Hypoxia accelerates the progression of angiosarcoma through the regulation of angiosarcoma cells and tumor microenvironment |
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Authors: | Saki Maeda-Otsuka Ikko Kajihara Yukino Tasaki Saori Yamada-Kanazawa Ryoko Sakamoto Soichiro Sawamura Mamiko Masuzawa Mikio Masuzawa Yasuyuki Amoh Daichi Hoshina Riichiro Abe Yoshihiro Komohara Hironobu Ihn |
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Institution: | 1. Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan;2. Department of Dermatology, Kitasato University School of Medicine, Kanagawa, Japan;3. Department of Molecular Diagnostics, School of Allied Health Sciences, Kitasato University, Kanagawa, Japan;4. Department of Dermatology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan;5. Department of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;6. Department of Cell Pathology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan |
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Abstract: | BackgroundAngiosarcoma is a rare malignant tumor with a poor prognosis. It is known that hypoxic condition activates tumor progression in several cancers. Additionally, hypoxic tumor microenvironment accelerates immune escape. However, the presence and significance of hypoxia in angiosarcoma has not been adequately investigated.ObjectiveTo study the role of hypoxia in the progression of angiosarcoma.MethodsThe protein level of hypoxia inducible factor-1α (HIF-1α) in angiosarcoma was examined using immunohistochemistry and immunoblotting. To study the effect of hypoxia on tumor progression, cell proliferation, migration, invasion, and tube formation assays were performed in angiosarcoma cells. The influence of tumor cell supernatant in hypoxia from angiosarcoma cells on immune escape and angiogenesis was analysed to investigate the modulatory effect of hypoxia on tumor microenvironment of angiosarcoma. The molecular mechanism related to these results was investigated using immunoblotting and real time RT-PCR.ResultsHIF-1α protein was over-expressed in angiosarcoma tissues and cell lines under hypoxic conditions, and there was heterogeneity of oxygen supply in angiosarcoma. Hypoxia enhanced the proliferation, migration, and invasion abilities and inhibited tube formation in angiosarcoma cells. Tumor cell supernatant in hypoxia from angiosarcoma cells activated the monocyte invasion ability, facilitated its differentiation into M2-like macrophages, and suppressed cell-adhesion. These in vitro results were compatible to the pathological findings of angiosarcoma patients.ConclusionHypoxia plays a major role in progression of angiosarcoma cells by enhancing cell proliferation, migration, and invasion and by modulating the tumor microenvironment. |
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Keywords: | HIF-1α hypoxia inducible factor-1α OH- HIF-1α hydroxy-hypoxia inducible factor-1α TME tumor microenvironment HDMEC human dermal microvascular endothelial cells PD-L1 programmed cell death-1 ligand-1 TCS tumor cell supernatant TAM tumor-associated macrophage ERK extracellular signal-regulated kinase FAK focal adhesion kinase MMP-2 matrix metalloproteinase-2 Angiosarcoma Hypoxia HIF-1α (hypoxia inducible factor-1α) Tumor microenvironment Angiogenesis Heterogeneity |
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