Abstract
BackgroundGrowing evidence suggests that circulating tumor cell (CTC) clusters may be an important factor in the metastatic process, but their role in hepatocellular carcinoma (HCC) remains unclear. This study aimed to characterize the molecular and clinical features of CTC cluster-positive human HCC and to assess its prognostic value in HCC patients.MethodsThe CTCs and CTC clusters were evaluated in 204 HCC patients using CellSearch™ System. The counts of CTCs and CTC clusters were correlated with different clinical features, while their associations with progression-free survival (PFS) and overall survival (OS) were evaluated integrally and hierarchically by Kaplan–Meier estimates or Cox proportional regression analysis. Five cases each of CTC cluster-negative and cluster-positive patients were selected for RNA-sequencing analysis. The results of gene enrichment analysis were further verified using tissue microarray (TMA) by immunohistochemistry (IHC).ResultsCTCs and CTC clusters were detected in 76 (37.3%) and 19 (9.3%) of 204 preoperative samples, respectively. CTC cluster-positive HCC represented an aggressive HCC phenotype with larger tumor size, more frequent microvascular invasion, and higher tumor stages. The survival of HCC patients utilizing CTCs and CTC clusters individually showed prognostic significance, while joint analysis revealed patients in Group III (CTC ≥ 2 and CTC cluster > 0) had the worst outcome. Stratified analysis of outcomes in Barcelona Clinic Liver Cancer (BCLC) and tumor–node–metastasis (TNM) stages indicated that patients with CTC clusters had significantly poorer prognosis in each stage than those without CTC clusters. Moreover, the RNA sequencing and TMA staining results showed that CTC cluster-positive HCCs were usually associated with Wnt/β-catenin signaling activation.ConclusionThe presence of CTC clusters characterizes an aggressive HCC subtype. CTC clusters may be used as a biomarker in predicting the prognosis on each stage of malignancy in HCC, which provides evidence for formulating therapeutic strategies for more precise treatment.
Highlights
Tumor metastasis describes the spread of a solid tumor from the primary site to other distal organs, which diffuse through the blood circulation, and causes a worse prognosis in a variety of cancer diseases
The results showed that surgical liver resection was associated with an increase in circulating tumor cells (CTCs) counts, and increased postoperative CTC numbers were associated with a worse prognosis in patients with hepatocellular carcinoma (HCC) [12]
Patients with CTC clusters were significantly associated with liver cirrhosis, tumor size, microvascular invasion (MVI), Barcelona Clinic Liver Cancer (BCLC) stage, and tumor–node– metastasis (TNM) stage (p < 0.05) than patients without them
Summary
Tumor metastasis describes the spread of a solid tumor from the primary site to other distal organs, which diffuse through the blood circulation, and causes a worse prognosis in a variety of cancer diseases. Tumor cells that detach from the primary cancer and enter the systemic vasculature are defined as circulating tumor cells (CTCs). Many studies have verified that the number of CTCs could be used as a biomarker in the auxiliary diagnosis of cancer to evaluate the curative effects of radiotherapy and chemotherapy and to predict recurrence and metastasis in several cancers [1,2,3,4]. In hepatocellular carcinoma (HCC), a National Institutes of Health (NIH)sponsored clinical trial (NCT02973204) to study CTCs as a clinical auxiliary tool for HCC is underway. Growing evidence suggests that circulating tumor cell (CTC) clusters may be an important factor in the metastatic process, but their role in hepatocellular carcinoma (HCC) remains unclear. This study aimed to characterize the molecular and clinical features of CTC cluster-positive human HCC and to assess its prognostic value in HCC patients
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