Discovery of VEGFR-2 inhibitors exerting significant anticancer activity against CD44+ and CD133+ cancer stem cells (CSCs): Reversal of TGF-β induced epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignancy characterized by neoangiogenesis, which is an augmented production of proangiogenic factors by the tumor and its adjacent infected cells. These dysregulated angiogenic factors are the therapeutic targets in anti-angiogenic drug development. The signaling pathway of vascular endothelial growth factor (VEGF)/VEGFR-2 is crucial for controlling the angiogenic responses in endothelial cells (ECs). In this study, we carried out a rational drug design approach wherein we have identified the novel orally bioavailable compound VS 8 as a potent VEGFR-2 inhibitor, which remarkably suppresses hVEGF and hVEGFR-2 expression in HUVECs and exhibits significant anti-angiogenic effects in CAM assay. Besides, VS 8 significantly induces apoptosis in HCC cell line (Hep G2). Later we examined its effectiveness against CD44+ and CD133+ CSCs. Here, VS 8 was found to be active against CSCs, and adequate for the cessation of the cell cycle at 'G0/G1' and 'S' phase in CD44+ and CD133+ CSCs respectively. Factually, transforming growth factor-β (TGF-β) stimulated epithelial-mesenchymal transition (EMT) induces invasion and migration of HCC cells, which results in the metastasis. Therefore, we studied the effect of VS 8 on EMT markers using flow cytometry, which suggested that VS 8 significantly upregulates E-cadherin (epithelial biomarker) and downregulates vimentin (mesenchymal biomarker). Further, VS 8 downregulates the expression of EMT-inducing transcription factors (EMT-TFs), i.e., SNAIL. Altogether, our findings indicate that VS 8 could be a promising drug candidate for cancer therapy.

Modi SJ ，Kulkarni VM 《-》

Evaluation of piperine against cancer stem cells (CSCs) of hepatocellular carcinoma: Insights into epithelial-mesenchymal transition (EMT).

Cancer stem cells (CSCs) are involved in recurrent hepatocellular carcinoma (HCC), yet there is a lack of effective treatment that targets these CSCs. CD44+ and CD133+ CSCs are markedly expressed in HepG2 cells and were isolated and characterized using fluorescence-activated cell sorting (FACS) analysis. Since piperine is known as an effective molecule against metastasis, we thought to investigate the effect of piperine against CD44+/CD133+ CSCs. Herein, piperine was found to be active against these CSCs. Also, it was found appropriate to respite at the 'subG0/G1 and G0/G1' phase of the cell cycle analysis, respectively. TGF-β activated epithelial-mesenchymal transition (EMT) has been involved in the invasion and metastasis of HepG2 cells in hepatocellular carcinoma. Therefore, we next investigated the effect of piperine on different biomarkers that remarkably takes part in the process of EMT using flow cytometric analysis. Piperine was found able to repress the epithelial marker (E-cadherin) but was unable to restore the level of Vimentin (mesenchymal marker) and SNAIL (EMT-inducing transcription factor). Therefore, the findings of this study revealed that piperine could be an effective treatment strategy for recurrent hepatocarcinogenesis.

Tiwari A ，Modi SJ ，Gabhe SY ，Kulkarni VM ... -  《-》

Transforming growth factor-β-induced plasticity causes a migratory stemness phenotype in hepatocellular carcinoma.

As part of its potential pro-tumorigenic actions, Transforming Growth Factor-(TGF)-β induces epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) cells. Whether EMT induces changes in tumor cell plasticity has not been fully explored yet. Here, we analyze the effects of TGF-β on the EMT and stem-related properties of HCC cells and the potential correlation among those processes. The translational aim of the study was to propose a TGF-β/EMT/stem gene signature that would help in recognizing HCC patients as good candidates for anti-TGF-β therapy. Results indicate that when TGF-β induces EMT in HCC cells, a switch in the expression of stem genes is observed and their stemness potential and migratory/invasive capacity are enhanced. However, TGF-β may induce a partial EMT in some epithelial HCC cells, increasing the expression of mesenchymal genes and CD44, but maintaining epithelial gene expression. Epithelial cells show higher stemness potential than the mesenchymal ones, but respond to TGF-β increasing their migratory and invasive capacity. In HCC patient samples, TGFB1 expression most frequently correlates with a partial EMT, increase in mesenchymal genes and CD44 expression, as well as maintenance or over-expression of epithelial-related genes.

Malfettone A ，Soukupova J ，Bertran E ，Crosas-Molist E ，Lastra R ，Fernando J ，Koudelkova P ，Rani B ，Fabra Á ，Serrano T ，Ramos E ，Mikulits W ，Giannelli G ，Fabregat I ... -  《-》

ZnAs@SiO(2) nanoparticles as a potential anti-tumor drug for targeting stemness and epithelial-mesenchymal transition in hepatocellular carcinoma via SHP-1/JAK2/STAT3 signaling.

Huang Y ，Zhou B ，Luo H ，Mao J ，Huang Y ，Zhang K ，Mei C ，Yan Y ，Jin H ，Gao J ，Su Z ，Pang P ，Li D ，Shan H ... -  《Theranostics》

Cancer stem-like cells enriched with CD29 and CD44 markers exhibit molecular characteristics with epithelial-mesenchymal transition in squamous cell carcinoma.

Geng S ，Guo Y ，Wang Q ，Li L ，Wang J ... -  《-》