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Induced Neural Stem Cells - A Safe and Effective Means to Treat Brain Tumors?

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Review of “Therapeutically engineered induced neural stem cells are tumour-homing and inhibit progression of glioblastoma” from Nature Communications by Stuart P. Atkinson

Through the combination of tumor tropism and engineered delivery of anti-cancer therapeutics, neural stem cells (NSCs) represent an exciting anti-tumor strategy. One problem moving forward is the difficulty in harvesting human adult NSCs and the possible tumorigenicity of NSCs derived from the differentiation of pluripotent stem cells (PSCs). 

To obviate these problems, researchers from the laboratory of Shawn D. Hingtgen (University of North Carolina at Chapel Hill, USA) sought to assess the possibility of transdifferentiating fibroblasts directly into induced NSCs (iNSCs) to use in anti-tumor therapeutics [1]. Their new study, published in Nature Communications, suggests that engineered iNSCs may represent a safe and effective means to inhibit the progression of cancers of the central nervous system [2].

The transdifferentiation strategy used lentiviral vectors encoding Brn2, Sox2 and FoxG1 to convert fibroblasts to iNSCs. These cells proliferated, formed neurospheres, displayed expected NSCs markers (Nestin and Sox2), and demonstrated the ability to differentiate into astrocytes and neurons. The cells also survived for up to one month following transplantation into the mouse brain and migrated selectively towards glioblastoma multiforme (GBM) tumor cells in a co-culture assay (in vitro) and following transplantation into the brain (in vivo).

This all suggests that iNSCs could be the ideal cell to carry anti-tumor therapeutics and the authors tested this by engineering an iNSC line to express a secreted variant of the pro-apoptotic molecule tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL). This cell engineering did not alter any of the desired characteristics of the iNSCs, and release studies using a diagnostic variant of TRAIL demonstrated the stable and sustained release of cargo over 10 days in vitro. 

Excitingly, the TRAIL-laden iNSCs displayed efficient tumor cell killing effects in vitro at iNSC to cancer cell ratios of as little as 0.2:1, and in vivo where intracranial implantation of TRAIL-laden iNSCs mediated a significant tumor reduction. This also enhanced survival in mice with established solid and diffuse patient-derived orthotopic glioblastoma xenografts. Importantly, TRAIL secretion did not affect the viability of host NSCs, neurons, or astrocytes suggesting a cancer-specific cytotoxic effect of TRAIL-engineered iNSCs.

All in all, engineered iNSCs seem to be a perfect treatment modality for patients with aggressive brain tumors. The authors do note that treated animals did eventually succumb to GBM tumor formation, suggesting for the need of repeated treatments or synergistic treatment with differently engineered iNSCs carrying additional anti-tumor therapeutics. The authors have shown the latter hypothesis to be successful in overcoming resistant tumor populations [3, 4], and so this seems an ideal strategy to pursue in relation to iNSCs. Furthermore, the authors suggest that moving to a reprogramming system which does away with viral transfection may also enhance the clinical relevance of this exciting treatment option.

References

  1. Lujan E and Wernig M The many roads to Rome: induction of neural precursor cells from fibroblasts. Curr Opin Genet Dev 2012;22:517-522.
  2. Bago JR, Alfonso-Pecchio A, Okolie O, et al. Therapeutically engineered induced neural stem cells are tumour-homing and inhibit progression of glioblastoma. Nat Commun 2016;7:10593.
  3. Hingtgen S, Kasmieh R, Elbayly E, et al. A first-generation multi-functional cytokine for simultaneous optical tracking and tumor therapy. PLoS One 2012;7:e40234.
  4. Hingtgen S, Ren X, Terwilliger E, et al. Targeting multiple pathways in gliomas with stem cell and viral delivered S-TRAIL and Temozolomide. Mol Cancer Ther 2008;7:3575-3585.