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Cells isolated from residual intracranial tumors after treatment express iPSC genes and possess neural lineage differentiation plasticity.

ABSTRACT: BACKGROUND:The goal of this study is to identify and characterize treatment resistant tumor initiating cells (TRTICs) using orthotopic xenografts. METHODS:TRTICs were enriched from GBM cell lines using mouse xenografts treated with fractionated doses of radiation and temozolomide. TRTICs were characterized by neurosphere clonogenicity and self-renewal, serial xenotransplantation, differentiation potential, and mRNA & miRNA transcriptomic profiling. We use an unbiased approach to identify antigens encoding TRTIC and glioma stem cells (GSC) populations. Co-culture experiments of TRTIC and differentiated cells were conducted to evaluate the reliance of TRTIC differentiation on the secretome of differentiated cells. FINDINGS:TRTICs acquire stem-like gene expression signatures and increased side population staining resulting from the activation of multi-drug resistance genes. Genetic and functional characterization of TRTICs shows a striking resemblance with GSCs. TRTICs can differentiate towards specific progeny in the neural stem cell lineage. TRTIC-derived tumors display all the histological hallmarks of glioblastoma (GBM) and exhibit a miRNA-transcript and mRNA-transcriptomic profile associated with aggressiveness. We report that CD24+/CD44+ antigens are expressed in TRTICs and patient-derived GSCs. Double positive CD24+/CD44+ exhibit treatment resistance and enhanced tumorigenicity. Interestingly, co-culture experiments with TRTICs and differentiated cells indicated that the regulation of TRTIC differentiation could rely on the secretome in the tumor niche. INTERPRETATION:Radiation and temozolomide treatment enriches a population of cells that have increased iPSC gene expression. As few as 500 cells produced aggressive intracranial tumors resembling patient GBM. CD24+/CD44+ antigens are increased in TRTICs and patient-derived GSCs. The enrichment for TRTICs may result in part from the secretome of differentiated cells. FUND: NIH/NCI 1RC2CA148190, 1R01CA108633, 1R01CA188228, and The Ohio State University Comprehensive Cancer Center.

SUBMITTER: Palanichamy K

PROVIDER: S-EPMC6197705 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Cells isolated from residual intracranial tumors after treatment express iPSC genes and possess neural lineage differentiation plasticity.

Palanichamy Kamalakannan K Jacob John R JR Litzenberg Kevin T KT Ray-Chaudhury Abhik A Chakravarti Arnab A

EBioMedicine 20180927

<h4>Background</h4>The goal of this study is to identify and characterize treatment resistant tumor initiating cells (TRTICs) using orthotopic xenografts.<h4>Methods</h4>TRTICs were enriched from GBM cell lines using mouse xenografts treated with fractionated doses of radiation and temozolomide. TRTICs were characterized by neurosphere clonogenicity and self-renewal, serial xenotransplantation, differentiation potential, and mRNA & miRNA transcriptomic profiling. We use an unbiased approach to i ...[more]

PMID: 30269995

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Cells isolated from residual intracranial tumors after treatment express iPSC genes and possess neural lineage differentiation plasticity.

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Cells isolated from residual intracranial tumors after treatment express iPSC genes and possess neural lineage differentiation plasticity.

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