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Published on: September 1, 2018
Hallmarks of tumor-associated microglia response to experimental U87 human glioblastoma xenograft
Tihomir Dugandžija1, Jovana Drljača2, Dragica Bulajić2
1Faculty of Medicine, Department of Epidemiology, University of Novi Sad, Hajduk Veljkova 3, Novi Sad, 21000, Serbia; Oncology Institute of Vojvodina, Put doktora Goldmana 4, Sremska Kamenica, 21204, Serbia.
Abstract:
Glioblastoma (GBM) is one of the deadliest primary brain neoplasm, heavily infiltrated with tumor-associated microglia/macrophages (TAM), which has received a great deal of interest. Bearing in mind that the number of peripheral macrophages by the 14th day is negligible, in our study TAM were referred to as microglia. Here we evaluated histopathological characterization of TAM and kinetics of their infiltration in U87 orthotopic GBM, a commonly used model in preclinical research. To mimic different stages of GBM growth, we evaluated three-time points. Our data showed that the highest areal density of TAM was 7 days after GBM inoculation, with ability to proliferate early after initiation of GBM growth. The areal density of TAM within the tumor correlated with GBM growth and proliferation. Moreover, microglia underwent substantial morphological changes upon exposure to GBM cells. A transition from ramified morphology in peritumoral area to ameboid shape with larger soma and shortened, thick branches in the tumor core was observed. Higher areal fraction of blood vessels also correlated with the areal density of TAM. Given these pro-invasive features of microglia, this GBM model represents a good basis for further testing microglia as a target and new strategy to fight with.
Insights
Tumor-associated microglia (TAM) infiltrate glioblastoma (GBM) early and proliferate, correlating with tumor growth. These microglia change shape within the tumor, suggesting a role in GBM progression and offering a potential therapeutic target.
Area of Science:
- Neuro-oncology
- Immunology
- Cancer Biology
Background:
- Glioblastoma (GBM) is a highly aggressive brain tumor.
- Tumor-associated microglia/macrophages (TAM) are key components of the GBM microenvironment.
- Understanding TAM kinetics and characteristics is crucial for developing novel therapies.
Purpose of the Study:
- To histopathologically characterize TAM and their infiltration kinetics in an orthotopic U87 GBM model.
- To evaluate TAM proliferation and morphological changes during GBM progression.
- To correlate TAM density with tumor growth and vascularization.
Main Methods:
- Orthotopic U87 GBM xenograft model in rodents.
- Histopathological analysis of TAM at three distinct time points post-inoculation.
- Assessment of TAM morphology, density, proliferation, and co-localization with blood vessels.
Main Results:
- TAM infiltration and proliferation were observed early after GBM initiation, peaking at 7 days.
- TAM density positively correlated with GBM growth and proliferation.
- Microglia exhibited morphological changes, transitioning from ramified to ameboid shapes within the tumor core.
- Increased TAM density was associated with a higher blood vessel fraction.
Conclusions:
- The U87 GBM model effectively recapitulates TAM infiltration and dynamic changes.
- Microglia play a significant role in GBM progression, exhibiting pro-invasive features.
- Targeting microglia presents a promising therapeutic strategy for glioblastoma.
