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Int J Mol Sci. 2017 Oct 10;18(10). pii: E2119. doi: 10.3390/ijms18102119.

Transforming Growth Factor-β Drives the Transendothelial Migration of Hepatocellular Carcinoma Cells.

Author information

1
Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria. koudelkova.petra@yahoo.com.
2
Institute for Clinical Chemistry, Medical Faculty Mannheim, University of Heidelberg, University Hospital Mannheim, 68167 Mannheim, Germany. Victor.Costina@umm.de.
3
Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria. gerhard.weber@meduniwien.ac.at.
4
Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg Mannheim, 68167 Mannheim, Germany. steven.dooley@medma.uni-heidelberg.de.
5
Institute for Clinical Chemistry, Medical Faculty Mannheim, University of Heidelberg, University Hospital Mannheim, 68167 Mannheim, Germany. Peter.Findeisen@umm.de.
6
GenXPro GmbH, 60438 Frankfurt am Main, Germany. pwinter@genxpro.de.
7
GenXPro GmbH, 60438 Frankfurt am Main, Germany. raag@genxpro.de.
8
Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, 1090 Vienna, Austria. schlangen@spengergasse.at.
9
Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria. wolfgang.mikulits@meduniwien.ac.at.

Abstract

The entry of malignant hepatocytes into blood vessels is a key step in the dissemination and metastasis of hepatocellular carcinoma (HCC). The identification of molecular mechanisms involved in the transmigration of malignant hepatocytes through the endothelial barrier is of high relevance for therapeutic intervention and metastasis prevention. In this study, we employed a model of hepatocellular transmigration that mimics vascular invasion using hepatic sinusoidal endothelial cells and malignant hepatocytes evincing a mesenchymal-like, invasive phenotype by transforming growth factor (TGF)-β. Labelling of respective cell populations with various stable isotopes and subsequent mass spectrometry analyses allowed the "real-time" detection of molecular changes in both transmigrating hepatocytes and endothelial cells. Interestingly, the proteome profiling revealed 36 and 559 regulated proteins in hepatocytes and endothelial cells, respectively, indicating significant changes during active transmigration that mostly depends on cell-cell interaction rather than on TGF-β alone. Importantly, matching these in vitro findings with HCC patient data revealed a panel of common molecular alterations including peroxiredoxin-3, epoxide hydrolase, transgelin-2 and collectin 12 that are clinically relevant for the patient's survival. We conclude that hepatocellular plasticity induced by TGF-β is crucially involved in blood vessel invasion of HCC cells.

KEYWORDS:

SILAC; TGF-β; bioinformatics; hepatocellular carcinoma; proteomics; transendothelial migration

PMID:
28994702
PMCID:
PMC5666801
DOI:
10.3390/ijms18102119
[Indexed for MEDLINE]
Free PMC Article

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