A new study suggests that long-term inflammation may physically change the colon in ways that promote early-onset colorectal cancer (CRC). Researchers found that chronic inflammation can increase the stiffness of colon tissue, potentially creating conditions that help cancer develop and spread. The findings, published in Advanced Science, point to new possibilities for identifying people at risk and developing targeted treatments for this aggressive form of CRC.
"We consider this study a significant advancement toward identifying those at risk of early-onset CRC and finding new ways to treat them," said Emina Huang, M.D., M.B.A., Professor of Surgery in the Division of Colon and Rectal Surgery and Executive Vice Chair of Research for Surgery at UT Southwestern. She is also Professor of Biomedical Engineering and in the Harold C. Simmons Comprehensive Cancer Center.
The research was led by UT Southwestern Medical Center in collaboration with scientists from The University of Texas at Dallas.
"This is the first study to highlight the key role of biomechanical forces in the pathogenesis of early-onset CRC," said Jacopo Ferruzzi, Ph.D., Assistant Professor of Bioengineering at UT Dallas and Biomedical Engineering at UT Southwestern. "Our observations are consistent across multiple length scales and link connective tissue stiffening to altered biochemical signaling in cancer cells."
A Growing Cancer Trend Among Younger Adults
Colorectal cancers that are not linked to inherited genetic conditions and typically appear after age 50 are known as average-onset or sporadic CRCs. Over the past three decades, both diagnosis rates and deaths from these cancers have steadily declined. In contrast, colorectal cancers diagnosed before age 50, referred to as early-onset CRCs, have increased sharply during the same period.
Since 2020, early-onset CRC has accounted for roughly 12% of all colorectal cancer cases in the United States.
Despite this rapid rise, the underlying cause has remained unclear. Previous research has largely focused on lifestyle factors, obesity, and environmental exposures that may lead to chronic intestinal inflammation. However, the biological link between inflammation and early-onset CRC has been poorly understood.
How Chronic Inflammation May Reshape the Colon
According to Dr. Huang, ongoing inflammation can lead to scarring, which slowly alters tissue structure and increases stiffness over time. Similar changes are known to contribute to cancer development in other organs, including the breast and pancreas. Her team set out to determine whether this same process could play a role in early-onset CRC.
To investigate, researchers analyzed colon tissue from patients who underwent tumor removal surgery at William P. Clements University Hospital and Parkland Health. The study included 19 samples from individuals with average-onset CRC and 14 from patients with early-onset CRC. Each sample contained both tumor tissue and nearby noncancerous tissue.
Testing revealed that tissue from early-onset CRC patients was significantly stiffer than tissue from older patients, not only within tumors but also in surrounding healthy areas. This pattern suggests that increased stiffness may occur before cancer fully develops.
Collagen Changes Point to Scarring
To understand what caused this rigidity, the team examined collagen, a structural protein that becomes more abundant and changes form during scarring. Colon tissue from early-onset CRC patients contained collagen that was denser, longer, more mature, and more uniformly aligned compared with samples from average-onset cases. These features strongly indicate extensive scarring in early-onset CRC tissue.
When researchers analyzed gene activity, they found higher expression of genes involved in collagen metabolism, blood vessel formation, and inflammation in early-onset CRC samples. These findings further support the idea that chronic inflammation drives tissue stiffening.
Stiff Tissue Alters Cancer Cell Behavior
The researchers also detected increased activity in a pathway linked to mechanotransduction, the process by which cells sense and respond to physical forces. This suggests that cancer cells in early-onset CRC may change their behavior based on how stiff their surroundings are.
Lab experiments reinforced this idea. Colorectal cancer cells grown on stiffer surfaces multiplied more quickly and increased rigidity further. Three-dimensional organoid models created from CRC cells also grew larger and faster when placed in stiffer environments.
Implications for Detection and Treatment
Taken together, the findings indicate that a rigid colon environment may help trigger and accelerate colorectal cancer in younger patients, Dr. Huang said. The results also suggest that targeting mechanotransduction pathways could slow or stop cancer development, an approach already under investigation in other cancers.
Dr. Huang added that diagnostic tools designed to measure intestinal stiffness could one day help identify individuals at higher risk for early-onset CRC, similar to how colonoscopies are used to screen for average-onset disease.
Dr. Huang holds the Doyle L. Sharp, M.D. Distinguished Chair in Surgical Research. She is a member of the Cellular Networks in Cancer Research Program at Simmons Cancer Center.
Study Funding
This study was funded by the National Institutes of Health (R01 CA234307 and U01 CA214300), The University of Texas at Dallas Office of Research and Innovation through the CoBRA program, the Burroughs-Wellcome Trust, the American Society of Colon and Rectal Surgeons Resident Research Initiation Grant, The University of Texas at Dallas Bioengineering Research Award, the UT Southwestern Whole Brain Microscopy Facility, an Axioscan 7 Award, the Catherine and James McCormick Charitable Foundation supporting research in early-onset colorectal cancer, and a National Cancer Institute (NCI) Cancer Center Support Grant (P30 CA142543).
