Abstract
Simple SummaryDiffuse-type gastric carcinoma (DGC) is characterized by rapid infiltrative growth associated with massive stroma and frequent peritoneal dissemination, which leads to poor patient outcomes. In this study, we found that the oncogenic tyrosine phosphatase SHP2 is tyrosine-phosphorylated downstream of the amplified receptor tyrosine kinases (RTKs) Met and fibroblast growth factor receptor 2 (FGFR2) in DGC cell lines. SHP2 knockdown or pharmacological inhibition selectively suppressed the growth of DGC addicted to amplified Met and FGFR2. Moreover, targeting SHP2 abrogated malignant phenotypes, including peritoneal dissemination, of Met-addicted DGC and could overcome acquired resistance to Met inhibitors. Our findings suggest that SHP2 is a potential target for the treatment of DGC addicted to amplified RTK signaling.Diffuse-type gastric carcinoma (DGC) exhibits aggressive progression associated with rapid infiltrative growth, massive fibrosis, and peritoneal dissemination. Gene amplification of Met and fibroblast growth factor receptor 2 (FGFR2) receptor tyrosine kinases (RTKs) has been observed in DGC. However, the signaling pathways that promote DGC progression downstream of these RTKs remain to be fully elucidated. We previously identified an oncogenic tyrosine phosphatase, SHP2, using phospho-proteomic analysis of DGC cells with Met gene amplification. In this study, we characterized SHP2 in the progression of DGC and assessed the therapeutic potential of targeting SHP2. Although SHP2 was expressed in all gastric carcinoma cell lines examined, its tyrosine phosphorylation preferentially occurred in several DGC cell lines with Met or FGFR2 gene amplification. Met or FGFR inhibitor treatment or knockdown markedly reduced SHP2 tyrosine phosphorylation. Knockdown or pharmacological inhibition of SHP2 selectively suppressed the growth of DGC cells addicted to Met or FGFR2, even when they acquired resistance to Met inhibitors. Moreover, SHP2 knockdown or pharmacological inhibition blocked the migration and invasion of Met-addicted DGC cells in vitro and their peritoneal dissemination in a mouse xenograft model. These results indicate that SHP2 is a critical regulator of the malignant progression of RTK-addicted DGC and may be a therapeutic target.
Highlights
Gastric cancer is one of the most common malignancy and the leading cause of cancerrelated death worldwide [1]
Phosphorylation of SHP2 at Y542 and Y580 was preferentially detected in several diffuse-type gastric carcinoma (DGC) cell lines with gene amplification of receptor tyrosine kinases (RTKs): MKN45, 58As1, 58As9, and SNU-5, which have Met gene amplification [46,47]; KATO-III and HSC43, which have fibroblast growth factor receptor 2 (FGFR2) gene amplification [48]
Quantitative analyses confirmed that the phosphorylation of SHP2 at Y542 and Y580 was significantly higher in cell lines with Met or FGFR2 gene amplification than in other cell lines (Figure 1B,C)
Summary
Gastric cancer is one of the most common malignancy and the leading cause of cancerrelated death worldwide [1]. Hallmarks of diffuse-type gastric carcinoma (DGC) include the presence of poorly differentiated carcinoma cells and abundant desmoplastic stroma, rapid infiltration into the submucosa, and high incidence of peritoneal dissemination, a critical determinant for the poor outcome and quality of life [3,4]. Due to these aggressive phenotypes, patients with DGC have a poor prognosis [5,6]. Gene amplification of Met and FGFR2 has been correlated with poor prognosis in patients with gastric cancer [8,13,14,15]. Other groups and we demonstrated that Met and FGFR inhibitors have therapeutic efficacy in preclinical models [18,19,20,21,22]; as a result, some of them were tested in clinical trials [23]
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