胆管癌（CCA）是一种起源于胆管上皮的肝胆系统高致死性肿瘤，可分为肝内型、肝门型和肝外型。由于起病隐匿，早期临床症状不典型，总体预后较差。神经周围浸润（PNI）的发生是导致CCA预后不良的重要因素之一，但其如何导致PNI发生的具体机制仍不清楚。本研究的主要目的是探讨导致PNI发生的分子机制，为临床治疗提供新思路。刺激CCA细胞系和雪旺细胞（SCs），观察细胞行为的变化。对与肿瘤上清液共培养的SCs和在正常培养基中培养的SCs进行转录组测序，以筛选显着上调的基因。随后用SC上清液培养两种类型的肿瘤细胞，观察肿瘤细胞行为的变化。通过坐骨神经向非肥胖糖尿病-严重联合免疫缺陷病（NOD-SCID）小鼠注射补充有神经生长因子（NGF）的细胞悬液。 4周后，对小鼠实施安乐死，取出肿瘤切片并染色。CCA组织中肿瘤细胞侵犯神经很常见。肿瘤组织中可见SC，且肿瘤组织中SC的数量和PNI程度均远高于正常组织或无PNI的组织。合并 PNI 的 CCA 患者的总生存时间比不合并 PNI 的患者短。 SC 在 CCA 组织中富集，表明 PNI 的存在并与 CCA 患者的不良预后相关。体外研究发现 CCA 可促进 SC 分泌 NGF。 CCA细胞培养基中添加外源NGF后，CCA细胞的增殖活性和迁移能力显着增加，提示SCs可以通过分泌NGF促进CCA的增殖和迁移。反过来，观察到 NGF 通过原肌球蛋白受体激酶 A (TrkA) 促进 CCA 的上皮-间质转化，从而促进其进展。小鼠肿瘤生长表明，NGF可以促进CCA中的PNI。在CCA中，肿瘤细胞可以促进SCs分泌NGF，通过与其高亲和力受体TrkA结合，促进CCA和PNI的进展，导致预后不良。 2024 年胃肠肿瘤学杂志。版权所有。

Cholangiocarcinoma (CCA), a highly lethal tumor of the hepatobiliary system originating from bile duct epithelium, can be divided into the intrahepatic, hilar, and extrahepatic types. Due to its insidious onset and atypical early clinical symptoms, the overall prognosis is poor. One of the important factors contributing to the poor prognosis of CCA is the occurrence of perineural invasion (PNI), but the specific mechanisms regarding how it contributes to the occurrence of PNI are still unclear. The main purpose of this study is to explore the molecular mechanism leading to the occurrence of PNI and provide new ideas for clinical treatment.CCA cell lines and Schwann cells (SCs) were stimulated to observe the changes in cell behavior. SCs cocultured with tumor supernatant and SCs cultured in normal medium were subjected to transcriptome sequencing to screen the significantly upregulated genes. Following this, the two types of tumor cells were cultured with SC supernatant, and the changes in behavior of the tumor cells were observed. Nonobese diabetic-severe combined immunodeficiency disease (NOD-SCID) mice were injected with cell suspension supplemented with nerve growth factor (NGF) via the sciatic nerve. Four weeks later, the mice were euthanized and the tumor sections were removed and stained.Nerve invasion by tumor cells was common in CCA tissues. SCs were observed in tumor tissues, and the number of SCs in tumor tissues and the degree of PNI were much higher than were those in normal tissues or tissues without PNI. The overall survival time was shorter in patients with CCA with PNI than in patients without PNI. SCs were enriched in CCA tissues, indicating the presence of PNI and associated with poor prognosis in CCA patients. CCA was found to promote NGF secretion from SCs in vitro. After the addition of exogenous NGF in CCA cell culture medium, the proliferation activity and migration ability of CCA cells were significantly increased, suggesting that SCs can promote the proliferation and migration of CCA through the secretion of NGF. NGF, in turn, was observed to promote epithelial-mesenchymal transition in CCA through tropomyosin receptor kinase A (TrkA), thus promoting its progression. Tumor growth in mice shows that NGF can promote PNI in CCA.In CCA, tumor cells can promote the secretion of NGF by SCs, which promotes the progression of CCA and PNI by binding to its high-affinity receptor TrkA, leading to poor prognosis.2024 Journal of Gastrointestinal Oncology. All rights reserved.