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Malentacchi et al. J Cancer Metastasis Treat 2020;6:34 I http://dx.doi.org/10.20517/2394-4722.2020.34 Page 11 of 18

Protein circulating than CA125
[77]
Only two studies investigated proteins related to EC. Tessitore et al. reported an increase of circulating
leptin in gynecological malignancies and breast cancer related to the increase of corresponding mRNA
in primary tumor tissue. This increase was related to cachexia and hormonal markers such as estrogen
receptor (ER) and progesterone receptor and, only in post-menopause, to an increase in circulating
estradiol.

[78]
Qu et al. evidenced the increase of serum epididymis protein 4 (HE4) level and suggested its use as a
biomarker for the management of ovarian and endometrial cancer patients.

mRNA
Recently, specific mRNAs have been investigated in LB of EC patients. Few studies have been conducted,
and a single article reports that hTERT mRNA was detected only in cancer patients in comparison to
[79]
healthy subjects and that levels increased with tumor stage .

Extracellular vesicles
Extracellular micro- and nano-membrane vesicles produced by different cells progressively attract
the attention of the scientific community. They function as mediators of intercellular communication
transporters of genetic material and signaling molecules between cells. In the context of keeping
homeostasis, extracellular vesicles contribute to the regulation of various systemic and local processes.
Exosomes, microvesicles, also referred to as microparticles or ectosomes, and large oncosomes were
defined as actively released vesicles.

Because extracellular vesicles (EVs) contents reflect the contents of the cell of origin, multiple studies on
EVs from body fluids, in the context of cancer diagnosis, prediction, and prognosis, have been performed.
EV-based LB provided an overview of the main EV constituents as potential biomarkers: surface proteins,
intravesicular soluble proteins, lipids, DNA, and RNAs, including mRNA (intact and fragmented), miRNA,
piwiRNA (piRNA), transfer RNA (tRNA), fragments of ribosomal RNA (rRNA), long noncoding RNA
[80]
(lncRNA), and circular RNAs (circRNAs) .
EVs have been identified as the main mediators of cell-to-cell communication between tumor and stromal
cells in local and distant microenvironments participating in the formation of the premetastatic niche prior
[81]
[82]
to CTC colonization . EVs can be involved in the response to immunotherapy , and, moreover, they
[83]
may be used as drug delivery systems . They can be isolated from several biospecimens such as blood,
urine, CSF, lymphatics, tears, saliva, nasal secretions, ascites, and semen.
Few studies have dealt with the investigation of EV levels in EC, and these studies were performed on
[84]
circulating EVs. In particular, Xu et al. explored the role of circRNAs in EVs isolated from the serum
of affected patients. They found 275 circRNAs to be differentially expressed, among which 209 were
upregulated and 66 downregulated. All circRNAs have been identified thanks to wide-expression analysis,
and two of them (hsa_circ_0109046 and hsa_circ_0002577) were confirmed by RT-qPCR.

An interesting article evidenced in advanced EC, via CellSearch® technology, the presence of CTCs in high-
risk EC patients. Those CTCs were characterized by an EMT-expression profile correlated with the increase
of EVs that have been found containing extracellular-matrix-like collagens (COL18A1), proteoglycans
(VCAN, AGRN, and HSPG2), glycoproteins (TNC), constituents of the cytoskeleton (ACTG1, TUBA1B,
and TUBB), integrins (ITGA3), and laminins (LAMA5). The above-cited proteins are all associated with
tumor cell adhesion to the endothelium and to the promotion of their adhesion and colonization at
distant sites. In particular, the authors found, by means of targeted proteomics, that the adhesion protein