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

Toshiyuki Seki,Kazuaki Takahashi,Nozomu Yanaihara,Masataka Takenaka,Yasushi Iida,Misayo Miyake,Haruka Matsuzawa,Aikou Okamoto,Ayako Kawabata,Ryo Yokomizo,Satoshi Yanagida,Misato Saito,Takafumi Kuroda,Junya Tabata,Jason Solomon Shapiro,Jiro Suzuki,Daito Noguchi

doi:10.1038/s41598-021-86913-9

Toshiyuki Seki, Kazuaki Takahashi + Show 15 more

Open Access

https://doi.org/10.1038/s41598-021-86913-9

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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.

Highlights

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
We examined the modulatory actions of IL-6 on Bev anti-angiogenic efficacy by conducting tube formation assays in co-cultures of OCCC cell lines and human umbilical vein endothelial cells (HUVEC) in the presence or absence of Bev and/or anti-IL-6 antibody
To investigate the influence of IL-6 signaling on anti-angiogenic therapy in OCCC, we first assayed the level of IL-6 production of a series of OCCC cell lines

Summary

Introduction

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. The anti-angiogenic drug bevacizumab (Bev), a monoclonal antibody against human vascular endothelial growth factor (VEGF), has been incorporated into first-line chemotherapy and follow-up maintenance therapy for advanced EOC. These findings suggest that IL-6 signaling may potentiate the anti-angiogenic actions of VEGF blockade by Bev. In this study, we examined the modulatory actions of IL-6 on Bev anti-angiogenic efficacy by conducting tube formation assays in co-cultures of OCCC cell lines and human umbilical vein endothelial cells (HUVEC) in the presence or absence of Bev and/or anti-IL-6 antibody. Results suggested that IL-6 promotes the anti-angiogenic efficacy of Bev by suppressing angiopoietin-1 (Ang1) release. We present evidence that IL-6 suppresses Ang[1] production in human OCCC tissue These results provide valuable information for the development of individualized OCCC treatment strategies

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