Page 43 - Read Online

Shephard et al. Role of exosomes in prostate cancer

It has long been recognized that platelets can play a ATP-binding cassette transporter that is involved in
role in tumor progression by promoting angiogenesis, the transportation of various substances across the
resulting in leaky capillaries, and therefore facilitating plasma membrane.
tumor metastasis. The mechanism of their action has
however remained unclear until relatively recently. In a Drug-resistant prostate cancer cell lines can transfer
study by Janowska-Wieczorek et al. [110] , it was shown drug resistance to non-resistant cells via uptake of
that platelet-derived EV, and exosomes released from exosomes [121] , and other EV [122] , shed from drug-
α-granules, can contribute to metastatic spread via resistant cells. The initiation of drug-resistance is
phosphorylation of mitogen activated protein kinase triggered by vesicular-mediated metabolic alteration
p42/44 and serine/threonine kinase as well as the of drug-sensitive cells towards a drug-resistant
expression of membrane type 1-MMP (MT1-MMP). phenotype, with an increase in glycolysis and
The authors also showed that platelet-derived EV glycolytic capacity [123] . Such changes in metabolic
are capable of inducing MMP-9 mRNA expression. profile may also be reflected in cargo of EV secreted
This study demonstrates that platelet-derived EV can from the cancer, and may represent a source of
simultaneously activate MT1-MMPs and induce de biomarkers useful for both diagnosis and monitoring
novo expression of MMPs within cancer cells. prognosis of disease [124] .
Collectively, these studies suggests that exosomes In addition, cancer-associated fibroblasts can also
may be capable of direct contribution to matrix regulate metabolic processes within neighboring
remodeling both within the tumor microenvironment cancer cells [125] . It was recently shown that cancer-
and potentially at distant sites away from the associated fibroblast-derived exosomes can reprogram
primary tumor. prostate cancer cell metabolism by downregulating
mitochondrial function [126] . Specifically, fibroblast-
EXOSOME-REGULATED METABOLISM AND derived exosomes were shown to inhibit mitochondrial
DRUG RESISTANCE oxidative phosphorylation, resulting in an increase
in glycolysis. This may be in part due to delivery of
Altered cell metabolism is a hallmark of cancer, with metabolite cargo consisting of lactate, acetate, amino
many cancer cells demonstrating an increase of aerobic acids, tricarboxylic acid cycle intermediates and lipids
glycolysis. This results in subsequent lowering of pH, from fibroblast-exosomes [126] . Activated stromal cells
leading to increased tumor invasion, proliferation, therefore appear capable of inducing the Warburg
migration and drug resistance [111,112] . There is growing effect [127,128] , an increased rate of glycolysis followed
interest in the role of exosomes, and other EV, as by lactic acid fermentation, in surrounding cancer
modulators of cancer cell metabolism. It has been cells through EV mediated processes. Despite further
reported that pH of the tumor microenvironment is a studies being required to clarify the effects of metabolic
key factor in regulating both the release and uptake of change on cancer progression, stromal cell EV appear
exosomes by cancer cells [113] , suggesting a positive- to contribute to cancer proliferation and survival in
feedback mechanism resulting in elevated secretion environments low in oxygen and nutrients.
of EV from the tumor microenvironment.
CONCLUSION
Several studies have demonstrated a link between
altered cell metabolism and the development of As studies into the role of exosomes in prostate
multidrug resistance in multiple cancer types [114-116] , cancer continue, we are likely to learn of further ways
including prostate [117] . Prostate cancer progression is in which exosomes regulate disease progression.
a complex process. In early stage disease the cancer Whilst studies specifically on prostate cancer/stroma-
remains androgen sensitive and can be treated with derived exosomes may appear limited in number
androgen-deprivation therapy. Over time, however, there is a great wealth of knowledge on the role of
the cancer cells become androgen insensitive. exosomes within other solid cancers that remain
Chemotherapeutic agents, such as docetaxel, can useful in informing us of the potential role of exosomes
be used to treat androgen-independent disease [118] . in prostate cancer [Figure 1].
By this stage, however, disease relapse is extremely
likely and the development of multidrug resistant Prostate cancer exosomes have been shown to
cancers results in impaired treatment. Several regulate angiogenesis, which may occur through
factors have been linked to multidrug resistance [119] exosome-mediated delivery of growth factors or RNAs.
including the overexpression of transporter proteins Prostate cancer exosomes have also been shown to
such as P-glycoprotein [120] , a well characterized further regulate the tumor microenvironment through
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 6, 2017 295