Abstract
Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. As such, its microenvironment plays a crucial role in its progression. Among the brain stromal cells, the microglia were shown to facilitate GB invasion and immunosuppression. However, the reciprocal mechanisms by which GB cells alter microglia/macrophages behavior are not fully understood. We propose that these mechanisms involve adhesion molecules such as the Selectins family. These proteins are involved in immune modulation and cancer immunity. We show that P-selectin mediates microglia-enhanced GB proliferation and invasion by altering microglia/macrophages activation state. We demonstrate these findings by pharmacological and molecular inhibition of P-selectin which leads to reduced tumor growth and increased survival in GB mouse models. Our work sheds light on tumor-associated microglia/macrophage function and the mechanisms by which GB cells suppress the immune system and invade the brain, paving the way to exploit P-selectin as a target for GB therapy.
Highlights
Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis
We found that PD-GB4 cells facilitate the proliferation and migration of human microglia as well (Supplementary Fig. 1A, B), indicating the reciprocal activation of microglia following the interaction with GB cells in our models
This suggests that GB cells may induce microgliosis in the brain as a result of the neuroinflammation induced by their crosstalk
Summary
Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. The reciprocal mechanisms by which GB cells alter microglia/macrophages behavior are not fully understood We propose that these mechanisms involve adhesion molecules such as the Selectins family. We show that P-selectin mediates microglia-enhanced GB proliferation and invasion by altering microglia/macrophages activation state We demonstrate these findings by pharmacological and molecular inhibition of P-selectin which leads to reduced tumor growth and increased survival in GB mouse models. GAMs may possess a pro-inflammatory/anti-tumorigenic phenotype in which they are phagocytic, cytotoxic, and bear antigen-presentation capabilities[8] This phenotype allows microglia/macrophages to attack transformedcancerous cells and harness cytotoxic T cells against the tumor. Mixed populations are found in GB tumors, GAMs contribute to immune-escape and promote tumor progression, and have been shown to actively enhance glioma growth and invasion, and secrete angiogenic factors[10]. This emphasizes the need for alternative or combination approaches[11]
Published Version (Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.