Studying Animals that Dont Get Cancer to See What Works in Human Cancer
Why Don't They Get Cancer?They won't win any beauty contests but apparently an animal called the naked mole rat does not get cancer. Or at least no one has ever detected cancer in it. A recent NYT article said "People have stronger defenses against cancer, as is necessary for a long-lived animal: the disease accounts for 23 percent of human mortality. But the mole rat has taken its anticancer defenses even further: it seems not to get the disease at all. “These animals have never been observed to develop any spontaneous neoplasms,” Vera Gorbunova and colleagues said in an article in the Proceedings of the National Academy of Sciences.
Normally, mammalian cells stop replicating when they come into dense contact with one another, but cancer cells ignore this signal and continue to proliferate, which allows them to clump into tumors in the body. The researchers measured the growth of mole–rat cells and found that cellular growth in the animals was hypersensitive to first contact, compared to mouse cells that continued growing into a dense layer. Naked mole–rat cells forced into high-density situations arrested their growth or even died.
The authors Gorbunova and Selunov, investigated the pathways responsible for this early contact inhibition and report that two fibroblast pathways are likely responsible for the key anticancer mechanism. Their research shows that inactivating these tumor-suppressor pathways can allow the mole rats to develop cancer.
How Can They Live So Long Without Oxygen?But wait there's more! Dr. Thomas Park and researcher John Larson report "that the brains of adult naked mole rats can withstand oxygen deprivation for a half-hour or more. That knowledge could eventually help in stroke research, Park said".
Why 2 Cancer Protection Pathways Trump Only OneThe report in the PNAS said that the rats’ cells have a double system for inhibiting irregular (cell) proliferation (like cancer), compared with the single system in human cells. Gorbunova believes she has found the primary reason these small animals are staying cancer-free, and it appears to be a kind of overcrowding early-warning gene that the naked mole rat expresses in its cells.
When Gorbunova and her team began specifically investigating mole rat cells, they were surprised at how difficult it was to grow the cells in the lab for study. The cells simply refused to replicate once a certain number of them occupied a space. Other cells, such as human cells, also cease replication when their populations become too dense, but the mole rat cells were reaching their limit much earlier than other animals' cells.
"Since cancer is basically runaway cell replication, we realized that whatever was doing this was probably the same thing that prevented cancer from ever getting started in the mole rats," says Gorbunova.
What p16 and p27 do against cancerLike many animals, including humans, the mole rats have a gene called p27 that prevents cellular overcrowding, but the mole rats use another, earlier defense in gene p16. Cancer cells tend to find ways around p27, but mole rats have a double barrier that a cell must overcome before it can grow uncontrollably.
"We believe the additional layer of protection conferred by this two-tiered contact inhibition contributes to the remarkable tumor resistance of the naked mole rat," says Gorbunova in the PNAS paper.Gorbunova and Seluanov are now planning to delve deeper into the mole rat's genetics to see if their cancer resistance might be applicable to humans.
"The findings, presented in The Proceedings of the National Academy of Sciences, show that the mole rat's cells express a gene called p16 that makes the cells "claustrophobic," stopping the cells' proliferation when too many of them crowd together, cutting off runaway growth before it can start. The effect of p16 is so pronounced that when researchers mutated the cells to induce a tumor, the cells' growth barely changed, whereas regular mouse cells became fully cancerous.
"We show that a combination of activated Ras and SV40 LT fails to induce robust anchorage-independent growth in naked mole-rat cells, while it readily transforms mouse fibroblasts. The mechanisms responsible for the cancer resistance of naked mole-rats were unknown. Here we show that naked mole-rat fibroblasts display hypersensitivity to contact inhibition, a phenomenon we termed “early contact inhibition.” Contact inhibition is a key anticancer mechanism that arrests cell division when cells reach a high density. In cell culture, naked mole-rat fibroblasts arrest at a much lower density than those from a mouse. We demonstrate that early contact inhibition requires the activity of p53 and pRb tumor suppressor pathways."
""We think we've found the reason these mole rats don't get cancer, and it's a bit of a surprise," says Vera Gorbunova, associate professor of biology at the University of Rochester and lead investigator on the discovery. "It's very early to speculate about the implications, but if the effect of p16 can be simulated in humans we might have a way to halt cancer before it starts."