Células malignas de glioblastoma interagem com células normais gliais vizinhas, modulando o seu secretoma para benefício próprio

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Células malignas de glioblastoma interagem com células normais gliais vizinhas, modulando o seu secretoma para benefício próprio

Quinta, 08.02.2018

O glioblastoma (GBM) é o tumor mais maligno do cérebro e o seu prognóstico é muito reservado. Estudos recentes demonstraram que o microambiente tumoral pode ter um papel importante na regulação do crescimento dos tumores, através da interação com as células tumorais. Nesse contexto, investigámos de que modo as células de GBM são capazes de interagir com as células não-tumorais de glia, e como essa interação poderia influenciar de volta o fenótipo maligno das células de GBM. Os nossos resultados demonstram que as células da glia podem ser moduladas por células de GBM, tendo impacto na patofisiologia destes tumores. Especificamente, o secretoma das células tumorais é capaz de modular o secretoma das células gliais, influenciando fenómenos críticos de malignidade, tais como viabilidade e invasão. Estes dados podem abrir novas oportunidades de intervenção terapêutica ao nível deste “crosstalk” entre células tumorais e normais.

 

Autores e afiliações:

Ana Isabel Oliveira1,2, Sandra I. Anjo3,4, Joana Vieira de Castro1,2, Sofia C. Serra1,2, António J. Salgado1,2, Bruno Manadas3#, Bruno M. Costa1,2#

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

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

3CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

4Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal.

#Contributed equally.


Abstract:

Glioblastoma (GBM), the most malignant primary brain tumor, leads to poor and unpredictable clinical outcomes. Recent studies showed the tumor microenvironment has a critical role in regulating tumor growth by establishing a complex network of interactions with tumor cells. In this context, we investigated how GBM cells modulate resident glial cells, particularly their paracrine activity, and how this modulation can influence back on the malignant phenotype of GBM cells.

Conditioned media (CM) of primary mouse glial cultures unexposed (unprimed) or exposed (primed) to the secretome of GL261 GBM cells were analyzed by proteomic analysis. Additionally, these CM were used in GBM cells to evaluate their impact in glioma cell viability, migration capacity and activation of tumor-related intracellular pathways.

The proteomic analysis revealed that the pre-exposure of glial cells to CM from GBM cells led to the upregulation of several proteins related to inflammatory response, cell adhesion and extracellular structure organization within the secretome of primed glial cells. At the functional levels, CM derived from unprimed glial cells favored an increase in GBM cell migration capacity, while CM from primed glial cells promoted cells viability. These effects on GBM cells were accompanied by activation of particular intracellular cancer-related pathways, mainly the MAPK/ERK pathway, which is a known regulator of cell proliferation.

Together, our results suggest that glial cells can impact on the pathophysiology of GBM tumors, and that the secretome of GBM cells is able to modulate the secretome of neighboring glial cells, in a way that regulates the “go-or-grow” phenotypic switch of GBM cells.

 

Revista: Cell Communication and Signaling

 

Link: https://www.ncbi.nlm.nih.gov/pubmed/28969644