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\begin{document}

\title{The Diagnostic and Therapeutic Prospects of Exosomes in Ovarian Cancer}



\author[1]{qianrun Chen}%
\author[2]{Jiayan Shi}%
\author[3]{Danhua Ruan}%
\author[1]{ce Bian}%
\affil[1]{Sichuan University West China Second University Hospital}%
\affil[2]{Affiliation not available}%
\affil[3]{Sichuan University}%


\vspace{-1em}



  
  \date{May 22, 2024}


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\selectlanguage{english}
\begin{abstract}
Exosomes are nano-sized vesicles derived from the endosomal system and
involved in multitudinous biological and pathological processes.
Emerging evidence has demonstrated that exosomes are closely related to
the tumorigenesis and progression of ovarian cancer. Ovarian
cancer-related exosomes have cell-specific constituents that could be
leveraged for diagnosis. Additionally, exosomes are promising to treat
ovarian cancer through functioning as delivery systems or participating
in immunotherapy or serving as direct targets. In this review, we
discussed the association of exosomes in ovarian cancer progression and
look forward to the clinical significance of exosomes relevant to
diagnosis and treatment.%
\end{abstract}%



\sloppy


\textbf{1. Introduction}

Ovarian cancer, one of the most common malignancies in the female
reproductive system, has the highest mortality rate among gynecological
cancers \textsuperscript{{[}1{]}}. Albeit the five-year relative
survival rate of patients diagnosed at the early stage (FIGO stage I or
II) can reach 90\%, more than 70\% of patients are diagnosed with
advanced stage (FIGO stages III-IV) for lack of early symptoms and
sensitive diagnosis \textsuperscript{{[}2{]}}. Patients diagnosed at
advanced stages are generally accompanied by poor prognosis, which
possibly subsumes extensive peritoneal dissemination, massive ascites,
acquired chemoresistance, and a five-year survival rate of less than
25\%\textsuperscript{{[}3{]}}. Despite the indisputable fact that novel
therapies, such as targeted therapy and immunotherapy, have been
continuously emerging in recent years, current treatments for ovarian
cancer are still limited\textsuperscript{{[}4{]}}. Hence, there is an
urgent need to identify specific diagnostic biomarkers and potential
therapeutic interventions for ovarian cancer.

Recently, as promising biomarkers of ovarian cancer, exosomes have been
widely investigated and have exhibited their immense potential in the
medical field due to their diverse functions in
pathology\textsuperscript{{[}5,6{]}}. After the discovery of membrane
exfoliation vesicles by Eberhard G. Trams, the term ''exosome'' was
initially used by Johnstone to describe the specific type of
extracellular vesicles (EVs) in 1987 \textsuperscript{{[}7,8{]}}.
Nowadays, exosomes specifically refer to those membranous vesicles with
a diameter of \textasciitilde{}40 to160 nm (average \textasciitilde{}100
nm) that have the same topology as the cells and are enriched in lipids,
nucleic acids, and protein complexes\textsuperscript{{[}5,9{]}}.
Research has revealed that exosomes abnormally initiate or suppress
various signaling pathways in cancer cells though transmitting
heterogeneous cargoes, which potentially contribute to the development
of cancer\textsuperscript{{[}10{]}}. In ovarian cancer, exosomes play a
crucial role in mediating epithelial-to-mesenchymal transition (EMT),
non-mutational epigenetic reprogramming, immune modulation, thus
involved in the promotion of tumorigenesis, peritoneal dissemination,
and drug resistance \textsuperscript{{[}11{]}}. Apart from this,
exosomes are promising biomarkers in biological fluids for the
multicomponent diagnosis of ovarian cancer \textsuperscript{{[}12{]}}.
Herein, this review is aimed to describe the characteristics of
exosomes, with a particular focus on their emerging functions and
mechanisms in ovarian cancer, we hope to bring new insights into the
latest advances in diagnosis and treatment of ovarian cancer.

\textbf{2.Biological characteristics ofexosomes}

The biogenesis of exosomes occurs within the endosomal system, covering
the involution of cell membranes to form endosomes, the generation of
intraluminal vesicles (ILVs) inside the multivesicular bodies (MVBs),
and the fusion between the MVBs and the plasma membrane to release
exosomes (Figure 1)\textsuperscript{{[}5{]}}. The exosomal membranes
mainly consist of lipid layers, and some specific lipids are enriched in
exosomes compared to their parent cells \textsuperscript{{[}13{]}}.
Additionally, exosomes possesses several families of proteins unique to
the endosomal pathway, such as tetraspanins (CD9, CD63, CD81),
tumor-sensitive gene 101 (TSG101), heat shock proteins (Hsc70),
lysosomal proteins (Lamp2b) and fusion proteins (flotillin and annexin),
which are commonly used to characterize exosomes and distinguish them
from other vesicles \textsuperscript{{[}14{]}}. Moreover, exosomes
contain multiple types of bioactive molecules such as cargos including
proteins, nucleic acids, lipids, and
metabolites\textsuperscript{{[}5{]}}. A straightforward approach based
on analyzing the variation of key contents is helpful to uncover the
biological functions of exosomes coming from different cell types. For
more extensive information about bio-active contents in exosomes
identified in multiple organisms, ExoCarta (http://www.exocarta.org) can
provide further information for researchers to conduct in-depth
exploration.

\textbf{3.Roles of exosomes in ovarian cancer}

Exosomes presenting in biological fluids are tightly connected with
multiple pathological and physiological processes. Generally, exosomes
participate in expelling excess and/or nonfunctional cellular
components, recycling materials between cells for intercellular
communication, remodeling the tumor microenvironment (TME), and many
more \textsuperscript{{[}15{]}}. Studies have shown that tumor cells
secrete more exosomes than normal cells, and exosomes derived from tumor
cells have a potent capacity to promote tumor progression by modifying
both local and distant microenvironments \textsuperscript{{[}16{]}}.
Herein, we summarize the functions of exosomes in the metastasis,
chemotherapy resistance, and immune regulation of ovarian cancer (Figure
2).

\textbf{3.1 Role inmetastasis}

Recent studies have unraveled the significant contribution of TME to
ovarian cancer metastasis, of which exosomes are an important
composition\textsuperscript{{[}17{]}}. Exosomes are chiefly involved in
the formation of pre-metastatic niches and the process of promoting
metastasis. Primary ovarian tumor-derived exosomes can prepare the
distant tumor microenvironment via regulating intercellular
communication between tumor cells and normal stroma, cancer-associated
fibroblasts, and local immune cells to promote metastatic
invasion\textsuperscript{{[}18{]}}. Plasma cells are capable of
mediating phenotypic switch and shaping the mesenchymal identity of
ovarian cancer in an exosome-dependent manner
\textsuperscript{{[}19{]}}. Specifically, plasma cell-derived exosomes
contain miR-330-3p, thereby uplifting the expression of junctional
adhesion molecule B in non-mesenchymal ovarian cancer cells in a
noncanonical fashion. Moreover, exosomes in ascites promote
epithelial-mesenchymal transition (EMT) of ovarian cancer cells by
delivery of miR-6780b-5p and eventually facilitate ovarian cancer
metastasis\textsuperscript{{[}20{]}}. Other exosomal miRNAs can be
synthesized and secreted by ovarian cancer cells as well. It has been
found that miR-205 was up-regulated in ovarian cancer tissues and
promoted ovarian cancer metastasis in an exosome-dependent manner by
inducing angiogenesis\textsuperscript{{[}21{]}}. Furthermore, proteomic
analysis reveals that exosomes from ovarian cancer cells contain a
specific set of proteins that are representative of their origin and
invasive capacity\textsuperscript{{[}22{]}}. Similarly, Alharbi \emph{et
al.} unveiled that 40 proteins associated with Wnt canonical pathway
(\selectlanguage{greek}β-\selectlanguage{english}catenin) were differentially expressed in tumor tissues between mice
injected with high invasiveness capacity cell line (exo-SKOV-3) and low
invasiveness capacity cell line (exo-OVCAR-3), and exosomes secreted by
a high invasiveness capacity cell line boosted tumor metastasis \emph{in
vivo}\textsuperscript{{[}23{]}}. To sum up, exosomes modulate TME via
autocrine-paracrine signaling that reinforces the formation of
pre-metastatic niches and enhances the invasion and migration of ovarian
cancer cells.

\textbf{3.2 Role inchemotherapyresistance}

Apart from metastasis, chemotherapy resistance is the major cause of
treatment failure in patients with ovarian cancer, especially in
patients with advanced ovarian cancer \textsuperscript{{[}24{]}}. And
exosomes released in TME are prone to bring about chemotherapy
resistance. For instance, exosomal miRNA miR-1246 assists in
establishing paclitaxel resistance in ovarian cancer via targeting the
Cav1/p-gp/M2-type macrophage axis \textsuperscript{{[}25{]}}. Au
Yeung\emph{et al.} demonstrated that exosomes transfer stroma-derived
miR21 from cancer-associated adipocytes (CAAs) and fibroblasts (CAFs) to
the cancer cells, therefore helping ovarian cancer cells to develop
paclitaxel resistance through targeting APAF1
\textsuperscript{{[}26{]}}. And Zhu \emph{et al} . indicated that
macrophages-derived exosomes deliver miR-223 to epithelial ovarian
cancer (EOC) cells to elicit a chemo-resistant phenotype
\textsuperscript{{[}27{]}}. To put it more specifically, this study
emphasized the role of exosomes in the crosstalk between macrophages and
EOC cells for chemotherapy resistance through the exosomal
miR-223/PTEN-PI3K/AKT signaling pathway. Lately, a hypothesis has been
proposed that hypoxia-induced changes in exosomes composition and
bioactivity might render carboplatin resistant to target cells
\textsuperscript{{[}28{]}}. Conformably, hypoxia-induced exosomes carry
more STAT3 and FAS that are capable of inducing
chemo-resistance\textsuperscript{{[}29{]}}. Besides, plasma gelsolin
(pGSN) transported by exosomes upregulates HIF1\selectlanguage{greek}α-\selectlanguage{english}mediated pGSN
expression in chemo-resistant ovarian cancer cells in an autocrine
manner, coupled with leading to cisplatin resistance in other
chemo-sensitive ovarian cancer cells in a paracrine
manner\textsuperscript{{[}30{]}}. Notably, exosomes are also a direct
mechanism of intercellular drug transfer. What's more, exosomes promote
drug efflux in a drug concentration-dependent manner and exceed the
p-glycoprotein efflux when it is saturated \textsuperscript{{[}31{]}}.

\textbf{3.3 Role inimmune regulation}

The double-edged role of exosomes originating from TME in immune
regulation has gained continuously increasing attention. Most
tumor-associated exosomes have immunosuppressive effects, which
collectively inhibit the antitumor response of tumor-specific T cells
and induce the functional arrest of adoptively transferred
tumor-specific T cells or chimeric antigen receptor T
cells\textsuperscript{{[}32{]}}. Consistent with this, Zhou \emph{et
al.} found that exosomes released from tumor-associated macrophages
deliver miRNAs, including miR-29a-3p and miR-21-5p, into
CD4\textsuperscript{+} T cells, which could induce a Treg/Th17 cell
imbalance in EOC \textsuperscript{{[}33{]}}. Additionally, exosomes
carry PD-L1 on their surface, thus contributing to immunosuppression by
anti-PD-1 response \textsuperscript{{[}34{]}}. For immunosuppressive
exosomes, targeting exosomal phosphatidylserine by ExoBlock, a novel
PS-binding molecule, represents a promising strategy to enhance
antitumor T-cell responses in TME \textsuperscript{{[}35{]}}. However,
some exosomes have antipodal effects. In other words, these exosomes can
activate dendritic cells (DCs), natural killer cells, and T cells to
exert an antitumorigenic effect through stimulating both the innate and
adaptive immune systems \textsuperscript{{[}36{]}}. Since the immune
microenvironment of ovarian cancer is of considerable complexity,
supererogatory studies are required to help thoroughly understand the
role of exosomes in immune regulation to provide the possibility for
effectively designing immunotherapeutic regimens.

\textbf{4.Exosomes serve as biomarkers of ovarian cancer}

To date, in actual clinical application, the dominating diagnostic and
prognostic biomarkers of ovarian cancer have been carbohydrate antigen
125 (CA125) and human epididymis protein 4
(HE4)\textsuperscript{{[}37,38{]}}. Nevertheless, these markers usually
present superior sensitivity and poor specificity or vice versa and are
linked with several other pathological conditions. Recent studies have
revealed that exosomes turn out to be ideally noninvasive or
less-invasive biomarkers for ovarian cancer diagnosis and
monitoring\textsuperscript{{[}39{]}}. Because exosomes represent mobile
information regarding the molecular makeup of parental tumors and can be
conveniently detected in many physical fluids such as blood, urine,
saliva, and malignant effusions of ascites. In this section, we mainly
summarize exosomal proteins and miRNAs as diagnostic and prognostic
biomarkers of ovarian cancer (Figure 3). Remarkably, in addition to
exosomal proteins and miRNAs, long noncoding RNAs (lncRNAs) and
phosphatidylserine (PS) carried by exosomes can also be potential and
attractive biomarkers. For example, exosome-delivered lncRNA SOX2-OT
contributed to motility and proliferation of ovarian cancer cells and
was highly expressed in ovarian cancer. PS-expressing exosomes in
patient blood and ascites can be a surrogate biomarker for ovarian
cancer, since exosome membranes derived from the plasma membrane of
parental tumor cells commonly expose PS \textsuperscript{{[}40{]}}.

\textbf{4.1Exosomal proteins asbiomarkers}

Compared with exosomes derived from normal tissue, exosomes from ovarian
cancer contain some types of protein with significantly increased
levels, such as CD24 and Claudin-4, suggesting that exosomal protein can
serve as biomarkers probably connected with FIGO classification
\textsuperscript{{[}41,42{]}}. Other potential biomarkers, small heat
shock proteins have remarkably high expression levels in exosomes from
serum and peritoneal fluid of ovarian cancer patients, while more
studies are needed to exploit their diagnostic
value\textsuperscript{{[}43{]}}. In addition, the exosomal proteome of
the ovarian cancer ascites may provide monitoring for the therapeutic
response to different therapy strategies. Meshach\emph{et al.} have
reported that elevated expression of plasma gelsolin (pGSN) transported
by exosomes (Ex-pGSN), correlated with poorer overall survival and
relapse-free survival in patients with ovarian
cancer\textsuperscript{{[}30{]}}. Consistently, exosome-mediated pGSN
confers cisplatin resistance in chemosensitive ovarian cancer cells in
an autocrine manner. Indeed, in drug-resistant cancer cells derived
exosomes, chemoresistance-related proteins, such as annexin A3, MRP2,
ATP7A, and ATP7B, are highly expressed, indicating the potential value
to predict the effectiveness of chemotherapy methods in patients with
ovarian cancer\textsuperscript{{[}44{]}}. Surprisingly, a microfluidic
device enabled the isolation of exosomes and the establishment of their
protein profiles for the early detection of high-grade serous ovarian
cancer (HGSOC)\textsuperscript{{[}45{]}}.

\textbf{4.2Exosomal miRNAs as biomarkers}

While previous studies have reported that the aberrant expression of
miRNAs could represent diagnostic and prognostic markers for ovarian
cancer, most of these studies regarding miRNAs expression were based on
findings from tumor tissue specimens. MiRNA profiling of circulating
tumor exosomes in the patient's plasma has shown the clinical relevance
of exosomal miRNAs as circulating biomarkers for
cancer\textsuperscript{{[}46{]}}. Taylor\emph{et al.}have observed that
8 miRNAs of tumor-derived exosomes had specific expression in ovarian
cancer\textsuperscript{{[}47{]}}. Kanlikilicer \emph{et al.} have
reported that exosomal miR-6126 is ubiquitously released in high
abundance from both chemosensitive and chemoresistant ovarian cancer
cells \textsuperscript{{[}48{]}}. Furthermore, Pan \emph{et al.} have
found that miR-21, miR-100, miR-200b, and miR-320 were significantly
enriched in exosomes from plasma of EOC patients compared with those of
healthy women, whereas miR-16, miR-93, miR-126, and miR-223 were
down-regulated\textsuperscript{{[}49{]}}. In particular, the levels of
exosomal miR-200b and miR-200c correlate with the tumor marker CA125 and
patient overall survival in advanced EOC\textsuperscript{{[}50{]}}.
Additionally, ovarian cancer cell-secreted exosomal miR-205 was markedly
enriched in the serum of patients, and further research found that the
high level of exosomal miR-205 promoted ovarian cancer metastasis via
inducing angiogenesis \textsuperscript{{[}21{]}}. Conclusively, despite
the existing findings, we are still in sore need of more studies to
elucidate the feasibility of exosomal miRNAs in ovarian cancer diagnosis
and prognosis, further enabling exosomal miRNAs to be used in ovarian
cancer patients soon.

\textbf{5. Therapeutic Potential of Exosomes}

In this section, the therapeutic potential of exosomes will be
elucidated in the following three aspects, (1) exosome-mediated delivery
system, (2) exosome-based immunotherapy, and (3) exosomes as therapeutic
targets. Beyond that, we discuss future perspectives that exosomes can
serve as therapeutic modalities as well as therapeutic targets for
ovarian cancer treatment (Figure 3).

\textbf{5.1Exosome-mediated delivery system}

Compared to non-host vehicles, exosomes are startlingly stable in
circulation and do not elicit immune rejection. Consequently, their
clinical applications as agents delivery nanoplatforms can be leveraged
for treating ovarian cancer\textsuperscript{{[}51,52{]}}. Specifically,
not only can the advances of in bio-engineering nanotechnology enable
the encapsulation of therapeutic agents such as RNA, peptides, and
chemotherapeutic drugs into exosomes, but also modify the exosomes with
diverse ligands for tumor-targeting
strategies\textsuperscript{{[}53{]}}. For instance, Zhao\emph{et al.}
found that injection of RGD-modified exosomes loaded with miR-484 in
xenograft model induced vessel normalization and in turn sensitized the
ovarian cancer cells to chemotherapy\textsuperscript{{[}54{]}}.
Bioinspired hybrid nanoparticles, which were formed by CD47-expressing
exosomes and the target peptide cRGD-modified liposomes with miRNA-497
and triptolide, induced ovarian cancer cells apoptosis by inhibiting the
PI3K/AKT/mTOR signaling pathway and overcame drug resistance in ovarian
cancer via regulating macrophage polarization
\textsuperscript{{[}55{]}}. Besides, Pisano \emph{et al.} proposed that
development immune derived exosome mimetics (IDEM) as a scalable
biomimetic drug-delivery system can target and treat ovarian
cancer\textsuperscript{{[}56{]}}. This monocyte-derived exosome mimetic
can efficiently encapsulate doxorubicin with reduced immunogenicity.
Prominently, natural products, such as curcumin and triptolide, show
promising therapeutic effects on ovarian cancer, yet the low
bioavailability and non-specific selectivity often hinder their clinical
applications\textsuperscript{{[}57,58{]}}. Combining exosomes with these
natural anticancer products based on nanotechnology has exhibited its
high efficiency for the treatment of ovarian cancer
\textsuperscript{{[}59,60{]}}. Accordingly, a phase I clinical trial is
currently ongoing to investigate the feasibility and ability of plant
exosomes to deliver curcumin (NCT01294072).

\textbf{5.2 Exosomes-basedimmunotherapy}

Cancer immunotherapy is a novel type of treatment based on manipulating
the host immune system to reactivate the antitumor immune response
and/or overcome the pathway leading to tumor
escape\textsuperscript{{[}61{]}}. Evidence has revealed shown exosomes
generally contribute to immunosuppression and tumor immunity escapes via
a variety of biological mechanisms\textsuperscript{{[}62{]}}.
Explicitly, Li \emph{et al.} reported that ovarian cancer cells secrete
exosomes in TME to suppress antitumor immunity based on
lymphocyte-cancer cell cross-talk\textsuperscript{{[}63{]}}. And Peng
\emph{et al.} concluded that exosomes existing in ascites of ovarian
cancer patients induce apoptosis of cells in the immune system, such as
dendritic cells (DCs) and peripheral blood mononuclear cells
(PBMCs)\textsuperscript{{[}64{]}}. Therefore, eliminating
immunosuppressive exosomes in TME of ovarian cancer is expected to
enhance antitumor immune responses for immunotherapy. Unexpectedly, some
exosomes with immunogenicity can induce cytotoxic T lymphocyte-dependent
antitumor response\textsuperscript{{[}65{]}}. Previous studies
demonstrated that exosomes containing tumor antigens for APC activation,
which consequently manipulate the immune system to recognize and attack
cancer cells\textsuperscript{{[}66{]}}. In agreement, according to Li
\emph{et al} , ovarian cancer-derived exosomes with tumor-specific
antigens can be presented by dendritic cells (DCs) derived from
unrelated umbilical cord blood to induce tumor-specific
cytotoxicity\textsuperscript{{[}67{]}}. These provided another
perspective that exosomes may employ their immunogenicity to open new
avenues for immunization against ovarian cancer.

\textbf{5.3 Exosomes astherapeutic targets}

We considering that exosomes play pivotal roles in ovarian cancer
progression, and targeting exosomes have potential clinical implications
for therapy\textsuperscript{{[}68{]}}. Removing exosomes from peripheral
circulation and blocking exosome production and secretion from cancer
cells are the mainstay of exosome-targeting strategies. Studies\emph{in
vitro} have demonstrated the selective removal of exosomes from patient
blood by using Hemopurifier, an extracorporeal hemofiltration device
containing fibers with a high affinity for
exosomes\textsuperscript{{[}69{]}}. Apart from this, emerging evidence
has suggested that proteins of the Rab family of GTPases play an
important part in the biogenesis and secretion of
exosomes\textsuperscript{{[}70{]}}. Indeed, Ostrowski \emph{et al.}
found that Rab27a or Rab27b silencing reduces MVE docking to the plasma
membrane, hence indicating that targeted inhibition of the Rab27
subfamily led to reduced exosome secretion \textsuperscript{{[}71{]}}.
Moreover, the sphingomyelinase inhibitor GW4869 blocks the production of
exosomes through depleting ceramide, which is a part of exosomes
production \textsuperscript{{[}72{]}}. In ovarian cancer, GW4869
inhibited CD47 overexpressed-exosome secretion in TME and consequently
promoted phagocytosis by macrophages\textsuperscript{{[}73{]}}. In
conclusion, targeted elimination of exosomes as well as reducing exosome
production and secretion are useful for inhibiting the communication
between cancer cells and other cells, thus making them alternative
therapeutic strategies.

\textbf{6. Conclusions and Perspectives}

Over the past two decades, the spectacularly rapid development of
molecular biological techniques has magnificently contributed to the
breakthrough of discoveries in exosomes. As a part of TME, exosomes
exert a pivotal role in tumorigenesis, metastasis, drug resistance, and
immune regulation of ovarian cancer. Furthermore, due to their terrific
stability in body fluids and pathological features, exosomes have a
promising value for both ovarian cancer diagnosis and therapy.
Leveraging exosomes as a double-edged sword, novel strategies in ovarian
cancer therapy, such as stimulating exosomes secretion or eliminating
specific exosomes, are attractive. Nonetheless, on account of the
inestimable complexity of exosomes, more studies regarding the
involvement of exosomes in ovarian cancer are desperately needed to be
met prior to large-scale clinical utilization.

\textbf{Acknowledgements}

This work was supported by grants from the Medical Technology Project,
Health Commission of Sichuan Province (no.21PJ051), and Development and
Related Diseases of Women and Children Key Laboratory of Sichuan
Province (no. 2021YJ0011).

\textbf{Conflicts of Interest}

The authors declare no conflict of interest.

\textbf{Contribution to Authorship}

Conceptualization, C.B. and Q.C.; investigation, C.B. and Q.C.;
writing---original draft preparation, Q.C. and J.S.; writing---review
and editing, Q.C. and D.R.; visualization, J.S. and D.R.; supervision,
C.B. All authors have read and agreed to the published version of the
manuscript.

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