Evaluating the Effects of Fluid Shear Stress on Ovarian Cancer Progression and Metastatic Potential

Most women die of ovarian metastasis rather than the effects of the primary tumor. However, little is known about the factors that support the survival and secondary outgrowth of exfoliated ovarian cancer cells. In addition to genetic and molecular factors, the unique environment of the peritoneal cavity exposes ovarian cells to biophysical forces, particularly fluid shear stress (FSS). These biomechanical forces, only recently identified as a hallmark of cancer, induce rapid signaling events in attached and aggregated cells, a process termed mechanotransduction. The cellular responses to these forces and their impact on tumor initiation, progression, and metastasis are not understood. In order to delineate these phenomena, dynamic and syngeneic cell models are needed that represent the development of the disease and can be used in relevant engineered testing platforms. Thus, in an interdisciplinary approach, this work bridges molecular and cancer biology, device engineering, fluid mechanics, and biophysics strategies. The results demonstrated that even a low level of continual FSS significantly and differentially affected the viability of epithelial ovarian cancer cells of various stages of progression over time, and enhanced their aggregation, adhesion, and cellular architecture, traits of more aggressive disease. Furthermore, benign cells that survived FSS displayed phenotypic and genotypic changes resembling more aggressive stages of the disease, suggesting an impact of FSS on early stages of tumor development. After identifying a biological affect, we designed an in vitro testing platform for controlled FSS investigations, and we modeled the system fluid mechanics to understand the platform's performance capability. A cylindrical platform divided into annular sections with lid-driven flow was selected to allow continuous experiments sustainable for long durations. Tuning of the lid speed or fluid height resulted in a wide range of FSS magnitudes (0- 20 N/m2) as confirmed by analytical and numerical modeling. Further, detailed numerical modeling uncovered that FSS magnitudes experienced by cell aggregates were larger than previously observed, suggesting an even larger role of FSS in ovarian cancer. Finally, we built and engineered the designed platform to investigate changes in benign and cancer cells as a function of time and FSS magnitude. Device precision was balanced with biological consistency needs, and a novel platform was built for controlled FSS investigations. This work provides a foundational understanding of the physical environment and its potential links to ovarian cancer progression and metastatic potential.

Name thesis:degree_name

Ph. D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Biomedical Engineering

Department dc:contributor.department

Department of Biomedical Engineering and Mechanics

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2018

Author dc:creator

• Hyler, Alexandra Rochelle

Chairs dc:contributor.committeechair

• Schmelz, Eva M.
• Davalos, Rafael V.

Committee members dc:contributor.committeemember

• Verbridge, Scott
• Bruus, Henrik
• Stremler, Mark A.

• Ovarian Cancer
• Fluid Shear Stress
• Cancer Microenviroment
• Subcellular Organization
• Malignant Phenotype
• Biophysics
• Device Design

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Dc Identifier Other

vt_gsexam:14743

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/94135