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RESEARCH PRODUCT
Cancer stem cell-based models of colorectal cancer reveal molecular determinants of therapy resistance
Giorgio RussoGiorgio StassiSara VitaleMarta BaiocchiAlessandro BrusellesFederica FrancescangeliEleonora PolicicchioEleonora PolicicchioEmanuela PilozziGabriele De LucaMaria Laura De AngelisRuggero De MariaMichele SignoreAlessandra BoeLucia Ricci-vitianiAnn ZeunerMarco TartagliaCarla Azzurra AmoreoAlfredo Pagliucasubject
0301 basic medicineProteomicscancer stem cellsColorectal cancerDrug ResistanceMice SCIDAnti-EGFR therapy; Cancer stem cells; Cetuximab; Colorectal cancer; Proteomic arrays; Animals; Cells Cultured; Colorectal Neoplasms; Drug Resistance Neoplasm; Female; Gene Expression Profiling; Humans; Mice Inbred NOD; Mice SCID; Mice Transgenic; Microarray Analysis; Models Biological; Neoplastic Stem Cells; Protein Kinase Inhibitors; Proteomics; Signal Transduction; Developmental Biology; Cell BiologyTransgenicMiceMice Inbred NODModelsproteomic arrayscetuximabcell biologyEpidermal growth factor receptorCells CulturedCulturedCetuximabbiologyGeneral MedicinePrimary tumorNeoplastic Stem CellsFemaleSettore MED/46 - Scienze Tecniche Di Medicina Di LaboratorioStem cellColorectal Neoplasmsmedicine.drugSignal TransductionCellsMice Transgeniccolorectal cancerSCIDModels Biological03 medical and health sciencesdevelopmental biologyProteomic arrayCancer stem cellIn vivoSettore MED/04 - PATOLOGIA GENERALEmedicineAnimalsHumansProtein Kinase InhibitorsSettore MED/06 - ONCOLOGIA MEDICAMicroarray analysis techniquesbusiness.industryCancer stem cellGene Expression Profilingmedicine.diseaseMicroarray AnalysisBiological030104 developmental biologyanti-EGFR therapyDrug Resistance Neoplasmanti-EGFR therapy; cancer stem cells; cetuximab; colorectal cancer; proteomic arrays; cell biology; developmental biologyImmunologyCancer researchbiology.proteinNeoplasmInbred NODbusinessdescription
Abstract Colorectal cancer (CRC) therapy mainly relies on the use of conventional chemotherapeutic drugs combined, in a subset of patients, with epidermal growth factor receptor [EGFR]-targeting agents. Although CRC is considered a prototype of a cancer stem cell (CSC)-driven tumor, the effects of both conventional and targeted therapies on the CSC compartment are largely unknown. We have optimized a protocol for colorectal CSC isolation that allowed us to obtain CSC-enriched cultures from primary tumor specimens, with high efficiency. CSC isolation was followed by in vitro and in vivo validation, genetic characterization, and drug sensitivity analysis, thus generating panels of CSC lines with defined patterns of genetic mutations and therapy sensitivity. Colorectal CSC lines were polyclonal and maintained intratumor heterogeneity in terms of somatically acquired mutations and differentiation state. Such CSC-enriched cultures were used to investigate the effects of both conventional and targeted therapies on the CSC compartment in vivo and to generate a proteomic picture of signaling pathways implicated in sensitivity/resistance to anti-EGFR agents. We propose CSC lines as a sound preclinical framework to test the effects of therapies in vitro and in vivo and to identify novel determinants of therapy resistance. Significance Colorectal cancer stem cells (CSCs) have been shown to be responsible for tumor propagation, metastatic dissemination, and relapse. However, molecular pathways present in CSCs, as well as mechanisms of therapy resistance, are mostly unknown. Taking advantage of genetically characterized CSC lines derived from colorectal tumors, this study provides an extensive analysis of CSC response to EGFR-targeted therapy in vivo and an overview of factors implicated in therapy response or resistance. Furthermore, the implementation of a biobank of molecularly annotated CSC lines provides an innovative resource for future investigations in colorectal cancer.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2016-03-08 |