Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
Liver Int. 2020 Sep;40(9):2279-2290. doi: 10.1111/liv.14505. Epub 2020 Jun 17.
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.
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.
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.
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.
最近发现，成纤维细胞生长因子受体 3（FGFR3）剪接变体 FGFR3-IIIb 和 FGFR3-IIIc 在~50%的肝细胞癌（HCC）中过表达。在这里，我们旨在鉴定 FGFR3-IIIb/IIIc 配体，这些配体驱动 HCC 的进展。
通过 FACS、MTT 测定和/或生长曲线鉴定最有效地诱导人 HCC 来源的肝癌/肝癌细胞系生长的 FGFR3-IIIb/IIIc 配体。对最有效的 FGF 进行特征分析，包括其在肝和 HCC 的上皮细胞和基质细胞中的表达水平，以及对新生血管形成、克隆形成和肝癌/肝癌细胞侵袭性生长的影响。
在所测试的所有 FGFR3-IIIb/IIIc 配体中，FGF9 是肝癌/肝癌细胞最有效的生长因子。同时也刺激了血液/淋巴内皮细胞的复制和/或发芽。FGF9 主要存在于未改变的肝的基质细胞中，但存在于 HCC 的上皮细胞中。每五个 HCC 中就有一个表现出过表达的 FGF9，并频繁共同上调 FGFR3-IIIb/IIIc。在肝癌/肝癌细胞中，FGF9 增强了克隆形成能力和血液和淋巴内皮的崩解能力，在分别过表达 FGFR3-IIIb 或 FGFR3-IIIc 的细胞中最为明显。在肝癌/肝癌细胞中，任何 FGF9 作用均可通过应用 FGFR1-3 特异性酪氨酸激酶抑制剂 BGJ398 或 siFGFR3 完全阻断，而 siFGFR1/2/4 则大多无效。
FGF9 通过 FGFR3-IIIb/IIIc 作用增强 HCC 细胞的生长和侵袭性。因此，阻断 FGF9-FGFR3-IIIb/IIIc 轴可能是 HCC 患者的有效治疗选择。
