Mini-reviewExosomes: Emerging biomarkers and targets for ovarian cancer
Introduction
Exosomes were first identified in 1983 from sheep reticulocytes. They were merely called ‘externalized vesicles’ [1], whereas the term ‘exosomes’ was later proposed by Johnstone et al. in 1987 [2]. Nowadays, exosomes specifically refer to those disk-shaped membranous vesicles with a diameter of 30–100 nm. Exosomes can be isolated from cultured supernatants of cell lines and various types of body fluids including urine, blood and ascites. In vitro studies suggest that exosomes are important mediators of intercellular communication. However, the exact biological function of exosomes is still anticipated.
The biogenesis of exosomes begins with an inward invagination of the plasma membrane, resulting in the incorporation of membrane proteins in the early endosomes. The limiting membrane of the endosomes further invaginates, and cytosolic proteins and RNAs are selectively targeted and enclosed within the internal vesicles to form multivesicular bodies (MVBs) within the cytoplasm. These MVBs then fuse with the plasma membrane and release the exosomes to the outside space [3]. The exact mechanism of how exosomes interact with target cells is still under debate. Based on in vitro studies, three models are proposed, (1) direct fusion, (2) endocytosis and (3) binding through exosomal surface protein [4], [5], [6], [7], [8] (Fig. 1).
Although exosomes are secreted by most cell types, there are also data that suggest enhanced exosome release under pathological conditions, such as cancer. It is reasonable to speculate that these vesicles may play an important role in tumorigenesis since (1) they can mediate distant intercellular communication, (2) tumor-derived exosomes usually carry tumor antigens, and (3) functional proteins and/or RNAs can be transferred to recipient cells via exosomes.
More recently, exosomes have been identified in malignant ascites in patients of ovarian cancer, a highly aggressive tumor that is the leading cause of death of all gynecologic cancers worldwide [9], [10], [11]. Unlike most solid tumors, ovarian cancer rarely disseminates through the vasculature but has a high propensity to metastasize within the peritoneum. The formation of malignant ascites is a hallmark of advanced/metastatic ovarian cancer [12]. This unique metastatic mechanism also poses distinct therapeutic challenges, in which current treatments are not effective (5-year survival <25%). Therefore, a better understanding of the ascitic microenvironment is critically essential to our knowledge of ovarian cancer biology and may have important clinical applications.
Exosomes are an active area in cancer research; it will not be surprising to realize how fast information could accumulate. This review summarizes the key characteristics of exosomes and provides new information on their implications in cancer development and progression with a particular focus on ovarian cancer. We will also discuss the role of exosomes as predictive biomarkers and potential therapeutic targets in ovarian cancer with the supporting preclinical and clinical data.
Section snippets
Exosomal cargo and its potential significance
Over the past decade, a growing body of research clearly indicates the importance of exosomes. However, the problem of inconsistent nomenclature and lack of standard methods to obtain highly pure exosomes remains. The nomenclature could be based on site and tissue type, such as dexosomes (from dendritic cells) [13], [14] and oncosomes (from cancer cells) [15], [16]. Exosomes are sometimes muddled up with microvesicles, in which both are common extracellular vesicles (EVs). While exosomes are
Roles in ovarian tumor development and progression
Exosomes appear to be a new and powerful signal mediator between cancer cells and their microenvironment [31]. Major cell types in the tumor microenvironment include stromal cells, endothelial cells, and infiltrating immune cells, all of which communicate with cancer cells. The major non-cellular component of the tumor microenvironment is the extracellular matrix. A wide range of biological functions includes, but is not limited to, angiogenesis, metastasis, chemoresistance, and immune
Exosomes as predictive biomarkers in ovarian cancer
While serum CA125 is a widely used marker for ovarian cancer, not all ovarian cancer patients have increased CA125 levels [46]. Moreover, it may also be elevated in other cancers, such as breast, colon, and endometrial, and benign conditions, including uterine fibroids, endometriosis, and pelvic inflammatory disease, as well as in as many as 1% of healthy women. In a recent randomized study of around 70,000 asymptomatic women, CA125 screening together with transvaginal ultrasound did not seem
Exosomes as potential therapeutic targets in ovarian cancer
Current clinical applications of exosome research can be categorized into three directions, (1) exosome as a therapeutic target, (2) exosome-based immunotherapy, and (3) exosome-mediated delivery. Based on the US National Institute of Health's clinical trials database (clinicaltrials.gov), there are several ongoing exosome-based trials that are anticipated to add important pieces of information in the near future.
Conclusion and future perspective
Intensive research and many breakthrough discoveries in the past three decades have been made on exosomes. However, we are far from a complete understanding of the biology of these vesicles and many questions remain to be addressed. The limitation to isolate large quantities of pure exosomes could impact our overall study of exosomes, so it will be necessary in future studies to develop a rapid and efficient method. Devices which enable cost-effective, larger-scale purification, and efficient
Conflict of interest
There is no conflict of interest.
Acknowledgements
Our work is supported by the Hong Kong Research Grant Council General Research Fund (HKU781013M), Collaborative Research Fund (CUHK8/CRF/11R), and Theme-based Research Fund (T12-401/13-R). A.S.T.W. is Croucher Senior Research Fellow.
References (69)
- et al.
Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor
Cell
(1983) - et al.
Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes)
J. Biol. Chem
(1987) - et al.
Microenvironmental pH is a key factor for exosome traffic in tumor cells
J. Biol. Chem
(2009) - et al.
Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells
Blood
(2004) - et al.
Exosome uptake depends on ERK1/2-heat shock protein 27 signaling and lipid Raft-mediated endocytosis negatively regulated by caveolin-1
J. Biol. Chem
(2013) - et al.
Body fluid exosomes promote secretion of inflammatory cytokines in monocytic cells via Toll-like receptor signaling
J. Biol. Chem
(2013) Dexosomes as a therapeutic cancer vaccine: from bench to bedside
Blood Cells Mol. Dis
(2005)- et al.
Two distinct populations of exosomes are released from LIM1863 colon carcinoma cell-derived organoids
Mol. Cell. Proteomics
(2013) - et al.
Malignant ascites-derived exosomes of ovarian carcinoma patients contain CD24 and EpCAM
Gynecol. Oncol
(2007) - et al.
Characterization and proteomic analysis of ovarian cancer-derived exosomes
J. Proteomics
(2013)