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Shephard et al. Role of exosomes in prostate cancer

extracellular space. Vesicle secretion becomes This involves an “angiogenic” switch, regulated by both
elevated when cells are subjected to cellular stress [1,2] , anti- and pro-angiogenic cytokines, examples of which
which can also result in altered molecular cargo within include endothelial growth factor, fibroblast growth
the vesicle . This is particularly relevant in cancer factor (FGF), hepatocyte growth factor (HGF), platelet-
[3]
where stress can come from the hypoxic environment, derived growth factor (PDGF) and vascular endothelial
nutrient deficiency, altered extracellular matrix, and growth factor (VEGF) [14-16] . These responses may
other environmental factors. Such vesicles are often initially provide the tumor with more nutrients and
regarded as one of two broad subtypes, microvesicles oxygen, however, the structural organization of the
and exosomes. Microvesicles are large, tending vessel network is poor, and the continuously remodeled
[17]
to be greater than 200 nm in diameter, dense, and tumor vasculature is disorganized and leaky . This
are formed from outward budding of the plasma causes irregular blood flow and provides invasive
membrane. Exosomes are much smaller, typically 30 tumors with access to the circulatory system.
to 150 nm in diameter, float at a characteristic density
of 1.1 to 1.2 g/mL and originate within multivesicular PRO-ANGIOGENIC ACTIVITY OF EXOSOME-
[4]
endosomes . The secretion of small, exosome-like, ASSOCIATED PROTEINS
[4]
vesicles has also been reported from the plasma
membrane . It remains a challenge to accurately Cancer cell-derived EV have been shown in several
[5]
define vesicle subtypes based on size alone. To aid studies to promote angiogenesis. In the case of prostate
researchers, the International Society for Extracellular cancer it is well established that c-Src tyrosine kinase,
Vesicles has released a position paper detailing the insulin-like growth factor 1 receptor (IGF-1R) and focal
minimal experimental requirements for defining EV . adhesion kinase (FAK) play important roles in tumor
[6]
Although, the challenge of defining EV subtypes growth and disease progression . Src-family kinases
[18]
remains, and is further compounded by overlap in EV are normally expressed in prostatic epithelium and
composition , hence the term EV is often used. The reported to transform normal cells when constitutively
[7]
majority of EV present within both cell conditioned active and up-regulated during disease initiation and
media or biological fluids tend to be small , suggesting progression . Cross-talk between Src and IGF-1R has
[8]
[19]
a predominant exosome-like population. The biological previously been shown to promote angiogenesis .
[20]
significance of any one EV subtype compared to It has been reported that Src, IGF-1R and FAK are
another, however, remains unknown. enriched in prostate cancer exosomes . Src and
[21]
c-Src are also present in plasma exosomes derived
The role of EV in cancer has been the studied from prostate tumor bearing mice; suggesting that
intensively over recent years . Relatively few of these Src-enriched exosomes can promote angiogenesis in
[9]
studies have focused on the potential role of EV, and vivo. Src is known to stimulate transcription of VEGF
more specifically exosomes, in prostate cancer. In this and modulate angiogenesis whilst IGF-1R has been
[22]
current article, we review past studies into the role of demonstrated to induce VEGF-C expression and
exosomes, in diverse malignancies, to identify their stimulate angiogenesis . These observations suggest
[23]
potential functions in disease processes of relevance that prostate cancer exosomes enriched with c-Src,
to prostate cancer. IGF-1R and FAK may be able to stimulate angiogenic
activity within the tumor microenvironment.
EXOSOME-MEDIATED ANGIOGENESIS
Prostate cancer EV are also likely to be capable of
Angiogenesis, or the formation of new blood vessels delivering growth factors with known pro-angiogenic
from pre-existing vasculature, is a vital component in function. For instance, EV from aggressive prostate
numerous physiological and pathological responses. cancer cells have been shown to contain urokinase-
A variety of angiogenic signals are required to drive type plasminogen activator (uPA) , known to be
[24]
endothelial maturation and subsequent re-organisation involved in activation of the protease plasminogen
with vascular smooth muscle cells and pericytes to which is responsible for vascular remodeling .
[25]
form a functional vessel network , thereby allowing Addition of uPA positive vesicles to less aggressive
[10]
nutrient and waste product exchange [11,12] . In cancer, prostate cancer cells stimulated cell migration and
multiple modulators of vascular remodelling contribute invasiveness . Although this study did not investigate
[24]
to tumor growth and progression . Once a tumor the impact of uPA positive vesicles on the ability of
[13]
lesion forms it will become hypoxic and nutrient treated cells to drive angiogenesis, it is conceivable
deprived. The secretion of growth factors activates that prostate cancer derived EV can support endothelial
normal surrounding quiescent cells, to initiate a tubule formation via delivery of pro-angiogenic growth
cascade of events that become quickly dysregulated. factors. Additional pro-angiogenic factors have been
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 6, 2017 289