Proteome–Metabolome Profiling of Ovarian Cancer Ascites Reveals Novel Components Involved in Intercellular Communication

Abstract

aOvarian cancer ascites is a native medium for cancer cells that allows investigation of their secretome in a natural environment. This medium is of interest as a promising source of potential biomarkers, and also as a medium for cell-cell communication. The aim of this study was to elucidate specific features of the malignant ascites metabolome and proteome. In order to omit components of the systemic response to ascites formation, we compared malignant ascites with cirrhosis ascites. Metabolome analysis revealed 41 components that differed significantly between malignant and cirrhosis ascites. Most of the identified cancer-specific metabolites are known to be important signaling molecules. Proteomic analysis identified 2096 and 1855 proteins in the ovarian cancer and cirrhosis ascites, respectively; 424 proteins were specific for the malignant ascites. Functional analysis of the proteome demonstrated that the major differences between cirrhosis and malignant ascites were observed for the cluster of spliceosomal proteins. Additionally, we demonstrate that several splicing RNAs were exclusively detected in malignant ascites, where they probably existed within protein complexes. This result was confirmed in vitro using an ovarian cancer cell line. Identification of spliceosomal proteins and RNAs in an extracellular medium is of particular interest; the finding suggests that they might play a role in the communication between cancer cells. In addition, malignant ascites contains a high number of exosomes that are known to play an important role in signal transduction. Thus our study reveals the specific features of malignant ascites that are associated with its function as a medium of intercellular communication. Molecular & Cellular

Comparative Proteomics of Ovarian Cancer Aggregate Formation Reveals an Increased Expression of Calcium-activated Chloride Channel Regulator 1 (CLCA1)

“…As such, a couple of our top candidates were also discovered in previous proteomic analyses of ovarian cancer ascites fluid (26 -29), including FN1 and SERPIND1. Although, CLCA1 was not found in these fluids, several chloride channelrelated proteins, such as chloride intracellular channel protein (CLIC) 1, CLIC4, and CLIC5, were detected (27)(28)(29). These observations suggest that these proteins may have important roles in cancer progression.…”

Hypoxia-induced exosomes contribute to a more aggressive and chemoresistant ovarian cancer phenotype: a novel mechanism linking STAT3/Rab proteins

“…Given the hypoxic microenvironment of ascites in ovarian cancer, exosomes released from tumor cells in ascites carry oncogenic proteins that can alter the signaling pathways in the surrounding recipient tumor cells or normal cells, favoring tumor progression and metastasis 24, 30, 31, 32 . We have shown that activated STAT3, FAS, and other oncogenic proteins were detected in HEx and patient-derived ascites.…”

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

“…FAK phosphorylates β-catenin, which destabilizes the cell-cell junctions, resulting in increased vascular permeability [64]. Metabolome proiling of ascites has revealed signiicant diferences in faty acids, cholesterol, ceramide, glycerol-3-phosphate, glucose and glucose-3-phosphate compared to non-cancerous peritoneal efusions [65]. Whether these changes directly contribute to oncogenic signaling or they merely relect upregulation of pathways of the faty acid synthesis associated with increased metabolic activity in tumor cells remains to be determined.…”