title: Microparticle-associated nucleic acids mediate trait dominance in cancer.
abstract: Drug resistance is a major cause of cancer treatment failure, with multidrug resistance (MDR) being the most serious, whereby cancer cells display cross-resistance to structurally and functionally unrelated drugs. MDR is caused by overexpression of the efflux transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1). These transporters act to maintain sublethal intracellular drug concentrations within the cancer cell, making the population treatment unresponsive. Recently, we discovered a novel nongenetic basis to MDR whereby microparticles (MPs) transfer P-gp intercellularly from MDR donor cells to drug-sensitive recipient cells. MPs isolated from MDR leukemia and breast cancer cells were cocultured with their drug-sensitive counterparts. P-gp transfer was assessed by direct immunolabeling, and acquired transcripts and regulatory microRNAs by quantitative real-time PCR. We show that MDR MPs incorporate nucleic acids; MPs change recipient cells' transcriptional environment to reflect donor MDR phenotype, and distinct pathways exist among cancers of different origin that may be dependent on donor cells' ABCB1 overexpression. We demonstrate that this pathway exists for both hematological and nonhematological malignancies. By conferring MDR and "retemplating" the transcriptional landscape of recipient cells, MPs provide a novel pathway, having implications in the dissemination and acquisition of deleterious traits in clinical oncology.
authors.affiliation: Sydney Medical School and Bosch Institute, University of Sydney,Sydney, Australia.
authors.forename: Ritu
authors.initials: R
authors.lastname: Jaiswal
authors.forename: Joyce
authors.initials: J
authors.lastname: Gong
authors.forename: Shwetha
authors.initials: S
authors.lastname: Sambasivam
authors.forename: Valery
authors.initials: V
authors.lastname: Combes
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Mathys
authors.forename: Ross
authors.initials: R
authors.lastname: Davey
authors.forename: Georges E R
authors.initials: GE
authors.lastname: Grau
authors.forename: Mary
authors.initials: M
authors.lastname: Bebawy
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles / Q000473:pathology* / Q000648:ultrastructure; D018920:Coculture Techniques; D018432:Drug Resistance, Multiple / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D009696:Nucleic Acids / Q000378:metabolism*; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D021381:Protein Transport / Q000502:physiology
chemical_list: D035683:MicroRNAs; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009696:Nucleic Acids; C421109:multidrug resistance-associated protein 1