Ovarian cancer spreads via direct exfoliation of tumor cells from primary carcinoma into peritoneal cavity, further dissemination in form of single cells and multi-cellular aggregates (MCAs) with subsequent intraperitoneal adhesion, migration through mesothelial layer, invasion of submesothelial matrix and proliferation into secondary tumor masses. The mechanisms regulating initial cell detachment, MCA generation, survival in ascitic fluid and secondary anchorage and the role of unique cadherin dynamics in these steps remain poorly understood. The designed study modeled and comprehensively characterized cell/MCA behavior in their free-floating state based on cellular cadherin composition and elucidated changes in metastasis-associated behaviors caused by alterations in cadherin expression. Next, I delineated the essential role of N-cadherin cell network for the induction of cell invasion through the 3-dimentional collagen matrices. Importantly, I demonstrated successful suppression of cell invasive behavior by N-cadherin blocking peptides via abruption of cell-cell junctions. In addition, I showed enhancement of mesothelial clearance by ovarian cancer MCAs upon N-cadherin upregulation. Finally, I presented a novel technique for feasible and reproducible long-term exposure of fragile and heterogeneous 3-dimentional cellular structures to clinically relevant compressive forces and discovered patterns in gene expression alterations which may modulate cadherin switch in the context of high intraperitoneal pressure caused by malignant ascites. Taken together, my work has revealed the role of cadherin repertoires in the cell/MCA dynamics and metastasis-associated behavior, identified a novel possible mechanism regulating cadherin switch and suggested N-cadherin as a novel therapeutic target for intraperitoneal treatment of ovarian cancer metastasis.
Cadherin Switch, Ovarian Cancer Cell and Multi-Cellular Aggregate Dynamics and Metastasis-Associated BehaviorDoctoral Dissertation
|Contributor||M. Sharon Stack, Research Director|
|Degree Level||Doctoral Dissertation|
|Degree Discipline||Biological Sciences|
|Degree Name||Doctor of Philosophy|
|Departments and Units|