Interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma

Abstract Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) that is associated with elevated interleukin-6 (IL-6) expression, resistance to chemotherapy, and increased mortality. Although bevacizumab (Bev) is a widely used anti-angiogenic agent for EOC, the efficacy...

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Autores principales:	Toshiyuki Seki, Nozomu Yanaihara, Jason Solomon Shapiro, Misato Saito, Junya Tabata, Ryo Yokomizo, Daito Noguchi, Takafumi Kuroda, Ayako Kawabata, Jiro Suzuki, Kazuaki Takahashi, Haruka Matsuzawa, Misayo Miyake, Masataka Takenaka, Yasushi Iida, Satoshi Yanagida, Aikou Okamoto
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4e5e333a9dd74977baf25b7ae087534a
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spelling	oai:doaj.org-article:4e5e333a9dd74977baf25b7ae087534a2021-12-02T18:15:49ZInterleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma10.1038/s41598-021-86913-92045-2322https://doaj.org/article/4e5e333a9dd74977baf25b7ae087534a2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86913-9https://doaj.org/toc/2045-2322Abstract Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) that is associated with elevated interleukin-6 (IL-6) expression, resistance to chemotherapy, and increased mortality. Although bevacizumab (Bev) is a widely used anti-angiogenic agent for EOC, the efficacy of Bev and the role of IL-6 in modulating angiogenesis in OCCC are unknown. We performed tube formation assays using human umbilical vein endothelial cells (HUVEC) cultured in OCCC cell-conditioned medium and using cells directly co-cultured with OCCC cells. We observed that IL-6 inhibition significantly mitigated the ability of Bev to impede tube formation in both cases. Furthermore, IL-6 blockade disrupted the anti-angiogenic efficacy of Bev and its concomitant anti-tumor activity. In addition, IL-6 inhibition resulted in a significant increase in angiopoietin-1 (Ang1) secretion and decreased vascular endothelial growth factor (VEGF) expression. Clinical specimens also exhibited this reciprocal relationship between IL-6 and Ang1 expression. Finally, depletion of Ang1 abrogated the effects of IL-6 inhibition on Bev activity, demonstrating that IL-6 supports the anti-angiogenic activity of Bev by suppressing Ang1 expression and promoting dependence on VEGF for angiogenesis. Altogether, our data suggest that OCCC tumors with high IL-6 levels are candidates for Bev therapy.Toshiyuki SekiNozomu YanaiharaJason Solomon ShapiroMisato SaitoJunya TabataRyo YokomizoDaito NoguchiTakafumi KurodaAyako KawabataJiro SuzukiKazuaki TakahashiHaruka MatsuzawaMisayo MiyakeMasataka TakenakaYasushi IidaSatoshi YanagidaAikou OkamotoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Toshiyuki Seki Nozomu Yanaihara Jason Solomon Shapiro Misato Saito Junya Tabata Ryo Yokomizo Daito Noguchi Takafumi Kuroda Ayako Kawabata Jiro Suzuki Kazuaki Takahashi Haruka Matsuzawa Misayo Miyake Masataka Takenaka Yasushi Iida Satoshi Yanagida Aikou Okamoto Interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma
description	Abstract Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) that is associated with elevated interleukin-6 (IL-6) expression, resistance to chemotherapy, and increased mortality. Although bevacizumab (Bev) is a widely used anti-angiogenic agent for EOC, the efficacy of Bev and the role of IL-6 in modulating angiogenesis in OCCC are unknown. We performed tube formation assays using human umbilical vein endothelial cells (HUVEC) cultured in OCCC cell-conditioned medium and using cells directly co-cultured with OCCC cells. We observed that IL-6 inhibition significantly mitigated the ability of Bev to impede tube formation in both cases. Furthermore, IL-6 blockade disrupted the anti-angiogenic efficacy of Bev and its concomitant anti-tumor activity. In addition, IL-6 inhibition resulted in a significant increase in angiopoietin-1 (Ang1) secretion and decreased vascular endothelial growth factor (VEGF) expression. Clinical specimens also exhibited this reciprocal relationship between IL-6 and Ang1 expression. Finally, depletion of Ang1 abrogated the effects of IL-6 inhibition on Bev activity, demonstrating that IL-6 supports the anti-angiogenic activity of Bev by suppressing Ang1 expression and promoting dependence on VEGF for angiogenesis. Altogether, our data suggest that OCCC tumors with high IL-6 levels are candidates for Bev therapy.
format	article
author	Toshiyuki Seki Nozomu Yanaihara Jason Solomon Shapiro Misato Saito Junya Tabata Ryo Yokomizo Daito Noguchi Takafumi Kuroda Ayako Kawabata Jiro Suzuki Kazuaki Takahashi Haruka Matsuzawa Misayo Miyake Masataka Takenaka Yasushi Iida Satoshi Yanagida Aikou Okamoto
author_facet	Toshiyuki Seki Nozomu Yanaihara Jason Solomon Shapiro Misato Saito Junya Tabata Ryo Yokomizo Daito Noguchi Takafumi Kuroda Ayako Kawabata Jiro Suzuki Kazuaki Takahashi Haruka Matsuzawa Misayo Miyake Masataka Takenaka Yasushi Iida Satoshi Yanagida Aikou Okamoto
author_sort	Toshiyuki Seki
title	Interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma
title_short	Interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma
title_full	Interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma
title_fullStr	Interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma
title_full_unstemmed	Interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma
title_sort	interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4e5e333a9dd74977baf25b7ae087534a
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Interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma

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