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Shephard et al. Role of exosomes in prostate cancer

identified on EV from a variety of different cancer cell Sustained growth of the tumor mass often requires
types and are summarized in Table 1. Further studies new blood vessels to provide rapidly proliferating
are required to ascertain whether these factors are tumor cells with an adequate supply of metabolites
present on prostate cancer EV. and oxygen. Under hypoxic conditions the cellular
secretome becomes altered and a proportion of these
DELIVERY OF PRO-ANGIOGENIC RNAS BY changes may reside within the exosome fraction.
EXOSOMES Exosomes derived from solid tumors, which have
been cultured in hypoxic conditions, become enriched
Whilst direct evidence of RNA delivery by prostate with hypoxia-regulated mRNAs and proteins such as
cancer EV is currently lacking, EV from several cancer Caveolin 1, IL-8, matrix metalloproteinase (MMP) and
types are known to be enriched with mRNA transcripts PDGF, and are capable of promoting angiogenesis [31] .
related to pro-angiogenic function that can then be Similarly, under hypoxic conditions, the secretion of
translated by recipient cells [26,27] . Similar studies have exosomes from breast cancer [32] or leukemic cells [33]
shown an enhanced proliferative impact on endothelial demonstrate elevated levels of exosomal miR-210,
cells [28,29] and enhanced tubule formation within 3D cell with the capacity to enhance HUVEC tube formation
cultures . The transfer of exosomal miRNA, such as compared to exosomes from normoxic conditions.
[28]
miRNA-92a and miR-17-92, may also play a role in Although EV from hypoxic prostate cancer cells are yet
this process and miR-17-92 may play a role in this to be investigated, based on this evidence, it is highly
[30]
process . Furthermore, transmittance of the miR- likely that the cargo of prostate cancer exosomes is
[30]
17-92 cluster from EV to endothelial cells has been also influenced by hypoxic conditions. The impact
shown to attenuate endothelial expression of integrin of hypoxia-derived vesicles on angiogenesis and
α resulting in enhanced endothelial cell migration and subsequent development of prostatic tumors remains
v
tube formation . Numerous studies highlight a role of unknown.
[30]
cancer exosomes in delivery of RNAs to endothelial
cells, thereby promoting angiogenesis, and it is INDIRECT EXOSOME-MEDIATED
therefore likely that prostate cancer exosomes share ANGIOGENESIS
this functionality.
In addition to direct modulation of angiogenesis within
HYPOXIC TUMOR-DERIVED EXOSOMES the tumor microenvironment, exosomes have the
ENHANCE ANGIOGENESIS potential to regulate angiogenesis indirectly through
interactions with various non-endothelial cell types.
As a tumor grows diffusion distances from the existing Prostate cancer exosomes, expressing transforming
vascular supply increase, resulting in hypoxia. growth factor beta (TGFβ), can activate fibroblasts
Table 1: EV-associated pro-angiogenic proteins
Protein Pro-angiogenic function Cancer cell of EV origin Reference
Angiogenin Translocates to the nucleus of recipient cells and enhances RNA Multiple myeloma [131]
transcription, stimulating expression of pro-angiogenic proteins
EGFR Induces VEGF expression in recipient cells through Akt signaling Lung, glioma [132,133]
FAK Interactions between FAK, IGF-1R and Src result in various Prostate [21]
downstream signaling events and modulation of angiogenesis
FGF2 Promotes proliferation and differentiation of endothelial cells Multiple myeloma [131]
IGF-1R Interactions between FAK, IGF-1R and Src result in various Prostate [21]
downstream signaling events and modulation of angiogenesis
MMP-2, MMP-9 Degradation of extracellular matrix components Ovarian [134]
Src Activation of FAK, and subsequent formation of focal adhesions Prostate, myeloid leukemia [21,135]
between endothelial cells
Tspan8 Induces uPA, VEGFR and vWF in recipient endothelial cells Pancreatic [134,135]
uPA Activation of plasminogen leading to vascular remodeling Prostate [24]
VEGF Rearranges the cytoskeleton through the FAK/paxillin pathway, Multiple myeloma, ovarian [131,134]
induces capillary formation via RhoA/ROCK signaling and controls
vascular permeability through PLCγ
A selected overview of pro-angiogenic factors previously identified on EV. Association of pro-angiogenic proteins with EV has been
demonstrated in multiple cancers, but the precise involvement of some such proteins in prostate cancer remains unclear. EV: extracellular
vesicles; EGFR: epidermal growth factor receptor; VEGF: vascular endothelial growth factor; Akt: protein kinase B (serine/threonine specific
protein kinase); FAK: focal adhesion kinase; IGF-1R: insulin-like growth factor 1 receptor; Src: proto-oncogene tyrosine-protein kinase
Src; FGF2: fibroblast growth factor 2; MMP: matrix metalloproteinase; Tspan8: tetraspanin-8; uPA: urokinase-type plasminogen activator;
VEGFR: vascular endothelial growth factor receptor; vWF: von willebrand factor; RhoA: Ras homolg gene family, member A; ROCK: Rho-
associated, coiled-coil containing protein kinase; PLCγ: phospholipase C gamma
290 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 6, 2017