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.

Microvascular density and endothelial area correlate with Ki-67 proliferative index in surgically-treated pancreatic ductal adenocarcinoma patients

“…Of note, a close spatial association was observed between proliferating tumour cells and microvessels, as determined using image analysis data in the present study; this therefore indicated an anatomical association between neovessel formation and tumour cell proliferation. In addition, this anatomical link may be supported by the overexpression of several angiogenic cytokines, including vascular endothelial growth factor, fibroblast growth factor, thymidine phosphorylase and tryptase, which have been previously demonstrated to be present in PDAC tissue (32)(33)(34)(35). These cytokines, secreted from tumoral and stromal cells, have a role in the autocrine and paracrine growth stimulation of tumoral and endothelial cells (36)(37)(38).…”

Exploring the mechanism of WWOX growth inhibitory effects on oral squamous cell carcinoma

“…In the colorectal cancer NCI-H716 cell line, which exhibits a high expression of FGFR2, the inhibition of FGFR2 by small molecule inhibitors or FGFR2 short hairpin (sh)RNA was shown to decrease cell viability (28). In pancreatic cancer, tumor cells with FGFR2-shRNA transfection exhibited attenuated proliferation rates, migration and invasion levels, and a reduced level of phosphorylation of ERK compared with that of the control cells (29). These findings demonstrate that the inhibition of FGFR2 contributes to the suppression of cell proliferation and ERK phosphorylation.…”

Role of fibroblast growth factors in pancreatic cancer

“…Влияя на цис-регуляторные элементы, он активирует несколько генов [36], среди которых особенно важен ген IL-1. Секретируемый раковыми клетками IL-1 не влияет на сами эти клетки, но активирует близлежащие фибробласты, что приводит к повышению синтеза фибробластами FGF7, создавая таким образом положительную петлю обратной связи, усиливающую пролиферацию раковых клеток [37,38]. Одновременная экспрессия FGF7 и FGFR2-IIIb в тканях опухоли и стромы коррелирует с повышенной экспрессией VEGF-A (фактор роста сосудистого эндотелия А), венозной инвазией и негативным прогнозом.…”

“…Одновременная экспрессия FGF7 и FGFR2-IIIb в тканях опухоли и стромы коррелирует с повышенной экспрессией VEGF-A (фактор роста сосудистого эндотелия А), венозной инвазией и негативным прогнозом. FGFR2-IIIс потенцирует деление и миграцию клеток рака поджелудочной железы и придает им свойства, характерные для опухолевых стволовых клеток [21,37].…”