Breast cancer-derived microparticles display tissue selectivity in the transfer of resistance proteins to cells.

Ritu Jaiswal,Mary Bebawy,Frederick Luk,Penelope V Dalla,Georges Emile Raymond Grau,Connie J Eaves

doi:10.1371/journal.pone.0061515

Ritu Jaiswal, Mary Bebawy + Show 4 more

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https://doi.org/10.1371/journal.pone.0061515

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Abstract

Microparticles (MPs) play a vital role in cell communication by facilitating the horizontal transfer of cargo between cells. Recently, we described a novel “non-genetic” mechanism for the acquisition of multidrug resistance (MDR) in cancer cells by intercellular transfer of functional P-gp, via MPs. MDR is caused by the overexpression of the efflux transporters P-glycoprotein (P-gp) and Multidrug Resistance-Associated Protein 1 (MRP1). These transporters efflux anticancer drugs from resistant cancer cells and maintain sublethal intracellular drug concentrations. By conducting MP transfer experiments, we show that MPs derived from DX breast cancer cells selectively transfer P-gp to malignant MCF-7 breast cells only, in contrast to VLB100 leukaemic cell-derived MPs that transfer P-gp and MRP1 to both malignant and non-malignant cells. The observed transfer selectivity is not the result of membrane restrictions for intercellular exchange, limitations in MP binding to recipient cells or the differential expression of the cytoskeletal protein, Ezrin. CD44 (isoform 10) was found to be selectively present on the breast cancer-derived MPs and not on leukaemic MPs and may contribute to the observed selective transfer of P-gp to malignant breast cells observed. Using the MCF-7 murine tumour xenograft model we demonstrated the stable transfer of P-gp by MPs in vivo, which was found to localize to the tumour core as early as 24 hours post MP exposure and to remain stable for at least 2 weeks. These findings demonstrate a remarkable capacity by MPs to disseminate a stable resistant trait in the absence of any selective pressure.

Highlights

Cell-cell communication is vital for the co-ordination of physiological processes and for the regulation of the organism’s phenotype
We demonstrate that drug resistant MPs can confer the acquired multidrug resistance (MDR) phenotype to recipient cells in vivo, resulting in the transfer of P-gp within the tumour core as early as 24 hours post MP exposure
Multidrug Resistance-Associated Protein 1 (MRP1) was detected in all nonmalignant cells following resistant leukaemic cell-derived MP (E1000MP) co-culture (Figure 1B)

Summary

Introduction

Cell-cell communication is vital for the co-ordination of physiological processes and for the regulation of the organism’s phenotype. Cells communicate by direct cell-cell contact [1] or via supramolecular mechanisms involving cellular membrane blebs/fragments including; membrane vesicles or microparticles (MPs) [2,3], exosomes [4,5], apoptotic bodies [6], tunnelling nanotubes [7,8] and cytoneme or filopodial bridges [9]. Not as complex as that observed with soluble mediators, has been shown to contribute to many distinct processes. These include; microglial-astrocyte interactions [10], coagulation, inflammation [11,12], cell metabolism [13,14], HIV-1 [15], cancer progression [16,17] and drug resistance [2]. The horizontal transfer of mRNAs and miRNAs by tumour derived membrane vesicles have been shown to contribute to conferring numerous malignant traits [3,18]

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