Ravichandra Aashreya, Bhattacharjee Sonakshi, Affò Silvia
Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Adv Cancer Res. 2022;156:201-226. doi: 10.1016/bs.acr.2022.01.009. Epub 2022 Feb 24.
Cancer-associated fibroblasts (CAFs) are one of the most abundant stromal cell type in the tumor microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA), where they are actively involved in cancer progression through a complex network of interactions with other stromal cells. The majority of the studies investigating CAFs in iCCA have focused their attention on CAF tumor-promoting roles, remarking their potential as therapeutic targets. However, indiscriminate targeting of CAFs in other desmoplastic tumors has ended in failure with no effects or even accelerated cancer progression and reduced survival, indicating the urgent need to better understand the nuances and functions of CAFs to avoid deleterious effects. Indeed, recent single cell RNA sequencing studies have shown that heterogeneous CAF subpopulations coexist in the same tumor, some promoting- and other restricting- tumor growth. Moreover, recent studies have shown that in iCCA, diverse CAF subtypes interact differently with the cells of the TME, suggesting that CAFs may dynamically change their phenotypes during tumor progression, a field that remains uninvestigated. The characterization of heterogenous CAF subpopulations and their functionality, will provide a feasible and safer approach to facilitate the development of new therapeutic approaches aimed at targeting CAFs and their interactions with other stromal cells in the TME rather than solely tumor cells in iCCA. Here, we discuss the origin of CAFs, as well as their heterogeneity, plasticity, mechanisms and targeting strategies to provide a brief snapshot of the current knowledge in iCCA.
癌症相关成纤维细胞(CAFs)是肝内胆管癌(iCCA)肿瘤微环境(TME)中最丰富的基质细胞类型之一,它们通过与其他基质细胞的复杂相互作用网络积极参与癌症进展。大多数研究iCCA中CAFs的研究都集中在CAF的促肿瘤作用上,强调它们作为治疗靶点的潜力。然而,在其他促结缔组织增生性肿瘤中不加区分地靶向CAFs最终以失败告终,没有效果甚至加速了癌症进展并缩短了生存期,这表明迫切需要更好地了解CAFs的细微差别和功能以避免有害影响。事实上,最近的单细胞RNA测序研究表明,异质性CAF亚群共存于同一肿瘤中,一些促进肿瘤生长,另一些则限制肿瘤生长。此外,最近的研究表明,在iCCA中,不同的CAF亚型与TME中的细胞相互作用方式不同,这表明CAFs可能在肿瘤进展过程中动态改变其表型,而这一领域仍未得到研究。对异质性CAF亚群及其功能的表征,将提供一种可行且更安全的方法,以促进开发旨在靶向CAFs及其与TME中其他基质细胞相互作用而非仅iCCA中的肿瘤细胞的新治疗方法。在此,我们讨论CAFs的起源,以及它们的异质性、可塑性、机制和靶向策略,以简要概述iCCA的当前知识。