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Shephard et al. Role of exosomes in prostate cancer

in modulating normal myeloporesis and select for If lessons are to be gained from these studies of other
cells destined for suppressor-like differentiation [96,97] . diverse cancer types, it is indeed likely that EV of
It currently remains unclear as to whether this latter prostate cancer origin may also exert local and possibly
phenomenon is also true of solid cancers. distant influences on the myeloid cell components
of tissues, and profoundly impact the course of the
MECHANISMS OF MYELOID ACTIVATION BY disease. New studies are, however, required in order
EV to examine this further.

Whilst there remains much to be learned about how EXOSOME DRIVEN METASTASIS AND
EV exert such influences on myeloid cells, evidence MULTIDRUG RESISTANCE
points to delivery of EV-associated ligands to trigger
signaling cascades mediated through toll-like [98,99] A key step in the progression of various cancers is the
or other receptors [100,101] . Moreover, there is a likely invasion of cancer cells into surrounding tissues and
additional effect of EV-encapsulated RNAs which subsequent metastasis from the primary tumor site.
may also be delivered to myeloid cells. In one elegant The 5-year survival rates of patients with prostate
experimental system, cancer cells were engineered cancer drop dramatically following metastasis from
to express Cre-recombinase. Cre mRNA was the primary tumor. The primary site of metastasis
detectable in various EV sub-fractions secreted by of prostate cancer is the bone; such metastasis
these cells, with the predominant EV type appearing remains incurable. An increased concentration of
to be exosome-like. Transplantation of these cells circulating microvesicles has been reported in in
[74]
into mice with a Cre-reporter background led to vivo models of metastatic prostate cancer and
[43]
recombination events at the tumor site, as indicated studies by Peinado et al. have demonstrated a role
of exosomes in the support of tumor metastasis to
by β-galactosidase expression following receipt the bone.
of vesicular Cre mRNA. These Cre-recombined
cells were 90% CD45 leukocytes, principally of a EXOSOME-MEDIATED REGULATION OF
+
Gr1 CD11b MDSC phenotype [102] . The MDSC which
+
+
had taken up vesicular RNA exhibited more potent MMPS
suppressive functions compared to their counterparts
that had not. The study highlights the in vivo transfer Cancer cell invasion, and disease progression, has
of vesicle-encapsulated RNA to myeloid cells within been linked to an altered expression of MMPs, key
regulators of the extracellular matrix. Fibronectin-
the tumor microenvironment, resulting in enhanced mediated binding of exosomes to myeloma cells
immune-suppressive function of MDSC.
has been shown to activate p38 and ERK signaling,
resulting in elevate expression of DKK1 and MMP-
The influence of EV may, however, not be limited to [105]
the local environment. In a highly metastatic breast 9 and subsequent myeloma progression . More
recently, it has been shown that prostate cancer
cancer model EV were again taken up principally by exosomes can regulate MMP-9 expression within
CD45 bone marrow-derived cells present at distant osteoclast precursor cells and impair osteoclastic
+
sites of the lung and liver. These myeloid cells were differentiation [106] . Collectively these studies suggest a
implicated thereafter in aiding the colonization of role of prostate cancer exosomes in the modulation of
these organs by metastasizing cells. Part of this effect the bone environment, and subsequent preparation of
may also be due to localized natural killer and T cell the metastatic site.
suppressive effects attenuating anti-cancer immunity
in the premetastatic organs [103] . Dissemination of EV Proteomic analyses have revealed that both
may be more limited in some other cancer types, like cell surface-anchored and soluble matrix
glioma, where influences on myeloid phenotypes are metalloproteinases are present in EV isolated from
not always found in the periphery [104] . In one study, either cell conditioned media or from biofluids [107] .
attenuating TLR2-dependent interaction between Such vesicular-associated MMPs have been shown
cancer exosome and MSDS was an effective strategy to be proteolytically active, and may play a variety
for limiting MDSC numbers and activation in vivo, and of functional roles including direct interaction or
in fact potentiated the effect of chemotherapeutics cleavage of extracellular matrix proteins or removal
that would otherwise lead to heightened release of of membrane-anchored receptors from target
MDSC-activating vesicles. Preventing vesicle effects cells [108] . This is supported by further evidence
on MDSC may be a worthwhile therapeutic approach from Hakulinen et al. [109] demonstrating that cancer
to consider [99] . exosomes can express functionally active MMP-14.
294 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 6, 2017