Although they are quite ugly and confined to a life underground, naked mole rats have at least one attribute that other animals, even humans, might aspire to: They don't get cancer. Now, researchers have discovered that the secret to this rodent's good health is a complex sugar that helps keeps cells from clumping together and forming tumors.
Whether this sugar will be useful as an anticancer agent in humans is unclear. But because it exists in the spaces between cells called the extracellular matrix, "the work underlines the very important regulatory role of [the] extracellular matrix in cancer," says Bryan Toole, a cancer biologist at the Medical University of South Carolina in Charleston who was not involved with the study.
Many researchers study cancer in mice, which live no more than 4 years and are prone to tumors. Molecular and cell biologist Vera Gorbunova of the University of Rochester in New York wanted to take a different tack and focus on animals that seem protected from tumors. So she tracked down the lifespans of 20 different rodents, looking for the ones that live a long time. Beavers and gray squirrels last a couple of decades, but naked mole rats outlive those larger animals by 10 years. Furthermore, because naked mole rats have a unique social structure, with one queen that produces all the young for an underground colony full of helpers, they have been the subject of long-term research. Thanks to these studies, scientists know for sure that this species doesn't get cancer. Given that naked mole rats live long and are resistant to cancer, "we fell in love with them right away," Gorbunova says.
At first, she and her colleagues did not know where to look for the source of animals' cancer resistance. But when they grew naked mole rat cells in a lab dish, they noticed that cells wouldn't get too close together. Furthermore, the dish contents got very gooey over time, so much so that lab technicians found the cells hard to work with. When the technicians eliminated the goo, the cells would clump together, suggesting they might now form tumors. The researchers tracked the stickiness to a complex sugar called hyaluronan, which cells make and release into the extracellular matrix.
Hyaluronan exists in all animals, helping lubricate joints and serving as an essential component in skin and cartilage. It's been used in skin lotions and antiarthritis treatments, and some forms have even been proposed to promote cancer. However, naked mole rat hyaluronan is unusual in that each molecule is about 5 times the size of hyaluronan molecules from mice, rats, and humans. In addition, the researchers discovered that the enzyme that breaks down this sugar is not very active in naked mole rats, allowing the compound to accumulate to higher concentrations than it does in other animals. The researchers think that this sugar evolved to make naked mole rat skin more elastic and able to cope with the tight squeeze of the narrow underground tunnels.
But does it prevent cancer? Gorbunova and her colleagues tried to stimulate naked mole rat cells to form tumors by exposing them to viral proteins that in mice lead to tumor growth. These proteins inactivate genes that suppress cancer, yet still naked mole rat cells did not show uncontrolled growth. However, when the researchers interfered with the production of hyaluronan or revved up the activity of the enzyme that breaks the sugar down, thereby reducing its concentrations, tumors did form in live animals, they report online today in Nature.
The work is "very thought-provoking [and] adds an interesting wrinkle to the role of the extracellular matrix in cancer," says Roy Zent, a cell biologist at Vanderbilt University Medical Center in Nashville. Toole agrees. "It pushes our thoughts forward [about hyaluronan] in a very dramatic way," he notes. "It establishes hyaluronan as an important player in cancer."
"If we could alter our [hyaluronan] or stabilize it somehow, we may be able to suppress cancers," suggests Carlo Maley, an evolutionary cancer biologist at the University of California, San Francisco, who was not involved with the work. The next step, he adds, is to "put the naked mole rat [hyaluronan] gene into mice and test if they are cancer resistant."