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Page 2 of 9 Pastor et al. J Cancer Metastasis Treat 2020;6:39 I http://dx.doi.org/10.20517/2394-4722.2020.57

Pheidippides, one of the first marathon runners in 490 BC, is said to have run from Marathon to Athens
acting as a messenger to provide news of the victory of the battle of Marathon. He ran approximately 240 km
in two days from Athens to Sparta. Similar to the hemerodromes, exosomes serve as an intercellular
[9]
communication system between different cells . Pheidippides died after completing his mission. Most
[8]
probably, the exosomes are depleted as well once the message has been sent . They are produced by all cell
[9]
types, both healthy and malignant cells . They contain a variety of functional proteins and genetic cargo
such as DNA, mRNAs, miRNAs, and long non-coding RNAs.
Tumor-derived exosomes (TEX) share the characteristics of their parental cell but are known to enrich
certain factors. It is thought that there is a new chapter in biology behind this: exosomes seem to be part of
[10]
a messaging system and can deliver specific signals to distant cells . Because of these features, exosomes
are ideal candidates as non-invasive biomarkers, also called “liquid biopsy” . It is essential to mention
[10]
[11]
that exosome levels rise during pathological changes and decrease during convalescence , and therefore,
their protein content is highly informative . Thus far, therapy monitoring tools lag in oncology. As such,
[12]
PET/CT-scan is said to be one of the most sensitive imaging modalities in clinical routine: cancer detection
is only visible on the scan above 4 mm, and it cannot be performed monthly. Besides, other current
diagnostic tools such as endoscopy are invasive and may put the patient at risk of potential complications.
These facts point towards the use of exosomes as a diagnostic tool as non-invasive biomarkers to set the
[11]
patient at minimal risk .
TEX are highly enriched in HNSCC patients’ plasma. They carry several immunosuppressive proteins
and molecules, facilitating the epithelial-to-mesenchymal transition (EMT). Recent analysis alludes that
cancer therapies can affect the morphology and behaviour of tumor cells, somewhat encouraging rather
[13]
than inhibiting EMT. Moreover, TEX participate in the regulation of EMT, as shown by Franzen et al. ,
[15]
[14]
Min et al. and Theodoraki et al. . Most of the experiments on showing exosome involvement in EMT
have been conducted with cell lines or in mouse models. Besides, it has been shown that TEX isolated from
HNSCC patients’ plasma are highly immunosuppressive. TEX provoke immune cell dysfunction by acting
on immune cells through several mechanisms: they hinder the functions needed for antitumor responses,
programmed cell death of activated T effector cells, proliferation of suppressive activity in regulatory T
and B cells, manipulation of cellular differentiation and transfer of cells to the tumor . They bear immune
[16]
checkpoint proteins such as PD-1, PD-L1, and CTLA-4. PD-L1 exosomes produced by either normal or
tumor cells can alter immune responses and therefore affect disease activity . Since PD-1 and especially
[17]
PD-L1 inform about disease activity, it proves that exosomes can function as disease biomarkers.

TEX portray the communication network of the tumor to trigger autocrine, juxtacrine, and paracrine
[12]
signaling between several cells . They convey autocrine signals that lead to tumor progression.
Furthermore, they induce the production of cytokines, chemokines, growth factors and tumor
necrosis factor alpha (TNF-α). These factors represent juxtacrine and paracrine signaling which is the
communication with immune cells infiltrating tumors and stimulate the production of soluble factors
enhancing tumor growth .
[12]

There is an immune response modulation from exosomes released by cancer cells. These exosomes carry
damage-associated molecular patterns (DAMPs) such as DNA and RNA to myeloid cells as shown by
[18]
Kurywchak et al. : “Cancer cells release exosomes that carry DAMPs such as DNA and RNA to myeloid
cells which activate the intracellular virus-sensing pathways cyclic GMP-AMP synthase - stimulator of
interferon genes, retinoic acid-inducible gene I, and absent in melanoma 2 (AIM-2), and stimulate the
[18]
production of inflammatory cytokines such as interleukin (IL)-6, TNF-α, IL-8, and IL-1β.” .

Additionally, cancer exosomes have the characteristic to generate new vessel formation, which allows an
influx of oxygen and nutrients and waste removal and impact the metabolic reprogramming of cancer