Colon Cancer Linked to Physical Inactivity and Obesity

Obesity and physical inactivity are linked to a specific type of colorectal cancer (CRC), according to a new study. Shuji Ogino, MD, PhD, associate professor of pathology at Dana-Farber Cancer Institute, department of epidemiology at Harvard School of Public Health in Boston, and colleagues found a link between higher body mass index (BMI) and CTNNB1-negative CRC. Higher physical activity was associated with a lower risk of CTNNB1-negative CRC. The results, published in Cancer Research, suggest that energy balance and metabolism are important for colorectal tumor development.

The CTNNB1 gene encodes -catenin, one of the major coordinators of the WNT signaling pathway, whose overactivation contributes to tumor progression. Deregulation of the WNT pathway has been associated with colorectal tumor development, but how metabolism and obesity play a role in WNT signaling and how they contribute to colorectal cancer development in people has not been well studied. Previous studies have suggested that excess body fat and immobility can contribute to colorectal cancer risk. The current study now links the WNT pathway, responsible for both tumorigenesis and energy metabolism, to colorectal cancer.

“A role of CTNNB1 in cancer has been better studied, but there have been no data on interplay between obesity and CTNNB1 status in development of human cancer in the real world,” said Ogino. “Our data clearly show that CTNNB1 activation can make cells or tumor cells growth more sensitive to energy balance status [as measured by] obesity or physical activity.”

Ogino and colleagues used data from two prospective cohort studies-the Nurses’ Health Study and the Health Professionals Study-to study the association between BMI, exercise activity, and colorectal cancer risk. The studies included 109,046 women and 47,684 men who were divided by CTNNB1 expression status and followed up for colorectal cancer incidence. A total of 2,263 study participants were diagnosed with CRC; 861 had available tumor CTNNB1 expression status-467 (54%) of these were CTNNB1-negative and 394 (46%) were CTNNB1-positive.

An increased BMI was associated with a higher risk of CTNNB1-negative CRC for both men and women. An increasing BMI by 5 kg/m² increments was associated with a 34% higher risk of CTNNB1-negative CRC, but not CTNNB1-positive CRC (P < .0001). Increasing levels of physical activity, as reported by the study subjects, was associated with a lower risk of CTNNB1-negative CRC. While physical activity level was associated with a lower risk of CTNNB1-negative CRC for both men and women, statistical significance was not reached in men. There was no association of CRC risk and physical activity among those with CTNNB1-positive CRC. “The most important result is that obesity and physical inactivity differentially influence specific carcinogenesis pathways, CTNNB1-positive and negative pathways,” said Ogino. CTNNB1 activation appears to allow an independence from energy balance in colorectal tumor cells, while the downregulation of CTNNB1 may make tumor cells more highly susceptible to energy balance status.

It may be possible to develop a strategy to manipulate CTNNB1 and energy balance together against cancer, said Ogino. Preclinical studies to test the efficacy of agents that target the CTNNB1 pathway are first needed, followed by human clinical trials, but such an undertaking is not yet underway.

Whether CTNNB1 expression is linked to other cancer types remains to be seen. The link between obesity and many other cancer types, including breast cancer, has been well documented.

CTNNB1 may be used as a biomarker to identify those individuals who may be more prone to develop CTNNB1-negative CRC. For these individuals, physicians may recommend a higher physical activity level and weight monitoring.

The current study is an example of an interdisciplinary science-a combination of epidemiology with molecular pathology. “As attested by this study, molecular pathological epidemiology (MPE) research is very unique, and can generate unique human data, which no other study design can generate,” said Ogino. MPE studies are only possible with National Institute of Health support, and working with hospitals around the United States that provide tumor tissue samples, as well as general public participation. “Because of our well-established MPE database, we can continue to test unique hypotheses and generate novel data to improve medicine and public health,” Ogino noted, highlighting the need for continuing collaborations of the NIH, hospital networks, and the general public. According to Ogino, the integration of epidemiology, molecular pathology, and laboratory research needs to continue to improve public health and general knowledge about disease development.