The role of extracellular vesicles in the transfer of multidrug resistance in human ovarian cancer cells
Bibliographic record
Abstract
Ovarian cancer is the fifth most common cancer in Canadian women and has the highest mortality rate of all gynecologic malignancies. First-line treatment is typically cytoreductive surgery followed by a combination of paclitaxel and carboplatin. Unfortunately, patients frequently relapse with drug resistant disease, and only 45% of patients survive beyond 5 years. Drug resistance results from multiple mechanisms, one of which is mediated by one or more of the ATP-binding cassette (ABC) drug efflux transporters. The two ABC transporters considered clinically relevant in ovarian cancer are P-glycoprotein (P-gp) and multidrug resistance protein 1 (MRP1). These plasma membrane transporters can efflux an array of solutes from the cell, including paclitaxel. Extracellular vesicles (EVs) are a collective term for nano-sized membrane vesicles released from all mammalian cells that can serve as cell-free vehicles to deliver a variety of biomolecules to recipient cells. The human ovarian cancer cell lines A2780 and 2008, and their drug resistant variants, AD645 and 2008/MRP1, which overexpress P-gp and MRP1, respectively, were used to investigate whether transporter-containing EVs can transfer drug resistance to sensitive cells. All four cell lines were shown to release EVs isolated by differential ultracentrifugation (DUC) and size-exclusion chromatography (SEC), as indicated by the presence of EV markers CD63, CD81, and syntenin-1 in immunoblots of EV extracts. P-gp and MRP1 were also detected in EV extracts from AD645 and 2008/MRP1 cells, respectively. DUC- isolated AD645 EVs appeared toxic to A2780 recipient cells and there was no detectable transfer of paclitaxel resistance after co-culture. SEC-isolated AD645 EVs were more enriched than DUC-isolated EVs for CD63, CD81, and syntenin-1, and appeared less toxic to A2780 cells. However, P-gp was not enriched in SEC-isolated AD645 EVs and there was no detectable ii transfer of paclitaxel resistance or P-gp to A2780 cells. These observations suggest that the amount of functional P-gp transferred to recipient cells was insufficient to confer detectable resistance. These studies suggest that although P-gp and MRP1 can be detected in cellular material consistent with the presence of EVs, additional experiments are needed to optimize isolation of transporter-enriched EVs and co-culture conditions to detect the transfer of drug resistance.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".