Multi-drug resistance (MDR) is a unique type of resistance in which cancer cells, become cross-resistant to structurally and functionally unrelated drugs used in cancer treatment. Indeed, 90% of metastatic disease is multi-drug resistant. The overexpression of plasma membrane proteins belonging to the ABC superfamily of membrane transporters are synonymous with this problamatic phenotype. Typical members include P-glycoprotein (P-gp/ ABCB1) and Multidrug Resistance Protein 1 (MRP-1 / ABCC1). These plasma membrane transporters possess a remarkable capacity to efflux drugs out from cancer cells by virtue of ATP hydrolysis and maintain an intracellular drug accumulation deficit. This capacity for drug efflux renders cancer cells multi-drug resistant and unresponsive to treatment.
We first discovered that extracellular vesicles provide a novel pathway for the dissemination and acquisition of MDR in cancer. This occurs through the intercellular transfer of functional resistance proteins and nucleic acids and through a capacity for active and passive drug sequestration within the vesicle lumen. We have also shown that MPs derived from MDR cells readily re-template the transcriptional landscape in confering the donor cell traits within recipient cancer cell populations. We have also shown that vesicles shed from MDR cells also confer an enhanced metastatic capacity and altered tissue biomechanical properties to recipient cells. Our most recent studies describe the presence of a novel, distinct and parallel vesicle pathway supporting the survival of MDR cancer cells through the facilitation of immunological privilege. We propose that this pathway serves to prime distant sites to support colonisation by invading metastatic breast cancer cells.
This work was supported by research funds from the Cancer Council NSW (Grant RG-09-02), National Health and Medical Research Council, Australia (Project Grant APP1007613) and University of Technology Sydney to M.Bebawy.