Multidrug resistant tumour cells shed more microvesicle-like EVs and less exosomes than their drug-sensitive counterpart cells

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Multidrug resistant tumour cells shed more microvesicle-like EVs and less exosomes than their drug-sensitive counterpart cells

Tuesday, 21.06.2016

Extracellular vesicles (EVs) are released from all cells, being not only relevant for physiological processes but also for pathological processes such as cancer. Different types of EVs, including exosomes and microvesicles, have different intracellular origin and biogenesis (exosomes have endosomal origin and smaller sizes while microvesicles have a plasma membrane origin and bigger sizes). EVs may carry different types of molecules from the donor cells, such as proteins and microRNAs. Moreover, EVs present a membrane structure that helps to protect their contents from protease degradation and they are a less complex sample when compared to whole bodily fluids. Therefore, they could function as a source of excellent molecular biomarkers, to be used for diagnosis or prognosis of cancer patients.

This work describes for the first time that cancer multidrug resistant (MDR) cells shed larger EVs than their drug-sensitive counterpart cells, carrying a specific content of proteins that could be further studied as biomarkers to identify the MDR phenotype.

 

Authors and Affiliations:

Vanessa Lopes-Rodrigues1,2,3, Alessio Di Luca4, Diana Sousa1,2,5, Hugo Seca1,2, Paula Meleady4, Michael Henry4, Raquel T. Lima1,2,6, Robert O’Connor4, M. Helena Vasconcelos1,2,5,*

1 i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal

2 Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal;

3 ICBAS-UP - Institute of Biomedical Sciences Abel Salazar, University of Porto, 4099-003 Porto, Portugal;

4NICB - National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland

5Department of Biological Sciences, FFUP - Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal;

6Department of Pathology and Oncology, FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal

 

Abstract:

Background: Multidrug resistance (MDR) is a serious impediment to cancer treatment, with overexpression of drug efflux pumps such as P-glycoprotein (P-gp) playing a significant role. In spite of being a major clinical challenge, to date there is no simple, minimally invasive and clinically validated method for diagnosis of the MDR phenotype using non-tumour biological samples. Recently, P-gp has been found in extracellular vesicles (EVs) shed by MDR cancer cells. This study aimed to compare the EVs shed by MDR cells and their drug-sensitive cellular counterparts, in order to identify biomarkers of MDR.

Methods: Two pairs of MDR and drug-sensitive counterpart tumour cell lines were studied as models. EVs were characterized in terms of size and molecular markers and their protein content was investigated by proteomic analysis and Western blot.

Results: We found that MDR cells produced more microvesicle-like EVs and less exosomes than their drug-sensitive counterpart. EVs from MDR cells contained P-gp and presented a different content of proteins known to be involved in the biogenesis of EVs, particularly in the biogenesis of exosomes.

Conclusions: The determination of the size and of this particular protein content of EVs shed by tumour cells may allow the development of a minimally-invasive simple method of detecting and predicting MDR.

General Significance: This work describes for the first time that cancer multidrug resistant cells shed more microvesicle-like EVs and less exosomes than their drug-sensitive counterpart cells, carrying a specific content of proteins involved in EV biogenesis that could be further studied as biomarkers of MDR.

 

Journal: Biochimica et Biophysica Acta – General Subjects

 

Link: http://www.ncbi.nlm.nih.gov/pubmed/26708992