Conclusion: This pilot prospective study supports the hypothesis

Conclusion: This pilot prospective study supports the hypothesis that radiofrequency ablation could induce an early systemic immune response. Analysis of additional patients and correlation

with tumor relapse are on-going. Disclosures: Marianne Ziol – Grant/Research Support: Echosens Nathalie Ganne-Carrie – Advisory Committees or Review Panels: Roche, MSD; Speaking and Teaching: BMS, Gilead The following people have nothing to disclose: Jean-Charles Nault, Nathalie Bar-get, Lucie Del Pozo, Valerie Bourcier, Francoise Gondois-Rey, Bernadette Barbarat, Gisele Nkontchou, Veronique Grando, Pierre Nahon, Jean Claude Ku-0059436 mw Trinchet, Olivier Seror, Daniel R. Olive Sorafenib – a broad kinase inhibitor – is a standard therapy for hepatocellular carcinoma (HCC), and has been proposed as an anti-fibrosis approach to prevent liver cirrhosis, an underlying pathology in HCC patients. However, the effects of sorafenib on tumor fibrosis – and its consequences GSI-IX on treatment resistance – remain unknown. Here, we show that sorafenib has differential effects on tumor fibrosis versus liver fibrosis in murine models of liver disease. Sorafenib treatment intensifies tumor hypoxia, which increases stromal-derived factor 1α (SDF1α) expression – in cancer and stromal cells – and

Gr-1+ myeloid cell infiltration in ortotopically implanted and in spontaneous HCC. SDF1α/CXCR4 pathway directly promotes hepatic stellate cell (HSC) differentiation and activation via MAP kinase selleck kinase inhibitor pathway. SDF1α increases the survival of HSCs after treatment with sorafenib as well as their α-SMA and expression

of Collagen I, resulting in increased tumor fibrosis. Moreover, Gr-1 + myeloid cells mediate HSC differentiation/activation in a paracrine manner. CXCR4 inhibition in combination with sorafenib treatment prevents the increase in tumor fibrosis -despite elevated hypoxia – in part by reducing Gr-1+ myeloid cell infiltration, and inhibits HCC growth. Similarly, antibody blockade of Gr-1 also reduces tumor fibrosis and inhibits HCC growth when combined with sorafenib treatment. Thus, blocking SDF1α/CXCR4 or Gr-1 + myeloid cell infiltration may be a novel approach to inhibit HCC resistance to sorafenib by targeting pro-fibrosis signals activated by sorafenib treatment. Model of tumor-associated fibrosis regulation by SDF1α/CXCR4 pathway in HCC. Sorafenib has differential effects of fibrosis in the tumor versus the surrounding liver. These effects are the result of increased intratumoral hypoxia, SDF1α expression and Gr-1 + myeloid cell infiltration. Blocking CXCR4 prevents Gr-1+ myeloid cell infiltration and hepatic stellate cells differentiation and activation, and synergizes with the anti-tumor effects of sorafenib.

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