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Shephard et al. Role of exosomes in prostate cancer

resulting in elevated secretion of multiple pro- During wound healing myofibroblasts are present
angiogenic factors including VEGF, HGF, FGF-2, and to aid wound closure. In various cancers, however,
uPA [34,35] . Furthermore, prostate cancer exosomes a chronic wound response can occur resulting in
were shown to induce pro-angiogenic function within sustained presence of myofibroblasts within the tumor
primary prostate stromal cells and were shown to microenvironment .
[48]
facilitate in vivo tumor growth . Other studies have
[35]
reported cancer-associated myofibroblasts can Cancer associated myofibroblasts display an
secrete pro-angiogenic growth factors and promote altered phenotype compared to wound associated
angiogenesis at the primary tumor site [36-39] . Also, HGF myofibroblasts and have been termed activated
[49]
and stromal cell-derived factor-1 derived from these fibroblasts, tumor associated fibroblasts and cancer
myofibroblasts can indirectly enhance angiogenesis by associated fibroblasts. There is conflicting evidence
inducing the secretion of angiogenic factors from tumor as to whether myofibroblasts promote or suppress
[50]
cells [40,41] . Collectively, these studies demonstrate tumorigenesis. Rhim et al. observed that removal
that exosomes derived from solid tumors, including of myofibroblasts from the stroma of pancreatic
prostate cancer, drive activation of fibroblasts to a pro- ductal adenocarcinoma (PDAC) in vivo results in
angiogenic phenotype. more aggressive tumors and reduced mouse survival
rates. However, the prevailing view is that stroma rich
The ability of prostate cancer exosomes to trigger in myofibroblasts has an increased ability to drive
secretion of pro-angiogenic factors extends to bone tumor growth, angiogenesis, metastasis and treatment
marrow-derived mesenchymal stem cells (BM-MSCs), resistance [45,51,52] .
which can also gain exosome-induced pro-angiogenic
function . Exosome-activated MSCs were shown to ACTIVATION AND MODULATION OF
[42]
secrete elevated levels of HGF, VEGF and MMPs, STROMAL CELLS BY EXOSOMES
and support the formation of endothelial vessel-like
structures. Exosomes from metastatic melanomas Fibroblast differentiation is known to be induced
have also been shown to interact with bone marrow by TGFβ1 via SMAD dependent and independent
progenitor cells via the tyrosine kinase MET , which signaling pathways [53-55] . It has been established that
[43]
induced vascular leakiness at pre-metastatic sites and exosomes secreted by prostate cancer cells express
reprogrammed bone marrow progenitors towards a latent TGFβ1 , tethered to the exosome surface
[56]
pro-vasculogenic phenotype. This “reprogramming” of via proteoglycans and capable of activating SMAD3
the bone marrow progenitors resulted in significantly dependent signaling . The authors demonstrate
[34]
increased tumor vascular density in vivo. that prostate cancer derived exosomes, with greater
than 6 pg TGFβ1/µg exosome, can induce fibroblast
A wide range of studies have demonstrated various differentiation . Differentiation could be sustained for
[34]
roles of cancer exosomes in promoting angiogenesis at least 2 weeks in the absence of further exosome
either through direct or indirect interaction with treatment, indicating the resulting myofibroblast-
endothelial cells. Prostate cancer exosomes are like phenotype is self-maintaining. In contrast, EV
likely to be dynamic in response to hypoxia and may originating from MDA-MB231 breast cancer cells and
act as a means to deliver a variety of factors capable u87 glioblastoma cells could only induce transient
of supporting the formation of tumor-associated fibroblast differentiation , potentially suggesting
[57]
vasculature in vivo. differences between EV from distinct tissue types.
EXOSOME-DRIVEN TUMOR-STROMA A subsequent study by Webber et al. identified that
[35]
INTERACTIONS exosomal TGFβ1 induces a more aggressive, pro-
angiogenic myofibroblast phenotype compared to
Stromal cells surrounding a tumor can undergo a the soluble form of the growth factor. These results
desmoplastic response, characterized by aberrant were replicated in primary stromal cells from normal
cell growth and morphological transformation of prostate tissue, resulting in a myofibroblast-like
the stroma, resulting in a more aggressive tumor phenotype that matched that found within disease-
microenvironment . A key feature of this tumor reactive associated stromal tissue. Furthermore, pre-treating
[44]
stroma is the presence of cells with a myofibroblast- normal stroma with prostate cancer derived exosomes
like phenotype . Myofibroblasts are contractile cells, prior to administration enhanced tumor growth in mice.
[45]
characterized by the formation of α smooth muscle actin In contrast, pre-treatment with soluble TGFβ1 led to
(αSMA) stress fibers , loss of the spindle phenotype tumor control. Consistent with this report, a separate
[46]
and formation of a hyaluronic acid pericellular coat . study showed that metastatic rat prostate tumor EV are
[47]
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 6, 2017 291