Related Experiment Video
Updated: Jun 22, 2025
Intratibial Osteosarcoma Cell Injection to Generate Orthotopic Osteosarcoma and Lung Metastasis Mouse Models
Published on: October 28, 2021
Comparative responses to demethylating therapy in animal models of osteosarcoma
Shan Huang1, Ling Ren1, Jessica A Beck1
1National Cancer Institute, NIH.
Background:
The demethylating agent decitabine (DAC) effectively inhibits tumor growth and metastasis by targeting ESR1 methylation to restore estrogen receptor alpha (ERα) signaling and promoting cellular differentiation in models of human osteosarcoma (OSA). Whether this pathway can be targeted in canine OSA patients is unknown.
Methods:
Canine OSA tumor samples were tested for ERα expression and ESR1 promoter methylation. Human (MG63.3) and canine (MC-KOS) OSA cell lines and murine xenografts were treated with DAC in vitro and in vivo, respectively. Samples were assessed using mRNA sequencing and tissue immunohistochemistry.
Results:
ESR1 is methylated in a subset of canine OSA patient samples and the MC-KOS cell line. DAC treatment led to enhanced differentiation as demonstrated by increased ALPL expression, and suppressed tumor growth in vitro and in vivo. Metastatic progression was inhibited, particularly in the MG63.3 model, which expresses higher levels of DNA methyltransferases DNMT1 and 3B. DAC treatment induced significant alterations in immune response and cell cycle pathways.
Conclusion:
DAC treatment activates ERα signaling, promotes bone differentiation, and inhibits tumor growth and metastasis in human and canine OSA. Additional DAC-altered pathways and species- or individual-specific differences in DNMT expression may also play a role in DAC treatment of OSA.
Insights
Decitabine (DAC) targets estrogen receptor alpha (ERα) methylation to inhibit osteosarcoma (OSA) growth and metastasis in both human and canine models. This demethylating agent promotes cellular differentiation and activates ERα signaling, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Osteosarcoma (OSA) is a bone cancer with limited treatment options.
- Decitabine (DAC), a demethylating agent, shows promise in human OSA by targeting ESR1 methylation to restore estrogen receptor alpha (ERα) signaling and promote differentiation.
- The efficacy of DAC in canine OSA remains unexplored.
Purpose of the Study:
- To investigate the potential of decitabine (DAC) as a therapeutic agent for canine osteosarcoma (OSA).
- To determine if DAC can target ESR1 methylation and activate ERα signaling in canine OSA models.
- To evaluate the effects of DAC on tumor growth, differentiation, and metastasis in both human and canine OSA.
Main Methods:
- Analysis of ERα expression and ESR1 promoter methylation in canine OSA samples.
- In vitro treatment of human (MG63.3) and canine (MC-KOS) OSA cell lines with DAC.
- In vivo treatment of murine xenografts with DAC.
- Assessment of samples using mRNA sequencing and immunohistochemistry.
Main Results:
- ESR1 methylation was observed in a subset of canine OSA samples and the MC-KOS cell line.
- DAC treatment enhanced cellular differentiation (increased ALPL expression) and suppressed tumor growth in vitro and in vivo.
- Metastasis was inhibited by DAC, particularly in the MG63.3 model, which has higher DNA methyltransferase (DNMT) expression.
- DAC treatment modulated immune response and cell cycle pathways.
Conclusions:
- Decitabine (DAC) activates ERα signaling, promotes bone differentiation, and inhibits tumor growth and metastasis in both human and canine osteosarcoma (OSA).
- DAC demonstrates therapeutic potential for OSA across species.
- Further research into DAC-altered pathways and species-specific DNMT expression is warranted.
