Kornmann M, Ishiwata T, Matsuda K, Lopez ME, Fukahi K, Asano G, Beger HG, Korc MThe IIIc isoform of fibroblast growth factor receptor 1 is overexpressed in human pancreatic cancer and enhances tumorigenicity of hamster ductal cells. Gastroenterology 123: 301-313
Department of General Surgery, University of Ulm, Ulm, Germany. Gastroenterology
(Impact Factor: 16.72).
07/2002; 123(1):301-13. DOI: 10.1053/gast.2002.34174
Fibroblast growth factors (FGFs) are mitogenic polypeptides that signal via FGF receptors (FGFRs). Pancreatic ductal adenocarcinomas (PDACs) overexpress multiple FGFs, implying a potential for growth modulation. In this study we investigated the importance of the IIIc splice variant of FGFR-1 (FGFR-1 IIIc) in PDAC.
Expression of FGFR-1 IIIc was determined by a ribonuclease protection assay in pancreatic cancer cell lines and in tissues. In situ hybridization was used to localize FGFR-1 IIIc messenger RNA (mRNA) in pancreatic tissues. A cDNA encoding FGFR-1 IIIc was stably transfected into the well-differentiated TAKA-1 pancreatic ductal cell line that is not responsive to FGF5 and does not express FGFR-1.
FGFR-1 IIIc was expressed in 5 of 7 pancreatic cancer cell lines and in the majority of the cancer cells in 4 of 7 PDAC samples. In vitro, TAKA-1 cells stably transfected with FGFR-1 IIIc exhibited increased basal growth; enhanced basal tyrosine phosphorylation of FGFR substrate-2 (FRS2), Shc, and phospholipase Cgamma; and increased activation of mitogen-activated protein kinase (MAPK). PD98059, an inhibitor of MAPK, suppressed the basal growth of parental and transfected clones, but the effect was more marked in clones expressing FGFR-1 IIIc. In vivo, tumor formation in nude mice was dramatically enhanced with FGFR-1 IIIc transfected (20 of 20) in comparison with sham transfected (0 of 10) cells.
Our data indicate that FGFR-1 IIIc is expressed in human pancreatic cancer cells, promotes mitogenic signaling via the FRS2-MAPK pathway, and has the potential to enhance pancreatic ductal cell transformation.
Available from: Max Bachem
- "We recently showed that over-expression of FGFR1-IIIb in PDAC cells reverted the malignant phenotype inhibiting proliferation, single cell movement , and migration in vitro, as well as xenograft formation and growth in vivo (Liu et al, 2007b). On the other hand, it is well known that over-expression of FGFR1-IIIc enhances the malignant phenotype of PDAC (Wagner et al, 1998; Kornmann et al, 2002). FGFR1-IIIb over-expression in PDAC cells resulted in strong p38-MAPK and JNK activitation (Liu et al, 2007a, b). "
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ABSTRACT: Secreted protein acidic and rich in cysteine (SPARC) is a multi-faceted protein-modulating cell-cell and cell-matrix interactions. In cancer, SPARC can be not only associated with a highly aggressive phenotype, but also acts as a tumour suppressor. The aim of this study was to characterise the function of SPARC and its modulation by fibroblast growth factor receptor (FGFR) 1 isoforms in pancreatic ductal adenocarcinoma (PDAC).
Exogenous SPARC inhibited growth, movement, and migration. ShRNA inhibition of endogenous SPARC in ASPC-1 and PANC-1 cells resulted in increased anchorage-dependent and -independent growth, transwell migration, and xenograft growth as well as increased mitogenic efficacy of fibroblast growth factor (FGF) 1 and FGF2. Endogenous SPARC expression in PANC-1 cells was increased in FGFR1-IIIb over-expressing cells, but decreased in FGFR1-IIIc over-expressing cells. The up-regulation of endogenous SPARC was abrogated by the p38-mitogen-activated protein kinase inhibitor SB203580. SPARC was detectable in conditioned medium of pancreatic stellate cells (PSCs), but not PDAC cells. Conditioned medium of PDAC cells reduced endogenous SPARC expression of PSCs.
Endogenous SPARC inhibits the malignant phenotype of PDAC cells and may, therefore, act as a tumour suppressor in PDAC. Endogenous SPARC expression can be modulated by FGFR1-III isoform expression. In addition, PDAC cells may inhibit endogenous SPARC expression in surrounding PSCs by paracrine actions.
British Journal of Cancer 11/2009; 102(1):188-95. DOI:10.1038/sj.bjc.6605440 · 4.84 Impact Factor
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ABSTRACT: Keratinocyte growth factor receptor (KGFR), also known as fibroblast growth factor receptor (FGFR)2 IIIb, is located in many types of epithelial cells and is activated by four known ligands (FGF-1, FGF-3, FGF-7 (also known as KGF) and FGF-10) that are predominantly synthesized by mesenchymal cells. In the early stage of atherosclerosis, vascular smooth muscle cells (VSMC) transform from a contractile to a synthetic phenotype, proliferate and migrate into the intima. Previously, FGF-7 mRNA expression was reported in VSMC, but KGFR mRNA was not detected. In the present study, we attempted to determine whether KGFR is localized in VSMC cultured from rat aorta and VSMC in human normal and atherosclerotic coronary arteries. Expression of KGFR mRNA and its protein was detected in cultured rat VSMC by reverse transcription-polymerase chain reaction and western blot analysis, respectively. Immunohistochemically, KGFR was localized in the VSMC of the outer layer of the media in normal human coronary arteries. Furthermore, it was localized in the VSMC of the media and thickened intima of atherosclerotic arteries. Recombinant FGF-7 and/or FGF-10 proteins stimulated the growth of cultured rat VSMC. These findings indicate that KGFR localized in VSMC may contribute to the proliferation of VSMC in normal and atherosclerotic arteries.
Pathology International 04/2003; 53(3):127-32. DOI:10.1046/j.1440-1827.2003.01445.x · 1.69 Impact Factor
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ABSTRACT: CW-pumped Nd:YVO4 lasers passively Q-switched with LiF:F2- and YAG:Cr4+ saturable absorbers are modeled and comparatively analyzed. The model takes into account the geometric factor representing the distributions of the orientations of F2- color centers and Cr4+ ions relatively to the corresponding crystalline hosts on the output parameters of the lasers. It is shown that the LiF:F2- Q-switch has evident advantages over the YAG:Cr4+ one in the senses of a much more expanded range of pump powers where the giant-pulse regime is supported in the laser and, as a consequence, potentially higher average output and peak pulse powers accessible.
Optics Communications 11/2004; 242(s 1–3):241–252. DOI:10.1016/j.optcom.2004.08.025 · 1.45 Impact Factor
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