Juliana H Azambuja1, Elita F da Silveira2, Taíse R de Carvalho3, Pathise S Oliveira3, Simone Pacheco3, Carlus T do Couto3, Fátima T Beira4, Francieli M Stefanello3, Rosélia M Spanevello3, Elizandra Braganhol5. 1. Programa de Pós-Graduação em Bioquímica e Bioprospecção, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Pelotas, RS, Brazil; Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre, Brazil. 2. Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande, Rio Grande, RS, Brazil. 3. Programa de Pós-Graduação em Bioquímica e Bioprospecção, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Pelotas, RS, Brazil. 4. Departamento de Fisiologia e Farmacologia, Instituto de Biologia, Universidade Federal de Pelotas, Pelotas, RS, Brazil. 5. Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre, Brazil. Electronic address: ebraganhol@ufcspa.edu.br.
Abstract
BACKGROUND: Glioblastomas are the most devastating brain tumor characterized by chemoresistance development and poor prognosis. Macrophages are a component of tumor microenvironment related to glioma malignancy. The relation among inflammation, innate immunity and cancer is accepted; however, molecular and cellular mechanisms mediating this relation and chemoresistance remain unresolved. OBJECTIVE: Here we evaluated whether glioma sensitive or resistant to temozolomide (TMZ) modulate macrophage polarization and inflammatory pathways associated. The impact of glioma-macrophage crosstalk on glioma proliferation was also investigated. METHODS: GL261 glioma chemoresistance was developed by exposing cells to increasing TMZ concentrations over a period of 6months. Mouse peritoneal macrophages were exposed to glioma-conditioned medium or co-cultured directly with glioma sensitive (GL) or chemoresistant (GLTMZ). Macrophage polarization, in vitro and in vivo glioma proliferation, redox parameters, ectonucleotidase activity and ATP cytotoxicity were performed. RESULTS: GLTMZ cells were more effective than GL in induce M2-like macrophage polarization and in promote a strong immunosuppressive environment characterized by high IL-10 release and increased antioxidant potential, which may contribute to glioma chemoresistance and proliferation. Interestingly, macrophage-GLTMZ crosstalk enhanced in vitro and in vivo proliferation of chemoresistant cells, decreased ectonucleotidase activities, which was followed by increased macrophage sensitivity to ATP induced death. CONCLUSIONS: Results suggest a differential macrophage modulation by GLTMZ cells, which may favor the maintenance of immunosuppressive tumor microenvironment and glioma proliferation. GENERAL SIGNIFICANCE: The induction of immunosuppressive environment and macrophage education by chemoresistant gliomas may be important for tumor recovery after chemotherapy and could be considered to overcome chemoresistance development.
BACKGROUND:Glioblastomas are the most devastating brain tumor characterized by chemoresistance development and poor prognosis. Macrophages are a component of tumor microenvironment related to glioma malignancy. The relation among inflammation, innate immunity and cancer is accepted; however, molecular and cellular mechanisms mediating this relation and chemoresistance remain unresolved. OBJECTIVE: Here we evaluated whether glioma sensitive or resistant to temozolomide (TMZ) modulate macrophage polarization and inflammatory pathways associated. The impact of glioma-macrophage crosstalk on glioma proliferation was also investigated. METHODS: GL261 glioma chemoresistance was developed by exposing cells to increasing TMZ concentrations over a period of 6months. Mouse peritoneal macrophages were exposed to glioma-conditioned medium or co-cultured directly with glioma sensitive (GL) or chemoresistant (GLTMZ). Macrophage polarization, in vitro and in vivo glioma proliferation, redox parameters, ectonucleotidase activity and ATPcytotoxicity were performed. RESULTS:GLTMZ cells were more effective than GL in induce M2-like macrophage polarization and in promote a strong immunosuppressive environment characterized by high IL-10 release and increased antioxidant potential, which may contribute to glioma chemoresistance and proliferation. Interestingly, macrophage-GLTMZ crosstalk enhanced in vitro and in vivo proliferation of chemoresistant cells, decreased ectonucleotidase activities, which was followed by increased macrophage sensitivity to ATP induced death. CONCLUSIONS: Results suggest a differential macrophage modulation by GLTMZ cells, which may favor the maintenance of immunosuppressive tumor microenvironment and glioma proliferation. GENERAL SIGNIFICANCE: The induction of immunosuppressive environment and macrophage education by chemoresistant gliomas may be important for tumor recovery after chemotherapy and could be considered to overcome chemoresistance development.
Authors: J H Azambuja; R S Schuh; L R Michels; I C Iser; L R Beckenkamp; G G Roliano; G S Lenz; J N Scholl; J Sévigny; M R Wink; M A Stefani; A M O Battastini; F Figueiró; H F Teixeira; E Braganhol Journal: Cancer Immunol Immunother Date: 2020-04-29 Impact factor: 6.968
Authors: J H Azambuja; R S Schuh; L R Michels; N E Gelsleichter; L R Beckenkamp; I C Iser; G S Lenz; F H de Oliveira; G Venturin; S Greggio; J C daCosta; M R Wink; J Sevigny; M A Stefani; A M O Battastini; H F Teixeira; E Braganhol Journal: Mol Neurobiol Date: 2019-08-12 Impact factor: 5.590
Authors: Linyong Shi; Hong Li; Junwei Gu; Chong Song; Junjie Li; Lei Chen; Qiang Zhou; Songtao Qi; Yuntao Lu Journal: Nan Fang Yi Ke Da Xue Xue Bao Date: 2021-01-30
Authors: Juliana H Azambuja; Nils Ludwig; Saigopalakrishna S Yerneni; Elizandra Braganhol; Theresa L Whiteside Journal: Int J Mol Sci Date: 2020-06-02 Impact factor: 5.923