Oncotarget

Research Papers:

Loss of E-cadherin disrupts ovarian epithelial inclusion cyst formation and collective cell movement in ovarian cancer cells

Pui-Wah Choi, Junzheng Yang, Shu-Kay Ng, Colleen Feltmate, Michael G. Muto, Kathleen Hasselblatt, Kyle Lafferty-Whyte, Lellean JeBailey, Laura MacConaill, William R. Welch, Wing-Ping Fong, Ross S. Berkowitz and Shu-Wing Ng _

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Oncotarget. 2016; 7:4110-4121. https://doi.org/10.18632/oncotarget.6588

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Abstract

Pui-Wah Choi1,2, Junzheng Yang2, Shu-Kay Ng3, Colleen Feltmate2, Michael G. Muto2, Kathleen Hasselblatt2, Kyle Lafferty-Whyte4, Lellean JeBailey4, Laura MacConaill5, William R. Welch6, Wing-Ping Fong1, Ross S. Berkowitz2 and Shu-Wing Ng2

1 School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China

2 Department of Obstetrics/Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Boston, Massachusetts, USA

3 School of Medicine, Griffith University, Meadowbrook, Australia

4 GeneGo, Thomson Reuters, New York, New York, USA

5 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

6 Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA

Correspondence to:

Wing-Ping Fong, email:

Shu-Wing Ng, email:

Keywords: ovarian cancer, three-dimensional culture, inclusion cyst, tumor invasion, collective movement

Received: August 19, 2015 Accepted: November 16, 2015 Published: December 13, 2015

Abstract

Increased inclusion cyst formation in the ovary is associated with ovarian cancer development. We employed in vitro three-dimensional (3D) organotypic models formed by normal human ovarian surface epithelial (OSE) cells and ovarian cancer cells to study the morphologies of normal and cancerous ovarian cortical inclusion cysts and the molecular changes during their transitions into stromal microenvironment. When compared with normal cysts that expressed tenascin, the cancerous cysts expressed high levels of laminin V and demonstrated polarized structures in Matrigel; and the cancer cells migrated collectively when the cyst structures were positioned in a stromal-like collagen I matrix. The molecular markers identified in the in vitro 3D models were verified in clinical samples. Network analysis of gene expression of the 3D structures indicates concurrent downregulation of transforming growth factor beta pathway genes and high levels of E-cadherin and microRNA200 (miR200) expression in the cancerous cysts and the migrating cancer cells. Transient silencing of E-cadherin expression in ovarian cancer cells disrupted cyst structures and inhibited collective cell migration. Taken together, our studies employing 3D models have shown that E-cadherin is crucial for ovarian inclusion cyst formation and collective cancer cell migration.


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