RESUMO
Human angiosarcoma is a rare malignant vascular tumor associated with extremely poor clinical outcome and generally arising in skin of the head and neck region. However, little is known about the molecular pathogeneses and useful immunohistochemical markers of angiosarcoma. To investigate the mechanisms of angiosarcoma progression, we collected 85 cases of human angiosarcoma specimens with clinical records and analyzed ISO-HAS-B patient-derived angiosarcoma cells. As control subjects, 54 cases of hemangioma and 34 of pyogenic granuloma were collected. Remarkably, consistent with our recent observations regarding the involvement of survivin expression following Hippo pathway inactivation in the neoplastic proliferation of murine hemangioendothelioma cells and human infantile hemangioma, nuclear survivin expression was observed in all cases of angiosarcoma but not in hemangiomas and pyogenic granulomas, and the Hippo pathway was inactivated in 90.3% of yes-associated protein (YAP) -positive angiosarcoma cases. However, survivin expression modes and YAP localization (Hippo pathway activation modes) were not correlated with survival. In addition, we confirmed that survivin small interference RNA (siRNA) transfection and YM155, an anti-survivin drug, elicited decreased nuclear survivin expression and cell proliferation in ISO-HAS-B cells which expressed survivin consistently. Conclusively, these findings support the importance of survivin as a good marker and critical regulator of cellular proliferation for human angiosarcoma and YM155 as a potential therapeutic agent.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Biomarcadores Tumorais/genética , Hemangiossarcoma/genética , Proteínas Inibidoras de Apoptose/genética , Fosfoproteínas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hemangiossarcoma/patologia , Via de Sinalização Hippo , Humanos , Imidazóis , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Naftoquinonas , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/genética , Survivina , Fatores de Transcrição , Proteínas de Sinalização YAPRESUMO
BACKGROUND: Previous studies have indicated that MFG-E8 enhances tumor cell survival, invasion and angiogenesis. However, the role of MFG-E8 in angiosarcoma (AS) has not been clarified. OBJECTIVE: Objective was to elucidate the mechanism of the regulation by MFG-E8 in AS and the association between MFG-E8 and clinicopathological features of AS. METHODS: The effects of the depletion of MFG-E8 by siRNA on tube formation, migration and proliferation in murine AS cells were examined. The effect of administration of anti-MFG-E8 antibody (Ab) on tumor growth of AS in mice was examined. The associations of MFG-E8 expression and clinicopathological features of human AS were assessed. RESULTS: The expressions of MFG-E8 in murine and human AS cells were significantly higher than those in melanoma cells, macrophages and endothelial cells. Depletion of MFG-E8 in murine AS cells by siRNA significantly inhibited the formation of capillary-like structures and migration, but not proliferation. Administration of anti-MFG-E8 Ab significantly inhibited tumor growth and decreased the number of tumor-associated macrophages (TAMs) in AS tumors. Tumor size and the number of TAMs in human AS with high expression of MFG-E8 were significantly increased compared to those of AS with low expression of MFG-E8. Progression-free survival and overall survival time of the patients of AS with high expression of MFG-E8 were significantly shorter than those of AS with low expression of MFG-E8. CONCLUSIONS: AS-derived MFG-E8 might enhance tumor growth via angiogenesis and the induction of TAMs in autocrine/paracrine manner, and administration of anti-MFG-E8 Ab could be a therapeutic potential for AS.
Assuntos
Antígenos de Superfície/metabolismo , Hemangiossarcoma/patologia , Proteínas do Leite/metabolismo , Neovascularização Patológica/patologia , Neoplasias Cutâneas/patologia , Idoso , Animais , Anticorpos/administração & dosagem , Antígenos de Superfície/genética , Biópsia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Hemangiossarcoma/irrigação sanguínea , Hemangiossarcoma/tratamento farmacológico , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Proteínas do Leite/antagonistas & inibidores , Proteínas do Leite/genética , Neovascularização Patológica/tratamento farmacológico , Pericitos , Células RAW 264.7 , RNA Interferente Pequeno/metabolismo , Pele/irrigação sanguínea , Pele/patologia , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/tratamento farmacológicoAssuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Docetaxel/administração & dosagem , Docetaxel/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Humanos , Doença Iatrogênica , Imunossupressores/efeitos adversos , Japão , Masculino , Taxoides/uso terapêuticoRESUMO
Fixed drug eruption is a common cutaneous adverse reaction in young patients with a characteristic clinical appearance. However, the diagnosis and identification of the substance may be difficult if food or food additives provoke the fixed eruption. A 26-year-old man had a history of two episodes of cutaneous erythema with residual pigmentation. Close examination of the history including his diet in addition to an oral challenge test and patch testing led to the diagnosis of fixed eruption secondary to quinine in tonic water. We examined for the presence of quinine in commercially available brands of tonic water using ultraviolet A and irradiation and high-performance liquid chromatography. Both Schweppes and CANADA DRY brands of tonic water emitted fluorescent light upon ultraviolet A irradiation, and contained quinine at concentrations of 67.9 and 61.3 mg/L, respectively. Quinine contained in some tonic waters may trigger fixed eruption.