Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, 65-Tsurumai, Showa, Nagoya, Aichi, Japan.
Br J Cancer. 2011 Dec 6;105(12):1839-49. doi: 10.1038/bjc.2011.459. Epub 2011 Nov 1.
Hyaluronan (HA) plays crucial roles in the tumourigenicity of many types of malignant tumours. 4-Methylumbelliferone (MU) is an inhibitor of HA synthesis. Several studies have shown its inhibitory effects on malignant tumours; however, none have focused on its effects on osteosarcoma.
We investigated the effects of MU on HA accumulation and tumourigenicity of highly metastatic murine osteosarcoma cells (LM8) that have HA-rich cell-associated matrix, and human osteosarcoma cell lines (MG-63 and HOS).
In vitro, MU inhibited HA retention, thereby reducing the formation of functional cell-associated matrices, and also inhibited cell proliferation, migration, and invasion. Akt phosphorylation was suppressed by MU (1.0 mM). In vivo, although MU showed only a mild inhibitory effect on the growth of the primary tumour, it markedly inhibited (75% reduction) the development of lung metastasis. Hyaluronan retention in the periphery of the primary tumour was markedly suppressed by MU.
These findings suggested that MU suppressed HA retention and cell-associated matrix formation in osteosarcoma cells, resulting in a reduction of tumourigenicity, including lung metastasis. 4-Methylumbelliferone is a promising therapeutic agent targeting both primary tumours and distant metastasis of osteosarcoma, possibly via suppression of HA retention.
透明质酸（HA）在多种恶性肿瘤的致瘤性中发挥着关键作用。4-甲基伞形酮（MU）是一种合成 HA 的抑制剂。多项研究表明其对恶性肿瘤具有抑制作用，但尚无研究关注其对骨肉瘤的影响。
我们研究了 MU 对 HA 积累和富含 HA 的细胞相关基质的高转移性鼠骨肉瘤细胞（LM8）以及人骨肉瘤细胞系（MG-63 和 HOS）的致瘤性的影响。
在体外，MU 抑制 HA 的保留，从而减少功能性细胞相关基质的形成，并且还抑制细胞增殖、迁移和侵袭。MU（1.0 mM）抑制 Akt 磷酸化。在体内，尽管 MU 对原发性肿瘤的生长仅表现出轻微的抑制作用，但它明显抑制了肺转移的发展（减少 75%）。MU 明显抑制了原发性肿瘤周围的 HA 保留。
这些发现表明，MU 抑制了骨肉瘤细胞中 HA 的保留和细胞相关基质的形成，从而降低了肿瘤的致瘤性，包括肺转移。4-甲基伞形酮可能通过抑制 HA 的保留，成为一种有前途的针对骨肉瘤原发性肿瘤和远处转移的治疗药物。
