The epithelial–mesenchymal transition (EMT) is closely associated with the acquisition of aggressive traits by carcinoma cells and is considered responsible for metastasis, relapse, and chemoresistance. Molecular links between the EMT and cancer stem cells (CSCs) have indicated that EMT processes play important roles in the expression of CSC-like properties. It is generally thought that EMT-related transcription factors (EMT-TFs) need to be downregulated to confer an epithelial phenotype to mesenchymal cells and increase cell proliferation, thereby promoting metastasis formation. However, the genetic and epigenetic mechanisms that regulate EMT and CSC activation are contradictory. Emerging evidence suggests that EMT need not be a binary model and instead a hybrid epithelial/mesenchymal state. This dynamic process correlates with epithelial–mesenchymal plasticity, which indicates a contradictory role of EMT during cancer progression. Recent studies have linked the epithelial–mesenchymal plasticity and stem cell-like traits, providing new insights into the conflicting relationship between EMT and CSCs. In this review, we examine the current knowledge about the interplay between epithelial–mesenchymal plasticity and CSCs in cancer biology and evaluate the controversies and future perspectives. Understanding the biology of epithelial–mesenchymal plasticity and CSCs and their implications in therapeutic treatment may provide new opportunities for targeted intervention.

Hepatocellular carcinoma (HCC) is a common malignancy worldwide, and the high ratio of recurrence and metastasis remains the main cause of its poor prognosis. Vascular invasion of HCC includes microvascular invasion (MVI) and portal vein tumor thrombosis (PVTT) and is regarded as a common roadmap of intrahepatic metastasis in HCC. However, the molecular mechanism underlying vascular invasion of HCC is largely unknown. Here, we analyzed the transcriptomes of primary tumors, PVTT tissues, and tumor tissues with or without MVI. We found that extracellular matrix-related pathways were involved in vascular invasion of HCC and that decorin secreted by cancer-associated fibroblasts was gradually downregulated from normal to tumor tissues and more so in PVTT tissues. We also established that low-level decorin expression is an independent risk factor for MVI and it is associated with a poor prognosis. Decorin downregulated integrin β1 and consequently inhibited HCC cell invasion and migration in vitro. Co-staining DCN and integrin β1 revealed that DCN dynamically regulated integrin β1 protein expression. Integrin β1 knockdown significantly inhibited HCC invasion and migration, and decorin combined with such knockdown synergistically augmented the anti-metastatic effects. Co-IP assay confirmed the direct interaction of decorin with integrin β1. Our findings showed that targeting cancer-associated fibroblast-related decorin is not only a promising strategy for inhibiting HCC vascular invasion and metastasis but also provides insight into the clinical treatment of patients with PVTT.

No abstract

Background: Hepatectomy is the most common treatment for hepatocellular carcinoma (HCC) meeting the Milan criteria; however, postoperative early recurrence (PER) compromises the survival time. This study aimed to construct a predictive nomogram for PER of HCC patients within the Milan criteria. And the underlying mechanism related to PER may associate with the independent risk factors used to construct the nomogram, therefore, we preliminarily investigated the potential mechanism of PER using The Cancer Genome Atlas (TCGA) database to provide an idea for preventing PER. Methods: Patients with HCC meeting the Milan criteria receiving hepatectomy in our center between 2009 and 2015 were enrolled. The clinical and histological data of all participants were collected. Followup was performed at outpatient and PER was defined as recurrence within 2 years after resection. All participants were randomly assigned to the training or validation cohort at a 4:1 ratio. A nomogram was constructed based on the independent risk factors in the training cohort. The accuracy and clinical utility of this nomogram were evaluated using the C-index, calibration plot, and decision curve analysis (DCA). The differentially-expressed genes (DEGs) between early-stage HCC patients with and without PER in TCGA database were identified. Enrichment analysis was performed to determine the potential relapse-related mechanism. Results: The independent risk factors were alpha-fetoprotein (AFP) ≥400 ng/mL, gamma-glutamyl transpeptidase (GGT) ≥60 U/L, Glisson's capsule invasion, microvascular invasion (MVI), and satellite lesions. The C-index value of the nomogram was 0.693 [95% confidence interval (CI): 0.632-0.754; P<0.001] in the training cohort and 0.658 (95% CI: 0.529-0.787; P=0.016) in the validation cohort. The calibration and decision curves demonstrated good accuracy and clinical utility of this nomogram respectively. 133 DEGs were identified and enrichment analysis showed the bile secretion pathway related to PER and two bile secretion pathway-related genes {ATP1A2 [P=0.027; hazard ratio (HR) =2.086, 95% CI: 0.916-4.749] and SLC5A1 (P=0.0016; HR =0.361, 95% CI: 0.145-0.898)} were significantly associated with disease free survival (DFS). Conclusions: Our nomogram has satisfactory accuracy and clinical utility in predicting the PER of patients with HCC meeting the Milan criteria. Aberrant bile secretion may be an important mechanism of PER.

Background Liver cirrhosis is a well-known risk factor for carcinogenesis of hepatocellular carcinoma (HCC). The aim of the present study was to construct individual prognostic models for HCC with cirrhosis. Methods The clinical differences between HCC patients with and without cirrhosis were compared using a large cohort of 1003 cases. The patients with cirrhosis were randomly divided into a training cohort and a validation cohort in a ratio of 2:1. Univariate and multivariate analyses were performed to reveal the independent risk factors for recurrence-free survival (RFS) and overall survival (OS) in HCC patients with cirrhosis. These factors were subsequently used to construct nomograms. Results Multivariate analyses revealed that five clinical variables (hepatitis B e antigen (HBeAg) positivity, alpha-fetoprotein (AFP) level, tumour diameter, microvascular invasion (MVI), and satellite lesions) and seven variables (HBeAg positivity, AFP level, tumour diameter, MVI, satellite lesions, gamma-glutamyl transpeptidase level, and histological differentiation) were significantly associated with RFS and OS, respectively. The C-indices of the nomograms for RFS and OS were 0.739 (P < 0.001) and 0.789 (P < 0.001), respectively, in the training cohort, and 0.752 (P < 0.001) and 0.813 (P < 0.001), respectively, in the validation cohort. The C-indices of the nomograms were significantly higher than those of conventional staging systems (P < 0.001). The calibration plots showed optimal consistence between the nomogram-predicted and observed prognoses. Conclusions The nomograms developed in the present study showed good performance in predicting the prognoses of HCC patients with hepatitis B virus-associated cirrhosis.