肺纤维化是抑制骨肉瘤肺转移的新治疗靶点,International Journal of Cancer

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肺纤维化是抑制骨肉瘤肺转移的新治疗靶点
International Journal of Cancer ( IF 5.7 ) Pub Date : 2022-03-28 , DOI: 10.1002/ijc.34008
Yoshihiro Yui ₁ , Jun Kumai ₁ , Kenta Watanabe _{1,

2} , Toru Wakamatsu ₃ , Satoru Sasagawa ₁

Affiliation

在过去的 30 年中，转移性和复发性骨肉瘤患者的预后没有改善，因为尚未建立有效的肺转移治疗策略。虽然改变细胞外环境的分子靶向药物，如抗纤维化药物，已被开发用于癌症治疗，但抗纤维化药物对骨肉瘤肺转移的抑制作用尚不清楚。骨肉瘤需要适应环境硬度和肺转移期间纤维化的相当大的变化，因此可能容易受到纤维化抑制，因为它们起源于具有大量纤维化的僵硬骨骼部位。在我们的研究中，我们调查了纤维化是否是抑制骨肉瘤转移的治疗靶点。来自患者和小鼠模型（LM8-Dunn 模型）的肺组织样本显示，骨肉瘤细胞的肺转移定植会导致大量肺纤维化。转移性骨肉瘤 LM8 细胞以支架依赖性方式增殖；增殖较少依赖于 YAP 介导的软聚丙烯酰胺凝胶上的机械转导。抗纤维化药物吡非尼酮和尼达尼布可抑制 LM8-Dunn 模型中的肺转移。在软环境中连续培养后，骨肉瘤细胞没有显示出增殖增加，正如在乳腺癌中报道的那样。我们推测抗纤维化剂是有效的，因为骨肉瘤细胞在软组织环境中保持支架依赖性。因此，

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Lung fibrosis is a novel therapeutic target to suppress lung metastasis of osteosarcoma

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.

更新日期：2022-03-28

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