Cancer-Associated Fibroblast-Derived Interleukin-8 Promotes Ovarian Cancer Cell Stemness and Malignancy Through the Notch3-Mediated Signaling

Zhaodong Ji; Wenjuan Tian; Wen Gao; Rongyu Zang; Huaying Wang; Gong Yang

doi:10.3389/fcell.2021.684505

Cancer-Associated Fibroblast-Derived Interleukin-8 Promotes Ovarian Cancer Cell Stemness and Malignancy Through the Notch3-Mediated Signaling

Front Cell Dev Biol. 2021 Jul 1:9:684505. doi: 10.3389/fcell.2021.684505. eCollection 2021.

Authors

Zhaodong Ji^{1

2}, Wenjuan Tian^{1

2

3}, Wen Gao⁴, Rongyu Zang⁵, Huaying Wang^{2

3}, Gong Yang^{1

2

6}

Affiliations

¹ Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
⁴ The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China.
⁵ Ovarian Cancer Program, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, China.
⁶ Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.

Abstract

As a significant component in ovarian cancer microenvironment, cancer-associated fibroblasts (CAFs) contribute to cancer progression through interaction with cancer cells. Recent studies demonstrate that interleukin-8 (IL-8) is overexpressed in multiple cancer types and is essential for tumor development. Nonetheless, the underlying mechanism that the CAF-derived IL-8 promotes ovarian tumorigenesis is unknown. Here, we show that IL-8 secreted from CAFs could activate normal ovarian fibroblasts (NFs) through multiple signaling and that IL-8 stimulated malignant growth of ovarian cancer cells in animals and increased the IC₅₀ of cisplatin (CDDP) in ovarian cancer cells. Further study showed that IL-8 induced cancer cell stemness via the activation of Notch3 and that the high level of IL-8 in ascites was positively correlated with the expression of Notch3 in ovarian cancer tissues. Collectively, IL-8 secreted from CAFs and cancer cells promotes stemness in human ovarian cancer via the activation of the Notch3-mediated signaling, which may provide a novel strategy for ovarian cancer treatment.

Keywords: IL-8; Notch3 signal pathway; cancer-associated ovarian fibroblasts; epithelial ovarian cancer; tumor stemness.