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GBM-Derived Wnt3a Induces M2-Like Phenotype in Microglial Cells Through Wnt/β-Catenin Signaling

  • Diana Matias
  • Luiz Gustavo Dubois
  • Bruno Pontes
  • Luciane Rosário
  • Valeria Pereira Ferrer
  • Joana Balça-Silva
  • Anna Carolina Carvalho Fonseca
  • Lucy Wanjiku Macharia
  • Luciana Romão
  • Tania Cristina Leite de Sampaio e Spohr
  • Leila Chimelli
  • Paulo Niemeyer Filho
  • Maria Celeste Lopes
  • José Garcia Abreu
  • Flavia Regina Souza Lima
  • Vivaldo Moura-Neto
Article

Abstract

Glioblastoma is an extremely aggressive and deadly brain tumor known for its striking cellular heterogeneity and capability to communicate with microenvironment components, such as microglia. Microglia-glioblastoma interaction contributes to an increase in tumor invasiveness, and Wnt signaling pathway is one of the main cascades related to tumor progression through changes in cell migration and invasion. However, very little is known about the role of canonical Wnt signaling during microglia-glioblastoma crosstalk. Here, we show for the first time that Wnt3a is one of the factors that regulate interactions between microglia and glioblastoma cells. Wnt3a activates the Wnt/β-catenin signaling of both glioblastoma and microglial cells. Glioblastoma-conditioned medium not only induces nuclear translocation of microglial β-catenin but also increases microglia viability and proliferation as well as Wnt3a, cyclin-D1, and c-myc expression. Moreover, glioblastoma-derived Wnt3a increases microglial ARG-1 and STI1 expression, followed by an upregulation of IL-10 mRNA levels, and a decrease in IL1β gene expression. The presence of Wnt3a in microglia-glioblastoma co-cultures increases the formation of membrane nanotubes accompanied by changes in migration capability. In vivo, tumors formed from Wnt3a-stimulated glioblastoma cells presented greater microglial infiltration and more aggressive characteristics such as growth rate than untreated tumors. Thus, we propose that Wnt3a belongs to the arsenal of factors capable of stimulating the induction of M2-like phenotype on microglial cells, which contributes to the poor prognostic of glioblastoma, reinforcing that Wnt/β-catenin pathway can be a potential therapeutic target to attenuate glioblastoma progression.

Keywords

Glioblastoma Microglia Wnt/β-catenin pathway Wnt3a M2-like phenotype 

Notes

Acknowledgements

This study was supported by the Brazilian agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Pró-Saúde Associação Beneficente de Assistência Social e Hospitalar, and Ary Frauzino Foundation for Cancer Research.

We would like to acknowledge Dra. Juliana Coelho Aguiar for giving us some primers, Dra. Graziella Ventura for helping us with the confocal microscopy acquisitions, and Geralda Cardoso for the lab technical support.

Compliance with Ethical Standards

Conflict of Interest

We confirm that this manuscript has been approved by all authors and that there are no known conflicts of interest associated with this publication.

Supplementary material

12035_2018_1150_MOESM1_ESM.avi (81.6 mb)
ESM 1 (AVI 83542 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Diana Matias
    • 1
    • 2
  • Luiz Gustavo Dubois
    • 1
    • 2
  • Bruno Pontes
    • 2
  • Luciane Rosário
    • 1
    • 7
  • Valeria Pereira Ferrer
    • 1
  • Joana Balça-Silva
    • 1
    • 3
    • 4
  • Anna Carolina Carvalho Fonseca
    • 2
  • Lucy Wanjiku Macharia
    • 1
    • 7
  • Luciana Romão
    • 2
    • 6
  • Tania Cristina Leite de Sampaio e Spohr
    • 1
  • Leila Chimelli
    • 1
  • Paulo Niemeyer Filho
    • 1
  • Maria Celeste Lopes
    • 3
    • 5
  • José Garcia Abreu
    • 2
  • Flavia Regina Souza Lima
    • 2
  • Vivaldo Moura-Neto
    • 1
  1. 1.Laboratório de Biomedicina do CérebroInstituto Estadual do Cérebro Paulo NiemeyerRio de JaneiroBrazil
  2. 2.Instituto de Ciências Biomédicas da Universidade Federal do Rio de Janeiro (ICB/UFRJ)Rio de JaneiroBrazil
  3. 3.Centro de Neurociências e Biologia celular e Instituto Biomédico da Imagem e das Ciências da Vida (CNC.IBILI)CoimbraPortugal
  4. 4.Faculdade de Medicina da Universidade de Coimbra (FMUC)CoimbraPortugal
  5. 5.Pólo das Ciências da SaúdeFaculdade de Farmácia da Universidade de CoimbraCoimbraPortugal
  6. 6.Campus Duque de CaxiasUniversidade Federal do Rio de JaneiroDuque de CaxiasBrazil
  7. 7.Programa de Pós-Graduação em Anatomia PatológicaFaculdade de Medicina da Universidade Federal do Rio de Janeiro -UFRJRio de JaneiroBrazil

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