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

Malfettone, Andrea; Soukupová, Jitka; Bertrán, Esther; Crosas‐Molist, Eva; Lastra, Raquel; Fernando, Joan; Koudelková, Petra; Rani, Bhavna; Fabra, Àngels; Serrano, Teresa; Ramos, Emilio; Mikulits, Wolfgang; Giannelli, Gianluigi; Fabregat, Isabel

doi:10.1016/j.canlet.2017.01.037

Cited by 75 publications

(86 citation statements)

References 29 publications

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“…Importantly, the detection of this CTC subpopulation emerged as an independent prognostic factor for increased risk of relapse. This is in line with preclinical data showing that the partial-EMT state is critical for the tumorigenic activity of CSCs (34,35). Although it is suggested that MET is required for the efficient colonization of tumor cells (36), the CSC þ /epithelial-like subset did not show any prognostic significance.…”

Section: Discussionsupporting

confidence: 85%

Circulating Tumor Cells with Stemness and Epithelial-to-Mesenchymal Transition Features Are Chemoresistant and Predictive of Poor Outcome in Metastatic Breast Cancer

Papadaki

Stoupis

Theodoropoulos

et al. 2019

Molecular Cancer Therapeutics

160

145

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Circulating tumor cells (CTCs) bearing phenotypes related to cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT) have been identified in breast cancer; however, their clinical significance is not clear. In the current study, we investigated the prognostic relevance of single CSC þ /partial-EMT þ CTCs in patients with metastatic breast cancer and the effect of first-line chemotherapy on their incidence. For this purpose, triple immunofluorescence against cytokeratin, ALDH1, and TWIST1 was performed in peripheral blood mononuclear cell (PBMC) cytospins from 130 patients before and after first-line chemotherapy. CSC þ / partial-EMT þ CTCs were characterized as cells co-expressing cytokeratin, high levels of ALDH1, and nuclear TWIST1. CSC þ /partial-EMT þ CTCs were evident in 27.7% of patients at baseline and were correlated to lung metastases (P ¼ 0.010) and decreased progression-free survival [PFS; median 10.2 (8.9-11.6) vs. 13.5 (11.3-15.7) months; P ¼ 0.024].Their detection was an independent factor predicting for increased risk of relapse [multivariate analysis; HR (95% confidence interval (CI)): 1.785 (1.171-2.720); P ¼ 0.007]. In HER-2-negative patients, CSC þ /partial-EMT þ CTCs were additionally associated with reduced overall survival (OS) [median 39 (26.2-51.9) vs. 51 (15.7-86.4) months; P ¼ 0.020] and increased risk of death [multivariate analysis; HR (95% CI): 2.228 (1.066-4.655); P ¼ 0.033]. Chemotherapy resulted in a significant increase in the incidence of CSC þ /partial-EMT þ CTCs (mean CTC% per patient: 59.4% post vs. 39.5% pre; P ¼ 0.018), which was subsequently confirmed only in HER2-negative patients (P ¼ 0.040) and in non-responders at the end of treatment (P ¼ 0.020). In conclusion, CSC þ /partial-EMT þ CTCs represent a chemoresistant subpopulation, which independently predicts for unfavorable outcome in metastatic breast cancer. Efficient targeting of these CTCs could potentially increase patient survival.

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Section: Discussionsupporting

confidence: 85%

Circulating Tumor Cells with Stemness and Epithelial-to-Mesenchymal Transition Features Are Chemoresistant and Predictive of Poor Outcome in Metastatic Breast Cancer

Papadaki

Stoupis

Theodoropoulos

et al. 2019

Molecular Cancer Therapeutics

160

145

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“…The migratory and invasive ability are related to the metastatic potential of cancer cells, which contribute to cancer progression and poor outcomes of patients [36,37]. In this study, we observed that OPE dose-dependently inhibited the migration and invasion of the HepG2 and SMMC-7721 cells, which concomitant with the decrease in the expression of MMP-2 and MMP-9.…”

Section: Discussionmentioning

confidence: 52%

Ethanol extract of Ophiorrhiza pumila suppresses liver cancer cell proliferation and migration

et al. 2020

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Background: Ophiorrhiza pumila, belonging to the genus Ophiorrhiza (Rubiaceae), is distributed throughout tropical and subtropical Asia. In this study, we evaluated for the first time the anti-proliferation and anti-migration effects of ethanol extract of O. pumila (OPE) on HepG2 and SMMC-7721 cells, and explored the related mechanism.Methods: OPE was prepared by percolation with 95% ethanol and its main compounds were analyzed by HPLC-MS 2 . The anti-proliferation effect of OPE was evaluated by the CCK-8 assay and colony formation assay. Cell cycle distribution, apoptosis, and reactive oxygen species (ROS) level were detected by flow cytometry. Migration and invasion abilities were detected by Transwell migration/invasion assays. The expression of correlated proteins was determined using western blotting.Results: A total of 5 tentative compounds were identified from OPE, including pumiloside, deoxypumiloside, camptothecin, aknadinine, and β-stigmasterol. OPE displayed strong cytostatic effects on HepG2 and SMMC-7721 cells. OPE induced G2/M phase cell cycle arrest, increased apoptosis, and augmented ROS production in these cell lines. In addition, OPE possessed a significant inhibition on cell migration and invasion by reduction of MMP-9 and MMP-2 expression. Moreover, OPE significantly suppressed the phosphorylation of p65. Conclusions:Our data showed that OPE suppresses liver cancer cell proliferation and migration, which is possibly involved with the inhibition of the NF-κB pathway.

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“…It is worth mentioning that CLTC expression had no prognostic value in those patients where TGFB1 expression was not high, whereas high TGFB1 expression significantly decreased the overall survival of patients that expressed high levels of CLTC. Interestingly, when we focused on the analysis of some mesenchymal genes whose expression was related to TGF-b in HCC cells, such as CXCR4 or CD44, 32,33 patients with higher expression of both TGFB1 and CLTC had higher expression levels of these mesenchymal genes in comparison to patients who expressed lower levels of TGFB1 and CLTC (Fig. S11).…”

Section: Levels Of Clathrin In Hcc Cells Affect the Response To Tgf-bmentioning

confidence: 99%

Clathrin switches transforming growth factor-β role to pro-tumorigenic in liver cancer

Caballero‐Díaz

Bertrán

Peñuelas‐Haro

et al. 2020

Journal of Hepatology

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

Cited by 75 publications

References 29 publications

Circulating Tumor Cells with Stemness and Epithelial-to-Mesenchymal Transition Features Are Chemoresistant and Predictive of Poor Outcome in Metastatic Breast Cancer

Circulating Tumor Cells with Stemness and Epithelial-to-Mesenchymal Transition Features Are Chemoresistant and Predictive of Poor Outcome in Metastatic Breast Cancer

Ethanol extract of Ophiorrhiza pumila suppresses liver cancer cell proliferation and migration

Clathrin switches transforming growth factor-β role to pro-tumorigenic in liver cancer

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