Complement C3a activates astrocytes to promote medulloblastoma progression through TNF-α
Biao Gong1, Duancheng Guo1, Chaonan Zheng1
1Laboratory of Molecular Neuropathology, Pediatric Cancer Center, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Journal of Neuroinflammation
|June 20, 2022
Summary
Complement C3a activates astrocytes, promoting medulloblastoma (MB) cell growth via TNF-α. Targeting C3a and TNF-α may offer new therapeutic strategies for this pediatric brain tumor.
Area of Science:
- Neuro-oncology
- Immunology
- Molecular Biology
Background:
- Medulloblastoma (MB) is a common pediatric brain tumor with a significant unmet need for effective treatments.
- Astrocytes in the tumor microenvironment (TME) are implicated in MB progression, but the mechanisms of their activation remain unclear.
Purpose of the Study:
- To elucidate the role of complement C3a in astrocyte activation and its contribution to medulloblastoma (MB) tumorigenesis.
- To investigate the potential of targeting C3a and TNF-α pathways for MB therapy.
Main Methods:
- Utilized genetically engineered mouse models (Math1-Cre/Ptch1loxp/loxp) for MB development.
- Isolated primary MB cells and astrocytes for in vitro co-culture and stimulation with C3a.
- Assessed astrocyte activation, cytokine production (TNF-α, IL-6), and MB cell proliferation using immunohistochemistry, western blotting, q-PCR, ELISA, and immunofluorescence.
- Investigated the involvement of the p38 MAPK pathway and TNF-α signaling.
- Evaluated therapeutic efficacy of C3a receptor and TNF-α receptor antagonists in vivo using transplanted MB mouse models.
Main Results:
- Complement C3a is enriched in human and murine MB tissues and its receptor is highly expressed on tumor-associated astrocytes (TAAs).
- C3a activates astrocytes and promotes MB cell proliferation through the p38 MAPK pathway, upregulating pro-inflammatory cytokines like TNF-α.
- C3a-induced astrocyte-secreted factors promote MB proliferation in a TNF-α-dependent manner.
- In vivo administration of C3a receptor or TNF-α receptor antagonists suppressed MB tumor progression.
Conclusions:
- C3a released during MB development activates astrocytes, leading to TNF-α production via the p38 pathway, which subsequently promotes MB cell proliferation.
- This study reveals a novel mechanism of astrocyte-mediated tumor promotion in MB involving C3a and TNF-α.
- Targeting C3a and TNF-α presents a promising therapeutic avenue for medulloblastoma.
