Hyperplasia Functions as a Link between Obesity and Cancer

Obesity is a well-established risk factor for several cancers, yet the underlying mechanisms remain incompletely understood. We hypothesized that as body size increases with obesity, organ size increases to meet metabolic demands, which in turn raises the number of cells at risk of malignant transformation. Measurement of the liver, pancreas, and kidney volumes in 747 adults across a wide body mass index (BMI) range (17.8-70.9 kg/m2) showed a strong positive correlation between BMI and organ size: a 5-unit increase in BMI was significantly associated with volume increases of 12% in the liver, 9% in both kidneys combined, and 7% in the pancreas. To determine the cellular basis of organ enlargement, kidney cell numbers were quantified using both autopsy samples (34,337 proximal tubular epithelial cells) and biopsy data from 25 individuals. The total number of cells increased substantially, indicating that approximately 61% of kidney enlargement was due to hyperplasia, with the remaining 39% increase attributable to hypertrophy. Moreover, organ volume ratios, relative to volume for normal-weight adults, strongly correlated with cancer risk across the three organs, indicating that a doubling in organ volume corresponded approximately to a doubling in cancer risk. These findings suggest a mechanism linking obesity to cancer: as body size and metabolic demands increase, organs expand primarily through hyperplasia that increases the number of cells susceptible to malignant transformation, complementing known pathways involving inflammation, hormones, and metabolic dysregulation. SIGNIFICANCE: Increasing body size corresponds to organ enlargement predominantly driven by hyperplasia that results in a greater number of cells at risk of malignant transformation, linking obesity to cancer risk.