Fat Chance for Cancer

Cancer risk rises with obesity and sedentary behavior, but researchers are uncertain what it is about fat that encourages certain diseases.

By Alicia Di Rado

Whether through stern warnings or subtle cajoling, public health experts have been sounding alarms for years about the dangers of obesity and sedentary living leading to diseases such as diabetes and heart disease.

Now there are a growing number of scientific studies that link obesity and lack of exercise to another health danger: cancer.

According to the World Health Organization, overweight and inactivity may account for a quarter to a third of the world’s cases of cancer of the breast, colon, endometrium, kidney and esophagus. But when Americans were asked to name major risk factors for developing cancer, only 6 percent of the more than 1,000 people questioned in a 2002 national survey mentioned obesity. And later, when asked which diseases are significantly influenced by obesity, only a quarter of Americans knew that the risk of cancer may be inflated through fatness.

Americans might be forgiven for being in the dark about the links between fat and cancer, though, considering that scientists themselves are uncertain about the connections.

“We know that risk for certain conditions, such as cancer, rises with obesity and sedentary behavior. But the question is: Why? We really don’t know what it is about fat that encourages these problems,” says obesity expert Michael I. Goran, Ph.D., professor of preventive medicine and physiology and biophysics at the Keck School of Medicine of USC and associate director of the USC Institute for Health Promotion and Disease Prevention Research. “That’s what we’re trying to find out.”

Distressed by both the nation’s growing waistlines and the growing links between tumors and too much fat, the National Institutes of Health wants to help Goran and his colleagues in their pursuit of some answers. Last fall, the National Cancer Institute (NCI), part of the National Institutes of Health, awarded Goran’s group more than $12 million over five years to create a center to study the relationship between obesity and cancer.

The Keck School is one of four institutions nationwide selected to conduct the five year, $54 million Transdisciplinary Research on Energetics and Cancer (TREC) initiative, which unites researchers who focus on diet, weight and physical activity and their effects on cancer. Other TREC center sites include Case Western Reserve University, Fred Hutchinson Cancer Research Center and the University of Minnesota.

“TREC will bring together outstanding scientists from many disciplines,” says Robert Croyle, Ph.D., director of the NCI division of cancer control and population sciences. “Together these experts will answer critical questions that will help guide our nation’s public health efforts. The NCI is determined to help avoid an increase in cancer deaths in the 21st century due to obesity like the one caused by tobacco in the 20th century.”

At large

Croyle’s comparison of obesity and tobacco is a compelling one—and particularly appropriate for USC researchers. Just as in tobacco use, the lifestyle factors that underpin obesity seem to fall into place during childhood.

A 2004 study in the British medical journal Lancet, for example, indicated that the average 3-year-old child was physically active for only 20 minutes a day—only one third of the recommended 60 minutes a day. The study found that toddlers were only burning 1,200 calories daily, significantly less than the 1,500 suggested.

Health experts are no more comfortable with children’s eating habits. When the United States Department of Agriculture in 2005 released its new food guidelines for children, MyPyramid for Kids, the American Heart Association (AHA) for the first time issued eating guidelines for children ages 2 and younger. According to the AHA, by 19 months of age, on any given day, one third of toddlers eat no fruit and French fries are the most commonly consumed vegetable.

With these challenges in mind, Keck School TREC researchers will address how to deter cancer by preventing and controlling obesity during childhood and later in adolescence—the critical, formative period that sets the stage for the remainder of life.

“We know that obesity and related factors such as poor diet and inactivity are known to contribute to cancer risk, and these are factors we can actually do something about,” says Goran, who directs the USC TREC Center. “Our goal is to study obesity from all directions—from physiology to behavior—and focus on children from high-risk ethnic groups to further understand ethnic disparities in the relationships between obesity, metabolism and health.”

Leslie Bernstein, Ph.D., AFLAC Chair in Cancer Research and professor of preventive medicine at the Keck School, serves as associate director of the USC TREC Center and also leads the center’s training and career development component. Bernstein is known for her extensive studies examining links between hormone exposure, obesity and physical activity and cancer risk.

“We know that being overweight or obese raises risk for several types of cancer and that physical activity reduces risk of some cancers,” Bernstein says. “By focusing on children, we hope to learn how to impact obesity early in life by increasing physical activity and changing environmental factors, and to uncover some of the biological mechanisms that link obesity and physical activity to cancer risk.”

The USC TREC Center research program focuses on children because obese children frequently become obese adults. Over the past two decades, the percentage of overweight teens in the United States has tripled—from 5 percent to 16 percent. And certain ethnic groups are more vulnerable to obesity than others; experts estimate that 44 percent of Latino and 40 percent of African-American teenagers are considered overweight, about double the prevalence among Caucasian teens.

Triple threat

Keck School scientists participating in TREC will lead three inter-related projects:

• Examining cancer-related metabolic risk factors in overweight African-American and Latino teens and the use of strength training as a way to reduce risk;

• Finding the physiological and psychosocial reasons that African-American and Latino girls slow or halt their physical activity in their teens; and

• Understanding how factors in the “built environment”—that is, the cities, roads and buildings that humans create—influence physical activity, dietary intake and obesity development during childhood.

Goran will lead the first of the three projects, which builds on his long background in studying obesity among African-American and Latino teens. Beyond lifestyle differences that may contribute to these children becoming overweight, growing evidence indicates that genetics is important, too.

In Goran’s recent studies, he found that African-American and Latino children not only are at high risk of being overweight, but they have a greater chance of becoming insulin-resistant than white children, regardless of build.

When people are insulin-resistant, it means that their tissues become less sensitive to the action of insulin. Insulin is a hormone the body uses to bring glucose, or sugar, from the blood into tissues to be used as an energy source.

Cells in the pancreas create insulin. Scientists have shown that, in general, when someone becomes resistant to insulin—less efficient at using it—the body tries to compensate by pushing the pancreatic cells to pump even more insulin into the blood stream.

But Goran’s group discovered that African-American children compensate for insulin resistance differently from Latino children.

Latino children tended to have high insulin levels in the bloodstream because their bodies responded to resistance by pumping out lots of insulin, as expected. But in African-American children, researchers found elevated insulin levels in the blood because the children’s livers were removing less of the insulin from circulation in the body.

Goran and his colleagues want to understand how these differences may contribute to cancer risk over time. Mounting evidence now suggests that high levels of circulating insulin not only increase risk of diabetes, but of cancer as well.

Insulin is an important growth factor for body tissues and can send signals to cells to proliferate, either directly or by boosting levels of other, even-more-powerful substances called insulin-like growth factors. And one of cancer’s hallmarks is the reckless proliferation of cells.

But genetics appear to be behind more than just the differences in how the children’s bodies deal with insulin resistance. Children may also have differences in where their body fat resides as well as differences in inflammatory processes. Researchers believe that these varying processes might explain, in some part, why African Americans face a greater long-term risk of developing certain cancers than Latinos and other ethnic groups do.

Beyond shedding light on metabolic risk factors, Goran and his colleagues will continue their studies on possible solutions. Most notably, they will test whether a strength-training program can improve levels of certain substances in overweight children’s bodies that may increase long-term cancer risk. If it works, such training could potentially provide a simple, noninvasive and drug-free way to reduce cancer risk.

Goran’s colleague, Donna Spruijt-Metz, Ph.D., assistant professor of research in preventive medicine at the Keck School, also focuses on physical activity among children and teens. But Spruijt-Metz, who oversees the TREC Center’s second project, has turned her attention to the needs of girls in particular.

Spruijt-Metz will expand her National Institutes of Health-sponsored studies that explore why so many Latina and African-American girls stop exercising before and during adolescence.

As Spruijt-Metz explains, people seem to become less active during their teen years regardless of their gender, ethnicity or nationality. Even animals easing into adulthood become less active, suggesting a biological reason for the behavior.

Unfortunately, puberty is a metabolically risky time when insulin resistance and weight gain may become a problem for Latinas and African-American girls—and cutting exercise may just make things worse.

Seizing on this critical stage, Spruijt-Metz will study 100 Latina and African-American girls going through puberty to understand how physical activity, behaviors, feelings, physical development and insulin resistance intersect.

Over three years, the researchers will periodically measure the girls’ insulin sensitivity and other metabolic markers; they will also monitor their physical activity and interview the girls to understand how they are developing psychologically and socially, as well as to understand their mood and feelings about physical activity.

Spruijt-Metz believes that when these girls hit puberty, the resulting bump in insulin resistance may make them feel less motivated to exercise. Ultimately, the researchers want to develop successful ways to help keep girls interested in being active throughout the teen years, so they may continue their healthy lifestyles through adulthood.

Finally, in the third TREC project, Michael Jerrett, Ph.D., associate professor of preventive medicine at the Keck School, will look for outside factors related to fitness, rather than factors that come from within.

Jerrett studies the “built environment” and its relationship to health. Over the last decades, researchers have come to see that the cities, roads and buildings of the built environment have a strong relationship to physical activity, obesity and dietary quality. For example, if children have few safe areas outside in which to play, or accessible friends to play with, they are unlikely to meet exercise goals.

To understand specifically how the built environment influences fatness, Jerrett plans to monitor children’s growth. In an expansive study, Jerrett will follow changes in body mass index over time in nearly 12,000 children from 16 communities across Southern California. He will then look for areas in which children progress strongly toward obesity, and relate these trends with aspects of the built environment that may contribute to the weight gain.

“It’s our hope that we can determine the variables in the environment that contribute significantly to obesity in children,” Jerrett says. “These findings could have public health implications and help our society better structure the built environment to prevent obesity.”

If the researchers have their way, the studies will not just result in slimmer physiques and a more energetic, active population; society just might face a little less heartbreak from diabetes, cardiovascular disease and cancer in the process.

For more information about the Transdisciplinary Research on Energetics and Cancer (TREC) initiative, visit www.cancercontrol.cancer.gov/TREC.