Elephants: Large, Long-Living and Less Prone to Cancer
By Carl Zimmer

In 1977, a University of Oxford statistician named Richard Peto pointed out a simple yet puzzling biological fact: We humans should have a lot more cancer than mice, but we don’t.

Dr. Peto’s argument was beguilingly simple. Every time a cell divides, there’s a small chance it will gain a mutation that speeds its growth. Cells that accumulate several of these mutations may become cancerous. The bigger an animal is, the more cells it has, and the longer an animal lives, the more times its cells divide. We humans undergo about 10,000 times as many cell divisions as mice — and thus should be far more likely to get cancer.

Yet humans and mice have roughly the same lifetime risk of cancer, a circumstance that has come to be known as Peto’s paradox.

A number of scientists have speculated that large, long-lived animals must evolve extra cancer-fighting weapons. And if that’s true, they reason, then the biggest, longest-lived animals should have an especially big arsenal. Otherwise, these species would go extinct.

“Every baby elephant should be dropping dead of colon cancer at age 3,” said Dr. Joshua D. Schiffman, a pediatric oncologist at the Huntsman Cancer Institute at the University of Utah.

Writing Thursday in The Journal of the American Medical Association, Dr. Schiffman and his colleagues report that elephants appear to be exceptional cancer fighters, using a special set of proteins to kill off damaged cells.

Working independently, Vincent J. Lynch, an evolutionary biologist at the University of Chicago, and his colleagues have come to the same conclusion. Those researchers posted a draft of their paper on Wednesday on the bioRxiv server. It is currently in review at the journal eLife.

Dr. Schiffman and his colleagues found in their research that elephants have a remarkably low rate of cancer. They reviewed zoo records on the deaths of 644 elephants and found that less than 5 percent died of cancer. By contrast, 11 percent to 25 percent of humans die of cancer — despite the fact that elephants can weigh a hundred times as much as we do.

To understand the elephants’ defenses, the scientists investigated a gene that is crucial for preventing cancer, called p53. The protein encoded by the gene monitors cells for damage to the DNA they contain. In some cases, it triggers the cells to repair the genes. In other cases, p53 stops cells from dividing further. And in still other cases, it even causes the cells to commit suicide.

One sign of how important p53 is for fighting cancer is what happens to people born with a defective copy of the gene. This condition, known as Li-Fraumeni syndrome, creates a lifetime risk of cancer of more than 90 percent. Many people with Li-Fraumeni syndrome get cancers as children and can have several types of cancer over their lifetimes.

Dr. Schiffman and his colleagues found that elephants have evolved new copies of the p53 gene. While humans have only one pair of p53 genes, the scientists identified 20 pairs in elephants.

Dr. Lynch and his colleagues also found these extra genes. To trace their evolution, the researchers made a large-scale comparison of elephants to other mammal species — including extinct relatives like woolly mammoths and mastodons whose DNA remains in their fossils.

The small ancestors of elephants, Dr. Lynch and his colleagues found, had only one pair of functional p53, like other mammals. But as they evolved to bigger sizes, they steadily evolved extra copies of p53.

“Whatever’s going on is special to the elephant lineage,” Dr. Lynch said.

To see whether these extra copies of p53 made a difference in fighting cancer, both teams ran experiments on elephant cells. Dr. Schiffman and his colleagues bombarded elephant cells with radiation and DNA-damaging chemicals, while Dr. Lynch’s team used chemicals and ultraviolet rays.

In all these cases, the elephant cells responded in the same way: Instead of trying to repair the damage, they simply committed suicide. Dr. Schiffman saw this response as a unique — and very effective — way to block cancer. “It’s almost as if they said, ‘We’re elephants — we’ve got plenty more cells where those came from,’ ” Dr. Schiffman said.

Patricia Muller, an oncologist at the MRC Toxicology Unit at the University of Leicester who was not involved in the studies, said the results, though compelling, didn’t firmly establish exactly how elephants use p53 to fight cancer. One possibility is that the extra copies don’t actually cause cells to commit suicide. Instead, they may act as decoys for enzymes that destroy p53 proteins. As a result, elephants can have higher levels of p53 than other animals. “All in all, it’s interesting, but the mechanism needs to be properly investigated,” she said.

Dr. Muller said it was especially important to understand precisely how elephants fight cancer before trying to mimic their strategies with drugs for humans. Experiments in which mice get extra amounts of p53 have shown that the molecule has a downside: It can accelerate aging. “It has to be kept under tight control,” Dr. Muller said.

Dr. Schiffman is now investigating how to translate the new findings on elephants into cancer treatments for people. But he said it would be useful to look at other big or long-lived animals as well. Naked mole rats, for example, live up to 30 years without ever getting cancer. One weapon they use is a protein that arrests the growth of fast-dividing cells. It senses when these cells bump into other cells and brings their division to a halt.

That is an entirely different solution from the one elephants appear to have evolved. And elephants are the only animals yet found that fight cancer with extra p53 genes. So Dr. Schiffman speculates that parrots, tortoises and whales may all have special longevity tactics of their own.

“The war on cancer was going on long before there were humans,” he said. “So let’s look at nature’s strategies.”

研究解密 大象抗癌機制

陸地最大動物大象的體重可達六公噸以上，壽命超過70歲，而且幾乎不會罹患癌症，這是因為牠們擁有可以阻止腫瘤生成的基因。

科學家表示，人類也擁有類似的保護基因，數量卻比較少，效力也比較薄弱。他們試圖破解大象抗癌天賦的奧祕，希望未來有助於提升人類的抗癌能力。

細胞的DNA如果突變，會發出錯誤的指令，導致細胞失控生長，最後成為癌症。

美國猶他大學韓茲曼癌症研究所的兒科腫瘤專家席福曼在8日透過「美國醫學會期刊」發表的研究報告中指出：「半數的男性與三分之一的女性會罹患癌症。失控的細胞分裂與基因組不穩定會形成癌症，也是老化產生的疾病，因為年紀愈大，我們愈無法修復受損的細胞。」

他說：「大象體型是人類的100倍，擁有許多細胞，壽命又長。我們可以合理的說，大象應該都會死於癌症。其實不然。」

裸鼠也具備抗癌的天賦，科學家對大象卻特別好奇。部分科學家認為，每一個細胞都可能致癌。如果細胞愈多，罹癌機率愈高。換言之，大象罹癌的機率應是人類的100倍。然而以動物園飼養的大象而言，死於癌症的比例不到全部的5%，人類則介於11%到25%。

研究人員比較36種哺乳動物的罹癌率，意外發現大象的罹癌率未隨體型、年齡增加。

科學家分析大象的全部基因組時，特別留意TP53基因。它們可以抑制腫瘤，修復受損的細胞，並在無法修復時消滅它們。研究人員發現，大象擁有20對TP53複製基因，人類只有1對，分別來自父母，要一對同時作用才能防癌。

研究人員採集八頭非洲象與亞洲象的血液樣本，比較取自11名健康民眾與另10名李．佛美尼症候群（Li–Fraumeni syndrome）患者的血液樣本，再將它們曝置於輻射線下，以使DNA受損。大象與人類的TP53基因起初反應類似。研究人員深入探究後發現，大象的TP53基因比較可能扮演殺手而不是醫師的角色，消滅的受損細胞比人類多很多。

李．佛美尼症候群的患者只擁有一個TP53基因，終身罹癌的機率高達90%。

席福曼說，大象TP53基因消滅受損細胞的數量是人類的兩倍，更是李．佛美尼症候群患者的五倍。他說：「我們不是說已經發現治療癌症的方法。然而我們自認已經瞭解大象的抗癌機制，可據以研究如何將它套用在人類的身上。」

原文參照：
http://www.nytimes.com/2015/10/13/science/why-elephants-get-less-cancer.html

紐約時報中文版翻譯：
http://cn.nytstyle.com/health/20151020/t20zimmer/zh-hant/

2015-10-10．聯合晚報．A5．國際．編譯陳世欽