Mary Bebawy

School of Pharmacy, Graduate School of Health, University of Technology, Sydney, NSW 2007, Australia

Abstract:

Background: Drug resistance is a major cause of cancer treatment failure with multidrug resistance (MDR) being the most serious phenotype. In MDR cancer cells display a broad cross-resistance to structurally and functionally unrelated drugs by virtue of the overexpression of the efflux transporters P-glycoprotein (P-gp) and Multidrug Resistance-Associated Protein 1 (MRP1). These drug efflux transporters maintain sublethal intracellular drug concentrations rendering the tumour population treatment unresponsive. Recently, we discovered a novel non-genetic basis to MDR whereby microparticles (MPs) transfer P-gp intercellularly from MDR donor cells to drug-sensitive recipient cells [1].

Objective: We aimed to examine the contribution of MPs in the transfer of cellular cargo in the occurrence and stability of the MDR phenotype in vitro and in vivo. Methods: MPs isolated from MDR leukemia and breast cancer cells were co-cultured with their drug-sensitive counterparts. MP - cell interactions were demonstrated by scanning electron microscopy. P-gp transfer was assessed by direct immunolabeling whereas acquired transcripts and regulatory microRNAs were assessed using microarray and quantitative real time PCR. MP-mediated P-gp protein transfer to sensitive cells was also shown in vivo using the MCF- 7 mouse tumour xenograft model.

Results: We show that MPs isolated from MDR cells carry nucleic acids and the machinery for miRNA biogenesis within their cargo. We also show that MPs ‘retmeplate’ the recipient cells’ transcriptional environment to reflect donor MDR phenotype within 4 hours exposure. We demonstrate that distinct pathways exist among cancers of different origin that may be dependent on donor cells resistance trait. We also show that P-gp was acquired and penetrated to the core of the recipient drug-sensitive tumor when drug sensitive tumours were exposed to subcutaneous MP exposure. This acquired P-gp was stable for at least 2 weeks in vivo.

Conclusions: We demonstrate a novel resistance pathway mediated by intercellular transfer of MP cargo from resistant cells. This pathway is evident across hematological and non-hematological malignancies. This novel pathway has enormous implications in the dissemination and acquisition of deleterious cancer traits. MPs also provide novel therapeutic opportunities in clinical oncology.

COMPETING INTERESTS

The authors declare that they have no competing interests.

This work was funded by the New South Wales Cancer Council and National Health and Medical Research Council.

REFERENCES

[1] Bebawy, M., Combes, V., Lee, E., Jaiswal, R., Gong, J., Bonhoure, A., and Grau, G. E. R (2009) Membrane microparticles mediate transfer of P-glycoprotein to drug sensitive cancer cells. Leukemia 23, 1643-1649.