Special Issue: Cancer and Obesity Research
Bridging Disciplines to Study Possible Cancer-Obesity Links
The WISER Survivor trial at the University of Pennsylvania TREC center will test the effects of exercise and weight loss on biomarkers for cancer recurrence, quality of life, and lymphedema in overweight breast cancer survivors.
When it comes to understanding the connections between obesity and cancer, one thing is clear: It's complicated. In an effort designed to address this complexity, NCI launched the Transdisciplinary Research on Energetics and Cancer (TREC) initiative in 2005. TREC is a multicenter program that brings together investigators from diverse disciplines, ranging from biochemistry and molecular biology to behavioral science and urban planning, to understand the obesity-cancer link.
"The TREC initiative challenged the research community to look at this problem from a very different approach and to broaden scientific partnerships in a truly transdisciplinary way," said Dr. Linda Nebeling of NCI's Division of Cancer Control and Population Sciences, who oversees the TREC program.
Transdisciplinary research emphasizes collaboration, information sharing, and integration across academic areas to achieve a common goal. For TREC, the ultimate goal is to reduce the incidence of cancers that are linked to obesity, poor diet, and low levels of physical activity, as well as to improve the length and quality of life for cancer survivors.
In 2005, NCI awarded 5-year grants to the first four TREC research centers and a coordination center. This June, NCI announced funding of four new TREC research centers and continuation of the coordination center, which is located at the Fred Hutchinson Cancer Research Center in Seattle.
The coordination center "serves as the communication and infrastructure hub for TREC," said the center's director, Dr. Mark Thornquist. The center also promotes and facilitates data sharing among TREC investigators and with the broader scientific community and helps NCI monitor TREC's progress and productivity.
Teaming up to Study Diet and Cancer Risk
Through meetings, training, and an emphasis on collaborative research, Dr. Nebeling noted, TREC "creates a greater opportunity for investigators from different fields to start learning each other's vocabulary, find common ground, and work together in team science."
At the Hutchinson Center, one of the first four TREC research centers, members of one transdisciplinary team examined the effects of certain dietary patterns in cells, an animal model, and human subjects.
Drs. Johanna Lampe and Marian Neuhouser of the Hutchinson Center led a clinical trial of the effects of low and high glycemic-load diets on possible cancer risk biomarkers in people with normal body weight and body mass index (BMI) and in people who were overweight or obese, with high BMI. Low glycemic-load diets (those rich in foods such as legumes and whole grains) lead to a gradual increase in blood glucose after a meal, whereas high glycemic-load diets (which include foods such as white bread, white rice, and potatoes), which may be associated with obesity, cause a rapid rise in blood glucose and excess insulin secretion.
Some observational and epidemiologic studies have suggested that low glycemic-load diets are associated with a lower risk of certain cancers, "but very few controlled studies have been done to see if tweaking diet changes markers associated with risk," Dr. Lampe said.
Dietitians at Hutchinson designed the diets used in the study so that participants would not lose weight, allowing the researchers to "focus on whether any effects we observed were specifically diet related, rather than due to body weight change," Dr. Lampe explained.
For a related animal study, Dr. Lampe said, "we prepared all the meals that we fed to humans, ground them up and froze them down into little rat-size portions." She and Dr. Neuhouser sent the frozen rat rations to Dr. Henry Thompson, their collaborator at Colorado State University, who fed the diets to a strain of rats that spontaneously develop mammary tumors. Dr. Thompson compared the effects of the two diets on tumor development, which was not feasible in the human study because the duration was too short and it included a relatively small number of people.
Another Hutchinson Center TREC researcher, Dr. David Hockenbery, studied the effects of high glucose levels at the cellular level, looking at signaling pathways and other cell responses that may play a role in cancer development.
Results of the human and rat studies have not yet been published, but the benefits of a transdisciplinary approach seem clear. Being part of the TREC initiative, Dr. Lampe said, "had me thinking more broadly about our own experimental approach for addressing these questions [about diet, obesity, and cancer]. I also learned a lot from my colleagues in other disciplines."
Taking It to the Streets
Taking a transdisciplinary approach to understanding and preventing cancer linked with obesity was "a no-brainer" for Dr. Leslie Lytle, a nutritionist and behavioral scientist at the University of Minnesota, site of another of the first group of TREC centers. "In a school of public health, [where] we look at how we can change and improve the health behavior of populations," she explained, "you immediately realize that one person can't be an expert on everything you have to know."
Dr. Lytle led a TREC center project dubbed IDEA, for Identifying Determinants of Eating and Activity, to identify obesity-related risk factors in adolescents at the individual, family, school, and community levels. "We can speculate on what's causing the obesity epidemic in kids and adults, but we have very little data that actually [explain] how risk factors at different levels may be related to each other and to obesity risk in populations," she noted.
To guide her research, Dr. Lytle developed a conceptual model of potential risk factors with input from scientists from fields ranging from physiology to urban planning. With the model in hand, Dr. Lytle's team began following 349 young people in the Minneapolis-St. Paul area along with one parent or guardian for each youth.
One of the chief technologies the team used to investigate risk factors at the community level was a geographical information system (GIS) to assess the physical environment of neighborhoods. With GIS, Dr. Lytle said, researchers can link a child's address with publicly available databases to get information on the walkability of a neighborhood, the types of food stores and recreation facilities within a certain radius of the child's home, proximity to public transportation, and a host of other factors.
We need behavioral interventions that help prevent cancer in the first place.
Dr. Lytle and her colleagues used GIS to show a relationship between the built environment (buildings, spaces, and products created by people) and metabolic syndrome (which is linked to obesity) in adolescents; to examine how neighborhood food environments might affect adolescent nutrition, dietary intake, and weight; and to identify factors that predict levels of physical activity among boys and girls.
Numerous studies have examined the possible connections between neighborhood environments and health characteristics, Dr. Lytle said. But "in the IDEA study we are able to drill down much closer to the individual level" to nail down elements of the larger environment that are related to indicators of obesity.
Results of the IDEA study and others like it will have implications for public policies aimed at curtailing the obesity epidemic, such as urban planning. For instance, Dr. Lytle said, the findings "provide information about how we design a neighborhood to be more walkable, the need for more full-service grocery stores in urban areas, and the importance of creating parks and recreation areas that are accessible, well-lit, and friendly."
As researchers learn more about the root causes of cancers linked to obesity, Dr. Lytle said, "I feel strongly that we need behavioral interventions that help prevent cancer in the first place," not just better drugs to treat cancer once it occurs.
Moving Obesity Research from Bench to Trench
In the new phase of TREC, "we have greater integration from basic science to population science" and beyond, said Dr. Nebeling. The new phase also includes studies with more connections to cancer patients and survivors.
The TREC center at the University of Pennsylvania, for example, "was designed to go all the way, not just from mouse to human trials, but from mouse to policy, or 'from bench to trench,'" said Dr. Kathryn Schmitz, the center's principal investigator.
Dr. Schmitz, an exercise physiologist, is leading the centerpiece project, the Women in Steady Exercise Research (WISER) Survivor trial. This randomized trial will follow 555 overweight breast cancer survivors to assess the effects of exercise, weight loss through caloric restriction, and the two combined, on biomarkers for recurrence, quality of life, and lymphedema—a chronic and often devastating adverse effect of breast cancer treatment.
The trial is a follow-up to previous work by Dr. Schmitz, which showed that weight training can reduce the likelihood of lymphedema flare-ups in breast cancer survivors.
A second project, led by cancer biologist Dr. Lewis Chodosh, will study the same interventions as in the WISER Survivor trial in a genetically engineered mouse model for breast cancer recurrence. "We can't study the women through recurrence because the study is for only 5 years," explained Dr. Schmitz. But the mouse study will show whether exercise and/or caloric restriction can affect recurrence in overweight animals.
The mouse study will also measure a range of possible biomarkers of recurrence in the mice to gain insights into molecular pathways that might mediate recurrence. Those results will in turn inform Dr. Schmitz's decisions on which biomarkers to focus on in the WISER Survivor participants.
The third TREC project at Penn, led by internal medicine professor Dr. J. Sanford Schwartz, is a cost-effectiveness analysis of the WISER Survivor trial. The results "will help determine whether a low-cost intervention for lymphedema, namely exercise, could save money in the long run," said Dr. Schmitz. If so, she said, "we could change health care policy to approve payment for rehabilitation exercise programs for breast cancer survivors."
Dr. Schmitz is an enthusiastic advocate of transdisciplinary research. She emphasized the need for more communication between scientists across diverse disciplines and within related fields. "It's so much more productive—and fun—when you can look at things from different vantage points," she said, adding, "My favorite quote is from Albert Einstein: 'Play is the highest form of research.'"
Related reading: "TREC Cancer Initiative Launches New Collaborative Relationships"