Abstract
BACKGROUNDChildhood 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. We hypothesize that RT-induced adipose tissue dysfunction contributes to the development of cardiometabolic disease in the expanding population of childhood cancer survivors.METHODSWe performed clinical metabolic profiling of adult childhood cancer survivors previously exposed to TBI, abdominal RT, or chemotherapy alone, alongside a group of healthy controls. Study participants underwent abdominal s.c. adipose biopsies to obtain tissue for bulk RNA sequencing. Transcriptional signatures were analyzed using pathway and network analyses and cellular deconvolution.RESULTSIrradiated adipose tissue is characterized by a gene expression signature indicative of a complex macrophage expansion. This signature includes activation of the TREM2-TYROBP network, a pathway described in diseases of chronic tissue injury. Radiation exposure of adipose is further associated with dysregulated adipokine secretion, specifically a decrease in insulin-sensitizing adiponectin and an increase in insulin resistance–promoting plasminogen activator inhibitor-1. Accordingly, survivors exhibiting these changes have early signs of clinical metabolic derangement, such as increased fasting glucose and hemoglobin A1c.CONCLUSIONChildhood 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.FUNDINGThis study was supported by Rockefeller University Hospital; National Institute of General Medical Sciences (T32GM007739); National Center for Advancing Translational Sciences (UL1 TR001866); National Cancer Institute (P30CA008748); American Cancer Society (133831-CSDG-19-117-01-CPHPS); American Diabetes Association (1-17-ACE-17); and an anonymous donor (MSKCC).
Highlights
Through decades of concerted multi-disciplinary effort, the average five-year survival rate for all childhood cancers exceeds 80% (1), resulting in a population of 400,000 survivors in the US in 2019 (2)
Childhood cancer survivors exposed to abdominal RT or total body irradiation (TBI) during treatment exhibit signs of chronic subcutaneous adipose tissue dysfunction, manifested as dysregulated adipokine secretion that may negatively impact their systemic metabolic health
Childhood cancer survivors remain vulnerable to premature morbidity and mortality from treatment-related late effects (3), including diabetes mellitus (DM), dyslipidemia, and cardiovascular disease (4), with a seven-fold increased risk of cardiac death compared to the age-matched general population (5)
Summary
Through decades of concerted multi-disciplinary effort, the average five-year survival rate for all childhood cancers exceeds 80% (1), resulting in a population of 400,000 survivors in the US in 2019 (2). The molecular and cellular mechanisms underlying this strong clinical association remain unknown, but have been postulated to arise from RT-induced injury to endocrine organs such as the hypothalamic-pituitary axis (8) and pancreas (9). Another important endocrine organ, the abdominal adipose tissue, has received comparatively less consideration as a target of RT-induced injury. 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. We hypothesize that RT-induced adipose tissue dysfunction contributes to the development of cardiometabolic disease in the expanding population of childhood cancer survivors
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