likely multi-factorial, the effect may in part be associated with the impact of radiation on the neurogenic niches. In the adult mammalian brain, the neurogenic niches are localized in the subventricular zone (SVZ) of the lateral ventricles and the dentate gyrus of the hippocampus, where the neural stem cells (NSCs) reside. Several reports showed that radiation produces a drastic decrease in the proliferative capacity of these regions, which is related to functional decline. In particular, radiation to the SVZ led to a reduced long-term olfactory memory and a reduced capacity to respond to brain damage in animal models, as well as compromised tumor outcomes in patients. By contrast, other studies in humans suggested that increased radiation dose to the SVZ may be associated with longer progression-free survival in patients with high-grade glioma. In this review, we summarize the cellular and functional effects of irradiating the SVZ niche. In particular, we review the pros and cons of using radiation during brain tumor treatment, discussing the complex relationship between radiation dose to the SVZ and both tumor control and toxicity.

Keywords: Brain tumor; Neural stem cells; Neurogenesis; Radiation; Subventricular zone.

Figure 1. Cell organization of the SVZ neurogenic niche

(A) Schematic representation of the SVZ in a coronal view of the mouse brain. The enlarged area depicts the cytoarchitecture of the neurogenic niche. (B) Electron microscopy image corresponding to the rodent SVZ in A. (C) Schematic representation of the SVZ in a coronal view of the human brain. The enlarged area depicts the four layers where the SVZ cells organize. (D) Electron microscopy image corresponding to the human SVZ in C. b, astrocyte-like cell; e, ependymal cell; Lv, lateral ventricle; o, oligodendrocytes. Scale bar 10 μm.

Figure 2. Tumorigenic role of the SVZ niche

Schematic representation of a coronal hemisection of the rodent brain, depicting the SVZ role on tumor formation. NSCs within the SVZ are potent tumor-initiating cells. Hypothetically, SVZ cells are able to migrate to other brain regions to originate a tumor mass.

Figure 3. Radiation disrupts the SVZ neurogenic niche

(A) Schematic representations of the rodent SVZ. In a pre-radiation condition the SVZ preserves its typical cell organization. Following radiation, the SVZ shows a notable depletion of fast proliferating precursors and neuroblasts. Some astrocytes remain after radiation and ependymal cells are not affected. Scale bar 10 μm.

Figure 4. Radiation is a frequent tool in the treatment of brain tumor patients

(A) MRI of a brain tumor patient before being treated. (B) MRI after brain tumor resection and four weeks post-radiation (60 Gy dose).