Lung fibrosis is a novel therapeutic target to suppress lung metastasis of osteosarcoma
Yoshihiro Yui1, Jun Kumai1, Kenta Watanabe1,2
1Research Institute, Nozaki Tokushukai Hospital, Daito, Japan.
Abstract:
The prognosis of patients with metastatic and recurrent osteosarcoma has not improved over the last 30 years because no effective treatment strategy has been established for lung metastases. Although molecular-targeted drugs that modify the extracellular environment, such as antifibrotic agents, have been developed for cancer treatment, the suppressive effects of antifibrotic agents on osteosarcoma lung metastasis are unclear. Osteosarcomas need to adapt to considerable changes with respect to the stiffness of the environment and fibrosis during lung metastasis and may thus be vulnerable to fibrotic suppression as they originate at the site of a stiff bone with considerable fibrosis. In our study, we investigated whether fibrosis was a therapeutic target for suppressing osteosarcoma metastasis. Lung tissue samples from patients and a mouse model (LM8-Dunn model) showed that lung metastatic colonization of osteosarcoma cells proceeded with massive lung fibrosis. Metastatic osteosarcoma LM8 cells proliferated in a scaffold-dependent manner; the proliferation was less dependent on YAP-mediated mechanotransduction on soft polyacrylamide gels. The antifibrotic agents pirfenidone and nintedanib suppressed lung metastasis in the LM8-Dunn model. The osteosarcoma cells did not show increased proliferation, as reported in breast cancer, after continuous culture in a soft environment. We speculated that the antifibrotic agents were effective because the osteosarcoma cells remained scaffold-dependent in the soft tissue environment. Thus, antifibrotic strategies may be useful in suppressing lung metastasis of bone and soft tissue tumors with stiff primary sites such as those in osteosarcoma.
Insights
Antifibrotic agents like pirfenidone and nintedanib show promise in suppressing osteosarcoma lung metastasis. This study found that targeting fibrosis may be a new therapeutic strategy for bone and soft tissue tumors.
Area of Science:
- Oncology
- Cancer Metastasis
- Extracellular Matrix Biology
Background:
- Prognosis for metastatic osteosarcoma remains poor due to ineffective lung metastasis treatments.
- Molecular-targeted drugs, including antifibrotic agents, are emerging cancer therapies, but their effect on osteosarcoma lung metastasis is unknown.
- Osteosarcoma adaptation to stiff, fibrotic environments during lung metastasis suggests vulnerability to antifibrotic suppression.
Purpose of the Study:
- To investigate if fibrosis is a viable therapeutic target for suppressing osteosarcoma lung metastasis.
- To evaluate the efficacy of antifibrotic agents in preclinical models of osteosarcoma lung metastasis.
Main Methods:
- Analysis of human lung tissue samples and a mouse model (LM8-Dunn) to assess lung fibrosis during osteosarcoma metastasis.
- In vitro culture of osteosarcoma cells on varying stiffness substrates to assess YAP-mediated mechanotransduction and scaffold dependence.
- Administration of antifibrotic agents (pirfenidone, nintedanib) in the LM8-Dunn mouse model to evaluate their impact on lung metastasis.
Main Results:
- Lung metastatic colonization of osteosarcoma cells correlated with significant lung fibrosis in both human samples and the mouse model.
- Osteosarcoma cell proliferation was scaffold-dependent and less reliant on YAP-mediated mechanotransduction in soft environments.
- Pirfenidone and nintedanib treatment significantly suppressed lung metastasis in the LM8-Dunn model.
- Unlike breast cancer, osteosarcoma cells did not exhibit increased proliferation in soft environments, suggesting continued scaffold dependence.
Conclusions:
- Fibrosis plays a critical role in osteosarcoma lung metastasis, making it a potential therapeutic target.
- Antifibrotic agents pirfenidone and nintedanib effectively reduce osteosarcoma lung metastasis in preclinical models.
- Antifibrotic strategies may offer a novel treatment approach for lung metastasis in osteosarcoma and other tumors originating from stiff primary sites.
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