Researchers uncover mechanism explaining how obesity increases cancer risk

Scientists at City of Hope and TGen (part of City of Hope) have explained a major mechanism for why gaining excess weight increases the risk of cancer across multiple organs. The findings emphasise the importance of maintaining a healthy weight from early childhood and propose a potentially more accurate way than body mass index (BMI) to predict the increase in cancer risk associated with obesity.

"People have long been told that obesity increases cancer risk, but they are rarely told why," said senior author, Dr Cristian Tomasetti, director of City of Hope's Center for Cancer Prevention, Early Detection and Monitoring and professor in the Early Detection and Prevention Division at TGen. "Our study reveals that excess weight doesn't just affect metabolism or hormones - it can physically enlarge organs, creating more opportunities for cancer to take hold. Understanding that process matters because it helps explain how everyday health choices can shape cancer risk years or even decades down the line."

In other words, as a person gains weight, their organs also grow in size by accumulating more cells to meet the higher energy needs of a bigger body. Having more cells boosts the odds of more DNA errors as cells divide, increasing the likelihood of cancer. This study is the first to analyse the size of multiple organs in a large cohort of individuals across the full BMI spectrum.

To test this hypothesis, Tomasetti and his collaborators conducted a two-pronged study. First, the team evaluated 747 adults whose weight in relationship to their height spanned the complete BMI spectrum, from underweight (18.5 BMI) all the way to severely obese (40-plus BMI). Using CT scans, the researchers measured the size of each adult's liver, kidneys and pancreas. They discovered that the organs grew larger as body weight increased. For every 5-point increase in BMI, the liver grew by 12%, kidneys by 9% and the pancreas by 7%.

Next, the research team counted the cells in samples of kidney tissue taken from autopsies and re-analysed biopsy data from living patients. The lab showed that more than 60% of the kidneys' growth resulted from an increase in the number of cells in the organ, a process called hyperplasia. The rest was due to individual cells growing bigger, or hypertrophy.

The City of Hope and TGen finding corrects earlier theories that larger organ size in obese individuals resulted primarily from fatter cells. Rather, obesity mainly increases the number of cells at risk for copying errors, uncontrollable growth, and potential malignancy. This increase in organ size has harmful consequences.

"Think of playing the lottery: The more tickets you buy, the greater your chances of winning," Tomasetti said. "Similarly, the more cells in an organ, the more mutations and the greater the risk of one cell going awry during division and becoming cancerous."

Overall, the study showed a strong link between organ size enlargement and cancer risk across all three organs, confirming the mathematical predictions. The finding provides evidence for this as a major mechanism of tumorigenesis induced by obesity, in addition to factors like inflammation and hormonal imbalances. This newly discovered effect of obesity can be large, with organs even doubling in size.

"When an organ doubles in size, it is expected to roughly double its risk of developing cancer," said first author, Dr Sophie Pénisson, associate professor at TGen. "BMI is a poor proxy for telling us what the size of an organ is, as BMI doesn't distinguish between fat and lean tissue. Our work suggests that, at least for some organs, their dimensions may predict cancer risk better than BMI."

Noting the relationship between diet and cancer, the authors emphasised the importance of maintaining a healthy weight from a young age.

"Organs take time to grow, and it can take decades for cells to turn malignant," added Tomasetti. "Childhood obesity gives organ cells a longer runway to accumulate mutations and evolve into something worse."

Future studies will explore whether losing weight can reduce organ size and cancer risk, and the potential effect of GLP-1 drugs on lowering cancer risk through weight loss.

"This exciting research deepens our understanding of how obesity may lead to cancer and highlights the role of organ growth in this process, which is also relevant for many individuals with diabetes,” said Dr Debbie C Thurmond, director of the Arthur Riggs Diabetes & Metabolism Research Institute and Chan Soon-Shiong Shapiro Distinguished Chair in Diabetes at City of Hope. “It will be important to see if the new anti-obesity drugs can revert this process for cancer prevention,"

The findings were reported in the paper, ‘Hyperplasia Functions as a Link Between Obesity and Cancer’, published in Cancer Research. To access this paper, please click here