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.
Highlights
Es www.impactjournals.com/oncotarget resembling the in vivo cellular structures in clinical samples
Single cells derived from normal human ovarian surface epithelial (OSE) primary cultures and HPVE6E7immortalized OSE cell lines, as well as a panel of ovarian cancer cell lines formed 3D cellular structures after 7 to 14 days in Matrigel, which contained the majority of basement membrane proteins (Figure S1)
Tumor-associated fibroblasts (TAFs) formed amorphous clusters of cells, which were distinctly different from the spheroids formed by ovarian epithelial cells
Summary
Es www.impactjournals.com/oncotarget resembling the in vivo cellular structures in clinical samples. Both the videos of the 3D collagen structures for MCAS (Supplementary Video S3) and OVCA432 (Supplementary Video S4) suggest the collective movement and elevated expression of E-cadherin in the migrating cancer cells.
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