Ascites-induced compression alters the peritoneal microenvironment and promotes metastatic success in ovarian cancer

Marwa Asem,Matthew J Ravosa,Vijayalaxmi Gupta,Allison Young,Dineo Khabele,Yueying Liu,Carlysa Oyama,M Sharon Stack,Alejandro ClaureDeLaZerda,Andrea Jewell

doi:10.1038/s41598-020-68639-2

Abstract

The majority of women with recurrent ovarian cancer (OvCa) develop malignant ascites with volumes that can reach > 2 L. The resulting elevation in intraperitoneal pressure (IPP), from normal values of 5 mmHg to as high as 22 mmHg, causes striking changes in the loading environment in the peritoneal cavity. The effect of ascites-induced changes in IPP on OvCa progression is largely unknown. Herein we model the functional consequences of ascites-induced compression on ovarian tumor cells and components of the peritoneal microenvironment using a panel of in vitro, ex vivo and in vivo assays. Results show that OvCa cell adhesion to the peritoneum was increased under compression. Moreover, compressive loads stimulated remodeling of peritoneal mesothelial cell surface ultrastructure via induction of tunneling nanotubes (TNT). TNT-mediated interaction between peritoneal mesothelial cells and OvCa cells was enhanced under compression and was accompanied by transport of mitochondria from mesothelial cells to OvCa cells. Additionally, peritoneal collagen fibers adopted a more linear anisotropic alignment under compression, a collagen signature commonly correlated with enhanced invasion in solid tumors. Collectively, these findings elucidate a new role for ascites-induced compression in promoting metastatic OvCa progression.

Highlights

The majority of women with recurrent ovarian cancer (OvCa) develop malignant ascites with volumes that can reach > 2 L
Using a suite of in vitro, ex vivo and in vivo assays, we report that ascites induced-compression enhances OvCa adhesion to peritoneum, alters the peritoneal mesothelial surface ultrastructure and sub-mesothelial collagen alignment and induces tunneling nanotube (TNT) formation between OvCa cells and mesothelial cells (MC) that enable mitochondria transport to OvCa cells
To investigate whether ascites-induced intraperitoneal pressure (IPP) influences early events in adhesion of OvCa cells to peritoneum, an in vivo artificial ascites assay was developed in which C57Bl/6 female mice were injected i.p. with red fluorescent protein (RFP)-tagged OVCAR5 or OVCAR8 cells in a large volume (5 mL) of PBS to mimic the ascites condition, relative to control mice that received tumor cells in a small volume (1 mL) of PBS (Fig. 1a)[20]

Summary

Introduction

The majority of women with recurrent ovarian cancer (OvCa) develop malignant ascites with volumes that can reach > 2 L. The resulting elevation in intraperitoneal pressure (IPP), from normal values of 5 mmHg to as high as 22 mmHg, causes striking changes in the loading environment in the peritoneal cavity. Peritoneal collagen fibers adopted a more linear anisotropic alignment under compression, a collagen signature commonly correlated with enhanced invasion in solid tumors These findings elucidate a new role for ascites-induced compression in promoting metastatic OvCa progression. Ascites accumulation results from increased vascular permeability accompanied by obstruction of the peritoneal lymphatics by disseminating cancer cells. In addition to facilitating dissemination of OvCa cells in the peritoneal cavity, malignant ascites provides a nurturing environment for cancer growth, due to the presence of growth factors and bioactive lipids that enhance tumor cell proliferation[2,5,9]. Increased IPP, generated via CO2 pneumoperitoneum, is correlated with enhanced abdominal metastasis in a murine OvCa model[14], suggesting that altered IPP can influence OvCa metastatic success

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