Colorectal cancer (CRC) is a serious global health concern, ranking as the third most common cancer and the second leading cause of cancer-related deaths. The 5-year survival rate for advanced CRC patients is alarmingly low, with recurrence and metastasis being the primary culprits. Perineural invasion (PNI), a process where cancer cells invade nerve bundles, is a critical factor in this grim prognosis. PNI is associated with an increased risk of disease recurrence and lymph node metastasis in CRC patients.
PNI is a complex process, involving cancer cell survival, nerve homeostasis, inflammatory responses, and nerve regeneration. Despite its growing recognition, the specific genes and molecular pathways driving PNI remain largely unknown.
Enter Cardiotrophin-like cytokine factor 1 (CLCF1), a member of the interleukin-6 (IL-6) family. CLCF1 acts as a powerful neurotrophic factor, stimulating B-cells and regulating pituitary corticotropin function. Previous studies have shown that CLCF1 expression is upregulated in certain cancers, promoting axon growth and influencing cancer cell behavior.
In this study, researchers delved into the impact of CLCF1 on CRC. They analyzed mRNA expression profiles and clinical data from CRC patients, identifying a unique signature of differentially expressed immune-related genes (DEIRGs) associated with PNI. The signature was validated and found to be a reliable predictor of CRC prognosis.
The results revealed that PNI is indeed a strong indicator of aggressive tumor behavior and poor clinical outcomes in CRC. PNI was more prevalent in advanced-stage tumors and was associated with elevated serum carcinoembryonic antigen levels. Patients with PNI had significantly poorer overall survival compared to those without PNI.
The researchers developed a seven-gene signature, including CLCF1, that effectively stratified CRC patients into high-risk and low-risk groups. The signature was further validated in internal test cohorts, demonstrating its robustness. Clinical correlation analysis confirmed that the signature was an independent predictor of overall survival, second only to metastasis.
The study also explored the tumor microenvironment, revealing that certain immune cells and immune checkpoints were associated with the risk signature. Patients with high-risk scores had elevated levels of immunosuppressive molecules, suggesting a more pronounced immunosuppressive environment.
To provide clinicians with a practical tool, the researchers developed a nomogram incorporating age, gender, stage, and risk scores. The nomogram accurately predicted survival outcomes, offering a user-friendly approach for CRC patient management.
Expression and survival analyses validated the selected genes, with CLCF1 emerging as a potential key player in PNI of CRC. In vitro experiments confirmed that CLCF1 knockdown inhibited the proliferation, invasion, and migration of CRC cells.
The study's findings offer new insights into the role of CLCF1 in CRC and highlight its potential as a diagnostic and therapeutic target. However, the researchers acknowledge limitations, including the lack of external dataset validation due to limited PNI information in online databases. Further research and prospective trials are needed to validate the seven-gene signature and explore the underlying mechanisms linking CLCF1 to CRC.
