�����鶹��Ƶ

How Elephants Defend Against Cancer

Researchers have been trying to understand why some animals like elephants get cancer at rates much lower than expected.Eric Peterson, Hogle Zoo.

Cancer is caused by genetic changes, or DNA mutations, that allow cells to grow and divide uncontrollably. Researchers have extensively studied factors known to damage DNA, such as UV light and tobacco smoke, along with the cellular mechanisms of DNA repair.

Cells also naturally accumulate a certain number of mutations with each division. If all mammalian cells were equally susceptible to mutations that could lead to cancer, then cancer risk should increase with body size (greater number of cells) and species life span (greater number of cell divisions). However, many large animals with long life spans, such as elephants, don’t appear to have higher rates of cancer.

A team led by Dr. Joshua Schiffman at the University of Utah set out to examine cancer rates in different species. They began by studying 14 years of autopsy data collected by the San Diego Zoo. They analyzed 36 species that spanned up to 6 orders of magnitude in size and life span—ranging from the 51-gram striped grass mouse, which lives a maximum of 4.5 years, to the elephant, which can live up to 65 years. They also analyzed 644 documented deaths from a global database of captive African and Asian elephants. The study, funded in part by NIH’s �����鶹��Ƶ Cancer Institute (NCI) and �����鶹��Ƶ Library of Medicine (NLM), appeared online in JAMA on October 8, 2015.

The researchers found no significant relationships between cancer risk and body size, life span, or basic metabolic rate among the species. For elephants, they estimated that the overall lifetime chance of dying from cancer was less than 5%. The lifetime cancer mortality rate for humans, in contrast, is about 20%.

To gain insight into how elephants avoid cancer, the researchers looked at the elephant genome, with a focus on the TP53 gene. TP53 codes for the protein p53, a crucial tumor suppressor that stops cells with damaged DNA from dividing. People have 2 alleles (copies) of TP53. One is inherited from each parent, and both are crucial to prevent cancer. TP53 is mutated in most human cancers. Having only one functional allele causes Li-Fraumeni syndrome, which is characterized by a more than 90% lifetime risk of cancer.

The team analyzed genomic sequences and found that African elephants have at least 40 TP53 alleles. Functional assays comparing elephant and human cells showed that in response to DNA damage, cells from elephants had higher cell death (apoptosis) rates but didn’t boost DNA repair mechanisms. Both are known p53-mediated responses to DNA damage. Cells obtained from people with Li-Fraumeni syndrome had significantly less apoptosis than the human controls and more than 5 times less than elephants.

These results suggest that elephants may have evolved to resist cancer by triggering apoptosis through p53 to efficiently remove mutant cells. “Nature has already figured out how to prevent cancer,” Schiffman says. “It’s up to us to learn how different animals tackle the problem so we can adapt those strategies to prevent cancer in people.”

—by Harrison Wein, Ph.D.