Another piece of the puzzle identified for why higher BMIs are associated with an increased risk of developing various cancers.
A new study suggests a fairly simple potential mechanism: larger organs have more cells that are capable of becoming cancerous.
A team of researchers from the US, France, Denmark and China have found that each doubling of organ volume increased the risk of developing cancer by 108%. Using CT imaging, organ biopsy and organ autopsy, they determined that obesity and overweight were associated with increased organ size, which in turn was associated with higher cancer risk.
In a study of 747 people with CT imaging, every five-point increase in BMI increased liver volume by 12%, pancreas volume by 7% and kidney volume by 9%. The researchers focused on these organs because their volumes remain relatively stable over short periods, unlike organs such as the stomach and bowel that fluctuate with food intake and distension.
Overall, BMI accounted for 34% of variation in liver size, 24% of variation in kidney size and 12% of variation in pancreas size, and organ volumes in the severely obese were between 50% and 100% larger than those in individuals with a normal BMI.
Using regression modelling, they estimated that an individual with a BMI of 50kg/m² would have significantly larger organs than someone with a BMI of 20kg/m². Liver volume associated with the larger BMI was 2372mL, pancreas was 112mL and combined kidney volumes were 453mL, compared to 1201mL, 72mL and 264mL respectively.
Additionally, in three people with kidney autopsy and 25 people with kidney biopsy, researchers found that up to 75% of enlargement in cortical tubules was attributable to increased cell number (hyperplasia), while 25% was linked to enlargement of individual cells (hypertrophy). Larger tubules also contained significantly more nuclei.
In other parts of the kidney, including the medulla and glomeruli, enlargement appeared to be driven entirely by hyperplasia, with little or no contribution from hypertrophy.
Using data from published cohort studies alongside their own organ volume measurements, the researchers found the correlation coefficient between organ volume ratios and cancer risk was 0.81. For individuals with a BMI of 40kg/m² or higher, their liver volume ratio 1.74 compared with normal-weight individuals and their relative liver cancer risk was 1.79.
The findings suggested that obesity-related cancer risk may partly reflect a simple numbers game: more cells create more opportunities for malignant transformation.
“Organ enlargement predominantly driven by hyperplasia increases the number of parenchymal cells at risk of malignant transformation,” the authors wrote.
According to the International Agency for Research on Cancer, obesity – defined as a body mass index (BMI) of 30kg/m² or greater – increases the risk of at least 13 cancers. These include breast (in postmenopausal women), colon, rectum, liver, pancreas, kidney, thyroid, gallbladder, uterus, ovary, oesophagus, gastric, cardia and bone marrow.
Notably, many of these cancers don’t arise from adipose tissue and aren’t confined to the digestive tract.
“This suggests the presence of at least one yet unrecognised carcinogenic mechanism that operates independently of adipose tissue pathology, the composition of one’s diet, and the gut microbiome,” researchers said.
The team also explored whether the same relationship might apply to other organs associated with obesity-related cancer risk. Using literature-derived estimates, they found that organ enlargement patterns were broadly consistent with observed increases in cancer risk in the gallbladder, gastric cardia and thyroid, but found the uterus behaved differently.
Uterine cancer risk increased far greater than organ size alone would predict. At a BMI of 40kg/m², uterine size increased by an estimated 1.47-fold, but the relative uterine cancer risk rose approximately 7.1-fold.
Researchers suggested this may be because most uterine cancers arise in the endometrium, which can expand without substantially changing total uterine size.
While the findings were significant, the authors emphasised that hyperplasia is unlikely to be the sole explanation for obesity-associated cancer. Obesity also alters hormonal signalling, inflammatory pathways, insulin regulation and tissue architecture, all of which may further promote carcinogenesis.
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The researchers noted that even partial increases in cell number could substantially increase cancer risk if those cells are simultaneously exposed to increased proliferative stress or growth-promoting metabolic environments.
They also highlighted that organ enlargement reflects more than just cellular growth. Vascular changes, extracellular matrix remodelling and stromal expansion may all contribute to increased organ volume without directly increasing the number of mutation-prone cells.
Nevertheless, the findings provide what the authors describe as “important new insights” into obesity-associated cancer risk.
“For the first time, we demonstrate a significant correlation between the liver, pancreas and kidney volumes and cancer risk, showing that a doubling in organ size roughly corresponds to a doubling in cancer risk,” they wrote.
The study also helps explain why obesity-associated cancers occur across multiple organ systems rather than being confined to fat tissue itself. As the body enlarges in response to excess caloric intake, organs appear to enlarge in parallel to meet increased metabolic demand, inadvertently increasing the number of cells vulnerable to cancer-causing mutations.
