New cellular tools reveal complex epithelial–mesenchymal interactions in hepatocarcinogenesis

Sagmeister, Sandra; Eisenbauer, Maria; Pirker, Christine; Mohr, Thomas; Holzmann, Klaus; Zwickl, Hannes; Bichler, Christoph; Kandioler, Daniela; Wrba, Friedrich; Mikulits, Wolfgang; Gerner, Christopher; Shehata, Medhat; Majdic, Otto; Streubel, Berthold; Berger, Walter; Micksche, M.; Zatloukal, Kurt; Schulte‐Hermann, Rolf; Grasl‐Kraupp, Bettina

doi:10.1038/sj.bjc.6604440

Cited by 39 publications

(47 citation statements)

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“…However, we did not observe significant polyploidy in TC Mps1 12-treated cells using flow cytometry (data not shown). This may be due to the slow doubling time of HepG2 and Hep3B cells: 48 and 25 h respectively (Sagmeister et al, 2008). If we had exposed the cells to TC Mps1 12 for more than 72 h, we may have detected hyperploidy.…”

Section: Discussionmentioning

confidence: 99%

TC Mps1 12, a novel Mps1 inhibitor, suppresses the growth of hepatocellular carcinoma cells via the accumulation of chromosomal instability

Choi

Min

Pyo

et al. 2017

British J Pharmacology

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contributed equally to the work. BACKGROUND AND PURPOSEChromosomal instability is not only a hallmark of cancer but also an attractive therapeutic target. A diverse set of mitotic kinases maintains chromosomal stability. One of these is monopolar spindle 1 (Mps1, also known as TTK), which is essential for chromosome alignment and for the spindle assembly checkpoint (SAC). Pharmacological inhibition of Mps1 has been suggested as a cancer therapeutic; however, despite the existence of a novel Mps1 inhibitor, TC Mps1 12, no such studies have been performed. EXPERIMENTAL APPROACHThe effects of TC Mps1 12 on cell viability, chromosome alignment, centrosome number, mitotic duration, apoptosis and SAC were determined in hepatocellular carcinoma (HCC) cells. In addition, the association of Mps1 expression with the overall survival of HCC patients was analysed. KEY RESULTSTreatment of human HCC cells with TC Mps1 12 led to chromosome misalignment and missegregation, and disorganization of centrosomes. Even in the presence of these errors, TC Mps1 12-treated cells overrode the SAC, resulting in a shortened mitotic duration and mitotic slippage. This mitotic catastrophe triggered apoptosis and, finally, inhibited the growth of HCC cells. In addition, the expression of the Mps1-encoding TTK gene was associated with poor overall survival of HCC patients. CONCLUSION AND IMPLICATIONSTC Mps1 12 results in the accumulation of chromosomal instabilities and mitotic catastrophe in HCC cells. Overall, these data demonstrate that the inhibition of Mps1 kinase using TC Mps1 12 is a promising therapeutic approach for liver cancer.Abbreviations HCC, hepatocellular carcinoma; MCC, mitotic checkpoint complex; Mps1 (TTK), monopolar spindle 1; SAC, spindle assembly checkpoint

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Section: Discussionmentioning

confidence: 99%

TC Mps1 12, a novel Mps1 inhibitor, suppresses the growth of hepatocellular carcinoma cells via the accumulation of chromosomal instability

Choi

Min

Pyo

et al. 2017

British J Pharmacology

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“…Two distinct liver cell lines were of particular interest as these cell types have been isolated from the HCC of one patient (20). Phase contrast analysis suggested an epithelial cell type, termed 3p, and a mesenchymal cell population, designated 3sp (Fig.…”

Section: Resultsmentioning

confidence: 99%

A Human Model of Epithelial to Mesenchymal Transition to Monitor Drug Efficacy in Hepatocellular Carcinoma Progression

Zijl

Mall

Machat

et al. 2011

Molecular Cancer Therapeutics

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The epithelial to mesenchymal transition (EMT) of malignant hepatocytes is a crucial event in hepatocellular carcinoma (HCC) progression and recurrence. We aimed to establish a human model of EMT to examine drug efficacy and specificity in HCC progression. Human HCC cell populations were characterized by immunofluorescence analysis, migration and invasion assays, array comparative genomic hybridization, whole-genome expression profiling, and promoter methylation. Therapeutic agents clinically used against HCC were examined for efficacy by determination of IC 50 values. We show that liver cancer cell lines exhibited either an epithelial or mesenchymal phenotype of which the latter showed strong migratory and invasive abilities in vitro. The common cellular origin of both cell types indicated that mesenchymal HCC cells have been derived from epithelial hepatocytes through EMT in the HCC patient. Drug exposure of mesenchymal HCC cells showed higher resistance to the targeted therapeutic agents sorafenib and erlotinib as compared to epithelial HCC cells, which were slightly more resistant to cytostatic drugs. Most remarkably, combined treatment with doxorubicin and sorafenib caused increased susceptibility of both HCC cell types resulting in enhanced drug efficacy. Taken together, this EMT model of human HCC allows the identification of molecular mechanisms and the assessment of therapeutic drug efficacy during liver cancer progression in preclinical studies. Mol Cancer Ther; 10(5); 850-60. Ó2011 AACR.

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“…Protein purification, separation, and detection followed published protocols . For further information on antibodies, see http://onlinelibrary.wiley.com/doi/10.1002/hep.28023/suppinfo.…”

Section: Methodsmentioning

confidence: 99%

Fibroblast growth factor receptor 3 isoforms: Novel therapeutic targets for hepatocellular carcinoma?

et al. 2015

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Fibroblast growth factor receptors (FGFRs) are frequently up-regulated in subsets of hepatocellular carcinoma (HCC). Here, we provide mechanistic insight that FGFR3 splice variants IIIb and IIIc impact considerably on the malignant phenotype of HCC cells. The occurrence of FGFR3 variants was analyzed in human HCC samples. In hepatoma/hepatocarcinoma cell lines, FGFR3 isoforms were overexpressed by lentiviral constructs or down-modulated by small interfering RNA (siRNA; affecting FGFR3-IIIb and -IIIc) or an adenoviral kinase-dead FGFR3-IIIc construct (kdFGFR3). Elevated levels of FGFR3-IIIb and/or -IIIc were found in 53% of HCC cases. FGFR3-IIIb overexpression occurred significantly more often in primary tumors of large (pT2-4) than of small size (pT1). Furthermore, one or both isoforms were enhanced mostly in cases with early tumor infiltration and/or recurrence at the time of surgery or follow-up examinations. In hepatoma/hepatocarcinoma cells, up-regulated FGFR3-IIIb conferred an enhanced capability for proliferation. Both FGFR3-IIIb and FGFR3-IIIc suppressed apoptotic activity, enhanced clonogenic growth, and induced disintegration of the blood/lymph endothelium. The tumorigenicity of cells in severe combined immunodeficiency mice was augmented to a larger degree by variant IIIb than by IIIc. Conversely, siRNA targeting FGFR3 and kdFGFR3 reduced clonogenicity, anchorage-independent growth, and disintegration of the blood/lymph endothelium in vitro. Furthermore, kdFGFR3 strongly attenuated tumor formation in vivo. Conclusions: Deregulated FGFR3 variants exhibit specific effects in the malignant progression of HCC cells. Accordingly, blockade of FGFR3-mediated signaling may be a promising therapeutic approach to antagonize growth and malignant behavior of HCC cells. (HEPATOLOGY 2015;62:1767-1778 H epatocellular carcinoma (HCC), the most frequent primary malignant liver tumor entity, is estimated to be the second-leading cause for cancer mortality worldwide. 1 Owing to the high inherent chemoresistance of this tumor type, standard chemotherapy is insufficient and only 15% of the patients are candidates for surgical resection or liver transplantation. As a result, HCC patients are usually left with an infaust prognosis. Thus, new therapeutic approaches are eagerly needed. 2,3 Up-regulation of growth/survival factors and their respective receptors is known to drive the formation, progression, and dissemination of HCC cells within the body. 2-4 Recently, we and others found overexpression of fibroblast growth factor (FGF) receptor (FGFR) 3 and/or FGFR4 in the majority of HCC cases and relatively rare up-regulation of FGFR1 and/or FGFR2, which was confirmed in the present study (Supporting Fig. 1). 5,6 Meanwhile, it is known that FGFR4 is involved in the

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New cellular tools reveal complex epithelial–mesenchymal interactions in hepatocarcinogenesis

Cited by 39 publications

References 50 publications

TC Mps1 12, a novel Mps1 inhibitor, suppresses the growth of hepatocellular carcinoma cells via the accumulation of chromosomal instability

TC Mps1 12, a novel Mps1 inhibitor, suppresses the growth of hepatocellular carcinoma cells via the accumulation of chromosomal instability

A Human Model of Epithelial to Mesenchymal Transition to Monitor Drug Efficacy in Hepatocellular Carcinoma Progression

Fibroblast growth factor receptor 3 isoforms: Novel therapeutic targets for hepatocellular carcinoma?

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