Recapitulation of Tumor Heterogeneity and Molecular Signatures in a 3D Brain Cancer Model with Decreased Sensitivity to Histone Deacetylase Inhibition
| Autor: | Stuart Smith, Felicity R. A. J. Rose, Andrew C. Peet, Ruman Rahman, Cheryl V. Rahman, Martin Wilson, Richard Grundy, Jennifer H. Ward, Donald Macarthur |
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| Rok vydání: | 2012 |
| Předmět: |
Clinical Research Design
medicine.drug_class Science Primary Cell Culture Brain tumor Gene Expression Antineoplastic Agents Biology Cell Growth Cell Line Tumor Spheroids Cellular Molecular Cell Biology Basic Cancer Research Tumor Cells Cultured Tumor Microenvironment medicine Cluster Analysis Humans Vorinostat Cell Proliferation Cellular Stress Responses Tumor microenvironment Multidisciplinary Brain Neoplasms Gene Expression Profiling Histone deacetylase inhibitor Modeling Histone Modification Genomics medicine.disease Extracellular Matrix Cell biology Oxygen tension Gene Expression Regulation Neoplastic Histone Deacetylase Inhibitors Gene expression profiling Phenotype Oncology Drug Resistance Neoplasm Cell culture Metabolome Medicine Genome Expression Analysis Ex vivo Research Article medicine.drug |
| Zdroj: | PLoS ONE, Vol 7, Iss 12, p e52335 (2012) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | IntroductionPhysiologically relevant pre-clinical ex vivo models recapitulating CNS tumor micro-environmental complexity will aid development of biologically-targeted agents. We present comprehensive characterization of tumor aggregates generated using the 3D Rotary Cell Culture System (RCCS).MethodsCNS cancer cell lines were grown in conventional 2D cultures and the RCCS and comparison with a cohort of 53 pediatric high grade gliomas conducted by genome wide gene expression and microRNA arrays, coupled with immunohistochemistry, ex vivo magnetic resonance spectroscopy and drug sensitivity evaluation using the histone deacetylase inhibitor, Vorinostat.ResultsMacroscopic RCCS aggregates recapitulated the heterogeneous morphology of brain tumors with a distinct proliferating rim, necrotic core and oxygen tension gradient. Gene expression and microRNA analyses revealed significant differences with 3D expression intermediate to 2D cultures and primary brain tumors. Metabolic profiling revealed differential profiles, with an increase in tumor specific metabolites in 3D. To evaluate the potential of the RCCS as a drug testing tool, we determined the efficacy of Vorinostat against aggregates of U87 and KNS42 glioblastoma cells. Both lines demonstrated markedly reduced sensitivity when assaying in 3D culture conditions compared to classical 2D drug screen approaches.ConclusionsOur comprehensive characterization demonstrates that 3D RCCS culture of high grade brain tumor cells has profound effects on the genetic, epigenetic and metabolic profiles of cultured cells, with these cells residing as an intermediate phenotype between that of 2D cultures and primary tumors. There is a discrepancy between 2D culture and tumor molecular profiles, and RCCS partially re-capitulates tissue specific features, allowing drug testing in a more relevant ex vivo system. |
| Databáze: | OpenAIRE |
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