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Hypoxia accelerates the progression of angiosarcoma through the regulation of angiosarcoma cells and tumor microenvironment

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
Journal of Dermatological Science 2019 January 15

BACKGROUND: Angiosarcoma 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.

OBJECTIVE: To study the role of hypoxia in the progression of angiosarcoma.

METHODS: The 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.

RESULTS: HIF-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.

CONCLUSION: Hypoxia 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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