Observational study finds increased tissue stiffness in early-onset colorectal cancer patients — Evidence Review
Published in Advanced Science, by researchers from UT Southwestern Medical Center, The University of Texas at Dallas
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Table of Contents
A new study finds that increased colon stiffness, likely resulting from chronic inflammation, is linked to early-onset colorectal cancer (CRC), suggesting a biomechanical pathway in cancer development. Related studies broadly support the role of tissue stiffness and extracellular matrix remodeling in CRC progression.
- Multiple studies confirm that stiffer tumor and peritumor tissues, often due to collagen crosslinking and remodeling, are associated with more aggressive colorectal cancer and poorer prognosis, aligning with the new findings 1 2 4 5 10.
- Mechanistic research highlights specific pathways—such as mechanotransduction, integrin signaling, and the actions of enzymes like lysyl oxidase—that connect increased tissue rigidity to enhanced cancer cell proliferation, invasion, and resistance to therapy 2 7 9 10.
- Some studies also indicate that targeting tissue stiffness or its molecular mediators can improve treatment response and may serve as a prognostic marker, underscoring the translational potential of the new observations 2 3 4.
Study Overview and Key Findings
Rising rates of early-onset colorectal cancer—diagnosed before age 50—have prompted concern, as the trend contrasts with declining rates among older adults. The causes of this increase remain uncertain. The study, recently published in Advanced Science, investigates a potential biomechanical mechanism: whether chronic inflammation leads to increased stiffness in colon tissue, thereby promoting cancer development in younger individuals. By comparing tissue samples from early- and average-onset CRC patients, the researchers sought to determine if increased rigidity predated malignancy and to explore the molecular underpinnings of this phenomenon.
| Property | Value |
|---|---|
| Study Year | 2025 |
| Organization | UT Southwestern Medical Center, The University of Texas at Dallas |
| Journal Name | Advanced Science |
| Authors | Nicole C. Huning, Munir H. Buhaya, Victor V. Nguyen, Afeefah Khazi-Syed, Haider A. Ali, Adil Khan, Angela Fan, Robert C. Fisher, Zhikai Chi, Indu Raman, Guangchun Chen, Chengsong Zhu, Mengxi Yu, Andrew R. Jamieson, Sara Roccabianca, Victor D. Varner, Cheryl M. Lewis, Emina H. Huang, Jacopo Ferruzzi |
| Population | Patients with colorectal cancer |
| Sample Size | n=33 (19 average-onset CRC, 14 early-onset CRC) |
| Methods | Observational Study |
| Outcome | Tissue stiffness, collagen characteristics, gene expression |
| Results | Early-onset CRC tissues were significantly stiffer than average-onset CRC tissues. |
Literature Review: Related Studies
To place these findings in context, we searched the Consensus database, which aggregates over 200 million research papers. The following search queries were used to identify relevant literature:
- colon stiffness early-onset CRC
- tissue stiffness colorectal cancer comparison
- mechanisms of stiffness in CRC tissues
Related Studies Table
| Topic | Key Findings |
|---|---|
| How does tissue stiffness influence colorectal cancer development and progression? | - Higher tumor stiffness is correlated with increased proliferation, invasion, and poorer prognosis in colorectal cancer patients 1 4 10. - Collagen crosslinking and extracellular matrix (ECM) remodeling promote increased tissue rigidity and cancer progression 2 5 10. |
| What are the molecular mechanisms linking tissue stiffness to cancer behavior? | - Lysyl oxidase (LOX)-induced collagen crosslinking increases matrix stiffness, which activates focal adhesion kinase (FAK) and downstream signaling pathways to drive CRC progression 2 10. - Stiffness promotes mechanotransduction, integrin clustering, and Rho/ERK pathway activation, all linked to enhanced malignant phenotypes and disrupted tissue architecture 7 9. |
| Can targeting tissue stiffness or its mediators improve CRC outcomes? | - Inhibiting LOX activity or reducing ECM stiffness may suppress tumor growth, metastasis, and improve therapeutic responses in metastatic CRC 2 3 10. - Lowering metastasis stiffness with specific drugs (e.g., renin-angiotensin inhibitors) enhances response to anti-angiogenic therapies like bevacizumab in metastatic CRC 3. |
| Are there diagnostic or prognostic applications for measuring tissue stiffness? | - Measurement of the elastic modulus in CRC tissue aids in more accurate staging and prognosis; high-stiffness tumors are linked to shorter disease-free survival 4. - Increased stiffness and collagen crosslinking in perilesional ECM may serve as predictive markers for invasive potential of colorectal cancer 5. |
How does tissue stiffness influence colorectal cancer development and progression?
Research consistently shows that stiffer tumor and peritumor environments foster more aggressive colorectal cancer behavior. The new study’s findings that early-onset CRC tissues are notably stiffer than average-onset CRC tissues parallels earlier observations that heightened rigidity is associated with increased proliferation, invasion, and reduced survival rates 1 4 10. Collagen remodeling and crosslinking are central contributors to this process 2 5 10.
- Higher tumor stiffness is correlated with advanced TNM stage and poorer prognosis 4 10.
- Collagen crosslinking and ECM remodeling increase tissue rigidity, facilitating cancer cell proliferation and metastasis 2 5 10.
- Stiff perilesional ECM can create a microenvironment conducive to tumor invasion, potentially serving as an early marker 5.
- These findings support the importance of the tumor microenvironment beyond genetic mutations 1 2 4 5 10.
What are the molecular mechanisms linking tissue stiffness to cancer behavior?
Mechanistically, increased tissue rigidity activates specific molecular pathways that promote malignant transformation and progression. The new study’s identification of upregulated mechanotransduction genes and collagen metabolism aligns with research on LOX-induced collagen crosslinking and FAK/SRC pathway activation 2 10. Integrin clustering, Rho/ERK signaling, and actomyosin tension are also implicated 7 9.
- LOX catalyzes collagen crosslinking, stiffening the ECM and activating FAK/SRC signaling, which promotes proliferation and invasion 2 10.
- Integrin-mediated mechanotransduction and cytoskeletal tension (via Rho/ERK) disrupt tissue architecture and enhance malignant potential 7.
- Stromal cell responses to increased stiffness, such as activin A secretion, further drive metastatic signaling 9.
- These pathways represent potential therapeutic targets for disrupting stiffness-driven cancer progression 2 7 9 10.
Can targeting tissue stiffness or its mediators improve CRC outcomes?
Several studies suggest that modulating tissue stiffness or its enzymatic regulators may have therapeutic benefits. Inhibiting LOX or reducing ECM rigidity can decrease tumor growth and metastasis, while drugs used for other conditions (e.g., hypertension) may improve responses to standard therapies by softening the tumor microenvironment 2 3 10.
- LOX inhibition reduces matrix stiffness and limits CRC progression in experimental models 2 10.
- Renin-angiotensin inhibitors decrease metastasis stiffness and enhance the efficacy of anti-angiogenic therapy in patients 3.
- These findings support the translational potential of targeting biomechanical properties in CRC treatment 2 3 10.
- The new study’s suggestion to disrupt mechanotransduction pathways or assess tissue stiffness diagnostically aligns with this therapeutic direction 2 3 10.
Are there diagnostic or prognostic applications for measuring tissue stiffness?
Multiple studies have evaluated the clinical utility of measuring tumor elasticity or ECM stiffness. A higher elastic modulus in CRC tissue is associated with more advanced disease and shorter disease-free survival, while changes in perilesional ECM may predict invasive potential 4 5. The new study’s proposal to develop diagnostic tests for intestinal stiffness is consistent with these findings.
- Measuring tumor stiffness can aid in staging and prognosis, offering more precise risk stratification 4.
- ECM stiffness in perilesional areas may identify adenomas with higher invasive risk and guide monitoring 5.
- Gene expression profiles differ between high- and low-stiffness tumors, suggesting a molecular basis for clinical applications 4.
- The concept of biomechanical phenotyping, as explored in the new study, builds upon these diagnostic advances 4 5.
Future Research Questions
Despite growing evidence linking tissue stiffness to colorectal cancer, several gaps remain. Further research is needed to clarify causal pathways, identify effective interventions, and translate biomechanical measurements into clinical practice. Addressing these questions could improve risk assessment, prevention, and treatment of early-onset and other colorectal cancers.
| Research Question | Relevance |
|---|---|
| Does reducing colon tissue stiffness prevent or delay early-onset colorectal cancer? | Establishing causality and prevention strategies requires intervention studies; current evidence is primarily observational or mechanistic 2 3 10. |
| What specific inflammatory factors drive increased collagen crosslinking in early-onset CRC? | Understanding the molecular link between chronic inflammation and tissue stiffening could reveal new therapeutic targets 2 5 9. |
| Can non-invasive imaging or biomarkers accurately measure colonic stiffness for risk assessment? | Translating biomechanical phenotyping into practice requires reliable, accessible diagnostic tools; current methods are largely ex vivo 4 5. |
| How do mechanotransduction pathways differ between early-onset and average-onset colorectal cancer? | Identifying unique pathways in early-onset CRC could explain rising incidence and inform targeted interventions 1 7 9. |
| Does modulating tissue stiffness improve outcomes for patients receiving standard CRC therapies? | Evidence suggests tissue rigidity affects therapy resistance; clinical trials are needed to assess benefits of combining stiffness-modulating agents with existing treatments 3 10. |