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DOI: 10.1055/s-0041-1740773
Crosstalk of hepatic stellate cells and uveal melanoma cells in the liver metastatic niche
Hepatic metastasis is the critical factor determining tumor-associated mortality in different types of cancer. This is particularly true for uveal melanoma (UVM) that almost exclusively metastasizes into the liver. Hepatic stellate cells (HSC) are the precursors of tumor-associated fibroblasts and support growth of metastases. However, the underlying mechanisms are widely unknown. Fibroblast growth factor (FGF) signalling is dysregulated in many types of cancer.
The aim of this study was to analyze the protumorigenic effects of HSC on UVM cells and the role of FGFs in this crosstalk.
Methods and Results Conditioned medium (CM) from activated human HSC significantly induced proliferation combined with enhanced ERK and JNK-activation in UVM-cells. High expression levels of FGF receptor 1 (FGFR1) significantly correlated with poor survival of UVM patients, while FGFR2/3/4 expression did not significantly influence survival. Protumorigenic effects of HSC-CM on UVM-cells were abrogated by the FGFR1/2/3 inhibitor BGJ398, whereas the selective FGFR4 inhibitor BLU9931 had no significant effect. Expression analysis revealed that the vast majority of the different paracrine FGFs is only expressed by HSC but not by UVM-cells, including FGF9. Immunofluorescence analysis confirmed HSC as cellular source of FGF9 in hepatic metastases of UVM-patients. Treatment with recombinant FGF9 significantly enhanced the proliferation UVM-cells and this effect was efficiently blocked by the FGFR1/2/3 inhibitor BGJ398.
Summary and conclusion Our study indicates that FGF9 released by HSC promotes the tumorigenicity of UVM cells, and thus, suggests FGF9 as a promising therapeutic target in hepatic metastasis.
Publication History
Article published online:
26 January 2022
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