The Cancer-resistant Blind Mole Rat: Clues from the Genome
Although the Naked Mole Rat and the Blind Mole Rat have similar sounding names, they are not close relatives. The two species diverged over 70 million years ago, and blind mole rats are more closely related to rats and mice than to naked mole rats. But both these species are resistant to cancer; in over 40 years of studying blind mole rats, not a single spontaneous tumour was recorded among thousands of captive animals. Intriguingly, the two animals have evolved this resistance independently. Studying the mechanisms for cancer resistance in these two animals can therefore provide a deeper understanding of how cancer arises at the cellular level. The recent publication of the blind mole rat’s genome sequence provides some intriguing hints about these mechanisms.
✤ The blind mole rat lives underground. Life underground requires several evolutionary adaptations. Of these, one of the most remarkable is its adaptation to low oxygen (highly hypoxic) environments found in underground burrows; O2 as low as 7.2% and CO2 as high as 6.1% have been reported. Low oxygen environments are also found inside tumours, and tumours are able to survive this environment through mechanisms I have explained here.
✤ Hypoxic environments typically cause cells to undergo apoptosis – a type of programmed cell suicide. This process is regulated by an important protein known as p53 (see here for more information about apoptosis). Hypoxia-induced apoptosis would be disastrous for an underground-dwelling blind mole rat, so their p53 protein has a mutation that prevents the induction of apoptosis. Even more interestingly, this mutation is almost identical to a similar p53 mutation found in many human cancers. Both mutations seem to encourage the cells to stop dividing, rather than to self-destruct.
✤ Understandably, the massive loss of cells due to hypoxia-induced apoptosis is undesirable for the blind mole rat, so the p53 mutation can be explained that way. But mutant p53 also means cancer, as many human cancers have a similar mutation. It sounds counter-intuitive that a cancer resistant animal has nearly the same mutation that actual cancers do. How does this work? Clearly, the blind mole rat has other mechanisms in place to compensate for this ‘weakened’ p53 status. But what are they?
✤ Instead of apoptosis, the blind mole rat relies on a different mechanism for guarding its cells against cancer. This mechanism is necrotic cell death; messier than apoptosis, it is a mechanism that involves the immune system and inflammation. The genome sequence of the blind mole rat has an extra copy of the gene Ifnb1 which encodes a protein known as interferon beta 1. In comparison, the mouse, rat and naked mole rat genomes have only one copy of Ifnb1. The blind mole rat has extra copies of this gene, which results in extra amounts of this protein, leading to a stronger necrotic cell death response. This compensates for the ‘weakened’ p53. Supporting this hypothesis is the fact that several other genes from the interferon signalling pathway, along with other genes that regulate cell death and inflammation are also expanded in the blind mole rat genome, indicating that this immuno-inflammatory response is heightened in the blind mole rat.
✤ In summary, the blind mole rat genome has acquired a mutant version of p53 (i.e. weakened) as an adaptation to underground hypoxic conditions. This would normally lead to a lowered ability to resist cancer, as p53 is vital for tumour suppression. Therefore as compensation, the blind mole rat genome has extra copies of genes involved in necrotic cell death in order to remain cancer resistant.
✤ It might seem a bit disconnected to study an underground dwelling blind mole rat that is so different from us, in order to understand our own cancers. But as these findings show, understanding the evolution of cancer resistance mechanisms can increase our knowledge of cancer; with this knowledge comes the power to someday develop therapies against cancer, or measures for cancer prevention.