ARTICLE IN PRESS Cancer Letters ■■ (2015) ■■–■■
Contents lists available at ScienceDirect
Cancer Letters j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c a n l e t
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Mini-review
Exosomes: Emerging biomarkers and targets for ovarian cancer Q2 Maggie K.S. Tang, Alice S.T. Wong * Q3 School of Biological Sciences, University of Hong Kong, Pokfulam Road, Hong Kong
A R T I C L E
I N F O
Article history: Received 14 May 2015 Received in revised form 13 July 2015 Accepted 13 July 2015 Keywords: Exosomes Ovarian cancer Protein RNA
A B S T R A C T
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 and communicators between cancer cells and other major cell types in the tumor microenvironment such as stromal fibroblasts, endothelial cells, and infiltrating 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. © 2015 Published by Elsevier Ireland Ltd.
31 Introduction
32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59
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 budding 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 extracellular 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 [4–8] (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
60 61 62 63
Q1
* Corresponding author. E-mail address: [email protected] (A.S.T. Wong).
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 [9–11]. 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
Contents lists available at ScienceDirect
Cancer Letters j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c a n l e t
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Mini-review
Exosomes: Emerging biomarkers and targets for ovarian cancer Q2 Maggie K.S. Tang, Alice S.T. Wong * Q3 School of Biological Sciences, University of Hong Kong, Pokfulam Road, Hong Kong
A R T I C L E
I N F O
Article history: Received 14 May 2015 Received in revised form 13 July 2015 Accepted 13 July 2015 Keywords: Exosomes Ovarian cancer Protein RNA
A B S T R A C T
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 and communicators between cancer cells and other major cell types in the tumor microenvironment such as stromal fibroblasts, endothelial cells, and infiltrating 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. © 2015 Published by Elsevier Ireland Ltd.
31 Introduction
32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59
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 budding 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 extracellular 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 [4–8] (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
60 61 62 63
Q1
* Corresponding author. E-mail address: [email protected] (A.S.T. Wong).
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 [9–11]. 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
