title: Inhibition of heat shock protein 90 exerts an antitumour effect in angiosarcoma: involvement of the vascular endothelial growth factor signalling pathway.
abstract: BACKGROUND
  Angiosarcoma is a rare malignant neoplasm derived from endothelial cells, and because advanced angiosarcoma is resistant to standard chemotherapy its prognosis is poor. Therefore, new therapies are urgently needed. Heat shock protein (HSP)90 has been identified as a molecular chaperone that regulates various cancer-related proteins. Numerous clinical trials are currently testing the effectiveness of HSP90 inhibitors in various types of malignancies.
  
  
  OBJECTIVE
  To investigate the role of HSP90 in the pathogenesis of angiosarcoma and whether the inhibition of HSP90 may have antitumour activity.
  
  
  METHODS
  The expression of HSP90 protein in angiosarcoma was examined using immunohistochemistry and immunoblotting. The effects of HSP90 inhibition were proven using proliferation, migration and invasion assay in angiosarcoma cells. The mechanism of antitumour effect by HSP90 inhibition was investigated by the transfection of small interfering RNA (siRNA).
  
  
  RESULTS
  The levels of HSP90 protein expression in cultured angiosarcoma cell lines were markedly increased compared with those in normal tissue cell lines. Immunohistochemical analyses revealed that the expression of HSP90 protein was strongly detected in angiosarcoma tissues compared with that in normal dermal vessels or senile angioma tissues. Ganetespib, an HSP90 inhibitor, with or without taxanes, inhibited the proliferation of angiosarcoma cells via apoptosis in a dose-dependent manner. HSP90 siRNA suppressed the proliferation, migration and invasion of angiosarcoma cells. Knock-down of HSP90 did not suppress vascular endothelial growth factor receptor 2 directly, but selectively suppressed several downstream targets of vascular endothelial growth factor signalling in angiosarcoma cells.
  
  
  CONCLUSIONS
  HSP90 could be a novel therapeutic target for angiosarcoma.
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yamada-Kanazawa
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Kajihara
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Fukushima
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Jinnin
authors.affiliation: Department of Dermatology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Masuzawa
authors.affiliation: Department of Molecular Diagnostics, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Masuzawa
authors.affiliation: Department of Dermatology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Amoh
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Hoshina
authors.affiliation: Department of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Abe
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ihn
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D016022:Case-Control Studies; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006394:Hemangiosarcoma / Q000517:prevention & control*; D006801:Humans; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000517:prevention & control*; D043823:Taxoids / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D018841:HSP90 Heat-Shock Proteins; C533237:STA 9090; D043823:Taxoids; D014230:Triazoles; D042461:Vascular Endothelial Growth Factor A; C080625:taxane