Detection of circulating tumor cells in hepatocellular carcinoma: applications in diagnosis, prognosis prediction and personalized treatment

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is associated with poor clinical prognosis, which is mainly caused by tumor recurrence and metastasis. Circulating tumor cells (CTCs) are tumor cells shed into the bloodstream and regarded as the "seeds" of tumor recurrent or metastatic lesions. Over the past decade, the clinical value of CTC analysis has been extensively explored. CTC analysis is a representative form of liquid biopsy, offering a novel solution that can bypass the problems of invasive biopsy procedures, enabling comprehensive, non-invasive, and real-time disease monitoring. In HCC, CTC analysis has facilitated early detection and prognosis prediction, as well as treatment monitoring and therapeutic intervention guiding. In this review, we summarize available literature and provide an overview of CTC biology, detection technologies, and clinical applications in the diagnosis, prognosis prediction, and personalized treatment of HCC.

A Seven-Gene Signature to Predict Prognosis of Patients With Hepatocellular Carcinoma

“…With the advent of the molecular signatures and high-throughput data platforms, several novel methods have been proposed as prognostic prediction models for the patients with HCC ( Dvorchik et al, 2007 ; Marquardt et al, 2012 ). At present, the pretreatment neutrophil–lymphocyte ratio ( Najjar et al, 2018 ; Hong et al, 2020 ), circulating tumor cells ( Qi et al, 2018 ; Wang et al, 2020 ), and cancer-related differentially expressed genes ( Sarathi and Palaniappan, 2019 ; Wang et al, 2019 ) have been used to predict the prognosis of patients with HCC, whereas most of those prediction models incorporated only one prognostic factor of HCC or lacking another prospective validation, resulting far away from the consensus of molecular prognostic prediction. Consequently, an objective and clinically ready prognostic prediction model is urgently required for the patients with HCC undergoing surgical resection, to determine whether or not adjuvant therapies are warranted for an individual patient.…”

Cellular, Molecular and Proteomic Characteristics of Early Hepatocellular Carcinoma

“…Having said that, detection of HCC at very early stages is still a challenging task. Recent sophisticated omics techniques have been applied for HCC and have reported possible prognostic models based on molecular signatures, but with low sensitivity and accuracy [ 17 , 18 , 19 ]. Consequently, the necessity of the development of more accurate and sensitive tools guiding early diagnosis and prognostic assessments in HCC patients remains.…”

“…The threshold cycles (Ct) generated by the qPCR system were used to calculate relative gene expression levels between different samples [ 13 , 19 ]. Briefly, the Ct of the target gene was subtracted from the Ct of the reference gene for the two groups, and the relative expression of each sample was determined using the 2 −ΔΔCt method.…”

“…The average calibrator ΔCq value in EPCAM was obtained from these samples, and individual ΔCqs of the calibrator were within 2 SDs of the average calibrator ΔCq value. Samples were classified as positive for a particular gene if the 2 −ΔΔCq was 2.0 or more (i.e., 100% or more than what is found in healthy blood) [ 19 ]. Additionally, prior to the determination of the cutoff points that would define positive from negative patients in the case of CTC and miRNA markers’ ROC, curve analysis was carried out using biomarkers’ continuous variables ( Figure S1 ).…”

Changes in Wnt and TGF-β Signaling Mediate the Development of Regorafenib Resistance in Hepatocellular Carcinoma Cell Line HuH7

“…The inter and intra-tumor heterogeneity of HCC plays a critical role in determining the patient’s therapy response. Thus, the future therapy direction of HCC should be focused on personalized treatment regimens and stratification of patients based on the efficacy of targeted therapies on HCC tumors with different molecular signatures (i.e., driver mutations, activated pathways) ( Couri and Pillai, 2019 ; Pérez et al, 2020 ; Wang et al, 2020 ).…”