Established gastric cancer cell lines transplantable into C57BL/6 mice show fibroblast growth factor receptor 4 promotion of tumor growth

摘要

Previously no mouse gastric cancer cell lines have been available for transplantation into C57BL/6 mice. However, a gastric cancer model in immunocompetent mice would be useful for analyzing putative therapies. N‐Methyl‐N‐nitrosourea (MNU) was given in drinking water to C57BL/6 mice and p53 heterozygous knockout mice. Only 1 tumor from a p53 knockout mouse could be cultured and the cells s.c. transplanted into a C57BL/6 mouse. We cultured this s.c. tumor, and subcloned it. mRNA expression in the most aggressive YTN16 subline was compared to the less aggressive YTN2 subline by microarray analysis, and fibroblast growth factor receptor 4 >( FGFR4) in YTN16 cells was knocked out with a CRISPR/Cas9 system and inhibited by an FGFR4 selective inhibitor, BLU9931. These transplanted cell lines formed s.c. tumors in C57BL/6 mice. Four cell lines (YTN2, YTN3, YTN5, style="fixed-case">YTN16) were subcloned and established. Their in vitro growth rates were similar. However, s.c. tumor establishment rates, metastatic rates, and peritoneal dissemination rates of style="fixed-case">YTN2 and style="fixed-case">YTN3 were lower than for style="fixed-case">YTN5 and style="fixed-case">YTN16. style="fixed-case">YTN16 established 8/8 s.c. tumors, 7/8 with lung metastases, 3/8 with lymph node metastases and 5/5 with peritoneal dissemination. style="fixed-case">FGFR4 expression by style="fixed-case">YTN16 was 121‐fold higher than style="fixed-case">YTN2. style="fixed-case">FGFR4‐deleted style="fixed-case">YTN16 cells failed to form s.c. tumors and showed lower rates of peritoneal dissemination. style="fixed-case">BLU9931 significantly inhibited the growth of peritoneal dissemination of style="fixed-case">YTN16. These studies present the first transplantable mouse gastric cancer lines. Our results further indicate that style="fixed-case">FGFR4 is an important growth signal receptor in gastric cancer cells with high style="fixed-case">FGFR4 expression.