Department of Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Clin Transl Med. 2023 Mar;13(3):e1213. doi: 10.1002/ctm2.1213.
Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy characterized by massive fibrosis and has ineffective adjuvant therapies. Here, we demonstrate the potential of angiotensin receptor blockers (ARBs) in targeting iCCA.
Masson's trichrome staining was used to assess the effect of ARBs in iCCA specimens, CCK8 and gel contraction assays in vitro and in xenograft models in vivo. RNA-seq and ATAC-seq were used for mechanistic investigations.
Patients with iCCA who were administered ARBs had a better prognosis and a lower proportion of tumour stroma, indicating alleviated fibrosis. The presence of AGTR1, the ARBs receptor, is associated with a poor prognosis of iCCA and is highly expressed in tumour tissues and cancer-associated fibroblasts (CAFs). The ARBs strongly attenuated the viability of CAFs in vitro and retarded tumour progression and fibrosis in xenograft models of co-cultured CAFs and iCCA cells. Still, they did not have a significant effect on CAFs. Moreover, ARBs decreased the secretion of CAF-derived MFAP5 via the Hippo pathway, weakened the interaction between CAFs and iCCA cells, and impaired the aggressiveness of iCCA cells by attenuating the activation of the Notch1 pathway in iCCA cells.
ARBs exhibit anti-fibrotic function by inhibiting the viability of CAFs. These findings support using ARBs as a novel therapeutic option for targeting iCCA.
肝内胆管癌（iCCA）是一种高度致命的恶性肿瘤，其特征是大量纤维化，且辅助治疗效果不佳。在这里，我们证明了血管紧张素受体阻滞剂（ARBs）在靶向 iCCA 中的潜力。
使用 Masson 三色染色评估 ARBs 在 iCCA 标本中的作用，体外 CCK8 和凝胶收缩试验以及体内异种移植模型。使用 RNA-seq 和 ATAC-seq 进行机制研究。
接受 ARBs 治疗的 iCCA 患者预后更好，肿瘤基质比例更低，表明纤维化减轻。AGTR1 的存在，即 ARBs 的受体，与 iCCA 的不良预后相关，在肿瘤组织和癌相关成纤维细胞（CAFs）中高表达。ARBs 在体外强烈抑制 CAFs 的活力，并在 CAFs 和 iCCA 细胞共培养的异种移植模型中延迟肿瘤进展和纤维化。然而，它们对 CAFs 没有显著影响。此外，ARBs 通过 Hippo 通路减少 CAF 衍生的 MFAP5 的分泌，削弱 CAFs 和 iCCA 细胞之间的相互作用，并通过减弱 Notch1 通路在 iCCA 细胞中的激活来削弱 iCCA 细胞的侵袭性。
ARBs 通过抑制 CAFs 的活力发挥抗纤维化功能。这些发现支持使用 ARBs 作为靶向 iCCA 的一种新的治疗选择。
