**3. Future directions**

*2.4.3. iPSC*

218 Brain Tumors - An Update

[12, 13, 16, 26, 48].

*2.5.1. Cytokine-based therapy*

*2.5.2. Oncolytic virus therapy*

*2.5.3. Suicide gene therapy*

shown in experimental gliomas [29, 58].

iPSCs can be established directly from adult cells. Four specific genes (Oct3/4, c-myc, Sox2, and Klf4) encoding transcription factors could convert adult cells into iPSCs. iPSCs hold great promise in the field of regenerative medicine. iPSCs can also overcome some problems such as ethical concerns and immune rejection. Recently, iPSCs can be established without c-myc and can prevent teratoma formation [46, 49]. An episomal vector is used for the transduction to prevent chromosomal insertion that cannot be accomplished by viral and plasmid vectors [50, 77]. In addition, iPSCs can be cultured under the feeder-free condition, and laminin-511 supports the stable culture of iPSCs [19]. The efficiency to culture iPSCs has been rapidly improved.

The first clinical trial for macular degeneration using autologous-induced stem cell-derived retinal cells has been completed in Japan in 2015. The feasibility of using iPSCs has been shown [38]. A clinical trial for Parkinson's disease is expected to use iPSCs in the near future

All types of stem cells have two important effects. First is the trophic effect, that is, supplying various nutrients and tissue-protective cytokines, and the second is the repairing effect, that is, identifying the damaged area and differentiating to an organized tissue after homing [23, 30].

IL-4-producing NSCs showed powerful antitumor effects compared with that of the virusmediated delivery of IL-4 [7]. In addition, NSCs and MSCs that produce IL-2, IL-7, IL-12, and IL-23 have been evaluated for brain tumor [15, 17, 47, 61, 78, 79]. TNF-related apoptosis-inducing ligand (TRAIL) triggers caspase-8-dependent apoptosis. The tumor-specific therapeutic effects of TRAIL-producing NSCs, MSCs, and ESCs-derived astrocytes have been

Some studies showed the advantages of stem cells (NSCs and MSCs) to deliver replicating HSV and adenovirus because stem cells suppress the host immune response of the virus. In addition, stem cell therapy has become a promising approach because it can deliver viruses at further distance within the invaded malignant glioma [3, 5, 21, 68]. Actually, MSCs with replicating adenovirus showed that MSCs can suppress the immune response against the virus, which makes it possible to prolong viral activity and survival [4]. Some similar researches using NSCs with conditionally replicating HSV and adenovirus in preclinical studies were conducted [21].

Some reports showed that suicide gene therapy with HSVtk or CD using NSCs as cellular delivery vehicle could significantly prolong survival in animal models of brain tumor [28, 34, 37]. MSCs with HSVtk or CD were also used for the treatment of malignant glioma. Both NSCs

**2.5. Gene therapy using stem cells as delivery vehicle**

The treatment concept of gene therapy was appropriate for malignant glioma; however, viral vectors are not enough to cover the large invasion area. The migration ability of stem cells has been expected. Some types of stem cells can be established recently. However, a comparative analysis on which type of stem cell has the strongest migration ability and the tumoricidal effect is needed. In brain tumor, NSCs may be considered as the most effective cellular vehicle because of their affinity to the brain. iPSCs are attractive tools because NSCs could be efficiently differentiated from iPSCs. Gene therapy using stem cells as cellular delivery vehicles is expected to be further developed in the future.
