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Dis Model Mech. 2018 Sep 25;11(9). pii: dmm034199. doi: 10.1242/dmm.034199.

Modeling the effect of ascites-induced compression on ovarian cancer multicellular aggregates.

Author information

1
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.
2
Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46617, USA.
3
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
4
Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN 46556, USA.
5
Department of Mathematics, University of California, Riverside, CA 92521, USA.
6
Department of Mechanical and Energy Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA.
7
Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46617, USA sstack@nd.edu.
8
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. EOC dissemination is predominantly via direct extension of cells and multicellular aggregates (MCAs) into the peritoneal cavity, which adhere to and induce retraction of peritoneal mesothelium and proliferate in the submesothelial matrix to generate metastatic lesions. Metastasis is facilitated by the accumulation of malignant ascites (500 ml to >2 l), resulting in physical discomfort and abdominal distension, and leading to poor prognosis. Although intraperitoneal fluid pressure is normally subatmospheric, an average intraperitoneal pressure of 30 cmH2O (22.1 mmHg) has been reported in women with EOC. In this study, to enable experimental evaluation of the impact of high intraperitoneal pressure on EOC progression, two new in vitro model systems were developed. Initial experiments evaluated EOC MCAs in pressure vessels connected to an Instron to apply short-term compressive force. A Flexcell Compression Plus system was then used to enable longer-term compression of MCAs in custom-designed hydrogel carriers. Results show changes in the expression of genes related to epithelial-mesenchymal transition as well as altered dispersal of compressed MCAs on collagen gels. These new model systems have utility for future analyses of compression-induced mechanotransduction and the resulting impact on cellular responses related to intraperitoneal metastatic dissemination.This article has an associated First Person interview with the first authors of the paper.

KEYWORDS:

Ascites; Compression; Mechanobiology; Metastasis; Multicellular aggregates; Ovarian cancer

PMID:
30254133
PMCID:
PMC6176988
DOI:
10.1242/dmm.034199
[Indexed for MEDLINE]
Free PMC Article

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