A favorite among children at the zoo, naked mole rats are also known for their unusually long lifespan and rare ability to almost completely resist cancer. Although researchers know mole rats prevent cancer by arresting cell growth when cells come in to contact with each other or the extracellular matrix, the exact trigger of this phenomenon - called Early Contact Inhibition (ECI) - has remained unknown, until now.
In a study published this week in the journal Nature, scientists at the University of Rochester say they have discovered the trigger mechanism behind the naked mole rat’s resistance to cancer. The researchers found mole rat cells secrete a unique compound: a high-molecular-mass hyaluronan (HA) that is six times longer than that found in humans. The team determined that the hyaluronan interacts with the receptors on the cell surface to trigger cell cycle arrest, making the cell unusually sensitive to contact inhibition.
“Contact inhibition is sort of exaggerated in [naked mole rats], and we had found this to be important for their cancer resistance, but we didn’t know what triggers this phenomenon,” explained Vera Gorbunova, professor of biology and associate professor of oncology at the University of Rochester, who led the study. “This paper kind of solves that.”
Human cells also produce hyaluronan, which makes up networks of extracellular matrix that hold cells together, providing elasticity to tissues. However, Gorbunova says the functional properties of hyaluronan in naked mole rat cells are determined by the molecule’s length.
“A very short molecule might actually tell the cells to proliferate, while very long molecules give different signals saying ‘stay put, don’t move around, don’t proliferate’. In the naked mole rat, the molecules are so long and so good at keeping cells in check, I think that’s what makes naked mole rats’ resistance of cancer.”
Gorbunova believes naked mole rats may have evolved a higher concentration of high-molecular-mass hyaluronan in the skin to provide the elasticity needed for adapting to life in underground tunnels, subsequently co-opting the trait to provide cancer resistance and a longer lifespan. Interestingly, last year Gorbunova’s team also found evidence for another evolved cancer defense mechanism in the middle eastern blind mole rat .
“What is strange is that the blind mole rat is also resistant to cancer, but the mechanism seems to be different, so they are using hyaluronan for other purposes…maybe to live a long time but not necessarily for cancer resistance,” said Gorbunova. “But again, what is common about these two different mole rats is that they both live underground, so that is why we thought about this elastic skin that is needed to squeeze thought the tunnels underground.“
Gorbunova says her team initially faced problems analyzing the naked mole rat cells in culture due to poor growth. The lab later discovered this was in fact due to hyaluronan, which would accumulate in the culture media and inhibit the cell growth process early on. After experimenting with different growth conditions, Gorbunova’s group successfully cultured naked mole rat cells by seeding the cells at a lower density.
“We could see that sometimes the cells would grow a little better if we changed the media very frequently,” said Gorbunova. “Once we really played with this and identified that it was hyaluronan in the media that was arresting the cells, everything kind of fell into place.”
Finally, the lab was able to grow cells and make xenografts in mice in order to compare naked mole rat cells to mice cells and analyze how each would react to oncogenes in vivo. The mouse cells treated with oncogenes formed tumors, while naked mole rat cells did not. However, the mole rat cells became susceptible to malignant transformation when the team inhibited the enzyme responsible for making hyaluronan.
Gorbunova says that her lab will now research a broad range of subterranean species in order to see how different species may have evolved hyaluronan.
“What our study shows is that [hyaluronan] can be applied as a potential cancer treatment or prevention strategy”, said Gorbunova. “The next thing we want to see is whether this mechanism can be moved from the naked mole rat to another mammal.”
1. Tian, X., J. Azpurua, C. Hine, A. Vaidya, M. Myakishev-Rempel, J. Ablaeva, Z. Mao, E. Nevo, V. Gorbunova, and A. Seluanov. 2013. molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature (June)