Clinical Implication of Circulating Tumor Cells Expressing Epithelial Mesenchymal Transition (EMT) and Cancer Stem Cell (CSC) Markers and Their Perspective in HCC: A Systematic Review

SIMPLE SUMMARY: One of the major problems regarding hepatocellular carcinoma (HCC) is the development of metastasis and recurrence, even in patients with an early stage. Recently, circulating tumor cells (CTCs) enumeration has been intensively studied as a diagnostic and prognostic biomarker in HCC. Nevertheless, increasing evidence suggests the role of metastasis-associated CTC phenotypes, including epithelial–mesenchymal transition (EMT)-CTCs and circulating cancer stem cells (CCSCs). We performed a systematic review to investigate the correlation of different CTC subtypes with HCC characteristics and their prognostic relevance to clinical outcomes. A preliminary meta-analysis found that CTC subtypes had prognostic power for predicting the probability of early recurrence. This study highlights the potential of CTC subtyping analysis as a biomarker for HCC management and provides information on metastasis-associated CTCs for a deeper molecular characterization of specific CTC subtypes. ABSTRACT: Circulating tumor cells (CTCs) play a key role in hematogenous metastasis and post-surgery recurrence. In hepatocellular carcinoma (HCC), CTCs have emerged as a valuable source of therapeutically relevant information. Certain subsets or phenotypes of CTCs can survive in the bloodstream and induce metastasis. Here, we performed a systematic review on the importance of epithelial–mesenchymal transition (EMT)-CTCs and circulating cancer stem cells (CCSCs) in metastatic processes and their prognostic power in HCC management. PubMed, Scopus, and Embase databases were searched for relevant publications. PRISMA criteria were used to review all studies. Twenty publications were eligible, of which 14, 5, and 1 study reported EMT-CTCs, CCSCs, and both phenotypes, respectively. Most studies evaluated that mesenchymal CTCs and CCSCs positivity were statistically associated with extensive clinicopathological features, including larger size and multiple numbers of tumors, advanced stages, micro/macrovascular invasion, and metastatic/recurrent disease. A preliminary meta-analysis showed that the presence of mesenchymal CTCs in pre- and postoperative blood significantly increased the risk of early recurrence. Mesenchymal-CTCs positivity was the most reported association with inferior outcomes based on the prognosis of HCC recurrence. Our finding could be a step forward, conveying additional prognostic values of CTC subtypes as promising biomarkers in HCC management.