| Autor: |
Breitenecker K; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria., Heiden D; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria., Demmer T; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria., Weber G; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria., Primorac AM; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria., Hedrich V; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria., Ortmayr G; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria., Gruenberger T; Department of Surgery, HPB Center, Viennese Health Network, Clinic Favoriten and Sigmund Freud Private University, 1100 Vienna, Austria., Starlinger P; Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA.; Centre of Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria., Herndler-Brandstetter D; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria., Barozzi I; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria., Mikulits W; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria. |
| Abstrakt: |
The activation of the receptor tyrosine kinase Axl by Gas6 is a major driver of tumorigenesis. Despite recent insights, tumor cell-intrinsic and -extrinsic Axl functions are poorly understood in hepatocellular carcinoma (HCC). Thus, we analyzed the cell-specific aspects of Axl in liver cancer cells and in the tumor microenvironment. We show that tumor-intrinsic Axl expression decreased the survival of mice and elevated the number of pulmonary metastases in a model of resection-based tumor recurrence. Axl expression increased the invasion of hepatospheres by the activation of Akt signaling and a partial epithelial-to-mesenchymal transition (EMT). However, the liver tumor burden of Axl +/+ mice induced by diethylnitrosamine plus carbon tetrachloride was reduced compared to systemic Axl -/- mice. Tumors of Axl +/+ mice were highly infiltrated with cytotoxic cells, suggesting a key immune-modulatory role of Axl. Interestingly, hepatocyte-specific Axl deficiency did not alter T cell infiltration, indicating that these changes are independent of tumor cell-intrinsic Axl. In this context, we observed an upregulation of multiple chemokines in Axl +/+ compared to Axl -/- tumors, correlating with HCC patient data. In line with this, Axl is associated with a cytotoxic immune signature in HCC patients. Together these data show that tumor-intrinsic Axl expression fosters progression, while tumor-extrinsic Axl expression shapes an inflammatory microenvironment. |
