Exposing the naked truth about how mole-rats evade cancer

For Vera Gorbunova, PhD, professor of biology and medicine at the University of Rochester in New York, the moment of serendipity initially seemed like a nuisance. Dr Gorbunova’s laboratory studies why certain animals, such as the extremely long-lived, hairless, and so-ugly-they’re-cute subterranean dwellers known as naked mole-rats, are extraordinarily resistant to cancer. The unusual rodents from eastern Africa have a eusocial colony structure reminiscent of honeybees and can live more than 40 years in captivity, roughly 10-fold longer than mice.

As part of its research, Dr Gorbunova’s laboratory grew naked mole-rat fibroblast cells, which make and secrete collagen and other components of the framework for connective tissues. Graduate students noticed that the cells also were secreting a viscous substance into the cell culture dish. The substance was so thick and gooey that it clogged the vacuum pump used to suck up the growing medium from the dishes. “When people complained about it, we all thought, ‘Well, there must be something interesting,’” Dr Gorbunova recalls.

After initial tests suggested that the viscous substance was not an overabundant protein, a Google search hinted at hyaluronic acid, a natural lubricant and cushion for skin and other sensitive body parts in humans and other animals. Sure enough, confirmatory tests revealed that the secretions were a very long form of hyaluronic acid made by the HAS2 gene.¹

From additional experiments, the laboratory found that this version of hyaluronic acid binds to a specific cell receptor and appears to trigger an anticancer response by arresting cell growth and division. “Basically, when there is a lot of high-molecular weight hyaluronic acid in the tissue, it reduces cell proliferation and it also slows down premalignant hyperplastic cells,” Dr Gorbunova says. In transgenic mice, the introduced HAS2 gene granted the animals more longevity and resistance to both spontaneous and induced tumors.² “They didn’t become completely resistant like naked mole-rats, which means there are additional mechanisms that are different in the mole-rat, but the incidence was reduced significantly,” she says.

From an evolutionary perspective, Dr Gorbunova doubts that anticancer activity was the original purpose of the naked mole-rats’ hyaluronic acid production. In a wide range of other tunnel-dwelling species, the researchers recently reported that all produced the same high-molecular-weight compound.³ “What we proposed is that it really becomes upregulated with adaptation to subterranean life,” she says. One possibility is that because underground animals are constantly rubbing against tunnel walls, the acid helps to reinforce their skin.

When the laboratory ramped up hyaluronic acid production in mice, the animals likewise acquired “very stretchy, elastic skin,” she says. “But then once it’s overproduced in the skin, then other organs also start expressing the same gene.” Increased hyaluronic acid production provides a strong anti-inflammatory effect, which the researchers also observed in the mice. Because chronic inflammation has been strongly linked to cancer, the anti-inflammatory benefit may offer another mechanism by which the compound helps naked mole-rats to ward off cancer.

A model of resistance?

A separate group of scientists has focused on another potential anticancer mechanism that may derive, in part, from the “peculiar metabolism” of naked mole-rats in their low-oxygen burrows. A hallmark of most advanced cancers is increased production of lactate from glucose, which leads to a buildup—or lactic acidosis—in the tumor microenvironment. This Warburg effect, as it is known, benefits cancer growth in multiple ways, and most malignancies acquire it at some point during their evolution.

However, lactic acidosis is extremely limited in naked mole-rats, and this led the researchers to hypothesize that the animals’ low cancer incidence may be related to the strong inhibition of lactate production and buildup in their tissues, which thus deprives cancerous cells of a key advantage.⁴ “It certainly seems like, big picture, there’s something to this high lactate and cancer relationship,” says study coauthor Matthew Goodwin, MD, PhD, an assistant professor of orthopedic surgery and neurological surgery at Washington University in St. Louis. “The question is: What is it? Is it the Warburg effect?” The apparent absence of that effect in an animal with very low cancer rates, he says, can at least provide a basis of comparison to aid in the difficult task of identifying the true mechanism.

Kaori Oka, PhD, an assistant professor of aging and longevity research at Kumamoto University in Japan, likewise cautions that the hypoxia tolerance–cancer resistance link has not been clearly established yet. Even so, “the mechanisms that may accompany hypoxia tolerance—such as metabolic changes, the potentially reduced susceptibility to cellular damage under stressed conditions, and the possibly improved capabilities for repair and removal of damaged cells—could be related to cancer resistance,” she says. “Moreover, these mechanisms might help resist neurodegenerative diseases, such as Alzheimer’s disease, by safeguarding neuronal health.”

Introducing two additional mutations in the tumor suppressor genes Tp53 and Rb1 yielded lung tumors in 30% of the mole-rats, the researchers reported in a preprint—but only when all three mutations were present. Dr Shepard suggests that a combination of as-yet unclear protective mechanisms, such as enhanced DNA repair and unique immune system functions, may have protected the remaining 70%. At the very least, she and her colleagues believe that a naked mole-rat model may more closely approximate human susceptibility to lung cancer than a mouse model.

If it pans out, the model could yield a way to track the early stages of lung cancer when telltale physical symptoms are lacking. “Part of the reason lung cancer is so deadly is that most of the time it’s caught so late,” Dr Shepard says. New screening methods based on biomarkers of early cancer development might provide important new monitoring tools, and if the naked mole-rat provides a more accurate model of human lung cancer, it might offer a new system for testing treatments as well, she adds.

For investigating resistance mechanisms and identifying potential drug targets, Dr Gorbunova agrees that naked mole-rats may provide a better model, though she believes the highly susceptible mice are still better models for early tests of interventions. In aggregate, the diverse anticancer and antiaging mechanisms also could reveal new strategies for achieving “healthy longevity,” Dr Oka says. For naked mole-rats, at least, she and Dr Shepard agree that their harsh living conditions may be partly responsible for some of the unique adaptations.

Humans produce hyaluronic acid as well; the key difference, Dr Gorbunova says, is that both humans and mice degrade it more quickly than naked mole-rats do. In a forthcoming proof-of-principle study, the laboratory has identified an inhibitor of hyaluronic acid–degrading enzymes. When injected into mice with induced tumors, the inhibitor slowed hyaluronic acid’s destruction as well as the induced cancer’s metastasis.

If the line of research holds up, Dr Gorbunova believes that more potent inhibitors could help to prevent the destruction of our naturally occurring hyaluronic acid and thereby increase its anticancer properties. If so, slowing cancer metastasis would likely be the first application, although she also sees potential as a preventative in patients with a genetic predisposition for cancer or a high probability of relapse.

While naked mole-rats may be extreme examples of cancer resistance, Dr Gorbunova’s laboratory has begun studying even more remarkable paragons of longevity: bowhead whales, which can live for more than 200 years. Researchers once believed that larger animals would get cancer more often. “Well, nothing is larger than a whale,” Dr Gorbunova says. “But they don’t get cancer.” Their protective mechanisms, like those of their rodent counterparts, remain unclear. In the cancer modeling competition, though, Dr Oka points out that the mole-rats have one big advantage: They are far easier to raise and breed than a 90-ton marine mammal.