Increased nerve density adversely affects outcome in colorectal cancer and denervation suppresses tumor growth.

Publisher: BioMed Central Country of Publication: England NLM ID: 101190741 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-5876 (Electronic) Linking ISSN: 14795876 NLM ISO Abbreviation: J Transl Med Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2003-

Colorectal Neoplasms*/pathology ; Denervation*; Humans ; Animals ; Male ; Female ; Middle Aged ; Treatment Outcome ; ROC Curve ; Prognosis ; Aged ; Mice ; Kaplan-Meier Estimate ; Cell Proliferation/drug effects ; Proportional Hazards Models

Background: The colon and rectum are highly innervated, with neural components within the tumor microenvironment playing a significant role in colorectal cancer (CRC) progression. While perineural invasion (PNI) is associated with poor prognosis in CRC, the impact of nerve density and diameter on tumor behavior remains unclear. This study aims to evaluate the prognostic value of nerve characteristics in CRC and to verify the impact of nerves on tumor growth.
Methods: Tissue samples from 129 CRC patients were stained with immunofluorescent markers NF-L and S100B to detect nerves. Nerve diameter and density were measured and normalized. Kaplan-Meier survival analysis and Cox regression models were used to identify prognostic factors. Prognostic models were established using receiver operating characteristic (ROC) curve analysis to assess the predictive value of neural factors. A murine chemical denervation model was employed to disrupt sympathetic nerves using 6-hydroxydopamine, inhibit muscarinic receptor 3 with darifenacin, and ablate sensory neurons with capsaicin.
Results: The total nerve density was 0.72 ± 0.59/mm², with intratumoral (0.42 ± 0.40/mm²) being significantly lower than extratumoral regions (1.00 ± 0.75/mm²). The average nerve diameter was 28.14 ± 6.04 μm, with no significant difference between intratumoral (28.2 ± 7.65 μm) and extratumoral regions (27.86 ± 6.72 μm). PNI was observed in 65 patients (50.4%). PNI and high normalized nerve density (NND) were associated with shorter overall survival and disease-free survival in CRC patients, with PNI identified as an independent prognostic factor. Patients with PNI exhibit higher NND. Incorporating PNI and NND into ROC curve analysis improved the sensitivity and specificity of survival predictions. In the murine model, chemical denervation of sympathetic, parasympathetic, and sensory nerves significantly reduced rectal tumor volume.
Conclusions: PNI and NND are critical factors influencing CRC patient survival and enhance the accuracy of survival prediction models. Moreover, chemical denervation effectively inhibits rectal tumor growth in vivo, highlighting the potential of neural targeting as a therapeutic strategy in CRC.
Competing Interests: Declarations. Ethics approval and consent to participate: Human Studies: This study was approved by the Ethics Committee of Ren Ji Hospital, affiliated with Shanghai Jiao Tong University (No. KY2021-120-B). Informed consent was obtained from all patients. All procedures were performed in compliance with relevant laws and institutional guidelines and were approved by the Ethics Committee of Ren Ji Hospital. Animal Studies: The animal experiments performed in this study were approved by the Ethics Committee of Ren Ji Hospital, affiliated with Shanghai Jiao Tong University (No. RA-2021-387). All animal experiments complied with the ARRIVE guidelines and were conducted in accordance with the U.K. Animals Act, 1986, and associated guidelines. Consent for publication: Not appliable. Competing interests: The authors declare no potential conflicts of interest.
(© 2025. The Author(s).)

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82260562, 82372922 Natural Science Foundation of China; PWRd2021-09 Academic Leaders Training Program of Pudong Health Bureau of Shanghai; Y-xsk2021-0003, Y-2022HER2AZMS-0181 CSCO research funding; DFPY2024015 Shanghai East Hospital Youth Training Fund

Keywords: Nerve density; Neural remodeling; Perineural invasion; Prognosis; Tumor denervation

Date Created: 20250124 Date Completed: 20250124 Latest Revision: 20250130

20250130

PMC11760110

10.1186/s12967-025-06104-2

39849539