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JCI Insight. 2017 Sep 21;2(18). pii: 91828. doi: 10.1172/jci.insight.91828. eCollection 2017 Sep 21.

ASK1-dependent endothelial cell activation is critical in ovarian cancer growth and metastasis.

Author information

1
Department of Pathology and the Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA.
2
Center for Translational Medicine, The First Affiliated Hospital, and.
3
Zhongshan Ophthalmology Hospital, Sun Yat-sen University, Guangzhou, China.
4
Gilead Sciences Inc., Foster City, California, USA.

Abstract

We have recently reported that tumor-associated macrophages (TAMs) promote early transcoelomic metastasis of ovarian cancer by facilitating TAM-ovarian cancer cell spheroid formation. ASK1 is known to be important for macrophage activation and inflammation-mediated tumorigenesis. In the present study, we show that ASK1 deficiency attenuates TAM-spheroid formation and ovarian cancer progression in an orthotopic ovarian cancer model. Interestingly, ASK1 in stroma, but not in TAMs, is critical for peritoneal tumor growth of ovarian cancer. Moreover, overexpression of an ASK1 inhibitory protein (suppressor of cytokine signaling-1; SOCS1) in vascular endothelium attenuates vascular permeability, TAM infiltration, and ovarian cancer growth. Mechanistically, we show that ASK1 mediates degradation of endothelial junction protein VE-cadherin via a lysosomal pathway to promote macrophage transmigration. Importantly, a pharmacological ASK1 inhibitor prevents tumor-induced vascular leakage, macrophage infiltration, and tumor growth in two mouse models. Since transcoelomic metastasis is also associated with many other cancers, such as pancreatic and colon cancers, our study provides ASK1 as a therapeutic target for the treatment of ovarian cancer and other transcoelomic metastasis cancers.

KEYWORDS:

Cancer; Macrophages; Oncology; Therapeutics; endothelial cells

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