Publicação
The role of extracellular vesicles in chemotherapy resistance mediated by the breast cancer-liver axis
| Resumo: | Abstract Breast cancer (BC) is a leading cause of cancer related death among women. Although progress has been made in BC treatment, chemotherapy resistance occurs frequently, hallmarked by altered drug metabolism. Extracellular vesicles (EVs) are involved in many biological processes, through cell-to-cell communication. This work aims to study the effect of BC-derived EVs on Phase I drug metabolizing enzymes expression in hepatic cells, the major site of drug metabolism, and their role in drug resistance (DR). For this purpose, doxorubicin (DOX), widely used in BC treatment, was applied as model drug. Spheroids of the hepatic model HepG2, and of the BC cell model MCF7 (either parental or resistant to DOX 45 nM), were established. HepG2 spheroids were incubated (24 hrs) with EVs, isolated from parental or resistant MCF7 spheroids. Expression of 92 genes of HepG2 cells, incubated with DOX (using DMSO as control) alone, or DOX in combination with the two types of MCF7 spheroids-derived EVs, was assessed by RT-qPCR. EV-titers from MCF7 resistant spheroids (EVR) were significantly higher, when compared with those of DOX-sensitive spheroids (EVS), suggesting their potential signalling role in chemoresistance. Genes involved in xenobiotic biotransformation, were upregulated by either type of EVs (e.g., CYP1B1, 2B6, 2E1 and 3A4), suggesting that BC cells may have mechanisms to induce augmented drug metabolism, independent of their DR status. When comparing EVS specific – PAM (with DOX), CYP19A1 (with DMSO); EVR specific – SQLE (with both DMSO and DOX), CYP1A1 (with DMSO). Interestingly, up-regulation of SQLE expression (involved in cholesterol metabolism) was exclusive for EVR. Genes found to be differentially expressed when comparing both types of EVs, are related to xenobiotic (some specific for DOX), fatty acid or cholesterol metabolism, previously implicated in tumour progression and/or chemoresistance. Overall, our data pinpoint to modulation of DR mediated by EVs in BC-liver axis. |
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| Autores principais: | Ramos, Carolina Severo |
| Assunto: | EXTRACELLULAR VESICLES CHEMOTHERAPY BREAST CANCER-LIVER AXIS |
| Ano: | 2023 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade Nova de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório Institucional da UNL |
| Resumo: | Abstract Breast cancer (BC) is a leading cause of cancer related death among women. Although progress has been made in BC treatment, chemotherapy resistance occurs frequently, hallmarked by altered drug metabolism. Extracellular vesicles (EVs) are involved in many biological processes, through cell-to-cell communication. This work aims to study the effect of BC-derived EVs on Phase I drug metabolizing enzymes expression in hepatic cells, the major site of drug metabolism, and their role in drug resistance (DR). For this purpose, doxorubicin (DOX), widely used in BC treatment, was applied as model drug. Spheroids of the hepatic model HepG2, and of the BC cell model MCF7 (either parental or resistant to DOX 45 nM), were established. HepG2 spheroids were incubated (24 hrs) with EVs, isolated from parental or resistant MCF7 spheroids. Expression of 92 genes of HepG2 cells, incubated with DOX (using DMSO as control) alone, or DOX in combination with the two types of MCF7 spheroids-derived EVs, was assessed by RT-qPCR. EV-titers from MCF7 resistant spheroids (EVR) were significantly higher, when compared with those of DOX-sensitive spheroids (EVS), suggesting their potential signalling role in chemoresistance. Genes involved in xenobiotic biotransformation, were upregulated by either type of EVs (e.g., CYP1B1, 2B6, 2E1 and 3A4), suggesting that BC cells may have mechanisms to induce augmented drug metabolism, independent of their DR status. When comparing EVS specific – PAM (with DOX), CYP19A1 (with DMSO); EVR specific – SQLE (with both DMSO and DOX), CYP1A1 (with DMSO). Interestingly, up-regulation of SQLE expression (involved in cholesterol metabolism) was exclusive for EVR. Genes found to be differentially expressed when comparing both types of EVs, are related to xenobiotic (some specific for DOX), fatty acid or cholesterol metabolism, previously implicated in tumour progression and/or chemoresistance. Overall, our data pinpoint to modulation of DR mediated by EVs in BC-liver axis. |
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