Early-onset colorectal cancer (EO CRC) is marked by unusually stiff, fibrotic colorectal tissue that actively promotes tumor growth, according to a new study that points to biomechanical remodeling as a defining — and potentially driving — feature of the disease.

Researchers found that colorectal tumors and nearby normal colon tissue from patients diagnosed before age 50 years were significantly stiffer and more viscous than tissues from older patients with CRC.

These physical changes were linked to altered collagen structure, pro-fibrotic gene activity in stromal cells, and increased proliferation of epithelial cancer cells through mechanosensitive signaling pathways.

“Together, these findings establish EO CRC as a disease marked by early and widespread biomechanical remodeling, suggesting that a fibrotic and stiffened tissue microenvironment may orchestrate EO CRC tumor initiation,” wrote Emina Huang, MD, UT Southwestern Medical Center, Dallas, and colleagues.

“The clinical implications include predictive modeling and potential treatments and preventive measures to limit transformation, but these are in the future and will require more research and clinical trials to demonstrate efficacy,” Huang told Medscape Medical News.

The study was published online in Advanced Science.

Unique Characteristics Identified

While screening has driven down CRC rates among adults over age 50 years, cases diagnosed in younger adults have steadily increased for decades and now account for roughly 12% of new CRC diagnoses in the US. Estimates indicate that the steepest increases are expected to occur among people in their twenties and thirties, and if current trends continue, the overall incidence of EO CRC is expected to rise by 124% by 2030, the authors wrote.

Most cases of EO CRC are sporadic, microsatellite-stable, and not linked to inherited cancer syndromes, suggesting that nongenetic factors, such as diet, inflammation, and the tissue microenvironment, may play a central role. Huang and colleagues tested whether physical changes in colon tissue could be a factor.

They used a variety of techniques to analyze primary tumor samples and matched normal tissue samples from 33 patients undergoing colorectal cancer surgery — 14 with early-onset disease and 19 diagnosed after age 50 years.

The researchers discovered that both cancerous and nearby normal tissues from EO CRC patients were significantly stiffer than those from older patients, suggesting that an increase in stiffness may precede EO CRC development.

EO CRC tissues and histologically normal adjacent tissue also contained denser, thicker, and more highly aligned collagen fibers, pointing to the role of biomechanical remodeling and scarring in EO CRC, the researchers noted.

At the cellular level, stromal cells in EO CRC tissues expressed increased levels of genes involved in collagen production, cross-linking, and matrix stabilization, along with inflammatory and angiogenic signals.

In EO CRC samples, epithelial cancer cells showed increased proliferation and heightened activity of the mechanosensitive transcription factor Yes-associated protein, which is known to promote growth and survival in stiff environments. In both two-dimensional and three-dimensional CRC models, increasing matrix stiffness also promoted proliferation of epithelial cells.

“Our findings suggest that biomechanical stiffening may serve as both a driver and diagnostic predictor of EO CRC. Overall, we identify increased tissue stiffness as a quantifiable hallmark of EO CRC, which could serve as a potential biomarker to stratify cancer risk in young populations,” the authors concluded.

They cautioned that the patient cohort was small and that mechanical testing was limited by tissue availability.

Future investigations should focus on clarifying the biochemical and biomechanical interactions between stromal and epithelial cells in EO CRC, as well as on evaluating mechanical and compositional features of the tumor microenvironment as potential biomarkers for disease progression and therapeutic development, the authors wrote.

The study reported receiving no commercial funding. The authors declared having no conflicts of interest.