Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China.
Br J Cancer. 2024 May;130(9):1505-1516. doi: 10.1038/s41416-024-02631-9. Epub 2024 Mar 7.
Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a 5-year survival rate of 12%. The abundant mesenchyme is partly responsible for the malignancy. The antifibrotic therapies have gained attention in recent research. However, the role of pirfenidone, an FDA-approved drug for idiopathic pulmonary fibrosis, remains unclear in PDAC.
Data from RNA-seq of patient-derived xenograft (PDX) models treated with pirfenidone were integrated using bioinformatics tools to identify the target of cell types and genes. Using confocal microscopy, qRT-PCR and western blotting, we validated the signalling pathway in tumour cells to regulate the cytokine secretion. Further cocultured system demonstrated the interplay to regulate stroma fibrosis. Finally, mouse models demonstrated the potential of pirfenidone in PDAC.
Pirfenidone can remodulate multiple biological pathways, and exerts an antifibrotic effect through inhibiting the secretion of PDGF-bb from tumour cells by downregulating the TGM2/NF-kB/PDGFB pathway. Thus, leading to a subsequent reduction in collagen X and fibronectin secreted by CAFs. Moreover, the mice orthotopic pancreatic tumour models demonstrated the antifibrotic effect and potential to sensitise gemcitabine.
Pirfenidone may alter the pancreatic milieu and alleviate fibrosis through the regulation of tumour-stroma interactions via the TGM2/NF-kB/PDGFB signalling pathway, suggesting potential therapeutic benefits in PDAC management.
胰腺导管腺癌（PDAC）是一种恶性肿瘤，5 年生存率为 12%。丰富的间质部分是其恶性程度的原因之一。抗纤维化治疗在最近的研究中受到了关注。然而，美国食品和药物管理局批准用于特发性肺纤维化的药物吡非尼酮在 PDAC 中的作用仍不清楚。
使用生物信息学工具整合接受吡非尼酮治疗的患者来源异种移植（PDX）模型的 RNA-seq 数据，以鉴定细胞类型和基因的靶点。通过共聚焦显微镜、qRT-PCR 和 Western blot 验证肿瘤细胞中调节细胞因子分泌的信号通路。进一步的共培养系统证明了调节基质纤维化的相互作用。最后，在小鼠模型中证明了吡非尼酮在 PDAC 中的潜力。
吡非尼酮可以重塑多种生物学途径，通过下调 TGM2/NF-kB/PDGFB 通路抑制肿瘤细胞 PDGF-bb 的分泌，发挥抗纤维化作用。从而导致 CAFs 分泌的胶原 X 和纤连蛋白减少。此外，小鼠原位胰腺肿瘤模型显示了抗纤维化作用，并有可能增敏吉西他滨。
吡非尼酮可能通过 TGM2/NF-kB/PDGFB 信号通路调节肿瘤-基质相互作用，改变胰腺微环境并减轻纤维化，这表明在 PDAC 治疗中有潜在的治疗益处。
