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Updated: Dec 2, 2025
Stimulation of Notch Signaling in Mouse Osteoclast Precursors
Published on: February 28, 2017
Blocking the Notch signal transduction pathway promotes tumor growth in osteosarcoma by affecting polarization of TAM
Shuguang Ren1, Xiangmei Zhang1, Yueyang Hu1
1The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Background:
Osteosarcoma is a primary malignant tumor that seriously affects the health and life of patients. It is of great clinical significance to explore the molecular mechanism of osteosarcoma development and develop the corresponding therapeutic targets. Th1/Th2 cytokines in the normal human body are in a state of dynamic balance. When this balance is destroyed, it is related to many diseases such as a tumor, autoimmune disease, microbial infection, transplant rejection, among many others.
Method:
The model of mouse tumor-associated macrophage (TAM) was induced by being co-cultured with inducer granulocyte-macrophage colony stimulating factor (GM-CSF) and osteosarcoma S180 cells. The Notch1 knockout mice were obtained by gene targeting technology. The distribution of M1- and M2-type TAMs in the tumor was visualized by immunofluorescence staining. And the western-blot testing was used to detect and quantified the protein level of Notch1 and Th1/Th2-type cytokines.
Results:
In this study, the polarization of TAMs to the M2 phenotype occurred after coculture with osteosarcoma S180 cells and secretion level Th1/Th2-type cytokines changed. Also, the expression level of Notch1 reduced significantly. Further, the critical transcription factor Notch1 of the Notch signaling pathway was knocked out in mice. The tumor volume of Notch1 knockout mice was significantly more extensive than of the control mice. The results of microstructural observation on tumor showed that M2-type TAMs infiltrated into tumor increased with increased expression of Th2-type cytokines, but M1-type TAMs reduced with reduced expression of Th1-type cytokines.
Conclusions:
According to our results, the Notch signal transduction pathway participates in tumor occurrence and growth with a negative role by maintaining Th1/Th2 balance.
Insights
The Notch signaling pathway negatively impacts osteosarcoma development by disrupting Th1/Th2 cytokine balance and promoting M2 tumor-associated macrophage polarization. This research identifies Notch1 as a potential therapeutic target for osteosarcoma.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Osteosarcoma poses a significant threat to patient health and life.
- Understanding its molecular mechanisms and identifying therapeutic targets are crucial.
- The balance of Th1/Th2 cytokines is vital and its disruption is linked to various diseases, including cancer.
Purpose of the Study:
- To investigate the role of the Notch signaling pathway in osteosarcoma development.
- To explore the relationship between Notch1, tumor-associated macrophages (TAMs), and Th1/Th2 cytokine balance in osteosarcoma.
- To identify potential therapeutic targets for osteosarcoma.
Main Methods:
- Induced a mouse model of tumor-associated macrophages (TAMs) using osteosarcoma S180 cells and GM-CSF.
- Generated Notch1 knockout mice via gene targeting.
- Utilized immunofluorescence staining to visualize M1/M2 TAM distribution and Western blotting to quantify protein levels of Notch1 and cytokines.
Main Results:
- Co-culture with osteosarcoma cells induced M2 TAM polarization and altered Th1/Th2 cytokine secretion.
- Notch1 expression significantly decreased in this model.
- Notch1 knockout mice exhibited larger tumor volumes, increased M2 TAM infiltration, and elevated Th2 cytokines, while M1 TAMs and Th1 cytokines decreased.
Conclusions:
- The Notch signal transduction pathway plays a negative role in osteosarcoma occurrence and growth.
- Maintaining Th1/Th2 balance is crucial, and Notch1 appears to be a key regulator.
- Targeting the Notch pathway may offer a novel therapeutic strategy for osteosarcoma.
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