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

Caymen M. Novak,Eric N. Horst,Geeta Mehta,Emily Lin

doi:10.3390/cancers12061521

Caymen M. Novak, Eric N. Horst + Show 2 more

Open Access

https://doi.org/10.3390/cancers12061521

Copy DOI

Journal: Cancers	Publication Date: Jun 10, 2020
Citations: 35	License type: CC BY 4.0

Affiliation: University of Michigan–Ann Arbor

Abstract

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.

Highlights

Ovarian cancer is subject to a variety of pathophysiological mechanical forces during initiation, progression, and metastasis [1]
With an aim of predicting the compressive forces experienced by high grade serous ovarian cancer cells within the compression bioreactor (Figure 1A,B), a COMSOL model of the cell-laden interpenetrating hydrogel and force applying deflection membrane was constructed
The bioreactor is capable of programmable compression functions, as well as static loading which is continuously monitored via LabVIEW programming

Summary

Introduction

Ovarian cancer is subject to a variety of pathophysiological mechanical forces during initiation, progression, and metastasis [1]. Primary ovarian tumors reach average diameters of 12 cm, displacing surrounding extracellular matrix and native cells [2,3]. This uncontrolled growth produces a circumferential compressive force on the tumor [4]. Ovarian cancer patients often present with ascites, or the retainment of fluid within the peritoneal cavity. This fluid build-up submerges the ovaries in an aberrant mechanical microenvironment that further compresses the primary tumor site through hydrostatic pressure. As patients go about their everyday routine, the movement and Cancers 2020, 12, 1521; doi:10.3390/cancers12061521 www.mdpi.com/journal/cancers

Results

Discussion

Conclusion