As células tumorais resistentes a múltiplos fármacos libertam mais microvesículas do que exosomas quando comparadas com as correspondentes células tumorais sensíveis

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As células tumorais resistentes a múltiplos fármacos libertam mais microvesículas do que exosomas quando comparadas com as correspondentes células tumorais sensíveis

Terça, 21.06.2016

As vesículas extracelulares (VEs) são libertadas por todo o tipo de células, sendo relevantes não só em processos fisiológicos, mas também em processos patológicos, como o cancro. Diferentes tipos de VEs, incluindo exosomas e microvesículas, têm diferentes biogéneses e origens intracelulares (exosomas têm uma origem endossomal e tamanhos mais pequenos enquanto que as microvesículas têm origem na membrana plasmática e são maiores). As VEs podem transportar no seu interior diferentes moléculas das células dadoras, tais como proteínas e microRNAs. Adicionalmente, a sua estrutura membranar permite a proteção desse conteúdo (nomeadamente da degradação por protéases). Para além disso, as VEs são amostras pouco complexas quando comparadas com fluidos corporais. Por estes motivos, podem funcionar como fonte de excelentes biomarcadores moleculares, úteis no diagnóstico ou prognóstico de doentes com cancro.

Este trabalho mostra, pela primeira vez, que as células tumorais resistentes a múltiplos fármacos libertam VEs maiores, quando comparadas com as VEs das correspondentes células tumorais sensíveis, transportando um conteúdo de proteínas “específico” que poderão vir a ser estudadas para ser usadas como biomarcadores de resistência a múltiplos fármacos.

 

Autores e afiliações:

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.

 

Revista: Biochimica et Biophysica Acta – General Subjects

 

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