A inibição do transporte de lactato diminui o crescimento in vivo de tumores de mama

envie a um amigo share this

A inibição do transporte de lactato diminui o crescimento in vivo de tumores de mama

Segunda, 07.09.2015

Uma das principais características dos tumores é a produção de lactato levando à acidificação do microambiente tumoral para favorecer o crescimento destas células. Deste modo vários estudos do grupo têm incidido na inibição dos transportadores de lactato (MCTs) impedindo que o lactato seja conduzido para o exterior da célula, acabando por levar à sua morte. Assim, neste estudo foi feito o silenciamento do gene do MCT1 e MCT4 em células humanas de cancro da mama, o qual levou à diminuição da proliferação celular, migração e invasão. Verificou-se ainda que estas células quando injetadas em ratinho, apresentaram diminuição na capacidade de crescimento tumoral, havendo alguns grupos experimentais que não formaram tumor. Estes resultados levam-nos a propor que a inibição do transporte de lactato poderá ser uma boa estratégia para o tratamento do cancro da mama, para os subtipos que atualmente ainda não dispõem de terapia molecular dirigida.

 

Autores e afiliações:

Filipa Morais-Santos1,2, Sara Granja1,2, Vera Miranda-Gonçalves1,2, António H.J. Moreira1,2, Sandro Queirós1,2, João L. Vilaça1,2,3, Fernando C. Schmitt 4,5,6, Adhemar Longatto-Filho1,2,7,8, Joana Paredes3, Fátima Baltazar1,2,* and Céline Pinheiro1,2,7,*

 

1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus of Gualtar, Braga, Portugal  

2 ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal 

3 DIGARC- Technology School, Polytechnic Institute of Cávado and Ave, Barcelos, Portugal

4 IPATIMUP - Institute of Molecular Pathology and Immunology of University of Porto, Porto, Portugal  

5 Medical Faculty of the University of Porto, Porto, Portugal  

6 Department of Pathology and Medicine, Laboratoire National de Sante, Luxembourg  

7 Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil

8 Laboratory of Medical Investigation (LIM-14), School of Medicine, University of Sao Paulo, Sao Paulo, Brazil 

9 Barretos School of Health Sciences, Dr. Paulo Prata - FACISB, Barretos, Sao Paulo, Brazil

*(F Baltazar and C Pinheiro contributed equally to this work)

 

Abstract:

Background: Most cancers, including breast cancer, have high rates of glucose consumption, associated with lactate production, a process referred as “Warburg effect”. Acidification of the tumour microenvironment by lactate extrusion, performed by lactate transporters (MCTs), is associated with higher cell proliferation, migration, invasion, angiogenesis and increased cell survival. Previously, we have described MCT1 up-regulation in breast carcinoma samples and demonstrated the importance of in vitro MCT inhibition. In this study, we performed siRNA knockdown of MCT1 and MCT4 in basal-like breast cancer cells in both normoxia and hypoxia conditions to validate the potential of lactate transport inhibition in breast cancer treatment.

Results: The effect of MCT knockdown was evaluated on lactate efflux, proliferation, cell biomass, migration and invasion and induction of tumour xenografts in nude mice. MCT knockdown led to a decrease in in vitro tumour cell aggressiveness, with decreased lactate transport, cell proliferation, migration and invasion and, importantly, to an inhibition of in vivo tumour formation and growth.

Conclusions: This work supports MCTs as promising targets in cancer therapy, demonstrates the contribution of MCTs to cancer cell aggressiveness and, more importantly, shows, for the first time, the disruption of   in vivo breast tumour growth by targeting lactate transport.

 

Revista: Oncotarget

 

Link: http://www.ncbi.nlm.nih.gov/pubmed/26203664