title: Therapeutic potential of hyaluronan oligosaccharides for bone metastasis of breast cancer.
abstract: Hyaluronan (HA) oligosaccharides were reported to have suppressive effects on various malignant tumors via disruption of receptor HA interactions. However, no studies have focused on the effects of HA oligosaccharides on bone metastasis of breast cancer. In this study, we clarified the effective size of HA oligosaccharides required to inhibit cell growth in the highly invasive breast cancer cell line, MDA-MB-231 cells. Based on the results of cell growth assay, we subsequently analyzed the effects of HA tetrasaccharides, HA decasaccharides, and high molecular weight HA on the other breast cancer cell behaviors in vitro and breast cancer bone metastasis in vivo. HA decasaccharides significantly inhibited cell growth, motility, and invasion, whereas tetrasaccharides did not. HAS2 mRNA expression was altered after the treatment with both tetrasaccharides and decasaccharides. Phosphorylation of Akt was suppressed after 1 h treatment with HA decasaccharides, and the effect was partially reversed by anti-CD44 monoclonal antibody. In vivo, local application of HA decasaccharides inhibited the expansion of osteolytic lesions in tibia on soft X-rays using mouse bone metastasis model of breast cancer. Histological analysis revealed HA accumulation in bone metastatic lesions was perturbed by decasaccharides. These results suggest that HA oligosaccharides suppressed progression of bone metastasis in breast cancer via interruption of endogenous HA-CD44 interaction, and as such, can be a novel therapeutic candidate to limit bone metastasis of breast cancer.
authors.affiliation: Department of Orthopedic Surgery, Nagoya University Graduate School and School of Medicine, 65 Tsurumai, Showa, Nagoya, Aichi 466-8550, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Urakawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nishida
authors.forename: Warren
authors.initials: W
authors.lastname: Knudson
authors.forename: Cheryl B
authors.initials: CB
authors.lastname: Knudson
authors.forename: Eisuke
authors.initials: E
authors.lastname: Arai
authors.forename: Eiji
authors.initials: E
authors.lastname: Kozawa
authors.forename: Naohisa
authors.initials: N
authors.lastname: Futamura
authors.forename: Junji
authors.initials: J
authors.lastname: Wasa
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000494:pharmacology*; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness / Q000473:pathology; D009844:Oligosaccharides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013977:Tibia / Q000473:pathology; D055675:Viscosupplements / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D009844:Oligosaccharides; D055675:Viscosupplements; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C523794:HAS1 protein, human; C101754:HAS2 protein, human; C105458:HAS3 protein, human; D000076002:Hyaluronan Synthases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt