Abstract
ABSTRACTEpithelial 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.
Highlights
We report the development of two unique model systems with which to examine the impact of altered peritoneal mechanobiology on epithelial ovarian carcinoma (EOC) multicellular aggregates (MCAs)
Increased peritoneal fluid pressure results from the presence of tense ascites in women with EOC; the potential impact of ascitesinduced compression of EOC MCAs has not been evaluated owing to a lack of appropriate model systems
As cadherins are important for the maintenance of MCA integrity, survival and metastatic dissemination (Klymenko et al, 2017a,b,c), the effect of compression on cellular cadherin expression profiles was examined
Summary
The presence of malignant ascites, an excess of fluid in the intraabdominal cavity as a consequence of peritoneal carcinomatosis, is. The pathophysiology of ascites accumulation is multifactorial and includes enhanced fluid secretion by the tumor, poor reabsorption through tumor-obstructed lymphatic channels in the diaphragm and increased microvascular permeability (Adam and Adam, 2004; Becker et al, 2006; Garrison et al, 1987; Rosenberg, 2006). Together with enhanced vascular permeability, peritoneal accumulation of malignant transudate is often observed in EOC even at early stages (I-III) of the disease (Burleson et al, 2006; Adam and Adam, 2004; Byrne et al, 2003; Hudson et al, 2008; Howlader et al, 2011). Effective ascites reduction with immunotherapeutic agents (Burges et al, 2007; Heiss et al, 2005), transforming growth factor-β (TGFβ) blockers (Liao et al, 2011), matrix metalloproteinase (MMP) inhibitors (Parsons et al, 1997) and vascular endothelial growth factor (VEGF) antagonists (Byrne et al, 2003; Hamilton et al, 2008) in preclinical and clinical studies are observed
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