Overactivation of the TGF-β pathway confers a mesenchymal-like phenotype and CXCR4-dependent migratory properties to liver tumor cells.

Abstract

UNLABELLED:

Transforming growth factor-beta (TGF-β) is an important regulatory suppressor factor in hepatocytes. However, liver tumor cells develop mechanisms to overcome its suppressor effects and respond to this cytokine by inducing other processes, such as the epithelial-mesenchymal transition (EMT), which contributes to tumor progression and dissemination. Recent studies have placed chemokines and their receptors at the center not only of physiological cell migration but also of pathological processes, such as metastasis in cancer. In particular, CXCR4 and its ligand, stromal cell-derived factor 1α (SDF-1α) / chemokine (C-X-C motif) ligand 12 (CXCL12) have been revealed as regulatory molecules involved in the spreading and progression of a variety of tumors. Here we show that autocrine stimulation of TGF-β in human liver tumor cells correlates with a mesenchymal-like phenotype, resistance to TGF-β-induced suppressor effects, and high expression of CXCR4, which is required for TGF-β-induced cell migration. Silencing of the TGF-β receptor1 (TGFBR1), or its specific inhibition, recovered the epithelial phenotype and attenuated CXCR4 expression, inhibiting cell migratory capacity. In an experimental mouse model of hepatocarcinogenesis (diethylnitrosamine-induced), tumors showed increased activation of the TGF-β pathway and enhanced CXCR4 levels. In human hepatocellular carcinoma tumors, high levels of CXCR4 always correlated with activation of the TGF-β pathway, a less differentiated phenotype, and a cirrhotic background. CXCR4 concentrated at the tumor border and perivascular areas, suggesting its potential involvement in tumor cell dissemination.

CONCLUSION:

A crosstalk exists among the TGF-β and CXCR4 pathways in liver tumors, reflecting a novel molecular mechanism that explains the protumorigenic effects of TGF-β and opens new perspectives for tumor therapy.

• Authors: Esther Bertran, Eva Crosas-Molist, Patricia Sancho, Laia Caja, Judit Lopez-Luque, Estanislao Navarro, Gustavo Egea, Raquel Lastra, Teresa Serrano, Emilio Ramos, Isabel Fabregat
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 58 Issue 6 Pg. 2032-44 (Dec 2013) ISSN: 1527-3350 [Electronic] United States
• PMID: 23813475 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 by the American Association for the Study of Liver Diseases.

Chemical References

• Chemokine CXCL12
• Receptors, CXCR4
• Receptors, Transforming Growth Factor beta
• Transforming Growth Factor beta1
• Diethylnitrosamine
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type I
• TGFBR1 protein, human
• Tgfbr1 protein, mouse

Topics

• Aged
• Aged, 80 and over
• Animals
• Carcinoma, Hepatocellular (pathology, physiopathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Chemokine CXCL12
• Diethylnitrosamine
• Epithelial-Mesenchymal Transition
• Female
• Humans
• Liver Neoplasms (pathology, physiopathology)
• Liver Neoplasms, Experimental (chemically induced)
• Male
• Mice
• Middle Aged
• Protein Serine-Threonine Kinases (drug effects)
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, CXCR4 (biosynthesis, metabolism)
• Receptors, Transforming Growth Factor beta (drug effects)
• Transforming Growth Factor beta1 (biosynthesis)