Abstract 1204: Fibroblast growth factor receptor 2 as a novel therapeutic target for cancer cell growth and angiogenesis in human pancreatic cancer
Authors: Toshiyuki Ishiwata, Yoko Matsuda, Kiyoko Kawahara, Tetsushi Yamamoto, Kiyoshi Teduka, Taeko Suzuki, Wei-Xia Peng, Murray Korc, Zenya Naito
Journal: Cancer Research (2011)

Abstract Background: Gene amplification or missence mutation of fibroblast growth factor receptor 2 (FGFR2) occurs in various cancer, and inhibition of activated mutation of FGFR2 induced apoptosis and growth inhibition of endometrial carcinoma. Therefore, FGFR2 has been considered as a potential therapeutic target in a variety of cancers. Due to alternative splicing, there are two isoforms of FGFR2, named FGFR2 IIIb and FGFR2 IIIc. Both FGFR2 isoforms are expressed in pancreatic ductal adenocarcinoma (PDAC). FGFR2 IIIb isoform, also known as keratinocyte growth factor receptor/KGFR, is expressed in approximately 40% of PDAC cases, and its expression correlates with VEGF-A expression and venous invasion. By contrast, FGFR2 IIIc isoform is expressed in 70% of PDAC cases and its expression correlates with retroperitoneal invasion, and increased growth rates and invasion of the cancer. These data suggests that both FGFR2 isoforms play crucial roles in promotion and progression of PDAC. However, it is not known whether FGFR2 can serve as a therapeutic target in PDAC. In the present study, we inhibited the expression of both FGFR2 isoforms by RNA silencing strategy to clarify the therapeutic effectiveness of FGFR2 knockdown in PDAC. Methods: FGFR2 IIIb and IIIc isoforms, and total FGFR2 expression levels were examined in six pancreatic cancer cell lines using real-time PCR analysis. FGFR2 short hairpin (sh) RNA targeting the common exon of IIIb and IIIc isoforms was prepared, and FGFR2 shRNA transfected PANC-1 cells (Sh cells) were established. Sham vectors were transfected into PANC-1 cells as negative controls (Sc cells). Decreased expression of FGFR2 mRNA and FGFR2 protein in the cell membrane was confirmed by real-time PCR and flow cytometry, respectively. The growth rates of Sh cells in vitro and in vivo were compared with Sc cells. Cell signaling was monitored by examining the activation of MAPK signaling pathways including JNK, p38 and ERK, and by assessing VEGF-A expression levels by immunofluorescence. Results: FGFR2, FGFR2IIIb and IIIc mRNA moieties were detected in all six pancreatic cancer cell lines. Sh cells showed decreased expression of FGFR2, FGFR2IIIb and IIIc mRNA, and FGFR2 protein in the cell membrane. The growth rates of Sh cells were lower than those of Sc cells in vitro and in the subcutaneous tissue of nude mice. Sh cells showed attenuation of phosphorylated of ERK pathway, but no alterations in JNK and p38 pathways, and expressed lower levels of VEGF-A. Conclusion: These findings indicate that FGFR2 signaling pathways exert important roles in pancreatic cancer cell growth and angiogenesis, and that inhibition of FGFR2 may serve as a therapeutic target in PDAC by suppressing cancer cell growth and angiogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1204. doi:10.1158/1538-7445.AM2011-1204