Conditional activation of fibroblast growth factor receptor (FGFR) 1, but not FGFR2, in prostate cancer cells leads to increased osteopontin induction, extracellular signal-regulated kinase activation, and in vivo proliferation.

Abstract	Changes in the fibroblast growth factor receptor (FGFR) axis are often associated with prostate cancer (CaP) progression. We have used chemically induced dimerization (CID) to elucidate the individual contributions of FGFR1 and FGFR2 to tumor etiology. Novel CaP cell lines stably expressing CID/AP20187-inducible FGFR1 (iFGFR1) and iFGFR2 were made using the tumorigenic transgenic adenocarcinoma of the murine prostate (TRAMP)-derived clone, TRAMP-C2N (C2N), to generate C2N.iFGFR1 or C2N.iFGFR2 cells. To test the effects of iFGFR activation on tumor growth, mice bearing s.c. C2N.iFGFR1- or C2N.iFGFR2-derived tumors were treated biweekly with CID. Activation of iFGFR1 led to rapid tumor growth as a result of increased proliferation. In contrast, expression of iFGFR2 inhibited tumor growth. Furthermore, we have ascertained that FGFR1 activation appears to be most important during the early stages of tumor development, but once established, tumors become rapidly CID independent. In these C2N-based lines, quantitative signaling differences were seen between the two receptors, with iFGFR1 leading to more robust extracellular signal-regulated kinase activation. Additionally, activation of iFGFR1, but not iFGFR2, led to strong up-regulation of osteopontin, a secreted glycoprotein involved in integrin activation and associated with CaP progression and metastasis. These studies support the hypothesis that observed changes in the FGFR axis in mammals during CaP progression are causally important.
Authors	Kevin W Freeman, Rama D Gangula, Bryan E Welm, Mustafa Ozen, Barbara A Foster, Jeffrey M Rosen, Michael Ittmann, Norman M Greenberg, David M Spencer
Journal	Cancer research (Cancer Res) Vol. 63 Issue 19 Pg. 6237-43 (Oct 01 2003) ISSN: 0008-5472 [Print] United States
PMID	14559809 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Receptors, Fibroblast Growth Factor Sialoglycoproteins Spp1 protein, mouse Osteopontin Fgfr1 protein, mouse Fgfr2 protein, mouse Receptor Protein-Tyrosine Kinases Receptor, Fibroblast Growth Factor, Type 1 Receptor, Fibroblast Growth Factor, Type 2 Mitogen-Activated Protein Kinase Kinases
Topics	Adenocarcinoma (enzymology, genetics, metabolism) Animals Apoptosis (physiology) Cell Division (physiology) Cell Line, Tumor Enzyme Activation Gene Expression Regulation, Neoplastic Male Mice Mitogen-Activated Protein Kinase Kinases (metabolism) Neoplasm Transplantation Osteopontin Phosphorylation Prostatic Neoplasms (enzymology, genetics, metabolism, pathology) Receptor Protein-Tyrosine Kinases (biosynthesis, genetics, physiology) Receptor, Fibroblast Growth Factor, Type 1 Receptor, Fibroblast Growth Factor, Type 2 Receptors, Fibroblast Growth Factor (biosynthesis, genetics, physiology) Sialoglycoproteins (biosynthesis) Signal Transduction (physiology) Transfection Up-Regulation

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!