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Open AccessArticle

Compressive Stimulation Enhances Ovarian Cancer Proliferation, Invasion, Chemoresistance, and Mechanotransduction via CDC42 in a 3D Bioreactor

by Caymen M. Novak 1, Eric N. Horst 1, Emily Lin 1 and Geeta Mehta 1,2,3,4,5,*
1
Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
2
Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USA
3
Macromolecular Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USA
4
Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
5
Precision Health, University of Michigan, Ann Arbor, MI 48109, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(6), 1521; https://doi.org/10.3390/cancers12061521
Received: 8 May 2020 / Revised: 29 May 2020 / Accepted: 4 June 2020 / Published: 10 June 2020
(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)
This report investigates the role of compressive stress on ovarian cancer in a 3D custom built bioreactor. Cells within the ovarian tumor microenvironment experience a range of compressive stimuli that contribute to mechanotransduction. As the ovarian tumor expands, cells are exposed to chronic load from hydrostatic pressure, displacement of surrounding cells, and growth induced stress. External dynamic stimuli have been correlated with an increase in metastasis, cancer stem cell marker expression, chemoresistance, and proliferation in a variety of cancers. However, how these compressive stimuli contribute to ovarian cancer progression is not fully understood. In this report, high grade serous ovarian cancer cell lines were encapsulated within an ECM mimicking hydrogel comprising of agarose and collagen type I, and stimulated with confined cyclic or static compressive stresses for 24 and 72 h. Compression stimulation resulted in a significant increase in proliferation, invasive morphology, and chemoresistance. Additionally, CDC42 was upregulated in compression stimulated conditions, and was necessary to drive increased proliferation and chemoresistance. Inhibition of CDC42 lead to significant decrease in proliferation, survival, and increased chemosensitivity. In summary, the dynamic in vitro 3D platform developed in this report, is ideal for understanding the influence of compressive stimuli, and can be widely applicable to any epithelial cancers. This work reinforces the critical need to consider compressive stimulation in basic cancer biology and therapeutic developments. View Full-Text
Keywords: mechanotransduction; ovarian cancer; bioreactor; compression; three dimensional; hydrostatic pressure; ovarian tumors; hydrogels; compressive stress; high grade serous mechanotransduction; ovarian cancer; bioreactor; compression; three dimensional; hydrostatic pressure; ovarian tumors; hydrogels; compressive stress; high grade serous
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MDPI and ACS Style

Novak, C.M.; Horst, E.N.; Lin, E.; Mehta, G. Compressive Stimulation Enhances Ovarian Cancer Proliferation, Invasion, Chemoresistance, and Mechanotransduction via CDC42 in a 3D Bioreactor. Cancers 2020, 12, 1521.

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