阐明胰腺癌中抗性机制的复杂性：体外和前体模型系统的见解
Unravelling the complexities of resistance mechanism in pancreatic cancer: Insights from in vitro and ex-vivo model systems
影响因子:15.70000
分区:医学2区 Top / 肿瘤学2区
发表日期:2024 Nov
作者:
Giulia Lencioni, Alessandro Gregori, Belén Toledo, Rita Rebelo, Benoît Immordino, Manoj Amrutkar, Cristina P R Xavier, Anja Kocijančič, Deo Prakash Pandey, Macarena Perán, Justo P Castaño, Naomi Walsh, Elisa Giovannetti
摘要
胰腺导管腺癌（PDAC）是一种侵略性癌症，预后不良，全球死亡增加。由于没有早期症状和生物标志物，晚期诊断主要限制了化学疗法的治疗，这很快就会遇到抗药性。 PDAC处理的创新受到其复杂和异质性的性质的阻碍，包括关键基因的突变和富含基质的，免疫抑制性肿瘤微环境。关于PDAC抗性的最新研究强调了适合体外和离体模型复制其复杂分子和微环境景观的需求。这篇综述总结了这些模型的进步，这些模型可以帮助打击化学耐药性并作为发现新疗法的平台。永生的细胞系具有同质性，无限的增殖和可重复性，但尽管存在许多耐吉西他滨的PDAC细胞系，但较少的模型可用于耐药性。来自PDAC患者的类器官在模仿肿瘤异质性和化学敏感性方面表现出希望。生物反应器，共培养系统和器官型切片（结合基质和免疫细胞）正在开发出来，以了解肿瘤 - 细胞肿的相互作用以及肿瘤微环境在耐药性中的作用。最后，另一种创新的方法是三维生物打印，它创建了类似于PDAC结构的组织样结构，可以进行药物筛查。这些高级模型可以指导研究人员选择最佳的体外测试，可能改善治疗策略和患者的结果。
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis and rising global deaths. Late diagnosis, due to absent early symptoms and biomarkers, limits treatment mainly to chemotherapy, which soon encounters resistance. PDAC treatment innovation is hampered by its complex and heterogeneous resistant nature, including mutations in key genes and a stromal-rich, immunosuppressive tumour microenvironment. Recent studies on PDAC resistance stress the need for suitable in vitro and ex vivo models to replicate its complex molecular and microenvironmental landscape. This review summarises advances in these models, which can aid in combating chemoresistance and serve as platforms for discovering new therapeutics. Immortalised cell lines offer homogeneity, unlimited proliferation, and reproducibility, but while many gemcitabine-resistant PDAC cell lines exist, fewer models are available for resistance to other drugs. Organoids from PDAC patients show promise in mimicking tumour heterogeneity and chemosensitivity. Bioreactors, co-culture systems and organotypic slices, incorporating stromal and immune cells, are being developed to understand tumour-stroma interactions and the tumour microenvironment's role in drug resistance. Lastly, another innovative approach is three-dimensional bioprinting, which creates tissue-like structures resembling PDAC architecture, allowing for drug screening. These advanced models can guide researchers in selecting optimal in vitro tests, potentially improving therapeutic strategies and patient outcomes.