Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Department of General Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Gut. 2024 Jul 11;73(8):1350-1363. doi: 10.1136/gutjnl-2023-331715.
The correlation between cholangiocarcinoma (CCA) progression and bile is rarely studied. Here, we aimed to identify differential metabolites in benign and malignant bile ducts and elucidate the generation, function and degradation of bile metabolites.
Differential metabolites in the bile from CCA and benign biliary stenosis were identified by metabonomics. Biliary molecules able to induce mast cell (MC) degranulation were revealed by in vitro and in vivo experiments, including liquid chromatography-mass spectrometry (MS)/MS and bioluminescence resonance energy transfer assays. Histamine (HA) receptor expression in CCA was mapped using a single-cell mRNA sequence. HA receptor functions were elucidated by patient-derived xenografts (PDX) in humanised mice and orthotopic models in MC-deficient mice. Genes involved in HA-induced proliferation were screened by CRISPR/Cas9.
Bile HA was elevated in CCA and indicated poorer prognoses. Cancer-associated fibroblasts (CAFs)-derived stem cell factor (SCF) recruited MCs, and bile N,N-dimethyl-1,4-phenylenediamine (DMPD) stimulated MCs to release HA through G protein-coupled receptor subtype 2 (MRGPRX2)-Gαq signalling. Bile-induced MCs released platelet-derived growth factor subunit B (PDGF-B) and angiopoietin 1/2 (ANGPT1/2), which enhanced CCA angiogenesis and lymphangiogenesis. Histamine receptor H1 (HRH1) and HRH2 were predominantly expressed in CCA cells and CAFs, respectively. HA promoted CCA cell proliferation by activating HRH1-Gαq signalling and hastened CAFs to secrete hepatocyte growth factor by stimulating HRH2-Gαs signalling. Solute carrier family 22 member 3 (SLC22A3) inhibited HA-induced CCA proliferation by importing bile HA into cells for degradation, and deletion resulted in HA accumulation.
Bile HA is released from MCs through DMPD stimulation and degraded via SLC22A3 import. Different HA receptors exhibit a distinct expression profile in CCA and produce different oncogenic effects. MCs promote CCA progression in a CCA-bile interplay pattern.
胆管癌（CCA）进展与胆汁之间的相关性很少被研究。本研究旨在鉴定良性和恶性胆管胆汁中的差异代谢物，并阐明胆汁代谢物的产生、功能和降解。
通过代谢组学鉴定 CCA 和良性胆管狭窄胆汁中的差异代谢物。通过体外和体内实验，包括液相色谱-质谱（MS）/MS 和生物发光共振能量转移测定，揭示能够诱导肥大细胞（MC）脱颗粒的胆汁分子。通过单细胞 mRNA 序列绘制 CCA 中的组氨酸（HA）受体表达图谱。通过在人源化小鼠和 MC 缺陷型小鼠的原位模型中使用患者来源的异种移植（PDX）来阐明 HA 受体功能。通过 CRISPR/Cas9 筛选参与 HA 诱导增殖的基因。
CCA 胆汁中 HA 升高，提示预后较差。癌相关成纤维细胞（CAF）衍生的干细胞因子（SCF）募集 MC，胆汁 N,N-二甲基-1,4-苯二胺（DMPD）通过 G 蛋白偶联受体亚型 2（MRGPRX2）-Gαq 信号刺激 MC 释放 HA。胆汁诱导的 MC 释放血小板衍生生长因子亚基 B（PDGF-B）和血管生成素 1/2（ANGPT1/2），增强 CCA 血管生成和淋巴管生成。组氨酸受体 H1（HRH1）和 HRH2 分别在 CCA 细胞和 CAF 中主要表达。HA 通过激活 HRH1-Gαq 信号促进 CCA 细胞增殖，并通过刺激 HRH2-Gαs 信号加速 CAF 分泌肝细胞生长因子。溶质载体家族 22 成员 3（SLC22A3）通过将胆汁 HA 导入细胞进行降解来抑制 HA 诱导的 CCA 增殖，而 SLC22A3 缺失则导致 HA 积累。
MC 通过 DMPD 刺激从胆汁中释放 HA，并通过 SLC22A3 摄取进行降解。不同的 HA 受体在 CCA 中表现出不同的表达谱，并产生不同的致癌作用。MC 以 CCA-胆汁相互作用模式促进 CCA 进展。
