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Shephard et al. Role of exosomes in prostate cancer

capable of activating primary rat prostate fibroblasts, in stromal cells. EV transfer of mRNA, miRNA and
leading to upregulation of αSMA, HGF and VEGFA . membrane proteins have all been implicated. For
[58]
Exosomes therefore appear to play a crucial role in instance, acute myeloid leukemia cell exosomes
communication between prostate cancer cells and the promote proliferation and migration of bone marrow
surrounding stroma, with exosome-associated TGFβ1 stromal cells via transfer of IGF-IR mRNA . Similar
[69]
essential for inducing fibroblast differentiation towards results have been shown in solid cancers whereby
a disease supporting phenotype. exosomal miRNAs regulate stromal cell behavior.
Metastatic breast cancer cells, for example, were
The exact origin of disease-associated myofibroblasts shown to enhance vascular permeability, and promote
remains unclear, and it has been shown that other tumor metastasis, via the suppression of the tight
cells are capable of myofibroblastic differentiation. junction protein ZO-1 by exosome delivered miR-
MSCs, a multipotent cell type capable of generating 105 . Gastric cancer exosomes stimulate primary
[70]
many different types of connective tissue, can also mouse liver myofibroblasts and hepatic pericytes by
differentiate into myofibroblasts in response to exosome mediated delivery of the membrane protein
secreted factors from tumors . MSCs make up 1.1% epidermal growth factor receptor (EGFR) . After
[40]
[71]
of cells within the prostate cancer stroma and exhibit insertion into the stromal cell membrane, where it
[59]
similar tumor promoting effects to cancer associated co-localizes with E-cadherin, EGFR activates HGF
stroma [40,60,61] . secretion by potentially suppressing upstream miRNAs
such as miR-26a/b. The subsequent increase in HGF
Exosomes secreted by breast , ovarian and secretion promotes gastric cancer cell proliferation,
[62]
[63]
gastric cancer cells induce TGFβ1-dependent migration and invasion.
[64]
differentiation of adipose or cord blood derived MSCs
to myofibroblasts. In addition, chronic lymphocytic Exosomes are not the only EV subgroup shown to
leukemia exosomes have been shown to enhance alter the prostate stroma phenotype. Prostate cancer
tumor growth in vivo by inducing differentiation of cells also secrete large oncosomes, EV between
BM-MSCs . Adipose derived MSCs, meanwhile, 100-400 nm in diameter [72] , which have sustained
[65]
differentiate in response to EV from metastatic breast AKT1 activity [73,74] . A recent study by Minciacchi et al.
[75]
cancer in 2D and 3D culture. This process was shown reported that internalization of large oncosomes by
to require TGFβ dependent MAPK signaling involving prostate fibroblasts resulted in the induction of a
phosphorylation of ERK1/2 and JNK1/2 . αSMA-positive myofibroblast phenotype. Interestingly,
[66]
induction of other myofibroblast markers, such as
Chowdhury et al. demonstrated that prostate cancer MMP1, thrombospondin-1 (TSP-1) and TGFβ1 did not
[42]
exosomes can also drive BM-MSC differentiation, occur, potentially suggesting that oncosomes induce
resulting in myofibroblasts with increased VEGFA, a distinct myofibroblast-like phenotype. Analysis of
HGF and MMP secretion, capable of enhancing cancer transcription factor DNA binding in treated prostate
cell growth. Exosome differentiated BM-MSCs drove fibroblasts highlighted that MYC binding was essential
prostate cancer cell invasion in a 3D spheroid model for this induction of a myofibroblast-like phenotype.
and stimulated endothelial cell migration, proliferation The mechanism by which large oncosomes stimulate
and angiogenic potential. As previously observed, MYC-DNA binding has not yet been elucidated,
exosomal TGFβ1 treatment resulted in myofibroblasts however, as MYC has not been found to be present
with an enhanced pro-tumorigenic phenotype compared
to soluble TGFβ1. Interestingly, exosomes also inside the EV it appears MYC is activated rather than
modulated BM-MSC derived myofibroblast expression delivered. This study also explored the impact of large
of ITGB6 and ITGB8, encoding for components oncosomes in vivo and found that prostate fibroblasts
of integrins αvβ6 and αvβ8, which are involved in pre-treated with oncosomes facilitated enhanced
converting latent TGFβ1 to the active form [67,68] . This tumor growth. These findings are similar to the earlier
may therefore explain how latent TGFβ1 delivered results obtained with exosomes and lend support to
by exosomes becomes functionally active. The the critical role of diverse vesicle subtypes in tumor-
predominant population of myofibroblast precursors stroma communication in prostate cancer.
remains unclear. Regardless of the precursor cell, it
is evident that prostate cancer exosomes can trigger SECRETION OF STROMA-DERIVED
differentiation to a stromal phenotype with disease EXOSOMES
promoting properties.
Stromal cells activated by cancer cell secreted
Delivery of TGFβ1 is not the only mechanism by which EV can initiate a positive feedback mechanism
exosomes can stimulate pro-tumorigenic phenotypes via release of stromal cell EV which promote
292 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 6, 2017