Background & Aims
Recently, overexpression of the fibroblast growth factor receptor 3 (FGFR3) splice variants FGFR3‐IIIb and FGFR3‐IIIc was found in ~50% of hepatocellular carcinoma (HCC). Here, we aim to identify FGFR3‐IIIb/IIIc ligands, which drive the progression of HCC.
Methods
FACS, MTT assay and/or growth curves served to identify the FGFR3‐IIIb/IIIc ligand being most effective to induce growth of hepatoma/hepatocarcinoma cell lines, established from human HCC. The most potent FGF was characterized regarding the expression levels in epithelial and stromal cells of liver and HCC and impact on neoangiogenesis, clonogenicity and invasive growth of hepatoma/hepatocarcinoma cells.
Results
Among all FGFR3‐IIIb/IIIc ligands tested, FGF9 was the most potent growth factor for hepatoma/hepatocarcinoma cells. Replication and/or sprouting of blood/lymphendothelial cells was stimulated as well. FGF9 occurred mainly in stromal cells of unaltered liver but in epithelial cells of HCC. Every fifth HCC exhibited overexpressed FGF9 and frequent co‐upregulation of FGFR3‐IIIb/IIIc. In hepatoma/hepatocarcinoma cells FGF9 enhanced the capability for clonogenicity and disintegration of the blood and lymphatic endothelium, being most pronounced in cells overexpressing FGFR3‐IIIb or FGFR3‐IIIc, respectively. Any of the FGF9 effects in hepatoma/hepatocarcinoma cells was blocked completely by applying the FGFR1‐3‐specific tyrosine kinase inhibitor BGJ398 or siFGFR3, while siFGFR1/2/4 were mostly ineffective.
Conclusions
FGF9 acts via FGFR3‐IIIb/IIIc to enhance growth and aggressiveness of HCC cells. Accordingly, blockade of the FGF9‐FGFR3‐IIIb/IIIc axis may be an efficient therapeutic option for HCC patients.
Computed Tomography of Chemiluminescence (CTC) was used to reconstruct the instantaneous three-dimensional (3D) chemiluminescence field of a high-power industrial flame, which was made optically accessible, for the first time. The reconstruction used 24 projections that were measured simultaneously, in one plane and equiangularly spaced within a total fan angle of 172.5°. The 3D results were examined by plotting both vertical and horizontal slices, revealing highly wrinkled structures with good clarity. The results presented are one of a series of experimental demonstrations of CTC applications to turbulent gaseous flames. The work reveals the potential to use any kind of luminescence measurement, such as emission from heated particles in coal-fired flames, for analysis of the flame shape directly in 3D.
An evolutionary reconstruction technique (ERT) was developed for three-dimensional (3D) reconstruction of luminescent objects, in particular turbulent flames for the first time. The computed tomography (CT) algorithm is comprised of a genetic algorithm (GA) and a ray-tracing software. To guide the reconstruction process, a mask is introduced. It uses a Metropolis algorithm (MA) to sample locations where specific genetic operators can be applied. Based on an extensive parameter study, performed on several types of phantoms, the ability of our algorithm for 3D reconstructions of fields with varying complexities is demonstrated. Furthermore, it was applied to three experiments, to reconstruct the instantaneous chemiluminescence field of a bunsen flame, a highly turbulent swirl flame and the turbulent Cambridge-Sandia stratified flame. Additionally, we show direct and quantitative comparison to an advanced computed tomography of chemiluminescence (CTC) method that is based on an algebraic reconstruction technique (ART). The results showed good agreement between CTC and ERT using both phantom data from flame simulations, and experimental data.
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