背景:稳定同位素示踪剂已越来越多地用于临床前癌症模型系统,包括细胞培养和小鼠异种移植,探测各种癌症的代谢改变,如加速糖酵解和谷氨酰胺分解和生成糖代谢产物。关于不同临床前模型系统在概括肿瘤异常代谢方面的保真度的报道相对较少。
目的:我们一直在开发几种不同的实验模型系统,用于使用患者来源的组织对非小细胞肺癌(NSCLC1)进行系统生化分析,以评估代谢和表型分析的适当模型。
方法:为了解决保真度问题,我们对新鲜切除的组织切片进行了详细的稳定同位素分解代谢组学研究,小鼠患者来源的异种移植物(PDX),和使用13C6-葡萄糖和13C5,15N2-谷氨酰胺示踪剂从单个患者获得的细胞。
结果:尽管我们在三个模型中发现了相似的葡萄糖代谢,与原发性癌组织或直接组织异种移植物(PDX)相比,分离的细胞培养物和源自细胞培养物的异种移植物中的谷氨酰胺利用率明显更高。
结论:这表明在体外或异种移植物中使用患者来源的癌细胞解释癌症生物化学时需要谨慎。即使在很早的时候,并且对患者来源的组织切片的直接分析为离体代谢组学提供了最佳模型。需要进一步的研究来确定这些观察的一般性。
BACKGROUND: Stable isotope tracers have been increasingly used in preclinical cancer model systems, including cell culture and mouse xenografts, to probe the altered metabolism of a variety of cancers, such as accelerated glycolysis and glutaminolysis and generation of oncometabolites. Comparatively little has been reported on the fidelity of the different preclinical model systems in recapitulating the aberrant metabolism of tumors.
OBJECTIVE: We have been developing several different experimental model systems for systems biochemistry analyses of non-small cell lung cancer (NSCLC1) using patient-derived tissues to evaluate appropriate models for metabolic and phenotypic analyses.
METHODS: To address the issue of fidelity, we have carried out a detailed Stable Isotope-Resolved Metabolomics study of freshly resected tissue slices, mouse patient derived xenografts (PDXs), and cells derived from a single patient using both 13C6-glucose and 13C5,15N2-glutamine tracers.
RESULTS: Although we found similar glucose metabolism in the three models, glutamine utilization was markedly higher in the isolated cell culture and in cell culture-derived xenografts compared with the primary cancer tissue or direct tissue xenografts (PDX).
CONCLUSIONS: This suggests that caution is needed in interpreting cancer biochemistry using patient-derived cancer cells in vitro or in xenografts, even at very early passage, and that direct analysis of patient derived tissue slices provides the optimal model for ex vivo metabolomics. Further research is needed to determine the generality of these observations.