Scientists at City of Hope and the Translational Genomics Research Institute (TGen) have identified a mechanism explaining how obesity increases cancer risk across multiple organs. Their research, published in Cancer Research, a journal of the American Association for Cancer Research, found that as body size increases, organs enlarge in size through hyperplasia, an increase in the number of cells in each organ. This increase in the number of cells in an organ increases the odds of DNA errors from cell division, boosting the likelihood of cancer development.
“People have long been told that obesity increases cancer risk, but they are rarely told why,” said senior author Cristian Tomasetti, PhD, director of City of Hope’s Center for Cancer Prevention, Early Detection and Monitoring. “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.”
Obesity has long been known as a risk factor for at least 13 cancers, including breast, colon, liver, kidney, pancreas, and uterine cancers, yet the underlying biological mechanisms driving this increased risk have not been uncovered. Prior research efforts have focused obesity-related effects such as low-grade inflammation, hormonal disruptions, and metabolic changes that are associated with excess adipose tissue. But these effects alone have not fully explained the association.
Taking a different approach, the City of Hope and TGen team hypothesized that as body size increases with obesity, organs enlarge to meet the higher metabolic demands of a larger body. This enlargement occurs primarily through hyperplasia, an increase in the number of cells, as opposed to hypertrophy, the enlargement of individual cells. More cells increase the number of opportunities for mutations during cell division, which can lead to malignancy.
“Think of playing the lottery: The more tickets you buy, the greater your chances of winning. 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,” Tomasetti said.
To test this the researchers they analyzed CT scans of 747 adults representing the full spectrum of BMI, from underweight to severely obese, to measure liver, pancreas, and kidney volumes. The study revealed that for every five point increase in BMI, liver volume increased by 12%, kidney volume by 9%, and pancreas volume by 7%. Next, the team quantified cell numbers in kidney tissue using autopsy samples and biopsy data, finding that about 61% of the kidney enlargement was due to hyperplasia, with the remaining 39% from 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,” the researchers wrote.
By linking organ size directly to cancer risk, the findings suggest a potentially more accurate measure than BMI for predicting obesity-related cancer risk. “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,” said first author Sophie Pénisson, PhD, an associate professor at TGen.
The implications for future treatments for patients are many. Physicians could one day incorporate organ volume measurements into cancer risk assessments, particularly for high-risk patients or those with childhood obesity. Drug developers may investigate whether emerging anti-obesity treatments such as GLP-1 receptor agonists, can reduce organ size and, as a result, also lower cancer risk.
“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 Debbie C. Thurmond, PhD, director of the Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope. “It will be important to see if the new anti-obesity drugs can revert this process for cancer prevention.”
Future studies are expected to explore whether weight loss can reverse organ enlargement, and whether this correlates with a reduction in cancer risk. Additionally, research will be needed to confirm these findings in other organs, such as the thyroid, uterus, and gallbladder, and to understand the interplay of organ enlargement with inflammation, hormonal changes, and metabolic dysfunction.
