Cancer Letters

Cancer Letters

Volume 367, Issue 1, 10 October 2015, Pages 26-33
Cancer Letters

Mini-review
Exosomes: Emerging biomarkers and targets for ovarian cancer

https://doi.org/10.1016/j.canlet.2015.07.014Get rights and content

Highlights

  • The tumor microenvironment is the key determining factor to cancer development.

  • Exosomes are present in ovarian cancer and closely related with tumorigenesis, metastasis, and prognosis.

  • This review discusses the multifaceted and centric role of exosomes in ovarian cancer microenvironment.

  • This review discusses the application of exosomes as a biomarker for diagnosis and a target for treatment.

Abstract

The limitations of current chemotherapies have motivated research in developing new treatments. Growing evidence shows that interaction between tumors and their microenvironment, but not tumor cells per se, is the key factor in tumor progression and therefore of obvious scientific interest and therapeutic value. Exosomes are small (30–100 nm) extracellular vesicles which have emerged as key mediators of intercellular communication between tumor cells and major cell types in the tumor microenvironment such as fibroblasts, endothelial cells, and immune cells as well as noncellular extracellular matrices through paracrine mechanisms. This review is to highlight the emerging role of exosomes in particular types of cancer, such as ovarian cancer, owing to its unique route of metastasis, which is capable of rapidly translating exosome research for clinical applications in diagnosis, prognosis, and potential treatment.

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.

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