Microparticles mediate trait dominance in cancer

Publication Type:
Thesis
Issue Date:
2015
Full metadata record
Files in This Item:
Filename Description Size
01front.pdf203.97 kB
Adobe PDF
02whole.pdf3.08 MB
Adobe PDF
Multidrug resistance (MDR) persists to be a major hindrance to the successful treatment in clinical oncology and is the cause of over 90% of treatment failure in cancer. The two main membrane spanning proteins, P-glycoprotein (ABCB1/P-gp) and Multidrug Resistance-associated protein 1 (ABCC1/MRP1) are responsible for the efflux of a plethora of unrelated anti-cancer drugs out of cells, resulting in MDR. Cancer cells overexpressing these efflux proteins are insensitive to chemotherapeutic treatments by maintaining sub-lethal intracellular cytotoxic drug concentrations. Given their enormous substrate profile, of which there is significant overlap, the expression of either efflux protein would result in a poor prognosis. In some cancers, the overexpression of these proteins is correlated with clinical stage, with early stage tumours expressing one efflux transporter and substituted by another transporter at an advanced stage. Our group has established the transfer and dissemination of ABC-transporter mediated MDR via a subset of extracellular vesicles known as microparticles (MPs). This study investigates the molecular mechanisms governing the alteration and acquisition of MDR traits in cancer cell populations via MPs. Spontaneously shed MPs from cancer cells represent a prominent modality for intercellular communication by virtue of their capacity to transport and disseminate bioactive cargo through the vasculature. Their ability to carry large membrane spanning proteins and nucleic acids, imparts their capacity to confer MDR among otherwise drug sensitive tumour cells. Herein, the study validates the MP-transfer and functionality of MRP1 in drug sensitive acute leukaemia cells. The study also introduces MP-mediated trait dominance and demonstrate the re-templating of a pre-existing MDR phenotype in recipient cells. To validate the transfer and translation of MP packaged nucleic acids, a novel methodology was developed, abolishing the requirement for labelled probes and interspecies models. Using, surface peptide shaving, detection of MP packaged P-gp was removed and showed transcript translation of transferred ABCB1 in drug sensitive recipient cells after more than 24 h. Finally, the study identifies transcript suppression mechanisms involved in MP-mediated trait dominance and identify a novel relationship between the function of miRNA with a non-target mRNA transcript. Specifically, the presence of a rival transcript ABCB1 facilitates the ABCC1 suppression by miR-326. These findings substantially advance our understanding on the molecular mechanisms leading to the alteration of MDR traits and can be translated into clinical oncology by providing prognostic information and additional therapeutic targets.
Please use this identifier to cite or link to this item: