title: Inhibition of hyaluronan retention by 4-methylumbelliferone suppresses osteosarcoma cells in vitro and lung metastasis in vivo.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, 65-Tsurumai, Showa, Nagoya, Aichi, Japan.
authors: E
authors: E
authors: Arai
authors: Y
authors: Y
authors: Nishida
authors: J
authors: J
authors: Wasa
authors: H
authors: H
authors: Urakawa
authors: L
authors: L
authors: Zhuo
authors: K
authors: K
authors: Kimata
authors: E
authors: E
authors: Kozawa
authors: N
authors: N
authors: Futamura
authors: N
authors: N
authors: Ishiguro
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006923:Hymecromone / Q000031:analogs & derivatives* / Q000494:pharmacology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D006923:Hymecromone; D006820:Hyaluronic Acid; D051057:Proto-Oncogene Proteins c-akt