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Page 2 of 10 Schulze et al. J Cancer Metastasis Treat 2020;6:42 I http://dx.doi.org/10.20517/2394-4722.2020.79
[2-5]
Exosomes are nanosized extracellular vesicles which are secreted by various cells throughout the body .
They carry important bioactive molecules including proteins, lipids, DNA (e.g., mitochondrial DNA
and genomic DNA), and RNAs [e.g., microRNAs (miRNAs), long non coding RNAs (lncRNAs), and
messenger RNA (mRNA)], and can transfer them to the recipient cells - thus playing a crucial role in cell-
[2-6]
cell communication . Exosomes are present in most bodily fluids including blood, breast milk, saliva,
[2-6]
urine, bile, pancreatic juice, cerebrospinal, and peritoneal fluids . Through the circulating flow, they
can transfer from their original cells to distant tissues where they localize to target cells by binding their
[2-6]
surface molecules to receptors on the surface of the target cells . Due to the advantage of their unique
biocompatibility and high stability, exosomes have attracted great interest in cancer treatment as an
effective anti-cancer drug delivery carrier or gene carrier. In this review, we provide an overview for studies
of exosomes application in cancer therapies, as well as their advantages and challenges.

DUAL ROLES OF EXOSOMES IN TUMORIGENESIS
According to the exosome database ExoCarta (www.exocarta.org), 9,769 proteins, 3,408 mRNA, 2,838 miRNA,
[7]
and 1,116 lipids have been identified in exosomes from different organisms and bodily fluids . By
transferring bioactive molecules from the donor cells to the recipient cells, exosomes play crucial roles in
cell-cell communication . Many studies have shown that cancer cells release a larger number of exosomes
[2-5]
to exchange information with other cells both nearby and at distance [8-10] . Through delivering their
bioactive cargoes (including proteins, miRNAs, and lncRNAs), cancer cell-derived exosomes contribute to
the formation of the pre-metastatic microenvironment, tumor growth and progression, immune escape,
angiogenesis, anti-apoptotic signaling, drug-resistance, and so on [8-10] [Figure 1]. Meanwhile, exosomes
from healthy cells, su ch as dendritic cells (DCs), B cells, and T cells, play an important role in inhibiting

tumor growth [11-14] [Figure 1]. To date, numerous miRNAs, lncRNAs, and proteins have been found to
play important roles in cancer progression [Table 1]. Therefore, depending on their cell of origin and their
bioactive cargo, exosomes can play dual roles in cancer regulation, either inhibiting or promoting growth.

EXOSOME-BASED CANCER THERAPIES
Since exosomes can unload bioactive cargo to cancer cells, they have attracted great interest in cancer
treatment [66-72] . Currently, several different methods have been developed for cancer therapies: (1) using
[66]
naturally derived exosomes from immune cells to suppress cancer cells ; (2) inhibiting the release of
[69]
cancer-derived exosomes; (3) using exosomes as gene carriers ; and (4) using exosomes as anti-cancer
drug carriers [68,71] [Figure 2].
Naturally derived exosomes for cancer therapy
In cancer-immunity, DCs are involved in the first step of tumor cell growth inhibition by capturing
neoantigens and triggering the tumor-specific cytotoxic lymphocyte response . DC-derived exosomes
[73]
(Dex) contain various bioactive cargoes responsible for antigen presentation, making them ideal for the
[76]
treatment of cancer [74,75] . In 1998, Zitvogel et al. found that tumor peptide-pulsed Dex were able to
activate the antigen-specific cytotoxic T lymphocytes response in vivo and eradicate or suppress growth of
[77]
established murine tumors in a T cell-dependent manner. Moreover, Munich et al. found that Dex can
directly kill tumor cells and activate naturel killer (NK) cells through TNF superfamily ligands. It has also
been found that cancer cell-derived exosomes have an immunostimulatory effect on anti-tumor DCs .
[66]
Thus, Dex represent an important strategy for cancer therapy.

Interfering with cancer cell-derived exosomes for cancer therapy
Cancer cell-derived exosomes are considered to accelerate cancer pathogenesis by contributing to the
formation of the pre-metastatic microenvironment, tumor growth and progression, immune escape,
angiogenesis, anti-apoptotic signaling, and drug-resistance [8-10] . Therefore, inhibition of the cancer cell-