Stem-cell research is of great therapeutic potential, as pluripotent stem cells can produce new cells of any adult cell type, and such cells can potentially be used to address many problematic medical conditions. One risk of stem-cell therapy, however, is that injected pluripotent stem cells can produce too many cells without regulation. This can lead to the formation of tumors called teratomas, which can become malignant.
In the context of this concern, Shingo Miyawaki (Hokkaido University) and a team of researchers examined the naked mole-rat, which shows a well-established resistance to cancer ( Nat. Commun. 10, 11471; 2016). The researchers created induced pluripotent stem cells (iPSCs) by reprogramming skin fibroblast tissue from adult mole-rats in order to test its capacity for forming tumors, also called tumorigenicity. They accomplished this by injecting iPSCs into the testes of immune-deficient mice; they also carried out similar injections using iPSCs derived from human tissue and iPSCs from mouse tissue. As expected, these latter injected iPSCs produced teratomas in the testes of immune-deficient mice; however, iPSCs from mole-rats did not.
To establish potential explanations for this tumor resistance, Miyawaki's team compared gene expression in mole-rat iPSCs to that of mole-rat fibroblasts and iPSCs derived from humans and mice. They identified that a tumor-suppressor gene, ARF, is highly expressed in mole-rat iPSCs but suppressed in human- and mouse-derived iPSCs. Additionally, mole-rat iPSCs have a disrupted ERAS gene, which is expressed in human- and mouse-derived iPSCs and is associated with tumorigenesis.
Armed with these putative causes, the researchers modulated these genes in the different types of iPSCs to observe how ARF and ERAS mediate tumorigenesis. In mole-rat iPSCs, the researchers disrupted ARF with targeted short hairpin RNAs and added the ERAS gene from mice; the resulting iPSCs, when injected, produced large tumors. Conversely, by forcing the expression of the Arf gene in mouse-derived iPSCs, the researchers achieved lower tumorigenicity after injection.
These findings provide convincing evidence that ARF and ERAS significantly affect the development of teratomas from iPSCs. In their manuscript, the authors note this potential direction for biomedical discovery, suggesting that further research into the mechanisms by which ARF suppresses tumors “may contribute to the generation of non-tumorigenic human-iPSCs enabling safer cell-based therapeutics.” On its own, however, this study demonstrates the value of the naked mole-rat as a model for cancer resistance, with work already underway to demystify and translate its unique resilience into biomedical applications.
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Larsen, G. Digging into the genome of naked mole-rats. Lab Anim 45, 282 (2016). https://doi.org/10.1038/laban.1077