Comparative Analysis of Tumor-Associated microRNAs and Tetraspanines from Exosomes of Plasma and Ascitic Fluids of Ovarian Cancer Patients

Abstract

Ovarian cancer (OC) is one of the most common and fatal types of gynecological cancer. In the early phase of OC detection, the current treatment and diagnostic methods are not efficient and sensitive enough. Therefore, it is crucial to explore the mechanisms of OC metastasis and discover valuable factors for early diagnosis of female cancers and novel therapeutic strategies for metastasis. Exosomes are known to be involved in the development, migration, and invasion of cancer cells, and their cargo could be useful for the non-invasive biopsy development. CD151- and Tspan8-positive exosomes are known to support the degradation of the extracellular matrix, and are involved in stroma remodeling, angiogenesis and cell motility, as well as the association of miR-24 and miR-101 with these processes. The objective of this study was to explore the relationship of these components of exosomal cargo, in patients with OC, to clarify the clinical significance of these markers in liquid biopsies. The levels of tetraspanins Tspan8+ and CD151+ exosomes were significantly higher in plasma exosomes of OC patients compared with healthy females (HFs). The relative levels of miR-24 and miR-101 in plasma exosomes of HFs were significantly higher than in plasma exosomes of OC patients, while the levels of these microRNAs in exosomes from plasma and ascites of ill females showed no difference. Our study revealed a strong direct correlation between the change in the ascites exosomes CD151+Tspan8+ subpopulation level and the expression levels of the ascites (R = 0.81, p < 0.05) and plasma exosomal miR-24 (R = 0.74, p < 0.05) in OC patients, which confirms the assumption that exosomal cargo act synergistically to increase cellular motility, affecting cellular processes and signaling. Bioinformatics analysis confirmed the involvement of CD151 and Tspan8 tetraspanins and genes controlled by miR-24-3p and miR-101 in signaling pathways, which are crucial for carcinogenesis, demonstrating that these tetraspanins and microRNAs are potential biomarkers for OC screening, and predictors of poor clinicopathological behavior in tumors.

The Composition of Small Extracellular Vesicles (sEVs) in the Blood Plasma of Colorectal Cancer Patients Reflects the Presence of Metabolic Syndrome and Correlates with Angiogenesis and the Effectiveness of Thermoradiation Therapy

“…In accordance with our previously published results on the analysis of subpopulations of sEV surface proteins in norm and in various diseases, the expression of CD9 was significantly higher than that of other markers [22,23]. Accordingly, the study of the CD9positive sEVs as the core population is most appropriate.…”

“…Transmission electron microscopy revealed clearly structured, low electron density cup-shaped particles with preserved membranes in a preparation of sEVs isolated from the blood plasma of CPPs and CRCPs (Figure 1A). It was found that their morphology did not differ from that of particles isolated from patients with other types of cancer [22,23]. Electron microscopy, negative staining with uranyl acetate; (B) size distribution of plasma sEVs isolated from the blood of CPPs and CRCPs.…”

Exosomal Cargo in Ovarian Cancer Dissemination

“…The targeted delivery of tumor-associated microRNA by exosomes to recipient cells enables not only additional stimulation of tumor growth but also reprogramming of tumor microenvironment and suppression of immune system cells (Figure 5, Table 2). The concentration of exosomes in plasma and ascites is much higher than in tumor cells (~10 8 versus 10) and is shown to be sufficient for the confident detection of several microRNAs in 1 mL of biological fluid [54,101]. Moreover, the revealed correlation of the exosomal microRNA levels in plasma and ascitic fluid inspires justified optimism that blood plasma is no less significant source of tumor markers than ascitic fluid [54].…”

“…It has also been shown that up to 40% of the unique proteins of ascitic fluid are part of exosomes [52]. According to various published sources, ascitic fluid exosomes contain proteins such as CD24, EpCAM, CD171, MMP-2, MMP-9, uPA, MT1-MMP, ADAM10, ADAM7, ADAM17, CD151, TSPAN8 [26,53,54], as well as several other proteins and metabolites that mediate EMT, premetastatic niche formation, and peritoneal dissemination [55,56]. The overexpression of EpCAM, CD24, ADAM-10, ADAM17, CD82, CD151, and TSPAN8 in the exosomes of serum and plasma of OC patients compared to healthy women has also been shown to correlate with the stage and of the disease [26,54,57,58].…”

“…Given that these proteins are primarily found in tumor-derived exosomes and have a strong influence on the progression of OC, they can be considered promising targets for the treatment of OC as well as possible prognostic markers of the disease [26,54,57,58]. In addition, the proteins ZBED2, ZBTB20, ABCC3, and UHMK1, which are involved in cell cycle regulation and drug transport, were found in exosomes derived from ascitic fluid [59].…”