Naked mole-rats (NMR) are the longest-living rodent species and exhibit extraordinary resistance to cancer. A Japanese research team found the induced pluripotent stem cells derived from NMR to be non-tumorigenic, shedding new light on their unique anti-cancer mechanism at the molecular level.
Scientists are getting closer to understanding the anti-cancer mechanism of the NMR by making induced pluripotent stem cells.
NMRs are the longest-living rodent species and exhibit "extraordinary" resistance to cancer. NMRs live up to 30 years, 10 times longer than mice, and captured colonies almost never show any type of cancer. Understanding these animals' anti-cancer mechanisms may help advance human treatment in the future, according to a collaborative research team from Hokkaido University and Keio University in Japan.
The research team took skin fibroblast tissue from adult NMRs and reprogrammed the cells to revert to pluripotent stem cells. These are called induced pluripotent stem cells (iPSCs) and, like embryonic stem cells, are capable of becoming any type of tissue in the body. However, these stem cells can also form tumors called teratomas when transplanted back into the animals.
When the NMRs’ iPSCs were inserted into the testes of mice with extremely weak immune systems, the team discovered that they didn't form tumors in contrast to human iPSCs and mouse iPSCs. Upon further investigation, they found that a tumor-suppressor gene called alternative reading frame (ARF), which is normally suppressed in mouse and human iPSCs, remained active in the NMR iPSCs.
The team also found that ERAS, a tumorigenic gene expressed in mouse embryonic stem cells and iPSCs, was mutated and dysfunctional in the NMR iPSCs. When the researchers disabled the ARF gene, forced the expression of the mouse ERAS gene in the NMR iPSCs, and then inserted them into the mice, the mice grew large tumors.
When researchers suppressed the ARF gene in NMR cells during the reprogramming process to iPSCs, the cells stopped proliferation with sign of cellular senescence, while the opposite happens with mouse cells. Researchers theorize that this further helps protect the NMR by reducing the chance for tumor formation. They call this ARF suppression-induced senescence (ASIS) and it appears to be unique to the NMR.
These findings could help researchers figure out how human iPSCs can be used for treating patients without forming tumors, which is one of the major challenges associated with undifferentiated iPSCs. "Further research into the detailed mechanisms underlying ASIS in NMRs may shed new light on cancer resistance in the NMRs and contribute to the generation of non-tumorigenic human-iPSCs, enabling safer cell-based therapeutics," said Kyoko Miura, an assistant professor at Hokkaido University.
Illustration: The NMR (Heterocephalus glaber) is the longest-lived rodent (longevity, 30 years) and exhibits extraordinary resistance to cancer. Credit: Image courtesy of Hokkaido University.
Hokkaido University News Release (06/16/16)
Science Daily (06/16/16)
Abstract (Nature Communications; 2016, 7: 11471.)