A molecule to prevent naked mole rat cancer

Jun 19 2013 Published by under Physiology/Pharmacology

Naked mole rats have a tough time getting cancer. Even though they have incredibly long lifespans for rodents, living up to 30 years (as compared to mice, which only live four years under the best conditions), they don't tend to develop the cancers that are seen in other rodent species like mice, rats, and guinea pigs. Why do naked mole rats have such a tough time getting cancer?

Obviously this isn't something they are sad about, instead, it raises a lot of questions. Why are naked mole rats resistant to cancer? The answer to this question could be complex, but it could also tell us a lot about how cancer forms, and give us new strategies for cancer treatment.

Tian et al. "High molecular weight hyaluronan mediates the cancer resistance of the naked mole-rat" Nature, 2013. DOI.
(And of course, it should be noted that everything is better with naked mole rats in it)
Credit: Photo by Brandon Vick/ University of Rochester

The authors of the current study have uncovered one of the ways in which naked mole rats might be resistant to cancer. There are several major things that need to happen for cancer to take hold in the body:

1: Cells need to increase replication, so something needs to allow them to keep proliferating even though they shouldn't.
2: Cells need to stop dying, meaning that they need to be able to ignore signals that would usually cause them to die, like becoming too close together.
3: Cells need to lose the need to stay tied down to something, allowing them to migrate through the body and for cancer to spread.

It turns out that what may help naked mole rats resist cancer has to do with point number 2. In this case, the phenomenon is called "early contact inhibition". When cells become too squished, or too close together, they are supposed to stop dividing. This is something that cancer cells lose the ability to do, they will keep dividing no matter how close they get to each other.

But not naked mole rat cells. While all healthy cells have early contact inhibition, naked mole rat cells seem to be even more sensitive to this contact than those of other rodents, they stop dividing at a much lower density in a dish than say, mouse or even human cells do. The question is, what makes the naked mole rat cells so sensitive to this contact?

The authors of this study looked at naked mole rat cells cultured in a dish. What they noticed that that, when you grow up naked mole rat cells, the media that they are in (on which they feed) became very viscous and gluey, something that did not happen with human cells, mouse cells, or guinea pig cells (a close relative of the naked mole rat). The naked mole rat cells were secreting a substance that made the media around them thicker. The scientists were able to identify this as hyaluronan, a glycan (long sugar group) found in connective tissues. But in this case, the hyaluronan was LARGE. The molecule was much larger than the same type found in mice (6-12 kDa in naked mole rats vs 0.5-2 kDa in mice). It was what they called high-molecular weight hyaluronan. And it was present all over the naked mole rat, from the skin to the kidneys to the heart.

This is particularly interesting because the bigger the high-molecular weight hyaluronan, the more it can do things like repress cell proliferation through different pathways. And since cell proliferation is one of the problems in cancer...this gives you a bit of a clue.

It turns out that the naked mole rat has a small change in its genetic code for the enzyme that makes hyaluronan, which makes the much larger expression of the high-molecular weight hyaluronan possible. Not only that, the naked mole rat also has lower levels of the enzyme that degrades hyaluronan. So it makes more, and what it makes stays around longer.

It turns out, the high production of hyaluronan and the low levels of degradation are protective against the development of tumors in the naked mole rat. If you add in more enzyme to degrade the hyaluronan, the naked mole rat cells become much more susceptible to dividing and forming tumors. When the hyaluronan was got rid of in the cancer cells, either by stopping its formation or increasing its breakdown, the cells readily began to form tumors in mice, which suggests that the hyaluronan itself is what renders naked mole rats cancer resistant.

So it looks like this big, connective tissue protein is much more important than you might think! While we probably can't start producing more hyaluronan to protect ourselves from cancer, it does give us new ideas of what makes cancer form, and how you might be able to attack a tumor to stop its growth.

But I wonder, if you knocked out HA in the naked mole rat, would you also get incidence of cancer? I think using the cells in mice is definitely a good start, but it doesn't answer the question of whether or not there's something ELSE at play in the naked mole rat that might help them resist cancer. It's possible that the mole rat cells in the mouse model are a much more unstable system to begin with. It would be interesting to see if knockouts for hyaluronan get cancer after all.

So WHY does the naked mole rat have this adaptation? Well, hyaluronan is highly expressed in connective tissues. The authors hypothesize that it's very important in the naked mole rat's underground lifestyle. Hyaluronan increases skin flexibility, which may make it easier for the naked mole rat to squeeze along in underground tunnels. The cancer-resisting effects of hyaluronan, which stops cells from getting too close together, may just be a side effect of more flexible skin. But for a side effect, it's pretty beneficial!

2 responses so far

  • Chris says:

    I'm glad you mention whether the HMM HA is actually the sole mediator of their cancer resistance.

    One of the (many) interesting traits of naked mole rats - they've evolved to become highly-resistant to high-CO2 and high-Ammonia environments, and do not endogenously produce the nociception-mediating peptide, Substance P. It's believed the animal's high-tolerance to pain is a result of this. Hell, you've probably even posted on Substance P on your blog before. As Substance P and the Neurokinin-1, -2, and -3 receptors play roles in both innate and adaptive immunity (and many many other physiological systems), it has long been "assumed" that the naked mole rat's cancer-avoidance was due to this unique trait.

    It would be great to see a follow-up study that further explores both the HA and SP aspects that make the naked mole rat so interesting!

  • In humans, the average MW of HA shrinks as we age, while the risk for cancer increases. Correlation is not causation and all that, but an interesting correlation nevertheless.

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