GBM-Derived Wnt3a Induces M2-Like Phenotype in Microglial Cells Through Wnt/β-Catenin Signaling
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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.
KeywordsGlioblastoma Microglia Wnt/β-catenin pathway Wnt3a M2-like phenotype
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.
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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.
- 5.Balça-Silva J, Matias D, Do Carmo A, Dubois LG, Gonçalves AC, Girão H, Silva Canedo NH, Correia AH et al (2017) Glioblastoma entities express subtle differences in molecular composition and response to treatment. Oncol Rep 38:1341–1352. https://doi.org/10.3892/or.2017.5799 CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Garcia C, Dubois LG, Xavier AL, Geraldo LH, da Fonseca ACC, Correia AH, Meirelles F, Ventura G et al (2014) The orthotopic xenotransplant of human glioblastoma successfully recapitulates glioblastoma-microenvironment interactions in a non-immunosuppressed mouse model. BMC Cancer 14:923. https://doi.org/10.1186/1471-2407-14-923 CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Fonseca ACC, da Romão L, Amaral RF et al (2012) Microglial stress inducible protein 1 promotes proliferation and migration in human glioblastoma cells. Neuroscience 200:130–141. https://doi.org/10.1016/j.neuroscience.2011.10.025 CrossRefPubMedGoogle Scholar
- 25.Dijksterhuis JP, Arthofer E, Marinescu VD, Nelander S, Uhlén M, Pontén F, Mulder J, Schulte G (2015) High levels of WNT-5A in human glioma correlate with increased presence of tumor-associated microglia/monocytes. Exp Cell Res 339:280–288. https://doi.org/10.1016/j.yexcr.2015.10.022 CrossRefPubMedGoogle Scholar
- 26.Faria J, Romão L, Martins S, Alves T, Mendes FA, de Faria GP, Hollanda R, Takiya C et al (2006) Interactive properties of human glioblastoma cells with brain neurons in culture and neuronal modulation of glial laminin organization. Differentiation 74:562–572. https://doi.org/10.1111/j.1432-0436.2006.00090.x CrossRefPubMedGoogle Scholar
- 34.Ajmone-Cat MA, D’Urso MC, di Blasio G, Brignone MS, de Simone R, Minghetti L (2016) Glycogen synthase kinase 3 is part of the molecular machinery regulating the adaptive response to LPS stimulation in microglial cells. Brain Behav Immun 55:225–235. https://doi.org/10.1016/j.bbi.2015.11.012 CrossRefPubMedGoogle Scholar