hymecromone and Osteosarcoma

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.

Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Humans; Hyaluronic Acid; Hymecromone; Immunohistochemistry; In Situ Nick-End Labeling; In Vitro Techniques; Lung Neoplasms; Osteosarcoma; Phosphorylation; Proto-Oncogene Proteins c-akt; Real-Time Polymerase Chain Reaction

Several studies have suggested that increased production of hyaluronan (HA) is associated with metastatic behavior in various malignant tumors. To our knowledge, HA molecular weights required for metastasis are still unsolved in osteosarcoma. We examined the size of HA and hyaluronan synthase (HAS) isoforms related to biological functions required for metastasis in the LM8 stably highly metastatic osteosarcoma cell line. We found that HA of molecular weight which HAS3 produces enhanced biological functions related to metastasis such as cell proliferation, invasion, and degradation of extracellular matrix. Moreover, cell proliferation and invasion were inhibited by suppressing the activity of HAS3 expressed in LM8 cells, using hyaluronan synthase suppressor, 4-methylumbelliferone (MU). HA with the molecular weight related to HAS2 was the most adherent to CD44 in LM8 cells, suggesting that HAS2 may play an important role in pericellular coat formation. These results suggest that HAS3-related HA enhances crucial biological activities necessary for metastasis and that HAS2-related HA offers an advantageous environment for osteosarcoma cells.

Topics: Animals; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Collagen; Dose-Response Relationship, Drug; Drug Combinations; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Focal Adhesion Kinase 1; Gene Expression Regulation, Neoplastic; Glucuronosyltransferase; Humans; Hyaluronan Receptors; Hyaluronan Synthases; Hyaluronic Acid; Hymecromone; Laminin; Matrix Metalloproteinase 2; Mice; Molecular Weight; Neoplasm Invasiveness; Neoplasm Metastasis; Osteosarcoma; Phosphorylation; Proteoglycans; Proto-Oncogene Proteins c-fos; RNA, Messenger