Inhibition of fibroblast growth factor receptor 2 attenuates proliferation and invasion of pancreatic cancer.

Abstract

The alternative splicing of the extracellular domain of fibroblast growth factor receptor (FGFR)-2 generates the IIIb and IIIc isoforms. Expression of FGFR-2 IIIb correlates with vascular endothelial growth factor-A (VEGF-A) expression and venous invasion of pancreatic ductal adenocarcinoma (PDAC). By contrast, FGFR-2 IIIc expression correlates with faster development of liver metastasis after surgery, and increased proliferation rates and invasion of the cancer. In this study, we analyzed the expression and roles of total FGFR-2 (both isoforms) to determine the effectiveness of FGFR-2-targeting therapy for PDAC. Immunohistochemically, FGFR-2 was highly expressed in 25/48 (52.1%) PDAC cases, and correlated with advanced stage cancer. In FISH analysis, FGFR2 was amplified in 3/7 PDAC cell lines. We stably transfected an FGFR-2 shRNA targeting the IIIb and IIIc isoforms into FGFR2-amplified PDAC cells. The proliferation rates, migration, and invasion of FGFR-2-shRNA-transfected cells were lower than those of control cells in vitro. In response to FGF-2, FGFR-2-shRNA-transfected cells showed decreased phosphorylation of ERK compared with control cells. The FGFR-2-shRNA-transfected cells also expressed lower levels of vascular endothelial growth factor-A than control cells, and formed smaller s.c. tumors in nude mice. These findings suggest that FGFR-2 is a therapeutic target for inhibition in PDAC.

• Authors: Yoko Matsuda, Hisashi Yoshimura, Taeko Suzuki, Eiji Uchida, Zenya Naito, Toshiyuki Ishiwata
• Journal: Cancer science (Cancer Sci) Vol. 105 Issue 9 Pg. 1212-9 (Sep 2014) ISSN: 1349-7006 [Electronic] England
• PMID: 24975163 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Chemical References

• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• FGFR2 protein, human
• Receptor, Fibroblast Growth Factor, Type 2

Topics

• Aged
• Animals
• Carcinoma, Pancreatic Ductal (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Female
• Gene Amplification
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Neoplasm Invasiveness
• Neoplasm Transplantation
• Pancreas (metabolism, pathology)
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• Receptor, Fibroblast Growth Factor, Type 2 (genetics, metabolism)
• Signal Transduction
• Vascular Endothelial Growth Factor A (metabolism)