Introduction
Cancer is a highly complex disease that is characterized by evolving
pathophysiological processes [1]. Hence, treatment decisions are
typically made according to the manifestation and progression of the
primary tumor [2]. Currently, tissue biopsy technology,
which excises or punctures
diseased tissue from the patient for pathological examination, is
considered the “gold standard” for cancer diagnosis and treatment
[3]. Nevertheless, as various tumor entities originate from internal
organs, acquiring diseased tissue can be highly risky and challenging.
Furthermore, clones differentiate into various subpopulations during the
biological process of tumorigenesis, resulting in tumor heterogeneity
[4,5]. This diversity and plasticity cannot be detected in
single-tissue biopsy samples owing to their spatial and temporal
heterogeneity, making it difficult to acquire comprehensive information
on the genetic and epigenetic variability of cancer [6].
Compared to tissue biopsy, liquid biopsy (LB) is a
minimally invasive diagnostic tool
that is less wound-inducing and can be conducted frequently, allowing
longitudinal monitoring of the
dynamic changes in tumors and thereby its malignancy [7]. Thus, a
straightforward assessment of tumor metastases and the biochemical
changes during blood-borne cancer dissemination becomes possible by cell
or molecular monitoring. In contrast
to tissue biopsy, LB mainly involves analyzing circulating tumor cells
(CTCs), circulating cell-free
nucleic acids, and exosomes from the peripheral blood of patients with
cancer (Fig. 1) [8,9]. CTCs are cancer cells that actively or
passively escape from the primary tumor site to the bloodstream and are
regarded as the culprits of cancer metastasis. CTC analysis has the
potential to provide disease-related information on tumor composition,
invasiveness, drug susceptibility, and treatment resistance [10,11].
Circulating cell-free nucleic acids, which mainly comprise circulating
cell-free DNA (cfDNA), are typically discharged from apoptotic and
necrotic tumor cells into the bloodstream [12]. Most cfDNA
originates from non-malignant cells, whereas circulating tumor DNA
(ctDNA) derived from tumor cells typically accounts for 0.1–10% of the
total cfDNA, depending on the tumor burden, inflammatory status,
cellular turnover, and accessibility of cancer cells to the blood
vessels [13]. Therefore, cell-free nucleic acid analysis can provide
detailed information relevant to cancer diagnosis and therapy [14].
Exosomes are extracellular vesicles secreted by healthy and tumor cells,
containing proteins, RNA, and DNA from patients’ tumors [15]. Thus,
tumor-derived exosomes can indicate the nature and status of tumor
entities, as they contain all cellular contents originating from their
tumor cells.