文章：

联合PET示踪剂方法揭示胰腺癌体外与体内基质细胞诱导的代谢变化

Combined PET Radiotracer Approach Reveals Insights into Stromal Cell-Induced Metabolic Changes in Pancreatic Cancer In Vitro and In Vivo

原文发布日期：4 October 2024

DOI: 10.3390/cancers16193393

类型: Article

开放获取: 是

英文摘要：

Background/ObjectivePancreatic stellate cells (PSCs) in pancreatic adenocarcinoma (PDAC) are producing extracellular matrix, which promotes the formation of a dense fibrotic microenvironment. This makes PDAC a highly heterogeneous tumor-stroma-driven entity, associated with reduced perfusion, limited oxygen supply, high interstitial fluid pressure, and limited bioavailability of therapeutic agents.MethodsIn this study, spheroid and tumor xenograft models of human PSCs and PanC-1 cells were characterized radiopharmacologically using a combined positron emission tomography (PET) radiotracer approach. [18F]FDG, [18F]FMISO, and [18F]FAPI-74 were employed to monitor metabolic activity, hypoxic metabolic state, and functional expression of fibroblast activation protein alpha (FAPα), a marker of activated PSCs.ResultsIn vitro, PanC-1 and multi-cellular tumor spheroids demonstrated comparable glucose uptake and hypoxia, whereas FAPα expression was significantly higher in PSC spheroids. In vivo, glucose uptake as well as the transition to hypoxia were comparable in PanC-1 and multi-cellular xenograft models. In mice injected with PSCs, FAPα expression decreased over a period of four weeks post-injection, which was attributed to the successive death of PSCs. In contrast, FAPα expression increased in both PanC-1 and multi-cellular xenograft models over time due to invasion of mouse fibroblasts.ConclusionThe presented models are suitable for subsequently characterizing stromal cell-induced metabolic changes in tumors using noninvasive molecular imaging techniques.

摘要翻译： 

背景/目的 胰腺导管腺癌（PDAC）中的胰腺星状细胞（PSC）产生细胞外基质，促进致密纤维化微环境的形成。这使得PDAC成为一种高度异质性的肿瘤-基质驱动实体，与灌注减少、氧供受限、间质液压力升高以及治疗药物的生物利用度受限相关。 方法 本研究采用正电子发射断层扫描（PET）放射性示踪剂联合方法，对人源PSC与PanC-1细胞的球体及肿瘤异种移植模型进行放射药理学表征。通过[18F]FDG、[18F]FMISO和[18F]FAPI-74监测代谢活性、缺氧代谢状态以及活化的PSC标志物——成纤维细胞活化蛋白α（FAPα）的功能性表达。 结果 体外实验中，PanC-1与多细胞肿瘤球体表现出相似的葡萄糖摄取和缺氧水平，而PSC球体中FAPα表达显著更高。在体内实验中，PanC-1与多细胞异种移植模型的葡萄糖摄取及向缺氧状态的转变程度相近。注射PSC的小鼠中，FAPα表达在注射后四周内逐渐下降，这归因于PSC的相继死亡。相反，在PanC-1和多细胞异种移植模型中，由于小鼠成纤维细胞的浸润，FAPα表达随时间推移而增加。 结论 本研究建立的模型适用于后续通过无创分子影像技术表征基质细胞诱导的肿瘤代谢变化。

原文链接：

Combined PET Radiotracer Approach Reveals Insights into Stromal Cell-Induced Metabolic Changes in Pancreatic Cancer In Vitro and In Vivo