Research progress on perineural invasion in colorectal cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LI Yanjie ¹ , YU Jianping ² , WANG Hongyu ¹ , WANG Jinbao ¹ , YANG Gaosheng ¹ ,  HAN Xiaopeng ²

1. The First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou 730000, P. R. China;
2. Department of General Surgery, Gansu Provincial Central Hospital, Lanzhou 730070, P. R. China;

Corresponding author：

HAN Xiaopeng, Email: hanxiaopeng74@163.com

Keywords：

colorectal cancer; perineural invasion; mechanism; diagnosis; treatment; prognosis; review

DOI：

10.7507/1007-9424.202407066

Video：

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Objective To comprehend the impact of perineural invasion (PNI) on the occurrence, development, and prognosis of colorectal cancer (CRC), providing a reference for the diagnosis and treatment of CRC. Method The latest literature relevant researches on the mechanism, diagnosis, treatment, and prognosis of PNI in CRC both domestically and internationally was reviewed. Results The mechanisms underlying PNI involved nerve growth factors, chemokines, and other signaling molecules, which regulated the interactions between the nerves and cancer cells to promote the tumor invasion and metastasis. The diagnostic approaches primarily relied on the histopathological examination with immunohistochemistry and radiomics. Therapeutically, the PNI-positive patients benefited from surgical intervention in combination with neoadjuvant or adjuvant treatment. Targeting the neural pathways and immune checkpoint inhibitors (such as programmed cell death 1 and cytotoxic T lymphocyte associated protein 4 inhibitors) showed potentials in reducing neural invasion and tumor progression. Emerging strategies that disrupted tumor-nerve interactions also represented promising therapeutic avenues. The PNI was recognized as a critical prognostic indicator for CRC, providing guidance in risk assessment and individualized treatment planning. Conclusions PNI serves as an important indicator for evaluating the prognosis of CRC, it has a guiding value for therapy decision-making. Further research of molecular mechanisms and diagnostic methods relevant PNI can potentially yield more effective therapeutic options and is expected to improve prognosis of patients with CRC.

Citation： LI Yanjie, YU Jianping, WANG Hongyu, WANG Jinbao, YANG Gaosheng, HAN Xiaopeng. Research progress on perineural invasion in colorectal cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2025, 32(2): 258-264. doi: 10.7507/1007-9424.202407066 Copy

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2. 黄理宾, 黄秋实, 杨烈. 全球及中国的结直肠癌流行病学特征及防治: 2022《全球癌症统计报告》解读. 中国普外基础与临床杂志, 2024, 31(5): 530-537.
3. Akert K, Sandri C, Weibel ER, et al. The fine structure of the perineural endothelium. Cell Tissue Res, 1976, 165(3): 281-295.
4. Batsakis JG. Nerves and neurotropic carcinomas. Ann Otol Rhinol Laryngol, 1985, 94(4 Pt 1): 426-467.
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8. Miller ME, Palla B, Chen Q, et al. A novel classification system for perineural invasion in noncutaneous head and neck squamous cell carcinoma: histologic subcategories and patient outcomes. Am J Otolaryngol, 2012, 33(2): 212-215.
9. Zhang M, Xian HC, Dai L, et al. MicroRNAs: emerging driver of cancer perineural invasion. Cell Biosci, 2021, 11(1): 117. doi: 10.1186/s13578-021-00630-4.
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11. Yaniv D, Mattson B, Talbot S, et al. Targeting the peripheral neural-tumour microenvironment for cancer therapy. Nat Rev Drug Discov, 2024, 23(10): 780-796.
12. Sun L, Chen S, Chen M. Schwann cells in the tumor microenvironment: need more attention. J Oncol, 2022, 2022: 1058667. doi: 10.1155/2022/1058667.
13. Zhang B, Guo X, Huang L, et al. Tumour-associated macrophages and Schwann cells promote perineural invasion via paracrine loop in pancreatic ductal adenocarcinoma. Br J Cancer, 2024, 130(4): 542-554.
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15. Silverman DA, Martinez VK, Dougherty PM, et al. Cancer-associated neurogenesis and nerve-cancer cross-talk. Cancer Res, 2021, 81(6): 1431-1440.
16. Jaiswal M, Ganapathy A, Singh S, et al. Morphology of enteric glia in colorectal carcinoma: A comparative study of tumor site and its proximal normal margin. Morphologie, 2021, 105(351): 267-274.
17. Jiffar T, Yilmaz T, Lee J, et al. Brain derived neutrophic factor (BDNF) coordinates lympho-vascular metastasis through a fibroblast-governed paracrine axis in the tumor microenvironment. Cancer Cell Microenviron, 2017, 4(2): e1566. doi: 10.14800/ccm.1566.
18. Okugawa Y, Tanaka K, Inoue Y, et al. Brain-derived neurotrophic factor/tropomyosin-related kinase B pathway in gastric cancer. Br J Cancer, 2013, 108(1): 121-130.
19. Sun J, Yu L, Qu X, et al. The role of peroxisome proliferator-activated receptors in the tumor microenvironment, tumor cell metabolism, and anticancer therapy. Front Pharmacol, 2023, 14: 1184794. doi: 10.3389/fphar.2023.1184794.
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21. Schonkeren SL, Thijssen MS, Vaes N, et al. The emerging role of nerves and glia in colorectal cancer. Cancers (Basel), 2021, 13(1): 152. doi: 10.3390/cancers13010152.
22. Godlewski J, Kmiec Z. Colorectal cancer invasion and atrophy of the enteric nervous system: potential feedback and impact on cancer progression. Int J Mol Sci, 2020, 21(9): 3391. doi: 10.3390/ijms21093391.
23. Zhang L, Yang L, Jiang S, et al. Nerve dependence in colorectal cancer. Front Cell Dev Biol, 2022, 10: 766653. doi: 10.3389/fcell.2022.766653.
24. Jobling P, Pundavela J, Oliveira SM, et al. Nerve-cancer cell cross-talk: A novel promoter of tumor progression. Cancer Res, 2015, 75(9): 1777-1781.
25. Takacs GP, Flores-Toro JA, Harrison JK. Modulation of the chemokine/chemokine receptor axis as a novel approach for glioma therapy. Pharmacol Ther, 2021, 222: 107790. doi: 10.1016/j.pharmthera.2020.107790.
26. Dansereau MA, Midavaine É, Bégin-Lavallée V, et al. Mechanistic insights into the role of the chemokine CCL2/CCR2 axis in dorsal root ganglia to peripheral inflammation and pain hypersensitivity. J Neuroinflammation, 2021, 18(1): 79. doi: 10.1186/s12974-021-02125-y.
27. Ryu S, Liu X, Guo T, et al. Peripheral CCL2-CCR2 signalling contributes to chronic headache-related sensitization. Brain, 2023, 146(10): 4274-4291.
28. Hirth M, Gandla J, Höper C, et al. CXCL10 and CCL21 promote migration of pancreatic cancer cells toward sensory neurons and neural remodeling in tumors in mice, associated with pain in patients. Gastroenterology, 2020, 159(2): 665-681.
29. Shi Y, Riese DJ, Shen J. The role of the CXCL12/CXCR4/CXCR7 chemokine axis in cancer. Front Pharmacol, 2020, 11: 574667. doi: 10.3389/fphar.2020.574667.
30. Capodanno Y, Hirth M. Targeting the cancer-neuronal crosstalk in the pancreatic cancer microenvironment. Int J Mol Sci, 2023, 24(19): 14989. doi: 10.3390/ijms241914989.
31. Sowparani S, Mahalakshmi P, Sweety JP, et al. Ubiquitous neural cell adhesion molecule (NCAM): Potential mechanism and valorisation in cancer pathophysiology, drug targeting and molecular transductions. Mol Neurobiol, 2022, 59(9): 5902-5924.
32. Kimura W, Watanabe T. Anatomy of the pancreatic nerve plexuses and significance of their dissection. Nihon Geka Gakkai Zasshi, 2011, 112(3): 170-176.
33. Bellis D, Marci V, Monga G. Light microscopic and immunohistochemical evaluation of vascular and neural invasion in colorectal cancer. Pathol Res Pract, 1993, 189(4): 443-447.
34. Conte GA, Qari O, Fasano GA, et al. S100 staining adds to the prognostic significance of the combination of perineural invasion and lymphovascular invasion in colorectal cancer. Appl Immunohistochem Mol Morphol, 2020, 28(5): 354-359.
35. Mizukami H, Shirahata A, Goto T, et al. PGP9. 5 methylation as a marker for metastatic colorectal cancer. Anticancer Res, 2008, 28(5A): 2697-2700.
36. Mitsui Y, Shiina H, Hiraki M, et al. Tumor suppressor function of PGP9.5 is associated with epigenetic regulation in prostate cancer—novel predictor of biochemical recurrence after radical surgery. Cancer Epidemiol Biomarkers Prev, 2012, 21(3): 487-496.
37. Sheng W, Zhang C, Mohiuddin TM, et al. Multiplex immunofluorescence: A powerful tool in cancer immunotherapy. Int J Mol Sci, 2023, 24(4): 3086. doi: 10.3390/ijms24043086.
38. Gadallah MS, Dawood M, Abdou A. The role of Beclin 1 and HER2 in colorectal carcinoma; An immunohistochemical study. Asian Pac J Cancer Prev, 2024, 25(2): 617-626.
39. Yang K, Stein TD, Huber BR, et al. Glioblastoma and malignant melanoma: Serendipitous or anticipated association? Neuropathology, 2021, 41(1): 65-71.
40. 杨彦松, 冯峰, 傅爱燕, 等. MR放射组学预测直肠腺癌患者神经周围侵犯的研究. 放射学实践, 2019, 34(11): 1192-1197.
41. Yang YS, Qiu YJ, Zheng GH, et al. High resolution MRI-based radiomic nomogram in predicting perineural invasion in rectal cancer. Cancer Imaging, 2021, 21(1): 40. doi: 10.1186/s40644-021-00408-4.
42. Liu J, Sun L, Zhao X, et al. Development and validation of a combined nomogram for predicting perineural invasion status in rectal cancer via computed tomography-based radiomics. J Cancer Res Ther, 2023, 19(6): 1552-1559.
43. Guo T, Cheng B, Li Y, et al. A radiomics model for predicting perineural invasion in stage Ⅱ–Ⅲ colon cancer based on computer tomography. BMC Cancer, 2024, 24(1): 1226. doi: 10.1186/s12885-024-12951-x.
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