Role of malignant ascites on human mesothelial cells and their gene expression profiles

Abstract

BackgroundMalignant ascites is often present at diagnostic in women with advanced ovarian cancer (OC) and its presence is associated with a worse outcome. Human peritoneal mesothelial cells (HPMCs) are key components of malignant ascites. Although the interplay between HPMCs and OC cells is believed to be critical for tumor progression, it has not been well characterized. The purpose of this study was to assess the effect of ascites on HPMCs and clarify the role of HPMCs in OC progression.MethodsHuman OC ascites and benign peritoneal fluids were assessed for their ability to stimulate HPMC proliferation. Conditioned medium from ascites- and benign fluid-stimulated HPMCs were compared for their ability to attenuate apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL). We conducted a comparative analysis of global expression changes in ascites-stimulated HPMCs using Agilent oligonucleotide microarrays.ResultsAs compared to benign peritoneal fluids, malignant ascites stimulated the proliferation of HPMCs. TRAIL-induced apoptosis was attenuated in OC cells exposed to conditioned medium from ascites-stimulated HPMCs as compared to OC cells exposed to conditioned medium from benign fluid-stimulated HPMCs. A total of 649 genes were differentially expressed in ascites-stimulated HPMCs. Based on a ratio of more than 1.5-fold and a P < 0.05, 484 genes were up-regulated and 165 genes were down-regulated in ascites-exposed HPMCs. Stimulation of HPMCs with OC ascites resulted in differential expression of genes mainly associated with the regulation of cell growth and proliferation, cell death, cell cycle and cell assembly and organization, compared to benign peritoneal fluids. Top networks up-regulated by OC ascites included Akt and NF-κB survival pathways whereas vascular endothelial growth factor (VEGF) pathway was down-regulated.ConclusionsThe results of this study not only provide evidence supporting the importance of the interplay between cancer cells and HPMCs but also define the role that the tumor environment plays in these interactions.

Ascites in Ovarian Cancer Progression: Opportunities for Biomarker Discovery and New Avenues for Targeted Therapies

“…By analogy, stromal cells found in malignant ascites could play a similar role in ovarian cancer progression. Indeed, recent studies suggest that stromal cells in ascites facilitate tumor growth, survival and invasion [17][18][19].…”

“…In EOC ascites, myoibroblastic-like cells are present in aberrantly high numbers and are diferent from normal mesothelial cells. Once these cells accumulate in ascites they can be "educated" by growth factors and cytokines in the surrounding environment to support tumor growth [19]. Upon stimulation by ascites, myoibroblastic-like cells have been shown to produce dipeptidyl peptidase IV [35], which is a multifunctional protein that have been associate with tumor growth in some context [36].…”

“…Upon stimulation by ascites, myoibroblastic-like cells have been shown to produce dipeptidyl peptidase IV [35], which is a multifunctional protein that have been associate with tumor growth in some context [36]. Exposure of myoibroblastic-like cells to ascites increased the secretion of VEGF and other pro-survival soluble factors [19,37]. Furthermore, data from our laboratory suggest that ascites stimulates the expression and release of MUC16 from the mesothelial cell membranes [38].…”

Quantum dot-based multiplexed imaging in&nbsp;malignant ascites: a new model for malignant ascites classification

“…Although cytology has long been used to detect malignant cells, it has rarely been used in studying the tumor cell microenvironment, except for studying mesothelial cells. 27,28 In the study by Matte et al 28 mesothelial cells and cancer cells had important interactions, and mesothelial cell proliferation was stimulated by cancer cells. However, this study did not directly observe the cancer cells and mesothelial cells in MA.…”

Ascitic Fluid in Ovarian Carcinoma – From Pathophysiology to the Treatment

“…Lysophosphatidic acid (LPA) produced by HPMC increases adhesion, migration, and invasion of ovarian cancer cells [74]. On the other hand, cancer-associated mesothelial cells have been proven to produce factors that stimulate chemoresistance in ovarian cancer cells [75]. In a response to exposure to malignant ascites, HPMC also produce dipeptidyl peptidase IV and VEGF [76,77].…”