Childhood cancer survivors who received abdominal radiotherapy (RT) or total body irradiation (TBI) are at increased risk for cardiometabolic disease, but the underlying mechanisms are unknown. Now, a new study finds that it may be necessary to find strategies that reduce the radiation dose delivered to fat.
Their findings are published in the journal JCI Insight in a paper titled, “Therapeutic radiation exposure of the abdomen during childhood induces chronic adipose tissue dysfunction.”
The researchers performed clinical metabolic profiling of adult childhood cancer survivors previously exposed to TBI, abdominal RT, or chemotherapy alone, alongside a group of healthy controls. Transcriptional signatures were analyzed using pathway and network analyses and cellular deconvolution.
“When physicians are planning radiation therapy, they are very conscious of toxicity to major organs. But fat is often not considered,” said Rockefeller’s Paul Cohen, MD, PhD. “Our results imply that the early exposure of fat cells to radiation may cause long-term dysfunction in the adipose tissue that puts childhood cancer survivors at higher risk of cardiometabolic disease.”
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 distinct group of childhood cancer survivors who were developing cardiometabolic disease at younger ages than expected, in the absence of typical risk factors like obesity,” he said.
Previous findings by Cohen’s lab and others had highlighted the importance of fat as an endocrine organ that helps regulate metabolism. “People once viewed fat as this passive bag of cells,” Cohen said. “We now appreciate that fat, with its constellation of immune cells and nerve projections, is much more than that. It’s a complex and dynamic organ.”
“Although adipose tissue is found throughout the body and has many physiologic functions, it is not considered an ‘organ at risk’ when radiation oncologists make their treatment plans, and thus can receive high doses that likely disrupt its normal function,” explained Xiaojing Huang, PhD, a postdoc in Cohen’s lab and first author on the study.
The researchers discovered “childhood cancer survivors exposed to abdominal RT or TBI during treatment exhibit signs of chronic s.c. adipose tissue dysfunction, manifested as dysregulated adipokine secretion that may negatively impact their systemic metabolic health.”
Cohen’s lab is currently developing a mouse model to better study the cellular and molecular consequences of radiation, which may lead to a better understanding of any underlying disease pathways.
“Nothing is going to change overnight,” Cohen said. “But these early findings may draw a clinician’s attention to the fact that adipose tissue can be affected by radiation, and that those effects could cause problems for their patients decades later.”