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A Preclinical Mouse Model of Osteosarcoma to Define the Extracellular Vesicle-mediated Communication Between Tumor and Mesenchymal Stem Cells
Published on: May 6, 2018
Tumor-derived microparticles promoted M2-like macrophages polarization to stimulate osteosarcoma progression
Cui Li1, Feifan Xiang2, Yuqi Gong3
1Department of Nosocomial Infection Control, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.
Abstract:
Microparticles (MPs) are a heterogeneous subpopulation of extracellular vesicles that originate from the plasma membranes of cells. There is increasing evidence that tumor-derived MPs (T-MPs) play a significant role in tumor progression and immune response in cancer. In our study, we found an increased secretion of MPs in osteosarcoma tissues obtained from metastatic patients. These T-MPs promoted polarization of M2-like macrophages and stimulated the migration and chemoresistance of osteosarcoma cells. Mechanistically, T-MPs promoted macrophage polarization to an M2-like phenotype through TBK1-STAT6 signaling. Consequently, these M2-like macrophages mediated osteosarcoma cell migration via CCL18/STAT3 signaling. Blockade of STAT3 signaling pathway improved the outcome of chemotherapy in LM8-bearing osteosarcoma mice model. Thus, our study reveals how tumor cells regulate macrophage polarization by releasing MPs and provides new insights into clinical osteosarcoma therapy.
Insights
Tumor-derived microparticles (T-MPs) from osteosarcoma promote M2-like macrophage polarization and cancer cell migration. Blocking STAT3 signaling improves chemotherapy outcomes, offering new therapeutic strategies for osteosarcoma.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Microparticles (MPs) are cell-derived vesicles implicated in intercellular communication.
- Tumor-derived microparticles (T-MPs) are increasingly recognized for their roles in cancer progression and immune modulation.
- Osteosarcoma progression and metastasis involve complex cellular interactions and signaling pathways.
Purpose of the Study:
- To investigate the role of T-MPs in osteosarcoma progression.
- To elucidate the mechanisms by which T-MPs influence macrophage polarization and osteosarcoma cell behavior.
- To evaluate the therapeutic potential of targeting T-MP-mediated signaling in osteosarcoma.
Main Methods:
- Analysis of MP secretion in osteosarcoma tissues from metastatic patients.
- In vitro studies on the effects of T-MPs on macrophage polarization (M2-like) and osteosarcoma cell migration/chemoresistance.
- Investigation of signaling pathways involved (TBK1-STAT6, CCL18-STAT3).
- In vivo validation using an osteosarcoma mouse model with STAT3 pathway blockade.
Main Results:
- Increased MP secretion observed in osteosarcoma tissues from metastatic patients.
- T-MPs induced M2-like macrophage polarization via TBK1-STAT6 signaling.
- T-MPs promoted osteosarcoma cell migration and chemoresistance.
- M2-like macrophages mediated osteosarcoma cell migration through CCL18/STAT3 signaling.
- STAT3 pathway blockade enhanced chemotherapy efficacy in a mouse model.
Conclusions:
- Osteosarcoma T-MPs actively regulate the tumor microenvironment by polarizing macrophages to an M2-like phenotype.
- The T-MP-macrophage-osteosarcoma cell axis, particularly via CCL18/STAT3 signaling, drives tumor progression and chemoresistance.
- Targeting the STAT3 signaling pathway presents a promising therapeutic strategy for improving osteosarcoma treatment outcomes.
