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Shephard et al. Role of exosomes in prostate cancer

tumorigenesis after internalization by tumor cells. Despite such studies, there is a surprising paucity
A study by Josson et al. highlighted this cyclical of information relating to prostate cancer exosomes
[76]
system in prostate cancer. Activated prostate and their influence on myeloid cells. This topic is
fibroblasts were shown to release miR-409 containing highly relevant, however, as the presence of CD14+
EV, which are taken up by prostate cancer cells. Upon macrophages and chronic inflammation within the
EV internalization miR-409 downregulates the tumor microenvironment is a key risk factor in prostate
suppressors Ras suppressor 1 and stromal antigen 2, cancer .
[82]
promoting cancer cell tumorigenesis and stimulating
EMT and stemness in epithelial cells. This effect EXOSOME-MEDIATED ANTIGEN
can also be observed in other tissues. For example, PRESENTATION
activated PDAC fibroblasts secrete ANXA6 positive EV
containing the ANXA6/LRP1/TSP1 complex. Uptake Some of the early discoveries of exosome function
of these EV by PDAC cells was shown to enhance have centered on their potential as immune-activating
tumorigenesis by stimulating cancer cell migration and factors , where professional antigen presenting cells
[4]
driving tumor growth in vivo . Activation of the Wnt- derived from monocyte precursors were able to secrete
[77]
planar cell polarity (PCP) pathway, and subsequent exosomes carrying MHC-peptide complexes that were
stimulation of cell motility and metastasis, can also be functional in T cell stimulation . Antigen presenting
[83]
induced by stromal cell EV. Luga et al. determined cells (APC), educated with cancer antigens in the form
[78]
that CD81 vesicles secreted from activated fibroblasts of protein or peptide fragments, therefore produce
+
are capable of activating the Wnt-PCP pathway in nanovesicles as APC-surrogates to disseminate the
breast cancer cells via transfer of Wnt11. activation of T cells. Isolated APC-exosomes can
also be manipulated directly, by pulsing with antigenic
Stromal cells can also confer chemoresistance on peptides of desired specificity, and this scheme has
surrounding tumor cells via EV communication. been proposed as a cancer vaccine strategy . APC
[84]
Activated fibroblasts resistant to the chemotherapy can, however, also receive a complex set of antigenic
drug Gemcitabine (GEM) release exosomes information in the form of exosomes secreted by tumor
containing miR-146a and mRNA for its upstream cells [85,86] , providing not only tumor-associated antigens
transcription factor Snail . Incubation of PDAC but importantly additional information such as cellular
[79]
cells with exosomes from GEM treated fibroblasts stress signals (e.g. heat shock proteins ), or even
[87]
results in increased levels of Snail mRNA and miR- encapsulated RNA , to modulate APC-phenotype
[88]
146a in the cancer cells, leading to cell proliferation and control subsequent functions. Some researchers
and chemoresistance. Similar findings have been argue that cancer cell-derived exosomes may be an
observed in colorectal and breast cancers , advantageous form of antigen delivery to APCs in
[81]
[80]
with the latter study identifying activation of antiviral vivo . There are, however, conflicting examples where
[89]
signaling pathways through stimulation of the pattern the interaction of cancer-exosomes with myeloid cells
recognition receptor RIG-I by exosomal RNA. may lead to disease exacerbating effects.
RIG-I activates STAT1 dependent signaling which
cooperates with NOTCH3 to mediate NOTCH target Amongst the earliest examples are reports detailing
gene transcription, supporting maintenance of therapy the skewing of dendritic cell differentiation away
resistant tumor initiating cells. from a competent antigen presentation phenotype,
and towards TGFβ producing myeloid cells capable
Activation of stromal cells by cancer cell-derived of negatively regulating T cell responses [90,91] . More
exosomes results in a pro-proliferative and pro- recent reports also point to this phenomenon, where
angiogenic stromal phenotype. In turn, EV and monocytes stimulated with cancer cell-derived EV
exosomes from activated stromal cells may then drive become alternatively-activated/M2-type macrophages,
surrounding cancer cells towards a more aggressive, expressing elevated levels of VEGF, IL6, Cox2, and
chemoresistant, phenotype. This suggests a network arginase-1 amongst many other tumor-supportive
of reciprocal communication based on EV exists to factors [92,93] . Similar modulation of myeloid cells are
exacerbate disease. seen using pancreatic cancer exosomes, giving a
suppressive CD14 HLA-DR low/neg phenotype akin to
+
EXOSOME MODULATION OF MYELOID those elevated within the circulation of patients .
[94]
CELLS Similarly, myeloma-derived EV present within the bone
marrow microenvironment can activate myeloid-derived
There have been numerous studies demonstrating suppressor cells (MDSC) and promote progression .
[95]
immunological control by EV, as reviewed previously . In acute myeloid leukemia, vesicles may play a role
[9]
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 6, 2017 293