The table summarizes the downregulation of myelinating markers (MBP, MPZ, MAG, EGR2) and the upregulation of neurotrophic factors’ genes (GDNF, ARTN, BDNF, NTF3, NGF); transmembrane proteins’ genes (NGFR, CDH2); and other molecular markers’ genes (the master transcriptional regulator JUN, GFAP) during rSC reprogramming. rSCs: repair Schwann cells; MBP: myelin basic protein; MPZ: myelin protein zero; MAG: myelin-associated glycoprotein; EGR2: early growth response protein 2; GDNF: glial cell line-derived neurotrophic factor; ARTN: artemin; BDNF: brain-derived neurotrophic factor; NTF3: neurotrophin-3; NGF: nerve growth factor; NGFR: NGF receptor; GFAP: glial fibrillary acidic protein.
Declarations
Acknowledgments
Prof. Raggi is a member of the European Network for the Study of Cholangiocarcinoma (ENSCCA) and participates in the initiatives COST Action EURO-CHOLANGIO-NET and Precision-BTC-Network granted by the COST Association (CA18122, CA22125).
Author contributions
LM: Conceptualization, Writing—original draft. FM: Writing—review & editing. CR: Writing—review & editing, Supervision, Funding acquisition. All authors read and approved the submitted version.
Conflicts of interest
Fabio Marra and Chiara Raggi, who are the Guest Editors and Editorial Board Members of Exploration of Digestive Diseases, had no involvement in the decision-making or the review process of this manuscript. The other author declares no conflicts of interest.
Ethical approval
Not applicable.
Consent to participate
Not applicable.
Consent to publication
Not applicable.
Availability of data and materials
Not applicable.
Funding
This work was provided by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG23117]. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.
References
Zahalka AH, Frenette PS. Nerves in cancer.Nat Rev Cancer. 2020;20:143–57. [DOI] [PubMed] [PMC]
Tan X, Sivakumar S, Bednarsch J, Wiltberger G, Kather JN, Niehues J, et al. Nerve fibers in the tumor microenvironment in neurotropic cancer-pancreatic cancer and cholangiocarcinoma.Oncogene. 2021;40:899–908. [DOI] [PubMed] [PMC]
Yan R, He Q, Liu Y, Ye P, Zhu L, Shi S, et al. Unpaired virtual histological staining using prior-guided generative adversarial networks.Comput Med Imaging Graph. 2023;105:102185. [DOI] [PubMed]
Yan R, He Q, Liu Y, Gou J, Sun Q, Zhou G, et al. DEST: deep enhanced Swin Transformer toward better scoring for NAFLD. In: Yu S, Zhang Z, Yuen P, Han J, Tan T, Guo Y, et al., editors. Pattern Recognition and Computer Vision. Cham: Springer Nature Switzerland; 2022. pp. 204–14.
Sun L, Chen S, Chen M. Schwann Cells in the Tumor Microenvironment: Need More Attention.J Oncol. 2022;2022:1058667. [DOI] [PubMed] [PMC]
Jessen KR, Mirsky R. The Role of c-Jun and Autocrine Signaling Loops in the Control of Repair Schwann Cells and Regeneration.Front Cell Neurosci. 2022;15:820216. [DOI] [PubMed] [PMC]
Zhang L, Xie J, Dai W, Lu B, Yi S. Schwann cells in regeneration and cancer.Front Pharmacol. 2025;16:1506552. [DOI] [PubMed] [PMC]
Balogh J, Victor D 3rd, Asham EH, Burroughs SG, Boktour M, Saharia A, et al. Hepatocellular carcinoma: a review.J Hepatocell Carcinoma. 2016;3:41–53. [DOI] [PubMed] [PMC]
Tsung C, Quinn PL, Ejaz A. Management of Intrahepatic Cholangiocarcinoma: A Narrative Review.Cancers (Basel). 2024;16:739. [DOI] [PubMed] [PMC]
Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management.Nat Rev Gastroenterol Hepatol. 2020;17:557–88. [DOI] [PubMed] [PMC]
Li W, Zhang J, Gao Y, Kong X, Sun X. Nervous system in hepatocellular carcinoma: Correlation, mechanisms, therapeutic implications, and future perspectives.Biochim Biophys Acta Rev Cancer. 2025;1880:189345. [DOI] [PubMed]
Wang X, Lan H, Shen T, Gu P, Guo F, Lin X, et al. Perineural invasion: a potential reason of hepatocellular carcinoma bone metastasis.Int J Clin Exp Med. 2015;8:5839–46. [PubMed] [PMC]
Zhang L, Tu Y, He W, Peng Y, Qiu Z. A novel mechanism of hepatocellular carcinoma cell apoptosis induced by lupeol via Brain-Derived Neurotrophic Factor Inhibition and Glycogen Synthase Kinase 3 beta reactivation.Eur J Pharmacol. 2015;762:55–62. [DOI] [PubMed]
Lam CT, Yang ZF, Lau CK, Tam KH, Fan ST, Poon RT. Brain-derived neurotrophic factor promotes tumorigenesis via induction of neovascularization: implication in hepatocellular carcinoma.Clin Cancer Res. 2011;17:3123–33. [DOI] [PubMed]
Guo D, Hou X, Zhang H, Sun W, Zhu L, Liang J, et al. More expressions of BDNF and TrkB in multiple hepatocellular carcinoma and anti-BDNF or K252a induced apoptosis, supressed invasion of HepG2 and HCCLM3 cells.J Exp Clin Cancer Res. 2011;30:97. [DOI] [PubMed] [PMC]
Zhang M, Zhang W, Wu Z, Liu S, Sun L, Zhong Y, et al. Artemin is hypoxia responsive and promotes oncogenicity and increased tumor initiating capacity in hepatocellular carcinoma.Oncotarget. 2016;7:3267–82. [DOI] [PubMed] [PMC]
Luo T, Zhang SG, Zhu LF, Zhang FX, Li W, Zhao K, et al. A selective c-Met and Trks inhibitor Indo5 suppresses hepatocellular carcinoma growth.J Exp Clin Cancer Res. 2019;38:130. [DOI] [PubMed] [PMC]
Zhu H, Huang M, Luo J, Ji X, Liu Q. Deficiency of GFRα1 promotes hepatocellular carcinoma progression but enhances oxaliplatin-mediated anti-tumor efficacy.Pharmacol Res. 2021;172:105815. [DOI] [PubMed]
Yang QX, Liu T, Yang JL, Liu F, Chang L, Che GL, et al. Low expression of NTF3 is associated with unfavorable prognosis in hepatocellular carcinoma.Int J Clin Exp Pathol. 2020;13:2280–8. [PubMed] [PMC]
Yang Z, Zhang H, Yin M, Cheng Z, Jiang P, Feng M, et al. Neurotrophin3 promotes hepatocellular carcinoma apoptosis through the JNK and P38 MAPK pathways.Int J Biol Sci. 2022;18:5963–77. [DOI] [PubMed] [PMC]
Fisher SB, Patel SH, Kooby DA, Weber S, Bloomston M, Cho C, et al. Lymphovascular and perineural invasion as selection criteria for adjuvant therapy in intrahepatic cholangiocarcinoma: a multi-institution analysis.HPB (Oxford). 2012;14:514–22. [DOI] [PubMed] [PMC]
Chen TC, Jan YY, Yeh TS. K-ras mutation is strongly associated with perineural invasion and represents an independent prognostic factor of intrahepatic cholangiocarcinoma after hepatectomy.Ann Surg Oncol. 2012;19:S675–81. [DOI] [PubMed]
de Franchis V, Petrungaro S, Pizzichini E, Camerini S, Casella M, Somma F, et al. Cholangiocarcinoma Malignant Traits Are Promoted by Schwann Cells through TGFβ Signaling in a Model of Perineural Invasion.Cells. 2024;13:366. [DOI] [PubMed] [PMC]
Gundlach JP, Kerber J, Hendricks A, Bernsmeier A, Halske C, Röder C, et al. Paracrine Interaction of Cholangiocellular Carcinoma with Cancer-Associated Fibroblasts and Schwann Cells Impact Cell Migration.J Clin Med. 2022;11:2785. [DOI] [PubMed] [PMC]
Qian X, Liu E, Zhang C, Feng R, Tran N, Zhai W, et al. Promotion of perineural invasion of cholangiocarcinoma by Schwann cells via nerve growth factor.J Gastrointest Oncol. 2024;15:1198–213. [DOI] [PubMed] [PMC]
Yang XQ, Xu YF, Guo S, Liu Y, Ning SL, Lu XF, et al. Clinical significance of nerve growth factor and tropomyosin-receptor-kinase signaling pathway in intrahepatic cholangiocarcinoma.World J Gastroenterol. 2014;20:4076–84. [DOI] [PubMed] [PMC]
Li C, Lan N, Chen YX. High expression of brain-derived neurotrophic factor in intrahepatic cholangiocarcinoma is associated with intraneural invasion and unfavorable prognosis.Int J Clin Exp Pathol. 2017;10:10399–405. [PubMed] [PMC]
Wang Q, Sun Z, Guo J, Li H, Zhang J, Zhang B, et al. Tumor-derived exosomal LINC01812 induces M2 macrophage polarization to promote perineural invasion in cholangiocarcinoma.Cancer Lett. 2025;617:217596. [DOI] [PubMed]
Chen F, Sheng J, Li X, Gao Z, Hu L, Chen M, et al. Tumor-associated macrophages: orchestrators of cholangiocarcinoma progression.Front Immunol. 2024;15:1451474. [DOI] [PubMed] [PMC]
