title: 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: Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Tokyo, Japan; Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
authors: Yoko
authors: Y
authors: Matsuda
authors: Hisashi
authors: H
authors: Yoshimura
authors: Taeko
authors: T
authors: Suzuki
authors: Eiji
authors: E
authors: Uchida
authors: Zenya
authors: Z
authors: Naito
authors: Toshiyuki
authors: T
authors: Ishiwata
mesh_terms: D000368:Aged; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005784:Gene Amplification; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2
keywords: FGFR-2 IIIb; FGFR-2 IIIc; fibroblast growth factor receptor-2 (FGFR-2); pancreatic cancer; short hairpin RNA