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Wang et al. Hepatoma Res 2020;6:61 I http://dx.doi.org/10.20517/2394-5079.2020.55 Page 11 of 15

In addition, the dynamic change of CTC counts reflected the treatment response in patients treated with
locoregional therapies, including TACE, radiotherapy, and radiofrequency ablation [63,71,102,103] . Li et al. [103]
found that the total number of CTCs and mesenchymal phenotype CTCs significantly increased three
days after percutaneous radiofrequency ablation of liver tumor. However, no significant correlation was
[104]
identified between changes in CTC levels and all the radiofrequency ablation factors. Recently, Rau et al.
demonstrated the clinical utilities of sequential CTC monitoring in a patient cohort (n = 17) with locally
advanced or metastatic HCC accepted systemic/targeted therapy. They found that a change in the CTC
count correlated with the patient treatment response in most of the cases and was particularly useful for
monitoring patients without elevated serum AFP levels.

Drug therapy is an important component of the comprehensive treatment of HCC. However, only a few
patients are sensitive to chemotherapy drugs. Compared with other liquid biopsy biomarkers, CTCs contain
more information on the functional characteristics and biological behaviors of tumor [105,106] . Thus, CTCs can be
[107]
a more relevant biomarker in guiding personalized therapeutic intervention for cancer patients. Yan et al.
monitored the effect of sorafenib on CTC count in an orthotopic HCC mouse model by IVFC. They showed
that the sorafenib treatment could dramatically reduce the number of CTCs, associated with a decreased
[108]
probability of lung metastasis. Zhu et al. . showed that the application of EGFR inhibitor could reduce CTC
numbers caused as a side effect of transcatheter arterial embolization. Moreover, Li et al. [109] presented a
novel system to simultaneously detect the expressions of the phosphorylated extracellular signal-regulated
kinase (pERK) and phosphorylated protein kinase B (pAkt) in CTCs. They showed that CTCs can be used
in place of tumor tissue for characterization of pERK/pAkt expression, and HCC patients with pERK+/
pAkt- CTCs were more sensitive to sorafenib treatment. Another potential application of CTCs in drug
therapy is to test the drug sensitivity by CTC culture. Zhang et al. [110] used a microfluidic chip to isolate and
release viable CTCs and then performed chemotherapeutic drug assay. The number of spheroids formed
by CTCs declined greatly when cultured with sorafenib or oxaliplatin. Furthermore, the novel single-cell
sequencing technology makes individual CTC profiling possible, which may provide more valuable drug
target information and guide individualized treatment in the future clinical practice [12,111,112] .

CONCLUSION
CTC analysis is an exciting field that is gaining increasing attention thanks to the significant technological
advancements in CTC isolation and detection. As an important component of “liquid biopsy”, CTC
analysis enables early cancer detection, prognosis prediction, therapy response monitoring, and novel
therapeutic target identification in patients with HCC. However, significant challenges still exist in
translating CTC analysis from bench to bedside. Most of the current studies in HCC used different
technologies or platforms to detect CTCs in a relatively small, single-centered cohort with widely varying
patient demographics, making it difficult to compare studies. Therefore, clinical utilities of CTC should
be validated in more multicenter, large, and long-term studies using a standardized CTC assay. Moreover,
CTCs hold great promise as a tool to deepen our knowledge of the complicated metastasis process. In
recent years, CTCs researches have moved beyond simple CTC enumeration towards more sophisticated
molecular analyses. Single-cell sequencing technology may pave the way for using CTCs to understand the
underlying mechanisms of cancer metastasis and provide critical insights for new therapeutic strategies.
Hopefully, routine CTCs evaluation will become a clinical reality in the near future.

DECLARATIONS
Authors’ contributions
Manuscript writing, design, planning: Wang PX, Cheng JW, Yang XR
Manuscript review and editing: Yang XR
Approved the final manuscript: Wang PX, Cheng JW, Yang XR