Summary: A new study reports glioblastoma influences microglia, causing them to stimulate tumor growth, rather than suppress it.
Source: Karolinska Institute.
Glioblastomas exert an influence on the microglia, immune cells of the brain, which causes them to stimulate cancer growth rather than attacking it. In a study published in the journal Nature Immunology, an international research team led from Sweden’s Karolinska Institutet now explains the molecular mechanisms behind this action.
Glioblastomas are one of the most malignant forms of brain tumour and are difficult to surgically remove because the tumour cells invade the surrounding healthy brain tissue. Glioblastomas also affect the microglia – immune cells of the brain – in such a way that they stimulate the tumour cells instead of attacking them.
The multi-national research group has previously shown that pro-inflammatory activation of microglia is controlled by a group of enzymes called caspases. In the present study, they sought to examine if the way the cancer cells affect microglia also includes similar mechanism. By cultivating microglia and glioblastoma cells together, the researchers were able to show that the cancer cells inhibit caspase-3 activity in the microglia.
“We show that it’s the same inhibition of caspase-3 that causes the microglia to stimulate the tumour cells instead of attacking them,” says Bertrand Joseph, Principal Investigator at Karolinska Institutet’s Department of Oncology-Pathology. “When we removed caspase-3 from the microglia in a glioblastoma mouse model, the tumours grew more quickly.”
According to the study authors, their results demonstrate that the glioma cells use a nitric oxide-dependent mechanism to force microglia to modify caspase-3 to form a tumour-stimulating form of these cells.
“Two things surprised us,” says Bertrand Joseph. “First and foremost, that affecting the signalling mechanism between glioblastoma cells and microglia that we discovered has such a major effect on tumour growth. Secondly, that basal caspase-3 activity, which is often considered to be an absence of activity, fulfills essential function in regulating microglia cell behavior.”
Funding: The lead authors of the study are Xianli Shen and Miguel Burguillos. Researchers from at the Universidad de Sevilla, Spain, Stockholm University, Sweden, and Yale University, USA, and others also contributed to this study. The research was financed with grants from, amongst others, the Swedish Research Council, the Swedish Childhood Cancer Foundation, the Swedish Cancer Society, the Swedish Brain Fund, StratCan, StratNeuro, and the ALF agreement with Stockholm County Council.
Source: Karolinska Institute
Image Source: This NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Glioma-induced inhibition of caspase-3 in microglia promotes a tumor-supportive phenotype” by Xianli Shen, Miguel A Burguillos, Ahmed M Osman, Jeroen Frijhoff, Alejandro Carrillo-Jiménez, Sachie Kanatani, Martin Augsten, Dalel Saidi, Johanna Rodhe, Edel Kavanagh, Anthony Rongvaux, Vilma Rraklli, Ulrika Nyman, Johan Holmberg, Arne Östman, Richard A Flavell, Antonio Barragan, Jose Luis Venero, Klas Blomgren and Bertrand Joseph in Nature Immunology. Published online September 12 2016 doi:10.1038/ni.3545
Glioma-induced inhibition of caspase-3 in microglia promotes a tumor-supportive phenotype
Glioma cells recruit and exploit microglia (the resident immune cells of the brain) for their proliferation and invasion ability. The underlying molecular mechanism used by glioma cells to transform microglia into a tumor-supporting phenotype has remained elusive. We found that glioma-induced microglia conversion was coupled to a reduction in the basal activity of microglial caspase-3 and increased S-nitrosylation of mitochondria-associated caspase-3 through inhibition of thioredoxin-2 activity, and that inhibition of caspase-3 regulated microglial tumor-supporting function. Furthermore, we identified the activity of nitric oxide synthase 2 (NOS2, also known as iNOS) originating from the glioma cells as a driving stimulus in the control of microglial caspase-3 activity. Repression of glioma NOS2 expression in vivo led to a reduction in both microglia recruitment and tumor expansion, whereas depletion of microglial caspase-3 gene promoted tumor growth. Our results provide evidence that inhibition of the denitrosylation of S-nitrosylated procaspase-3 mediated by the redox protein Trx2 is a part of the microglial pro-tumoral activation pathway initiated by glioma cancer cells.
“Glioma-induced inhibition of caspase-3 in microglia promotes a tumor-supportive phenotype” by Xianli Shen, Miguel A Burguillos, Ahmed M Osman, Jeroen Frijhoff, Alejandro Carrillo-Jiménez, Sachie Kanatani, Martin Augsten, Dalel Saidi, Johanna Rodhe, Edel Kavanagh, Anthony Rongvaux, Vilma Rraklli, Ulrika Nyman, Johan Holmberg, Arne Östman, Richard A Flavell, Antonio Barragan, Jose Luis Venero, Klas Blomgren and Bertrand Joseph in Nature Immunology. Published online September 12 2016 doi:10.1038/ni.3545