Microparticle-associated nucleic acids mediate trait dominance in cancer

作者：Jaiswal Ritu; Gong Joyce; Sambasivam Shwetha; Combes Valery; Mathys Jean Marie; Davey Ross; Grau Georges E R; Bebawy Mary^*

来源：The FASEB Journal, 2012, 26(1): 420-429.

DOI：10.1096/fj.11-186817

• multidrug resistance
• P-glycoprotein
• multidrug resistance-associated protein 1
• intercellular transfer

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%26apos; transcriptional environment to reflect donor MDR phenotype, and distinct pathways exist among cancers of different origin that may be dependent on donor cells%26apos; ABCB1 overexpression. We demonstrate that this pathway exists for both hematological and nonhematological malignancies. By conferring MDR and %26quot;retemplating%26quot; the transcriptional landscape of recipient cells, MPs provide a novel pathway, having implications in the dissemination and acquisition of deleterious traits in clinical oncology.-Jaiswal, R., Gong, J., Sambasivam, S., Combes, V., Mathys, J.-M., Davey, R., Grau, G. E. R., Bebawy, M. Microparticle-associated nucleic acids mediate trait dominance in cancer. FASEB J. 26, 420-429 (2012). www.fasebj.org

• 出版日期2012-1