Epithelial-to-mesenchymal plasticity of cancer stem cells: Therapeutic targets in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains one of the most common and lethal malignancies worldwide despite the development of various therapeutic strategies. A better understanding of the mechanisms responsible for HCC initiation and progression is essential for the development of more effective therapies. The cancer stem cell (CSC) model has provided new insights into the development and progression of HCC. CSCs are specialized tumor cells that are capable of self-renewal and have long-term repopulation potential. As they are important mediators of tumor proliferation, invasion, metastasis, therapy resistance, and cancer relapse, the selective targeting of this crucial population of cells has the potential to improve HCC patient outcomes and survival. In recent years, the role of epithelial-to-mesenchymal transition (EMT) in the advancement of HCC has gained increasing attention. This multi-step reprograming process resulting in a phenotype switch from an epithelial to a mesenchymal cellular state has been closely associated with the acquisition of stem cell-like attributes in tumors. Moreover, CSC mediates tumor metastasis by maintaining plasticity to transition between epithelial or mesenchymal states. Therefore, understanding the molecular mechanisms of the reprograming switches that determine the progression through EMT and generation of CSC is essential for developing clinically relevant drug targets. This review provides an overview of the proposed roles of CSC in HCC and discusses recent results supporting the emerging role of EMT in facilitating hepatic CSC plasticity. In particular, we discuss how these important new insights may facilitate rational development of combining CSC- and EMT-targeted therapies in the future

Epithelial-to-mesenchymal transition: A mediator of sorafenib resistance in advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide and its incidence is steadily rising. Currently, sorafenib remains the only approved standard treatment for patients with advanced HCC, as it has proven to increase survival in these patients. However, clinical and preclinical observations indicate that sorafenib treatment may have limited efficacy due to tumor progression from the rapid development of acquired resistance. Elucidation of the underlying mechanisms of evasive resistance to sorafenib is a major challenge in HCC research. In recent years, the role of epithelial-to-mesenchymal transition (EMT) in the advancement of HCC and development of drug resistance has gained increasing attention. EMT is a developmental multistep molecular and cellular reprogramming process that is hijacked by cancer cells to enable aggressiveness. In this review, we provide an overview of the currently available preclinical studies on the EMT mechanisms underlying resistance to sorafenib treatment. Recent studies report enrichment of cancer stem cells (CSCs) after sorafenib treatment. Interestingly, EMT process has been implicated in the generation of CSCs associated with therapy resistance. We discuss how combination of sorafenib with EMT inhibitors could enhance the clinical response to sorafenib, resulting in longer duration of responses, than observed with sorafenib monotherapy. In particular, we discuss how these new insights may facilitate rational development of combination therapies in the future to impact survival of patients with advanced HCC

Additional file 3: Figure S3. of Transketolase-like 1 ectopic expression is associated with DNA hypomethylation and induces the Warburg effect in melanoma cells

TKT and TKTL2 expression in melanoma cells. (A) TKT, (B) TKTL1 and (C) TKTL2 expression in LM-MEL-59 after treatment with two TKTL1 siRNAs or control siRNA for 72 h. Testis tissue was used as positive control for the expression of TKT, TKTL1 and TKTL2. (PPTX 69 kb

Additional file 5: Figure S5. of Transketolase-like 1 ectopic expression is associated with DNA hypomethylation and induces the Warburg effect in melanoma cells

TKTL1 expression in melanoma affects proliferation of cells. (A) Measurement of absorbance of LM-MEL-59 cells after TKTL1 siRNA or control siRNA treatment for 48 h by performing MTS assay. (B) Measurement of absorbance of LM-MEL-44 cells after overexpression of TKTL1 or empty vector for 48 h. (PPTX 57 kb

Additional file 1: Figure S1. of Transketolase-like 1 ectopic expression is associated with DNA hypomethylation and induces the Warburg effect in melanoma cells

TKTL1 is expressed in a subset of melanoma tumours and melanoma cell lines. (A) Representative staining patterns for TKTL1 in metastatic melanoma tumors are shown. Arrows indicate nuclear staining for Melanin. Original magnification, 200 Οm. (B) QRT-PCR for expression level of TKTL1 in a panel of 53 metastatic melanoma cell lines. (C) High magnification staining pattern of TKTL1 in melanoma cell line LM-MEL-59. Arrows indicate nuclear staining for Melanin. Original magnification, 200 Οm. (PPTX 1827 kb

Additional file 2: Figure S2. of Transketolase-like 1 ectopic expression is associated with DNA hypomethylation and induces the Warburg effect in melanoma cells

Correlation of TKTL1 gene expression with DNA methylation in melanoma patients. Exon expression data was compared to methylation patterns of TKTL1 and Spearman correlation coefficients were calculated. Methylation status at the CpG site (A) cg09892236 and (B) cg23106779 was inversely correlated with TKTL1 gene expression in melanoma samples. (PPTX 114 kb