Increased nerve density adversely affects outcome in colorectal cancer and denervation suppresses tumor growth
Abstract 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 diamet...
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| Language: | English |
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BMC
2025-01-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06104-2 |
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| author | Hao Wang Ruixue Huo Kexin He Weihan Li Yuan Gao Wei He Minhao Yu Shu-Heng Jiang Junli Xue |
| author_facet | Hao Wang Ruixue Huo Kexin He Weihan Li Yuan Gao Wei He Minhao Yu Shu-Heng Jiang Junli Xue |
| author_sort | Hao Wang |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-f1341ae23d594fdd960018ef1c356761 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-f1341ae23d594fdd960018ef1c3567612025-01-26T12:50:17ZengBMCJournal of Translational Medicine1479-58762025-01-0123111410.1186/s12967-025-06104-2Increased nerve density adversely affects outcome in colorectal cancer and denervation suppresses tumor growthHao Wang0Ruixue Huo1Kexin He2Weihan Li3Yuan Gao4Wei He5Minhao Yu6Shu-Heng Jiang7Junli Xue8Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji UniversityDepartment of Oncology, Shanghai East Hospital, School of Medicine, Tongji UniversityDepartment of Oncology, Shanghai East Hospital, School of Medicine, Tongji UniversityDepartment of Oncology, Shanghai East Hospital, School of Medicine, Tongji UniversityDepartment of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDepartment of Pathology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDepartment of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Systems Medicine for Cancer, Ren Ji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong UniversityDepartment of Oncology, Shanghai East Hospital, School of Medicine, Tongji UniversityAbstract 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.https://doi.org/10.1186/s12967-025-06104-2Perineural invasionNerve densityPrognosisTumor denervationNeural remodeling |
| spellingShingle | Hao Wang Ruixue Huo Kexin He Weihan Li Yuan Gao Wei He Minhao Yu Shu-Heng Jiang Junli Xue Increased nerve density adversely affects outcome in colorectal cancer and denervation suppresses tumor growth Journal of Translational Medicine Perineural invasion Nerve density Prognosis Tumor denervation Neural remodeling |
| title | Increased nerve density adversely affects outcome in colorectal cancer and denervation suppresses tumor growth |
| title_full | Increased nerve density adversely affects outcome in colorectal cancer and denervation suppresses tumor growth |
| title_fullStr | Increased nerve density adversely affects outcome in colorectal cancer and denervation suppresses tumor growth |
| title_full_unstemmed | Increased nerve density adversely affects outcome in colorectal cancer and denervation suppresses tumor growth |
| title_short | Increased nerve density adversely affects outcome in colorectal cancer and denervation suppresses tumor growth |
| title_sort | increased nerve density adversely affects outcome in colorectal cancer and denervation suppresses tumor growth |
| topic | Perineural invasion Nerve density Prognosis Tumor denervation Neural remodeling |
| url | https://doi.org/10.1186/s12967-025-06104-2 |
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