Secrets of a cancer-free rodent

Researchers have shed light on an unusual resistance to cancer displayed by the naked mole rat, a burrowing, long-lived desert-dwelling rodent. In these animals, a cell growth switch absent in more cancer-prone organisms turns off cell division before cells get too dense, as they would in a tumor, according to a study published online today in the Proceedings of the National Academy of Sciences (PNAS).

Image: Chris Hine,
Vera Gorbunova

"This is a really great discovery," said protein biochemist and aging researcher linkurl:Asish Chaudhuri;http://www.barshop.uthscsa.edu/main/facultystaff/barshopfaculty/u29 at the University of Texas Health Science Center in San Antonio, who was not involved in the research. If researchers can identify the same pathway in humans, "then we [may be able to] slow down the aging process [and] prevent the cancer before it starts." Naked mole rats have uncommonly long life spans of more than 28 years -- longer than any other rodent species -- and have never been observed to spontaneously develop tumors. Even in vitro, it has proven difficult to induce cancerous cell lines from the rodents. The biological explanation for this exceptional cancer resistance has long eluded scientists, and holds obvious implication for cancer and aging research. "It was really a big puzzle to us," said molecular biologist linkurl:Vera Gorbunova;http://www.rochester.edu/college/bio/professors/gorbunova.html of the University of Rochester in New York, who led the PNAS study. "We thought there must be some mechanism in the naked mole rat that [prevents the development of] tumors, [but] we had absolutely no idea what this could be." Gorbunova and her colleagues cultured the cells of naked mole rats to compare them with those of mice, which are often used to model human cancers. But they encountered a problem: the naked mole rat cells, when plated according to the normal specifications of mouse cell cultures, simply wouldn't grow. When the researchers tried plating fewer cells, however, the cells proliferated normally. This gave them the idea that naked mole rat cells may be hypersensitive to cell density. Sure enough, naked mole rat skin and lung fibroblasts plated at low densities proliferated to densities three times lower than mouse cultures. "We thought, 'Maybe this is the mechanism they use [for cancer prevention],'" Gorbunova recalled. The maximum cell densities of mouse cell cultures are determined by a phenomenon known as contact inhibition -- communication between neighbors that tells cells to stop dividing when they fully coat the substrate in a dense, single-cell layer. This cell cycle arrest is regulated by a molecular pathway involving the accumulation of p27, a cyclin-dependent kinase inhibitor. Increased cell-cell contact boosts p27 levels, which in turn puts the brakes on cell division. Another cyclin-dependent kinase inhibitor, p16, has also been implicated in this process, but its role in blocking cell growth was thought to be minor. In naked mole rats, however, the researchers found that p16 may be doing what p27 does in mice, but at much lower cell densities: They observed a robust increase in p16 around the time that the cells stopped dividing -- well before contact inhibition was observed in mouse cells. The researchers dubbed this phenomenon "early contact inhibition." Further evidence that p16 regulates cell growth in the rodents came from a naked mole rat stem cell line that had spontaneously mutated and lost early contact inhibition. In this line, the researchers did not detect higher levels of p16; without it, the cells became more like mouse cells -- showing a spike in p27 during the time of "regular" contact inhibition, and stopping growth around the same cell density as the mouse cell cultures. This suggested that naked mole rats have two layers of cell growth regulation -- both early and regular contact inhibition. The additional level of protection may explain how the rodents remain cancer-free for their entire lives. "Naked mole rats may have several mechanisms of cancer resistance that humans don't have," Gorbunova said. Mouse models are "useful for studying cancer therapies," she added, but "if we want to understand how to prevent cancer, we need to study [organisms] more resistant to cancer than that." This research "emphasizes that many important lessons can be learned from the study of cross-species differences," agreed linkurl:Ronald DePinho;http://www.hms.harvard.edu/dms/bbs/fac/depinho.html of Harvard Medical School, who was not involved in the research, in an email to The Scientist.
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