Viruses may explain why small animals are more prone to cancer

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Cancer is a numbers game. Larger, longer-lived animals with more cells should get more tumors than do small, short-lived animals. And yet mice are more susceptible to cancer than we are. Now, a new study offers a tantalizing explanation. The genomes of smaller mammals contain more viruses, which the authors suggest may account for their higher rates of cancer.

Aris Katzourakis, an evolutionary biologist at the University of Oxford in the United Kingdom, didn’t set out to explain rates of cancer in animals. He was interested in why over the last 10 million years the genomes of mice have accumulated 10 times more small RNA viruses, called endogenous retroviruses (ERVs), than has the human genome. He teamed up with researchers from Plymouth University and the University of Glasgow in the United Kingdom to mine for retroviruses in the genomes of a range of mammals—including shrews, humans, dogs, and dolphins. The researchers then tested whether differences in how long mammals live and in how quickly they mature affects how many ERVs they harbor.

By the time the team had identified more than 27,000 unique viral sequences across 38 different mammals, it saw a clear pattern emerging: Small mammals have more ERVs than do larger ones. Mice have more than 3000, whereas dolphins have just 55, and humans are somewhere in the middle with 348, the researchers report online today in PLOS Pathogens.

Larger animals have many more cells, and should therefore have more of these endogenous retroviruses. That they have fewer means they must have found efficient ways to remove them, Katzourakis says. That suggests ERVs can be harmful to their hosts, and this harm is more costly, in an evolutionary sense, to large animals.

How do ERVs harm their hosts? Katzourakis suspects that some ERVs cause cancer. The viruses embed in an organism’s genome and make copies of themselves, and these duplicates then split and reinsert randomly at different locations in the genome. More often than not, these viruses do no harm, but occasionally their reinsertion transforms a healthy cell into a cancerous one. One such event led to the untimely death of the world’s first cloned sheep, Dolly, who succumbed to lung cancer caused by the Jaagsiekte sheep retrovirus. Katzourakis proposes that the higher number of ERVs in small-bodied animals may account for their higher rates of cancer.

“It’s nice to see real experimental results that can help explain the vast differences in cancer susceptibility per gram of tissue between small, short-lived animals and large, long-lived animals,” says epidemiologist Richard Peto of the University of Oxford, who was unconnected to the new study. He first recognized the unexpected differences in cancer susceptibilities between animals of different body sizes in the 1970s, an observation that became known as “Peto’s Paradox.”

From an evolutionary perspective, Peto explains, it makes sense that larger animals are better at protecting their genomes from potentially cancer-causing viruses. Large animals tend to live longer and reproduce later, so it is more important for them to postpone the onset of cancer.

Although the findings pinpoint one mechanism underlying the vast difference in cancer rates, they don’t explain all cancers, says George Kassiotis, a virologist at the National Institute for Medical Research in London who studies ERVs in humans and mice. Despite having few ERVs, he explains, humans still get cancers. ERVs are therefore likely to be one of many factors contributing to cancer rates. “One important aspect of this new study is that it provides a framework to quantify the contribution of ERVs to cancer,” he says, “which in turn will inform the contribution of other causes of cancer.”

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Working in the Community to Reduce Health Disparities

The Helping Her Live team (left to right): Maria Trujillo (community health educator/navigator [CHE/N]), Melinda Medina (CHE/N), Jana Stringfellow (CHE/N), Chela Sproles (program manager), Oreletta Garmon (CHE/N), and Jackie Kanoon, MPH (program coordinator)
The Helping Her Live team (left to right): Maria Trujillo (community health educator/navigator [CHE/N]), Melinda Medina (CHE/N), Jana Stringfellow (CHE/N), Chela Sproles (program manager), Oreletta Garmon (CHE/N), and Jackie Kanoon, MPH (program coordinator)
Epidemiologist Kristi Allgood of the Sinai Urban Health Institute (SUHI) in Chicago, Illinois, is on a mission to get women to return to the hospital to follow up on suspicious mammograms. For 9 years, she has been involved in a community-based initiative that supports women whose health (and health care) is likely to be overlooked. Allgood and her SUHI colleagues are part of a growing movement across the United States that aims to reduce the nation’s health disparities by increasing the uptake of proven clinical treatments.

Allgood, who is now 39, didn’t set out to focus on breast cancer research. After completing a master’s degree in public health from the University of Illinois, Chicago (UIC), she was recruited to SUHI to evaluate HIV education in Chicago’s Mount Sinai Hospital. But Steve Whitman, SUHI’s director, drafted her into a new initiative attempting to mitigate the racial gap in breast cancer survival in the city where she grew up.

Funded since 2007, the Helping Her Live: Gaining Control of Breast Cancer project supports a team of community health care workers who help women in Chicago’s African-American and Hispanic communities navigate breast cancer screening, diagnosis, and treatment. Women in these communities, as in the rest of the country, are chronically under or uninsured—and it’s common for women without insurance to fail to return for a follow-up biopsy. The reasons are complex, but mostly have to do with “fear, time, and money,” Allgood says. The upshot: Breast cancer in this population of women tends to be diagnosed at an advanced stage, making it difficult to treat and offering grimmer odds of survival.

This breast cancer survival gap hasn’t always existed, explains Bijou Hunt, also an epidemiologist and Allgood’s colleague at SUHI. Twenty years ago, a woman’s race had little bearing on her chance of dying from the disease. Then, starting in the 1990s, white women began to benefit from numerous advances in treatment for breast cancer. African-American women didn’t share the gains.

A study published in 2014—Hunt was the lead author—found that in Chicago between 2005 and 2009, African-American women with breast cancer were, on average, 48% more likely than their white counterparts to die from the disease. That makes Chicago the nation’s seventh deadliest city for black women with breast cancer, but the same pattern is seen in many other major U.S. cities. Each year, nationwide, the disparity equates to 1700 extra breast cancer deaths among African-American women, or about five per day.

Figures like these motivated SUHI’s director to seek funding to help close the gap. In 2005, he secured half a million dollars to start a project that employed two hospital-based health care workers who would assist patients during procedures, provide guidance in the referral process, help physicians communicate medical concepts clearly, and sometimes “literally walk patients from place to place” at the hospital, Allgood says.

When the Avon Foundation for Women provided an additional $1.95 million in 2007, the hospital-based program expanded into the community and took the name “Helping Her Live.” Allgood took a road trip to New York City’s Harlem neighborhood, where a project with similar aims had been running since the early 1990s. She returned to Chicago full of fresh ideas, ready to recruit and train additional health care workers who, in contrast to their hospital-based peers, would work out in the community.

This story ties in with Science’s special issue on breast cancer.
Today, these community-based health care workers help women access routine breast screenings, and work to ease delays in test results and follow-ups. They attend community events, present workshops, and canvass women one-on-one to educate them about the reasons behind health disparities, how mammograms work, and how cancer is treated. Allgood describes them as compassionate, effective advocates and well-respected community members who understand the social issues facing the patients they serve. They are, Allgood says, the key to the project’s success.

Having got the ball rolling, Allgood was charged, along with Hunt, with evaluating the hospital and community-based projects. The two epidemiologists assemble mammogram results, pathology reports, and clinicians’ suggested treatments, and they combine them with data collected in the community. They then go to work analyzing it.

Last year, the project’s hospital-based workers saw more than 3000 patients and assisted them on 12,000 occasions in 50 distinct, documented ways. Over 3 years, the community-based health care workers responded to 5000 requests for help.

It is too early to report whether the project is reducing mortality rates, Allgood says. Their analysis shows, however, that their programs are radically improving some interim metrics. Today, 95% of African-American women in the project’s target communities return for a checkup after a suspicious mammogram, up from 66% before the project began.

Wanted: teamwork, statistics, and a passion for social justice

Cancer geneticist Rick Kittles, whose work at UIC identifies genetic and environmental factors that lead to cancer health disparities, says that statistical savvy is important in the work that Allgood is doing—but that social savvy is important, too. Whitman echoes that sentiment: “Too many young people coming into the field of epidemiology … do not know enough about the world and how it works,” he says. The work is highly interdisciplinary and depends on effective communication among scientists, staff, doctors, and patients—as well as with funders and policymakers.

Fundraising, in fact, is one of the job’s biggest challenges. “We work tirelessly to either keep the funding or find new avenues to fund [our] programs,” Allgood says. Allgood, Hunt, and the other epidemiologists write reports for and make presentations to stakeholders who can influence the health policies adopted by the city government.

To get involved in health disparities work, one must, of course, have the basic credential: at least a master’s degree in public health, Whitman says. One needs hands-on experience in gathering, curating, and analysing data; statistics is becoming ever more important as the field becomes more data-driven.

Alongside such training, those pursuing this career should have a passion for social justice and be ready to think critically about how society-level decisions impact individual health, says Jennifer Orsi, a data analyst at Walgreens in Deerfield, Illinois, who previously worked as an epidemiologist at SUHI. An affinity for teamwork is also essential.

The SUHI team is growing. Right now, SUHI is recruiting a community health educator. Since Allgood joined SUHI, the number of epidemiologists has doubled. Each is waging war against a different disease: asthma, diabetes, and HIV, along with more complex conditions such as chronic obstructive pulmonary disease and obesity. Many approaches are shared among projects. “We all work together to help each other,” Allgood says. “It is really nice to have that backup.”

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