The abundant nervous system in intestine provides the basis for perineural invasion (PNI) of colorectal cancer (CRC). PNI is defined as the invasion of the nerves by cancer cells. Although PNI is already known to be an independent prognostic factor in CRC, the molecular mechanism underlying PNI remains obscure. In this study, we first demonstrated that CD51 could promote the neurotropism of tumor cells through cleavage with γ-secretase to generate an intracellular domain (ICD). Mechanistically, ICD of CD51 could bind to the transcription factor NR4A3, and act as a coactivator to promote the expression of downstream effectors, such as NTRK1, NTRK3, and SEMA3E. Pharmacological inhibition of γ-secretase impedes PNI mediated by CD51 in CRC both in vitro and in vivo and may become a potential therapeutic target for PNI in CRC.

Background Prognosis varies among stage IV colorectal cancer (CRC). Our study aimed to build a robust prognostic nomogram for predicting overall survival (OS) of patients with stage IV CRC in order to provide evidence for individualized treatment. Method We collected the information of 16,283 patients with stage IV CRC in the Surveillance, Epidemiology, and End Results (SEER) database and then randomized these patients in a ratio of 7:3 into a training cohort and an internal validation cohort. In addition, 501 patients in the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) database were selected and used as an external validation cohort. Univariate and multivariate Cox analyses were used to screen out significant variables for nomogram establishment. The nomogram model was assessed using time-dependent receiver-operating characteristic curve (time-dependent ROC), concordance index (C-index), calibration curve, and decision curve analysis. Survival curves were plotted using the Kaplan–Meier method. Result The C-index of the nomogram for OS in the training, internal validation, and external validation cohorts were 0.737, 0.727, and 0.655, respectively. ROC analysis and calibration curves pronounced robust discriminative ability of the model. Further, we divided the patients into a high-risk group and a low-risk group according to the nomogram. Corresponding Kaplan–Meier curves showed that the prediction of the nomogram was consistent with the actual practice. Additionally, model comparisons and decision curve analysis proved that the nomogram for predicting prognosis was significantly superior to the tumor-node-metastasis (TNM) staging system. Conclusions We constructed a nomogram to predict OS of the stage IV CRC and externally validate its generalization, which was superior to the TNM staging system.

Background Current guidelines only propose the importance of perineural invasion(PNI) on prognosis in stage II colon cancer. However, the prognostic value of PNI in other stages of colorectal cancer (CRC) is ambiguous. Methods This single-center retrospective cohort study included 3485 CRC patients who underwent primary colorectal resection between January 2013 and December 2016 at the Sixth Affiliated Hospital of Sun Yat-sen University. Associations of PNI with overall survival (OS) and disease-free survival (DFS) were evaluated using multivariable Cox proportional hazards regression models. In addition, interaction analyses were performed to explore the prognostic effects of PNI in different clinical subgroups. Results After median follow-up of 61.9 months, we found PNI was associated with poorer OS (adjusted hazard ratio [aHR], 1.290; 95% CI, 1.087–1.531) and DFS (aHR, 1.397; 95% CI, 1.207–1.617), irrespective of tumor stage. Interestingly, the weight of PNI was found second only to incomplete resection in the nomogram for risk factors of OS and DFS in stage II CRC patients. Moreover, OS and DFS were insignificantly different between stage II patients with PNI and stage III patients (both P > 0.05). PNI was found to be an independent prognostic factor of DFS in stage III CRC (aHR: 1.514; 95% CI, 1.211–1.892) as well. Finally, the adverse effect of PNI on OS was more significant in female, early-onset, and diabetes-negative patients than in their counterparts (interaction P = 0.0213, 0.0280, and 0.0186, respectively). Conclusion PNI was an important prognostic factor in CRC, more than in stage II. The survival of patients with stage II combined with perineural invasion is similar with those with stage III. PNI in stage III CRC also suggests a worse survival.

Background The prognostic significance of primary tumor size in patients with stage IV colorectal cancer (CRC) has not been established. This study aimed to evaluate the prognostic value of tumor size in stage IV CRC. Methods We retrospectively analyzed the data of patients with stage IV CRC in the Surveillance, Epidemiology and End Results (SEER) database and patients with stage IV CRC treated at the Sixth Affiliated Hospital of Sun Yat-sen University (SYSU). The optimal cutoff value for tumor size was determined using the X-Tile program. Multivariable Cox regression analysis were used to examine whether tumor size was an independent predictor of prognosis. Results There were 16,283 patients in the SEER cohort and 462 in the SYSU cohort. With the help of the X-Tile program, we selected 60mm as the optimal tumor size cutoff. Multivariate analysis confirmed that tumor size (HR = 1.17, 95%CI: 1.13–1.22) was an independent prognostic factor in stage IV CRC. Across all subgroups in the SEER cohort, survival probability was significantly lower in patients with tumor size ≥ 60 mm than in patients with tumor size < 60 mm. Conclusions Tumor size appears to be an independent predictor of survival in patients with stage IV CRC. Patients with tumor size ≥ 60 mm have poor prognosis.

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