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Seminars in Cancer Biology xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

Seminars in Cancer Biology

journal homepage: www.elsevier.com/locate/semcancer

Review

The role of exosomes in cancer metastasis

Teresa Bernadette Steinbichler a , József Dudás a , Herbert Riechelmann a ,
Ira-Ida Skvortsova b,∗
a
Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Innsbruck, Innsbruck, Austria
b
Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Innsbruck, Austria

a r t i c l e i n f o a b s t r a c t

Article history: Exosomes are small membrane vesicles with a size ranging from 40 to 100 nm. They can serve as functional
Received 20 December 2016 mediators in cell interaction leading to cancer metastasis. Metastasis is a complex multistep process of
Accepted 9 February 2017 cancer cell invasion, survival in blood vessels, attachment to and colonization of the host organ. Exosomes
Available online xxx
influence every step of this cascade and can be targeted by oncological treatment. This review highlights
the role of exosomes in the various steps of the metastatic cascade and how exosome dependent pathways
Keywords:
can be targeted as therapeutic approach or used for liquid biopsies.
Tumor derived exosomes
© 2017 Elsevier Ltd. All rights reserved.
Premetastatic niche
Organotropic metastasis
EMT
Cancer-associated fibroblasts

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Biogenesis and morphology of exosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2. Biogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3. Exosomal content . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.4. Biological functions and effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.5. Isolation methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Initiation of metastasis in the host organ: exosomes as mediators in EMT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1. EMT and migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2. EMT and invasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.3. Exosomes and CAFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Engraftment of metastatic cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1. Exosomes and MErT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2. Exosomes and neoangiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3. Exosomes in organotropic metastatic growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.4. TDEs and organotropism in malignant melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.5. TDEs and organotropism in pancreatic cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Immune-modulating effects of exosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1. Maintenance of metastatic cells in the blood circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.2. Maintenance of metastatic cells in the host organ: TDEs and cellular immune response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.3. Maintenance of metastatic cells in the host organ:TDEs and humoral immune response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

∗ Corresponding author at: Laboratory for Experimental and Translational Research on Radiation Oncology (EXTRO-Lab), Department of Therapeutic Radiology and Oncology,
Medical University of Innsbruck, Anichstr. 35, A-602, Innsbruck, Austria.
E-mail addresses: Ira.Skvortsova@i-med.ac.at, Ira.Skvortsova@Tirol-kliniken.at (I.-I. Skvortsova).

http://dx.doi.org/10.1016/j.semcancer.2017.02.006
1044-579X/© 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: T.B. Steinbichler, et al., The role of exosomes in cancer metastasis, Semin Cancer Biol (2017),
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5.4. TDEs and cancer-promoting proinflammatory effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

6. Exosomes as a source for biomarkers predicting metastatic spread . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1. Exosomal protein markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.2. Exosomal miRNA as biomarker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7. Therapeutic approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.1. Exosomes as cancer vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.2. M-Trap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.3. Exosomes as chemotherapeutic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction receptor-ligand interaction or by direct fusion and dependent on

microenvironmental pH [14,15] (Fig. 2).
Most studies of the pathogenesis of metastasis focus on genetic
or phenotypic changes of the cancer cell itself, however, there is
growing evidence that cancer cells communicate with each other
and the surrounding stroma leading to metastasis [1]. 2.3. Exosomal content
Metastasis is a multistep process including invasion of the tumor
cell through the basal membrane and into blood vessels, survival Exosomes contain cytosolic proteins or proteins of the
in the blood circulation, attachment to the blood vessels, extrava- plasma/endosome membrane while proteins of the nucleus, mito-
sation and at last colonization and growth in the host organ [2]. chondria, endoplasmatic reticulum or golgi-appartus are absent
Cells can communicate with various types of extracellular mem- [16]. The sorting of proteins into exosomes is an area of current
brane vesicles. These include exosomes, proteasomes, apoptotic research and is at least in part dependent on protein ubiquitylation
blebs and microvesicles [3]. Since exosomes can promote a vari- and the ESCRT (endosomal sorting complex required for transport
ety of intratumoral biological processes, it seems likely that they machinery) [3,17,18] (Fig. 1). The ESCRT form small necks that occur
can also influence metastatic properties of malignant tumors. The at the plasma membrane during exosome formation. They contain
following review focuses on the role of exosomes in this multistep filaments, flat spirals, tubes and conical funnels that are thought to
metastatic process. direct membrane remodeling. Their assembly and disassembly is
ATP-dependent [19].
Exosomes contain a high amount of transport proteins like
2. Biogenesis and morphology of exosomes
tubulin, actin and actin-binding molecules [16] as well as several
proteins associated with specific functions of secreting cells [8].
2.1. Morphology
Nearly all exosomes carry MHC class I- molecules [20] and heat
shock protein (HSP), especially HSP 70 and HSP 90 [8,16]. HSP
Trams and co-authors first described exosomes in 1981
70 and HSP 90 are involved in antigen presentation and can bind
as microvesicles containing 5‘-nucleotidase activity which are
antigenic peptides to MHC class I-molecules [8]. Exosomes carry
released by neoplastic cell lines [4]. A few years later their endo-
high concentrations of tetraspanins – including CD9, CD63, CD81
cytic origin was proven [5]. Exosomes can be identified by a few
and CD82–that are rarely present in other microvesicles and are
characteristics. They have a size between 40 and 100 nm and are
involved in antigen presentation and adhesion through interaction
secreted after fusion of multivesicular endosomes with the cell sur-
with other transmembrane proteins. CD9 and CD82 inhibit migra-
face or by direct budding from the plasma membrane [6]. They
tion and invasion of tumor cells in vitro and in vivo by interaction
are round or have a cup shaped morphology and have a density
with integrins [21]. To date more than 41 860 different proteins
between 1.13 and 1.19 g/ml [3]. Exosomes can be identified by their
have been reported as cargo of exosomes and are listed in online
unique protein and lipid composition and double lipid layer due to
databases like Exocarta (http://www.exocarta.org) and Visclepedia
their origin in the fusion of late endocytic compartments with the
(http://www.microvesicles.org).
plasma membrane [7].
In addition to proteins, exosomes contain lipids, particularly
raft-lipids like ceramides, sphingolipids, cholesterol and glyc-
2.2. Biogenesis erophospholipids as well as micro-RNA, mRNA and DNA enabling
cells to exchange genetic information [22].
Exosomes ori ginate in a reverse budding event, causing the Mi-RNAs are small non-coding RNAs that bind within the 3 -UTR
vesicles to carry cytosol and expose the extracellular domain of 
(3 -untranslated region) of mRNAs leading to destabilisation and
surface receptors [8]. They constitutively fuse with the plasma fragmentation of these RNAs and consequently to reduced expres-
membrane either after Ca++ -dependent activation or after acti- sion of the encoded protein [23,24]. That miRNA is the major RNA
vation of Rab-GTPases [9]. Rab25 regulates exosome binding to component of exosomes and was first discovered at the Univer-
and tethering with the plasma membrane and Rab27b exosome sity of Gotteburg by the scientific group around Prof. J. Lotvall in
release [10,11] (Fig. 1). The increased secretion of exosomes by can- 2007 [25,26]. This mode of transportation makes the miRNA resis-
cer cells is induced by overexpression of Rab3D (a small GTPase, tant of degradation through extracellular ribonculeases [27]. The
[12]. Release of exosomes can also be induced by diverse signalling miRNA transported in TDEs (tumor derived exosomes) reflects the
pathways including the activation of the Wnt pathway, which is dysregulated miRNA profile of the cancer cells and can be trans-
especially important in deregulated exosome secretion in cancer ported to different cell types or to the pre-metastatic niche enabling
cells [13]. The acidic microenvironment around tumors stimulates wide spread influence on the gene expression of target cells [28].
the release of exosomes and enhances their cell fusion capabili- Despite solely transporting miRNA, exosomes are able to process
ties [14]. The uptake of exosomes is accomplished via endocytosis, pre-miRNAs to mature-miRNAs, allowing direct interaction with

Please cite this article in press as: T.B. Steinbichler, et al., The role of exosomes in cancer metastasis, Semin Cancer Biol (2017),
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Fig. 1. Exosomes originate in a reverse budding event, causing the vesicles to carry cytosol and expose the extracellular domain of surface receptors [8]. They form by invagi-
nation and budding from the plasma membrane, meaning that they are of endocytic origin. Intracellular exosomes are present in multivesicular bodies. The sorting of proteins
into exosomes is dependent on protein ubiquitylation and the ESCRT (endosomal sorting complex required for transport machinery) [3,17,18]. Exosomes constitutively fuse
with the plasma membrane either after Ca++ -dependent activation or after activation of Rab-GTPases [9]. Rab25 regulates exosome binding to and tethering with the plasma
membrane and Rab27b exosome release [10,11].

Fig. 2. Release of exosomes by donor cells can be induced by diverse signalling pathways and occurs in a reversed budding event as displayed in Fig. 1 [13]. The uptake of
exosomes is accomplished via endocytosis, receptor-ligand interaction or by direct fusion and dependent on microenvironmental pH [14,15].

the transcriptome of the recipient cell without the need of further
processing these miRNAs [29].
The second major RNA content of exosomes are lnRNAs (long
non-coding RNAs, >200 bp) that interfere with gene expression in
various ways such as direct annealing with genomic DNA or by
modifying histone complexes [30] (Fig. 3) (Table 1).
2.4. Biological functions and effects
Exosomes promote intercellular communication and are
involved in various physiological as well as pathological processes,
such as antigen presentation, immune regulation, tissue develop-
ment and remodelling and cell-to-cell spread of infectious agents
like the HI-virus. The release of exosomes discards membrane pro-
teins that have become useless as an alternative to the classical
lysosomal degradation [31].
In cancer development exosomes are further described as
functional mediators of tumor-stroma interaction [32]. This inter-
cellular communication is known to be involved in various
pathophysiological processes including migration, treatment resis-
tance and metastasis [33].
Exosomes enable intercellular communication without direct
cell-cell contact. They may confer epigenetic changes in the recip-
ient cells by transportation of microRNAs.

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Fig. 3. Exosomal content: Exosomes contain cytosolic proteins or proteins of the plasma/endosome membrane while proteins of the nucleus, mitochondria, endoplasmatic
reticulum or golgi-appartus are absent [16]. Furthermore they contain RNA, especially mi-RNA, DNA and lipids.

Table 1 Before performing functional assays or downstream proteomic

Exosomal content.
or genomic approaches, purity of isolated exosomes should be
cytoskeletal proteins e.g. actin, tubulin assessed [35]. This can be done by using different biomarkers,
signal transduction molecules e.g. G-proteins which distinguish between exosomes and other extracellular vesi-
chaperones e.g. HSP70, HSP 90 cles [39]. Another criticism is that studies with purified exosome
membrane transport/fusion e.g. Rab 25, Rab 27b, annexins isolation may not be physiological relevant due to the higher dilu-
antigen presentation e.g. MHC-I, MHC-II tion of exosomes in body fluids. Most exosome studies are either
adhesion molecules e.g. tetraspanins (CD9, CD63,
in vitro analyses or mouse models, while clinical studies are rare
CD81, CD82), integrins
ESCRT components [37].
other cytosolic proteins e.g. histones, ribosomal
proteins, proteasomes
other transmembrane proteins e.g. LAMPs
lipids e.g. sphingomyeline, ceramid,
3. Initiation of metastasis in the host organ: exosomes as
glycerophospholipids,
cholesterol mediators in EMT
nucleic acids mi-RNA, lnRNA, DNA
The invasion metastasis cascade describes the functional pro-
cess of building macrometastases in distant organs. Tumor cells
2.5. Isolation methods loose their adhesion to the stroma and migrate into the blood
stream. After reaching their pre-metastatic niche they either enter a
Differential ultracentrifugation is the current reference method dormant state as DTCs (dormant tumor cells) or proliferate to form
for exosome isolation. It consists of multiple centrifugation steps multicellular micrometastases, from which finally macrometas-
with increasing centrifugal strength to sequentially pellet cells tases arise. Metastasis is an inefficient process; only 0.01% of the
(300g), microvesicles (10,000g) and exosomes (100,000g) [34,35]. tumor cells that reach the blood stream are able to proliferate in
It is fast and simple but the exosome pellet contains large amounts distant organs.
of contaminating soluble proteins and non-exosomal particles EMT (epithelial to mesenchymale transition) frequently initi-
[36,37]. ExoQuick precipitation is also based on centrifugation, ates the metastatic process. EMT means that epithelial tumor cells
but before ultracentrifugation exosomes are chemically precipi- acquire mesenchymal characteristics under the influence of CAFs
tated with ExoPrep Solution (Hansa Bio Med, Tallinn, Estonia). This (cancer-associated fibroblasts) in the tumor stroma. Under EMT,
results in similar advantages and disadvantages [34]. ExoQuick is tumor cells loose their polarity and cell-cell junctions and turn to a
a proprietary polymer that precipitates exosomes. Currently, the low proliferation state with increased migratory and invasion capa-
purest exosome preparation can be obtained by density-gradient bilities [40]. Molecular markers of EMT are a loss of E-cadherin as
isolation methods using sucrose or iodixanol (OptiPrepTM , Sigma- epithelial marker and an increased expression of vimentin as mes-
Aldrich). Iodixanol is capable of forming iso-osmotic solutions at enchymal marker as well as a spindle-like cell shape [1,41]. These
all densities, thus better preserving the size of the vesicles in the morphological changes are strongly associated with activation of
gradient. These procedures are more time consuming and costly the Snail (zinc finger proteins Snail and Slug), Zeb (zinc finger and
[35,38]. Another purification method is microfluidic immunoiso- homeodomain proteins Zeb 1 and 2) and Twist (basic helix-loop-
lation, where serum flows through microchambers, which contain helix proteins E12, E47, Twist1, Twist 2 and Id) pathways [40]. Once
antibodies against exosomal markers like EpCAM or CD63. A key the tumor cells have reached the distant pre-metastatic niche the
limitation is that this method focuses only on the exosomes that reversed process takes place. This so-called MErT (mesenchymal to
express the target surface marker and will therefore fail to identify epithelial reverting transition) returns tumor cells to a high prolif-
other subpopulations of exosomes [35,37]. erative state and enables formation of macrometastases (Fig. 4).

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Fig. 4. EMT and MErT.
Epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial reverting transition (MErT) are two reversible events, which merge into one another. EMT is
characterised by an increased expression of mesenchymale markers like vimentin and a decreased expression of epithelial markers like E-cadherin and ␤-catenin. MErT is
characterised by an increased expression of these epithelial markers and a constant expression of the mesenchymal marker vimentin.
3.1. EMT and migration
Recent investigations suggest a major role of exosomes in EMT.
Exosomes from EBV infected nasopharyngeal carcinoma cells con-
tain high levels of LMP1 and HIF1␣ (hypoxia-inducible factor 1␣).
HIF1␣ interacts with the Snail pathway and increases Twist expres-
sion inducing EMT in nasopharyngeal carcinoma cells [42]. This
results in a more invasive phenotype in recipient cells. The increase
in HIF1␣ in nasopharyngeal carcinoma depends on the expression
of LMP1 (latent membrane protein1), an important oncogene of
EBV (Epstein-Barr-virus). LMP1 decreases the lysosomal degrada-
tion of HIF1␣ by stabilizing seven in absentia homolog and causing
activation of EMT pathways [43,44].
Treatment of urothelial cells with exosomes isolated from
muscle-invasive bladder cancer cells resulted in an EMT like
phenotype and increased migratory and invasive features. These
exosomes induced the expression of vimentin, Snail and Twist in
urothelial cell lines while decreasing E-cadherin and ␤-catenin
expression via the TGF- ␤1 pathway. In contrast, exosomes from
embryonic kidney cells failed to induce these EMT-like pheno-
typic changes, suggesting that not exosomes in general but tumor
derived exosomes (TDEs) in particular are able to induce EMT
and enhance migratory activity [45,46]. This pro-migratory, EMT-
inducing effect of TDEs was also observed in glioblastoma cell
lines, lung carcinoma cells and an in vivo model of gastric cancer
[47–49]. Exosomal miR-23a supports the EMT-promoting effect of
TGF-␤1 by inhibiting E-cadherin synthesis in lung carcinoma and
melanoma cells [50,51]. MiR-191 and let7a are two further miRNA
modulators of EMT found in exosomes of patients with malignant
melanoma, gastric cancer and colorectal cancer [52–54]. Further
mi-RNA transported in exosomes with pro- and anti-oncogenic
effects is displayed in Table 1 [55].
TDEs from tumor cells who have undergone EMT can in turn
stimulate neighbouring cells to acquire EMT like features, creating
a synergistic effect [56].
3.2. EMT and invasion
Apart from the pro-migratory effects of exosomes through
EMT-related pathways, TDEs directly influence invasion into blood
vessels by the secretion of miR-105. This process destroys tight
junctions via interaction with ZO-1 in breast cancer models
suspending a natural barrier against metastasis [28]. Exosomal
Please cite this article in press as: T.B. Steinbichler, et al., The role of exosomes in cancer metastasis, Semin Cancer Biol (2017),
http://dx.doi.org/10.1016/j.semcancer.2017.02.006
5
miR-105 in the serum of patients with breast cancer is a prognostic
marker for the later development of metastasis and serum miR-105
level correlates with the miR-105 level in the primary tumor [28].
Blocking of astrocyte-exosomes inhibits brain metastasis in vivo.
This effect is dependent on exosomal miRNA, which blocks PTEN in
brain-metastatic tumor cells [57].
Exosomal miR-21 level in the serum from patients with
esophageal cancer correlates with cancer recurrence and metas-
tasis [58] and was described as a marker of tumor recurrence in
lung cancer and malignant melanoma [59,60]. MiR-21 promotes
migration and invasion of recipient cells in esophageal and oral
squamous cell carcinoma [58,61].
3.3. Exosomes and CAFs
TDEs are not only able to force other cancer cells to acquire a
mesenchymal phenotype, but are also able to convert mesenchy-
mal stem cells into cancer-associated fibroblasts (CAFs) with an
increased expression of ␣-SMA (␣-smooth muscle actin) [62]. These
CAFs reciprocally cross talk with cancer cells and are characteris-
tically surrounded by a layer of hyaluronic acid, a condition which
normal fibroblasts lack. TDEs are able to induce such alterations
in the pericellular microenvironment [62]. CAFs in return stimu-
late EMT by secretion of TGF-␤1 (transforming growth factor ␤)
and consequently activate the TGF-␤1-SMAD (small mother against
decapentaplegic protein) signalling pathway. Interestingly, soluble
TGF-␤1 alone is not able to drive stroma differentiation to a cancer-
associated phenotype. Exosome-depleted cancer cells fail to gain a
stroma-mediated growth advantage in vivo and the TGF-␤1 effect
on stroma differentiation is abrogated by blocking of exosomes,
even if the TGF-␤1 levels in the tumor stroma remain constant [63].
These results suggest that the biophysical format of TGF-␤1 from
exosomes drives stroma-modifying effects [63].
CAFs themselves produce exosomes, which stimulate the Wnt-
pathway in breast cancer cells and enhance their migratory
capabilities [64].
CAFs produce tracks in the extracellular matrix with the help
of enzymes like matrix-metalloproteinases – e.g. MMP 13 – and
create tunnels through which the tumor cells can follow [65]. MMP-
13 expression is a prognostic marker for invasiveness and poor
clinical outcome in various cancer types such as head and neck can-
cer [66]. Exosomal MMPs stimulate tumor metastasis in sarcomas
[67] and exosomal CD81 functions in the context of CAF induced
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breast cancer cell mobility [68]. Exosomal CD151 supports matrix
degradation and mobility in an in vitro model of pancreatic adeno-
carcinoma [69]. It has been demonstrated that CAFs and tumor cells
jointly invade blood vessels and implant themselves in metastatic
sites [70].
4. Engraftment of metastatic cells
4.1. Exosomes and MErT
After metastatic cells have colonized in a secondary organ
they often display epithelial features, suggesting at least partial
mesenchymal-epithelial reverting transition (MErT). While mes-
enchymal markers like vimentin persist, they often express higher
amounts of E-cadherin than the primary tumor. MErT returns the
cancer cells to a highly proliferative but less migratory phenotype,
enabling the development of macrometastasis [71]. This is a con-
sequence of an increased membranous ␤-catenin expression in the
metastatic cells, which results in stable adherent junctions. Inter-
estingly, E-cadherin expression decreases with increasing size of
the metastasis, suggesting that MErT itself is reversible and the cells
can re-enter a mesenchymal phenotype after EMT [72]. In prostate
cancer patients these findings were confirmed in haematogenous
metastasis but not in metastatic cells in the surrounding lymph
nodes, where the tumor cells resemble the E-cadherin expression
of the primaries [73] (Fig. 4).
4.2. Exosomes and neoangiogenesis
After the metastasis reaches a critical size, neoangiogenesis
has to be stimulated to avoid cancer necrosis. Neoangiogenesis is
important for the nutrition and oxygen supply of the tumor and
acts as entry point for metastatic cells into systemic circulation
[74]. CAFs stimulate neoangiogenesis via secretion of exosomal
SDF-1 (stromal cell derived factor-1) [63,75]. The released SDF-1
is responsible for the recruitment of endothelial progenitor cells
by chemotaxis [76,77]. Similar results where found after treatment
of umbilical cord mesenchymal stem cells with gastric-cancer cells
derived exosomes or with exosomes from hepatic cancer cells [78].
TDEs stimulate endothelial progenitor cells to form tube-like struc-
tures [79]. Induction of neoangiogenesis is not only due to the
exosome’s transport of paracrine signalling factors but also due
to direct transport of relevant mRNA to the surrounding stroma,
influencing gene expression directly. In this process the transport
of EGFR (epidermal growth factor receptor)-mRNA [79] and mRNA
related with cell cycle progression of endothelial cells [80] is impor-
tant.
4.3. Exosomes in organotropic metastatic growth
Organotropic metastasis means that the side of metastasis is
not chosen randomly but is a rather a consequence of intricate
tumor-stroma interaction in the host organ [81]. This hypothesis
was first postulated in 1889 by Paget as “soil and seed hypothesis”,
which means that circulating tumor cells form metastasis only if
the seed (tumor cell) and host (organ) are compatible [82]. Fidler
et al. supported this hypothesis in 1973 and showed that metastatic
cancer cells derived from a particular tumor site display enhanced
metastatic ability to specific organs, independent of the anatomy
of blood and lymphatic vessels that drain the primary tumor site
[83]. A pre-metastatic niche formation is required for tumor cells
to engraft a distant organ. This pre-metastatic niche is formed with
the help of bone marrow derived cells (BMDCs, e.g. haematopoi-
etic cells), endothelial progenitor cells and mesenchymal cells [84].
Peinado et al. described that this pre-metastatic niche formation is
in part signalled through TDEs, which influence BMDCs in vivo and
Please cite this article in press as: T.B. Steinbichler, et al., The role of exosomes in cancer metastasis, Semin Cancer Biol (2017),
http://dx.doi.org/10.1016/j.semcancer.2017.02.006
in vitro in malignant melanoma [85]. TDEs promote education and
mobilization of BMDCs that support tumor vasculogenesis, inva-
sion and metastasis. TDEs recruit BMDCs through upregulation of
proinflammatory molecules and further enhance vascular leakiness
at the metastatic sites [85]. TDE miR-122 downregulates pyru-
vate kinase in non-malignant cells from the premetastatic niche by
impairing glucose utilization in non-malignant cells and increasing
the nutritional supply of the cancer cells [86,87] (Fig. 5).
These findings raise the question of how exosomes are directed
to the specific metastatic organs enabling organotropic metastatic
growth. Melanoma exosomes are home to sentinel lymph nodes
in vivo and recruit melanoma cells [88]. Exosomes from breast can-
cer cells move to lung tissue in orthotopic nude mouse models [89].
Hohsino et al. described in 2015 that TDEs are sufficient to redirect
metastatic tumor cells that normally lack the ability of organ spe-
cific metastasis, meaning that the host organ is prepared prior to
metastatic dissemination of the cancer cells [90]. Exosome biodis-
tribution matched the organotropic metastatic spread in vitro in cell
lines from various types of cancer such as breast and pancreatic can-
cer. The biodistribution of exosomes is at least in part mediated by
integrins. ITG␤4 (integrin beta 4) promotes lung tropism and ITG␤5
(integrin beta 5) promotes exosome adhesion in the liver. Accord-
ingly, increased ITG␤4 levels were expressed in exosomes from the
serum of patients with lung metastasis (regardless of the primary
tumor site) and increased ITG␤5 levels were found in the serum
of patients with liver metastasis (with pancreatic carcinoma) [90]
(Fig. 5).
4.4. TDEs and organotropism in malignant melanoma
Exosome protein concentrations in the plasma of patients with
stage IV Melanoma were significantly higher than in the plasma
of patients with lower stages or healthy individuals. Accordingly,
individuals with stage IV disease with lower exosome concentra-
tions in the plasma (<50 ␮g/ml) had a survival advantage over
ones with higher concentrations. Exosomes isolated from highly
metastatic melanoma cell lines achieve organ tropism of melanoma
cells by harbouring in the interstitial space of the lungs, bone mar-
row, kidney, liver and spleen – the organotropic sites for malignant
melanoma – but do not remain in the blood circulation. They fur-
ther enhance the permeability of the lung endothelium facilitating
tumor cell invasion. These exosomes enhance the expression of
genes like HSPs (especially HSP 90 and 70), S100A8 and S100A9
which are involved in extracellular matrix remodelling and inflam-
mation, annexin A6, CD44, especially CD44v6–a splice variant
strongly associated with metastasis promotion [91–93] – and the
Met oncoprotein. BMDCs expressed higher levels of Met, which
is a key player in migration, invasion, angiogenesis and bone
marrow cell mobilization via the mTOR (mammalian target of
rapamycin) and MAPK (mitogen activated protein kinase) path-
way [85]. Exosome educated bone marrow in a murine xenograft
model increased metastatic spread three fold and the number of
metastasis-associated BMDCs was higher in the typical metastatic
areas (Fig. 5).
4.5. TDEs and organotropism in pancreatic cancer
Similar observations were made in a mouse model for pan-
creatic ductal adenocarcinoma, where TDEs support engraftment
of metastatic cells in the liver by interaction with Kupffer-cells
[94]. Uptake of exosomes by Kupffer-cells causes activation of pro-
inflammatory and fibrotic pathways leading to the formation of a
pre-metastatic niche through MIF (migration inhibitory factor) sig-
nalling, which supports the production of TGF-␤1. TGF-␤1 in turn
supports the expression of fibronectin, which attracts BMDCs to the
liver stroma in mice. Significant higher levels of MIF where found
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Fig. 5. Organotropic metastatic growth and premetastatic niche formation.

Tumor derived exosomes (TDEs) are distributed to the specific metastatic sites via integrins. ITG␤4 promotes lung tropism and ITG␤5 promotes liver tropism. TDEs prepare
the metastatic organ to form a premetastatic niche, with the help of immigrating bone marrow derived progenitor cells (BMDCs). TDEs promote education and mobilization
of BMDCs that support tumor vasculogenesis, invasion and metastasis. TDEs recruit BMDCs through upregulation of proinflammatory molecules, like miR-122, S100 and
fibronectin, and enhance vascular leakiness at the metastatic sites [85]. After premetastatic niche formation cancer cells can invade the distant organ, begin colonialization
and form organspecific metastasis.

in the serum of patients with pancreatic ductal adenocarcinoma
with liver metastasis and progressive disease than in patients with
full remission, suggesting MIF as prognostic marker in pancreatic
carcinoma [94]. High levels of TGF-␤1, a down stream mediator of
MIF, are associated with a poor prognosis in pancreatic ductal ade-
nocarcinoma [95]. TGF-␤-inhibitors have been recently evaluated
with promising results in phase-I and phase-II clinical trials [96].
5. Immune-modulating effects of exosomes
adhesion to these metastatic cells shield them from NK cell activ-
ity and enables survival in the blood stream [105]. One mechanism
to abrogate NK cell activity is by coating tumor cells with fibrin,
reducing recognition by NK cells [101]. A second mechanism is that
exosomes from hypoxic tumor cells can impair NK cell function by
secretion of TGF-ß1, which leads to a decreased expression of NK
cell activating receptor (NKG2D) [106,107]. This interaction leads
to activation of the EMT-associated TGF-␤1 pathway, which plays
an important role in metastasis as mentioned before [108].

5.1. Maintenance of metastatic cells in the blood circulation
To survive in the blood circulation and to successfully prolif-
erate in the host organ, metastatic cells need to escape immune
surveillance. Platelets are effector cells in the primary haemosta-
sis but they are also immune competent. The first link between
platelets and cancer was observed in 1865 by Trousseau, who
diagnosed excessive blood clotting in cancer patients [97]. Platelet
derived exosomes contain P-selectin and GP IIb-IIIa (glycoprotein
IIa-IIIB) and interact with endothelial cells, leukocytes and cancer
cells [98,99]. Platelets accompany cancer cells in the blood stream
and enable their survival. They assist tumor cell adhesion at the
vessel endothelium, especially via P-selectin, enabling extravasa-
tion of tumor cells from the blood stream into the premetastatic
niche [100–102]. Platelet depletion inhibits metastasis in mice,
while reconstitution of these platelets restores metastatic activ-
ity [103]. Under normal circumstances, leukocytes and especially
natural killer (NK) cells are found in close relation to metastatic
cells in the blood stream and eliminate these cells [104]. Platelet
5.2. Maintenance of metastatic cells in the host organ: TDEs and
cellular immune response
After arrival at the pre-metastatic niche, TDEs establish an
immunosuppressive environment to maintain tumor cell prolif-
eration. Both, the cellular immune response and the humoral
immune response can be abjured by TDEs. TDEs reduce cellu-
lar immune response by inhibiting effector cells and stimulation
of regulatory T-cells. In an in vitro culture model of AML (acute
myeloid leukaemia), TDEs decreased the count of CD8+-T-cells by
activation of Fas/FasL-mediated apoptosis [109,110]. They further
promoted CD4+-T-cell proliferation and conversion into regulatory
T-cells with increased expression of IL-10 (interleukin-10), TGF-␤1,
CTLA-4 (cytotoxic lymphocyte antigen-4) and GrB (granzyme B).
These mediators reduce cytotoxic activity of NK cells [111,112]. In
an in vitro model of nasopharyngeal cancer, immunosuppressive
miRNAs (hsa-miR-24-3p, hsa-miR-891a, hsa-miR-106a-5p, hsa-
miR-20a-5p, and hsa-miR-1908) were found in TDEs [113,114].
Myeloid-derived suppressor cells are immature myeloid cells with

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the ability to suppress T-cell-activation [115]. TDEs activate human
myeloid derived suppressor cells through HSP72/TLR-2 (toll-like
receptor 2) via the STAT3 pathway and IL-6 expression [116].
5.3. Maintenance of metastatic cells in the host organ:TDEs and
humoral immune response
In addition to the effect of TDEs on cellular immune response,
TDEs also neutralize antitumor-antibodies. For the humoral
immune response against cancer cells antibody-dependent cyto-
toxicity (ADCC) is the major response mechanism and to a lesser
extent complement-dependent cytolysis. The activity of thera-
peutic antibodies is mainly dependent on ADCC [117]. In breast
cancer cells it was demonstrated that TDEs express Her2 (human
epidermal growth factor receptor 2) and EpCAM (epithelial cell
adhesion molecule) antigens, which bind and neutralize anti-
bodies interfering with ADCC of tumor cells expressing these
antigens. As a consequence, these TDEs may reduce the therapeu-
®
tic effect of Trastuzumab (Herceptin , mammalian Her2-antibody),
which is a major therapeutic drug in metastatic breast cancer
[118]. Accordingly, B-cell lymphoma cells secrete exosomes, which
carry CD20, neutralizing the therapeutic effect of Rituximab (anti-
CD20-antibody) in vivo. Rituximab induces the formation of the
membrane attack complex at the surface of TDEs. This reduces the
binding of Rituximab at the lymphoma cell surface, which results in
cell lysis and death by disruption of the cell membrane integrity via
the membrane attack complex by forming transmembrane chan-
nels. Interestingly, the treatment of lymphoma cells with Rituximab
induced the secretion of exosomes carrying CD20. Depletion of the
patient plasma from exosomes increased the therapeutic effect of
Rituximab [119].
5.4. TDEs and cancer-promoting proinflammatory effects
Inflammation stimulates tumor growth and prepares distant
sites of the body for hosting metastatic cells [84]. Besides suppres-
sion of antitumor immune response, TDEs create a protumorigenic
inflammatory response and support the establishment and main-
tenance of a pre-metastatic niche. Tumor-associated macrophages
support neoangiogenesis, invasion and matrix remodelling [120].
Increased density of macrophages in breast cancer histological
sections correlate with a poor prognosis [121]. TDEs stimulate
macrophages by activating NF-␬B (nuclear factor-␬B). These effects
are mediated through toll-like receptors (TLRs) on the surface of
macrophages, which interact with TDEs, especially TLR-2 [122].
Activation of macrophages by TLRs (TLR-7 and −8) could be
achieved by binding of exosomal miRNAs (mi-R21, mi-R29a) [123].
TDEs of pancreatic ductal adenocarcinoma cells interact with
Kupffer-cells in the liver to promote pre-metastatic niche forma-
tion. MIF (macrophage migratory inhibition factor) promotes the
release of TGF-␤1 by Kupffer-cells leading to increased fibronectin
production by hepatic stellate cells. Fibronectin deposits in the liver
promote the arrest of bone marrow derived cells in the liver creat-
ing a pre-metastatic niche [94].
6. Exosomes as a source for biomarkers predicting
metastatic spread
Normal human blood contains about 1.5 billion exosomes per
ml and the blood of cancer patients contains more than twice
this concentration [124]. Diseased organs and cancer cells generate
more exosomes than healthy tissue [125]. One limitation why these
biomarkers have not found their way in the clinical routine right
now is that the isolation is expensive and time consuming. A robust
method with the ability to minimize co-isolating protein aggre-
Please cite this article in press as: T.B. Steinbichler, et al., The role of exosomes in cancer metastasis, Semin Cancer Biol (2017),
http://dx.doi.org/10.1016/j.semcancer.2017.02.006
gates and other membranous particles is a prerequisite to identify
exosome-specific biomarkers [35].
6.1. Exosomal protein markers
Exosomes from cancer cells have unique properties, suggesting
that they can be used as early biomarkers for cancer detec-
tion, relapse and metastatic spread. Glypican-1–carrying exosomes
were detected in the serum of 246 pancreatic cancer patients
with 100% specificity and 100% sensitivity compared to 20 healthy
donors and 37 patients with benign pancreatic lesion. This suggests
it is a useful predictive biomarker to distinguish between benign
and malign pancreatic lesions. Further the Glypican-1–carrying
exosome concentration correlated with the tumor load allowing
diagnosis of relapse after surgery or metastatic spread [124]. These
Glypican-1-carrying exosomes can be detected in the serum of
patients with gliomas and breast cancer, too [124]. Another exam-
ple for exosomes as predictive biomarkers is exosomal TM256
(transmembrane protein 256) in urine of patients with prostate
cancer, which has a very high sensitivity (94%) and 100% specificity
[126].
6.2. Exosomal miRNA as biomarker
Besides those proteins, exosomal miRNA is a useful source
for predictive biomarkers. Tumors display unique sets of miRNA
expression profiles, suggesting that these profiles can be used for
early diagnosis and diagnosis of relapse [127]. In prostatic car-
cinoma patients exosomal miR-141 and miR-375 were observed
in higher concentrations in the plasma of patients with recurrent
disease after radical prostatectomy compared to patients with non-
recurrent disease [128–130]. MiR-141 was described as biomarker
for the presence of metastasis [131].
7. Therapeutic approaches
Exosomes stimulate tumor growth, invasiveness and metas-
tasis. Consequently, inhibiting TDEs as therapeutic approach
in cancer treatment seems reasonable. The chemical inhibitor
GW4869 blocks neutral sphingomyelinase 2, which is the key reg-
ulator of ceramide biosynthesis. Exosome release can be triggered
by a ceramide dependent pathway, which means that GW4869 is
able to inhibit TDE release in vitro [132].
7.1. Exosomes as cancer vaccination
Besides this approach of using TDEs as target for therapy, puri-
fied exosomes have been suggested as immunotherapy. Exosomes
carry antigen loaded MHC class I molecules. Antigen-presenting
cells (APC)-derived exosomes carry these MHC/tumor antigens
complexes and present them to dendritic cells, which then mediate
T-cell activation and T-cell dependent immune responses against
tumor cells in vivo. Consequently, these exosomes can be used as
cell-free anti-tumor vaccination [133]. APC-exosomes have some
limitations, as APCs are difficult to culture and specific tumor anti-
gens need to be transferred to APCs. They are also MHC-I dependent
and consequently require MHC-I haplotype matching, which means
they have to be prepared for each patient individually [134]. In
contrast to APC-exosomes, TDEs carry shared tumor antigens and
not only antigens specific to one tumor, so these shared tumor
antigens could probably provide cross-protection against various
cancer types. Furthermore, they have antitumor immunogenity
even without expressing MHC-I molecules, allowing creation of a
cell-free vaccine that does not need MHC-I matching resulting in
effective cancer immunization across tumor types and MHC haplo-
types [135]. One shared tumor antigen is hMUCI (human Mucin I),
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a large glycoprotein, which is associated with rapid tumor progres-
sion and poor outcome. Exosomes can be designed to carry MUCI
and act as anti-cancer vaccination in vitro in an MHC-I independent
manner against MUCI- expressing tumors [136].
Hsp70 can be induced in tumor cells and in their exosomes by
heat treatment of the cells. Hsp70 stimulates monocytes and den-
dritic cells and can amplify the immune response triggered by TDEs
[134]. Hsp70 is able to directly activate NK (natural killer) cells
and initiate NK-mediated apoptosis of tumor cells via secretion of
granzyme B [137]. Elsner et al. reported that activation of NK cells
results in a decreased size of the primary tumor and metastasis in a
murine melanoma model [138]. Andre et al. reported in 2002 that
exosomes isolated from ascites from cancer patients activate den-
dritic cells and in turn produce an antitumor T-cell-response [139].
Two phase-I-clinical trials following this approach showed promis-
ing results in patients with stage III/IV malignant melanoma [140]
and in patients with non-small lung carcinoma [141].
7.2. M-Trap
De la Fuente A. et al. proposed a very innovative approach of
using exosomes for therapy [142]. They designed a so called M-Trap
for metastatic cells, which is composed of exosomes embedded in
a 3-D scaffold, and implanted these M-traps into the peritoneum
of mice with ovarian cancer, establishing an artificial premetastatic
niche in these mice which competes with the natural peritoneum
for metastatic cells. These M-traps cause a significant survival
advantage in a murine model [142].
7.3. Exosomes as chemotherapeutic agents
In addition to the properties described above, exosomes or
synthetic exosomes like liposome preparations can also trans-
port classical chemotherapeutics − like Cisplatin (then called
Lipoplatin) and Doxorubicin − to the tumor cells. This technique
reduces the toxicity of the chemotherapeutic agents and should
be preferred against conventional chemotherapy [143,144]. Pacli-
taxel packed into exosomes is 50 times more cytotoxic against
drug-resistant lung cancer cells than conventional paclitaxel in vitro
[145]. In addition to classic chemotherapeutics, exosomes can also
transport so-called biologicals or tumorsuppressive mi-RNA to the
tumor cells [146,147]. Finally, they can be used for gene therapy
carrying wild-type p53 DNA to cancer cells [148].
8. Conclusion
Exosomes are involved in every step of the metastatic process
from invasion of the tumor cells into the surrounding tissues of
the primary organ to the engraftment in the metastatic organ.
The increasing knowledge about the biological function of these
microvesicles provides new insight into cancer biology and deliv-
ers biomarkers for cancer progression and new treatment options.
Therefore, identifying new therapeutic strategies and acquiring a
better understanding of the biological functions of exosomes in
cancer will be of uttermost relevance in modern molecular oncol-
ogy.
Funding
This study was supported by Austrian Science Fund (FWF,
P29457).
Conflict of interest statement
The authors indicate no potential conflicts of interest.
Please cite this article in press as: T.B. Steinbichler, et al., The role of exosomes in cancer metastasis, Semin Cancer Biol (2017),
http://dx.doi.org/10.1016/j.semcancer.2017.02.006
9
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