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Page 2 of 15 Wang et al. Hepatoma Res 2020;6:61 I http://dx.doi.org/10.20517/2394-5079.2020.55

INTRODUCTION
Hepatocellular carcinoma (HCC) is the sixth most prevalent malignancy worldwide and is currently
[1]
listed as the fourth leading cause of cancer-related death . HCC is a highly aggressive neoplasm; distant
[2]
organ metastasis can occur at a very early stage . Thus, early detection of HCC is of great importance
in the management of HCC. Surgical resection or liver transplantation remains the primary therapy for
HCC patients. However, only approximately 20%-30% of patients are eligible for surgical intervention
[3]
at the time of the first diagnosis, most patients have already reached an advanced cancer stage . The
5-year survival rate of HCC with Barcelona Clinic Liver Cancer (BCLC) stage 0-A treated with curative
therapeutic modalities is 40%-70%, but the median overall survival (OS) for patients with BCLC stage B-C
[4]
is only 11-20 months . Even after curative resection, the five-year cumulative recurrence rate is 50%-70%,
which results in the unsatisfactory long-term outcomes of HCC patients . Currently, early detection or
[5,6]
monitoring HCC recurrence mainly relies on imaging examinations and serum tumor biomarkers such as
alpha-fetoprotein (AFP); however, their diagnostic sensitivity is limited and often fails to foresee the tumor
[7,8]
metastatic potential . Therefore, there is an unmet need for reliable biomarkers for early HCC detection
and tumor recurrence monitoring.

In recent years, various “liquid biopsy” techniques have emerged and shown significant promise as novel
biomarkers for HCC. Liquid biopsy represents a modality of collecting bodily fluids instead of solid tissue
for pathophysiological or sequencing analysis. Liquid biopsy offers a solution that can bypass the problems
[9]
of invasive biopsy procedures, enabling repeated and real-time disease status monitoring . Circulating
tumor cells (CTCs) and circulating tumor DNA are two of the most widely studied biomarkers in liquid
[10]
biopsy . CTCs are the cells that derive from the primary or metastatic lesions and migrate into circulation
and are regarded as the “seeds” of tumor metastasis . CTCs represent a unique liquid biopsy form that
[11]
is different from any of the existing cancer biomarkers, as they are a sampling of the patient’s live tumor
cells, carrying comprehensive biological information of the primary tumor, including genomic mutations,
[12]
cancer subtypes, and drug sensitivity . CTC research has flourished over the past decade, spanning fields
including CTC detection, identification of prognostic significance, and evaluation for treatment response
and disease surveillance [13,14] .

In the context of HCC, excellent progress has been made using CTCs as blood-based biomarkers [9,14,15] .
Herein, to gain comprehensive insight into the role of CTCs in HCC, this review article provides an
overview of their biology, detection technologies, and clinical significance in HCC.

OVERVIEW OF CTC BIOLOGY
TM
To date, the definition of CTC from CellSearch system is considered as the current standard: a CTC is an
intact nucleated epithelial cell, expressing epithelial cell adhesion molecule (EpCAM) and/or cytokeratin
[16]
+
8, 18, and 19, and negative for the leukocyte-biomarker CD45 . EpCAM CTCs were also identified as a
[17]
stem cell-like subpopulation in HCC, with a highly invasive and metastatic capacity .
[18]
Thousands of tumor cells are shed into the bloodstream everyday ; however, most CTCs are eliminated
in the bloodstream by shear stress, immune attack, and anoikis [11,19] . Only a small number of viable and
highly metastatic subpopulations of CTCs could eventually survive and develop into metastatic lesions [20-22] .
However, the biological mechanism of how CTCs survive the bloodstream and home to distant organs
remains largely unknown. CTCs may undergo several adaptations to survive in a hostile environment.
A recent study used in vivo genome-wide CRISPR to screen and identify a subset of CTCs with the
deregulation of ribosomal protein expression and translation. This CTC subset was significantly associated
[23]
with enhanced metastatic capabilities and poor clinical outcome . Meanwhile, one of the key biological
events is epithelial-to-mesenchymal transition (EMT), during which CTCs downregulate epithelial
markers such as E-cadherin and gain mesenchymal markers, thus acquiring increased ability to invade the