Decades after battling childhood cancer, survivors are often faced with a new challenge: cardiometabolic disease. A spectrum of conditions that includes coronary artery disease and diabetes, cardiometabolic disease usually affects people who are obese, the elderly, or insulin resistant. For reasons as yet unknown, young, apparently healthy adults who have survived childhood cancer are also at risk.
Radiation therapy may be to blame. A new study finds that childhood cancer patients treated with abdominal or total body radiation grow up with abnormalities in their adipose tissue (fatty tissue), similar to those seen in obese individuals with cardiometabolic disease. The findings, published in JCI Insight, suggest it may be necessary to find strategies that reduce the radiation dose delivered to fat.
When doctors plan radiation therapy, they are very aware of toxicity to major organs. But fat is often not taken into account. Our results imply that the early exposure of fat cells to radiation may cause long-term dysfunction in the adipose tissue, putting childhood cancer survivors at higher risk for cardiometabolic disease.”
Paul Cohen, Rockefeller University
Beyond a bag of cells
Children with cancer are more likely to survive into adulthood than ever before. More than 80 percent of cancer patients under the age of 18 are still alive a year after an initial diagnosis. But their life expectancy remains stubbornly low, especially as many survivors develop cardiometabolic diseases. Studies suggest that, among those treated with radiation therapy, the risk of cardiac death is seven times higher than that of the general population.
Cohen, a Rockefeller physician-scientist with a joint appointment as a cardiologist at Memorial Sloan Kettering Cancer Center, wondered why. “While seeing patients, I kept returning to this particular group of childhood cancer survivors who developed cardiometabolic disease at a younger age than expected, in the absence of typical risk factors such as obesity,” he says.
He suspected that damaged fat played a role. Recent work by Cohen’s lab and others had emphasized the importance of fat as an endocrine organ that helps regulate metabolism. “People once thought of fat as a passive bag of cells,” says Cohen. “We now appreciate that fat, with its constellation of immune cells and nerve processes, is much more than that. It is a complex and dynamic organ.”
And like any other organ, fat can be vulnerable to radiation damage — with similarly dire consequences. “Although adipose tissue is found throughout the body and has many physiological functions, it is not considered an ‘organ at risk’ when radiation oncologists make their treatment plans, and thus may be given high doses that are likely to interfere with normal function,” says Xiaojing Huang . , a postdoc in Cohen’s lab and lead author of the study.
Cohen, Huang and a team of biostatisticians and nurses from Rockefeller University Hospital began investigating a possible link between radiation therapy in children and the mysterious metabolic diseases that follow them into adulthood.
For the study, Cohen and colleagues took biopsies from a small group of adults who had survived childhood cancer after treatment with total body or abdominal radiation therapy.
The volunteers also had a low risk of metabolic disease, with normal BMIs and waist-to-hip ratios. Still, the data indicated that their adipose tissue was packed with immune cells known as macrophages and contained several proteins involved in the body’s response to chronic injury. This kind of molecular profile is what Cohen expected to find in elderly, obese patients, non-healthy, young cancer survivors who had received a clean bill of health years ago. And their bodies were already showing the subtle indicators of metabolic disease brewing, such as rising blood sugar.
“We specifically selected younger people with a normal BMI, and yet the signature we found matches that of people who were much older and obese,” says Cohen. “Radiation is said to cause premature aging, and that’s consistent with what we saw here.”
Cohen cautions against drawing conclusions about causality from the study, but he hopes documenting the association between radiation exposure in children and damage to adipose tissue could open the door for further experimentation. His lab is currently developing a mouse model to better study the cellular and molecular consequences of radiation, work that could lead to a better understanding of any underlying disease pathways. Cohen also proposes the possibility that a larger study could uncover consistent molecular markers to indicate which childhood cancer survivors are most at risk of developing cardiometabolic disease.
In the meantime, he hopes the current findings will alert doctors to the importance of fat and the need to protect it. “Nothing changes overnight,” says Cohen. “But these early findings may draw a physician’s attention to the fact that adipose tissue can be affected by radiation, and that those effects can cause problems for their patients decades later.”
Huang, X., et al. (2021) Therapeutic radiation exposure of the abdomen during childhood causes chronic adipose tissue dysfunction. JCI Insight. doi.org/10.1172/jci.insight.153586.