Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
Cell Rep. 2021 Feb 23;34(8):108772. doi: 10.1016/j.celrep.2021.108772.
Evidence regarding intraductal papillary neoplasm of the bile duct (IPNB) as a type of precancerous lesion of cholangiocarcinoma is limited. Moreover, a reproducible in vivo model is lacking, and IPNB pathogenesis remains unclear. Here, we use a doxycycline-inducible tetracycline (Tet)-on mice model to control fibroblast growth factor 10 (FGF10) expression, which regulates branching and tubule formation. FGF10-induced IPNB mimics the multifocal and divergent human IPNB phenotypes via the FGF10-FGF receptor 2 (FGFR2)-RAS-extracellular-signal-regulated kinase (ERK) signaling pathway. A paracrine/autocrine growth factor is sufficient to initiate and maintain IPNB originating from the peribiliary glands, including biliary stem/progenitor cells. With Kras, p53, or p16 mutations or both, Fgf10-induced IPNB shows stepwise carcinogenesis, causing associated invasive carcinoma. Fgf10-induced papillary changes and progression are suppressed by the inhibition of the FGF10-FGFR2-RAS-ERK signaling pathway, demonstrating that the signal is a therapeutic target for IPNB and associated carcinoma.
胆管内乳头状肿瘤（IPNB）作为胆管癌的癌前病变类型的证据有限。此外，缺乏可重现的体内模型，IPNB 的发病机制仍不清楚。在这里，我们使用强力霉素诱导的四环素（Tet）启动子小鼠模型来控制成纤维细胞生长因子 10（FGF10）的表达，该因子调节分支和管腔形成。FGF10 诱导的 IPNB 通过 FGF10-FGFR2-RAS-细胞外信号调节激酶（ERK）信号通路模拟多灶性和发散性人类 IPNB 表型。旁分泌/自分泌生长因子足以启动和维持源自胆管周围腺体的 IPNB，包括胆管干细胞/祖细胞。带有 Kras、p53 或 p16 突变或两者兼有，Fgf10 诱导的 IPNB 显示逐步癌变，导致相关侵袭性癌。FGF10 诱导的乳头状变化和进展被 FGF10-FGFR2-RAS-ERK 信号通路的抑制所抑制，表明该信号是 IPNB 和相关癌的治疗靶点。
