Development of a novel conservative therapeutic modality for patients with bone metastasis focusing on hyaluronan network

我们建立了小鼠乳腺癌和肺癌的骨转移模型，发现骨转移灶中的恶性细胞和间质细胞包括肿瘤相关的成纤维细胞均有明显的透明质酸表达。透明质酸合成抑制剂4-甲基伞形酮(4-MU)显著抑制乳腺癌、肺癌和间质成纤维细胞的透明质酸合成，从而抑制骨转移灶。4-MU还通过抑制透明质酸合成影响细胞事件，细胞表面透明质酸受体CD44、Ezrin和肌动蛋白的共定位被4-MU取消。4-MU与日本允许用于骨转移患者的双膦酸唑来膦酸具有协同抑制骨转移的作用。4-MU与放射治疗也有协同作用，放射治疗是一种传统的抗骨转移治疗。

We established mouse bone metastasis model of breast and lung cancer, and revealed that metastatic lesion in bone had marked expression of hyaluronan in both malignant cells and stromal cells including tumor-associated fibroblasts. 4- Methylumbelliferone (4-MU), an inhibitor of hyaluronan synthesis significantly suppressed the hyaluronan synthesis of breast and lung cancer as well as stromal fibroblast, resulting in the suppression of metastatic lesion in bone. 4-MU also affected the cellular event via suppression of hyaluronan synthesis, that co-localization of CD44, a cell surface receptor of hyaluronan, ezrin, and actin was abrogated by 4-MU.4-MU had synergistic inhibitory effects on the progression of bone metastasis, with zoledronic acid, a bisphosphonate, which is allowed to use for patients with bone metastasis in Japan. 4-MU also had synergistic effects with radiotherapy, a conventional anti-bone metastatic treatment.