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. (Hepatology 2013; 58:2032–2044) Transforming growth factor-beta (TGF-β) is an important regulatory suppressor factor; however, paradoxically, it also modulates other processes that contribute to tumorigenesis, such as fibrosis, immune regulation, microenvironment modification, and cell invasion.[1] Indeed,

in addition to its suppressor effects, TGF-β induces antiapoptotic signals in fetal hepatocytes Trichostatin A supplier and hepatoma cells,[2, 3] through activation of the epidermal growth factor receptor (EGFR) pathway.[4] Cells that survive to TGF-β-induced apoptotic signals undergo epithelial-mesenchymal

transition (EMT).[3, Neratinib solubility dmso 5, 6] Upon progression of liver cancer, EMT is considered a key process that may drive intrahepatic metastasis.[7] TGF-β levels are increased in hepatocellular carcinoma (HCC) tissue, plasma, and urine and decreased in patients who underwent effective therapy for HCC.[8] Liver tumors expressing late TGF-β-responsive genes (antiapoptotic and EMT-related genes) display a higher invasive phenotype and increased tumor recurrence when compared to those that show an early TGF-β signature (suppressor genes).[9] Interestingly, blocking TGF-β up-regulates E-cadherin and reduces migration and invasion of HCC cells.[10] Recent studies place chemokines and their receptors

at the center not only of physiological cell migration, but also of pathological processes, such as metastasis in cancer.[11] 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 important molecules check details involved in the spreading and progression of a variety of tumors.[12] Different data suggest that molecular strategies to inhibit the CXCR4/CXCL12 pathway could be of therapeutic use for the treatment of HCC.[13] CXCR4 is up-regulated in human HCC,[14] correlating with progression of the disease.[15] Its ligand CXCL12 stimulates human hepatoma cell growth, migration, and invasion.[14] We have recently described that TGF-β up-regulates CXCR4 in rat hepatoma cells[16] and sensitizes cells to respond to CXCL12, which mediates cell scattering and survival. These results suggest a crosstalk between the increased protumorigenic response to TGF-β and the establishment of a functional CXCR4/CXCL12 axis. Nothing is known about whether a similar situation occurs in human liver tumorigenesis.