Article

Fibroblast growth factor (FGF) and FGF receptor-mediated autocrine signaling in non-small-cell lung cancer cells

Department of Craniofacial Biology, University of Colorado at Denver Anschutz Medical Campus, Aurora, CO 80045, USA.
Molecular pharmacology (Impact Factor: 4.12). 11/2008; 75(1):196-207. DOI: 10.1124/mol.108.049544
Source: PubMed

ABSTRACT Despite widespread expression of epidermal growth factor (EGF) receptors (EGFRs) and EGF family ligands in non-small-cell lung cancer (NSCLC), EGFR-specific tyrosine kinase inhibitors (TKIs) such as gefitinib exhibit limited activity in this cancer. We propose that autocrine growth signaling pathways distinct from EGFR are active in NSCLC cells. To this end, gene expression profiling revealed frequent coexpression of specific fibroblast growth factors (FGFs) and FGF receptors (FGFRs) in NSCLC cell lines. It is noteworthy that FGF2 and FGF9 as well as FGFR1 IIIc and/or FGFR2 IIIc mRNA and protein are frequently coexpressed in NSCLC cell lines, especially those that are insensitive to gefitinib. Specific silencing of FGF2 reduced anchorage-independent growth of two independent NSCLC cell lines that secrete FGF2 and coexpress FGFR1 IIIc and/or FGFR2 IIIc. Moreover, a TKI [(+/-)-1-(anti-3-hydroxy-cyclopentyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido-[4,5-d]pyrimidin-2-one (RO4383596)] that targets FGFRs inhibited basal FRS2 and extracellular signal-regulated kinase phosphorylation, two measures of FGFR activity, as well as proliferation and anchorage-independent growth of NSCLC cell lines that coexpress FGF2 or FGF9 and FGFRs. By contrast, RO4383596 influenced neither signal transduction nor growth of NSCLC cell lines lacking FGF2, FGF9, FGFR1, or FGFR2 expression. Thus, FGF2, FGF9 and their respective high-affinity FGFRs comprise a growth factor autocrine loop that is active in a subset of gefitinib-insensitive NSCLC cell lines.

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    • "To uncover the underlying mechanism of biphasic FGF signaling response and to simplify the interpretation of the results, we use a representative non-small cell lung cancer cell line NCI-H1703 that was previously shown to primarily express FGFR1c and to induce Erk1/2 phosphorylation upon stimulation with FGF2 [28]. The expression of FGFR1c was confirmed by qPCR (Materials and methods Section 1). "
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    Cell Communication and Signaling 05/2014; 12(1):34. DOI:10.1186/1478-811X-12-34 · 4.67 Impact Factor
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    • "The biological significance of FGF signaling system for human health and development is illustrated in recent observations [20]. The correct maintenance and regulation of FGF signaling is evident from human and mouse genetic studies, which showed a variety of developmental disorders including dominant skeletal diseases, infertility, and cancer if some signaling mutations lead to the disruption of FGFs [10] [21] [22]. "
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    • "Fibroblast growth factor receptor (FGFR) is a membrane-bound tyrosine kinase which binds to fibroblast growth factor.[76] There are many isoforms which belong to a complex family of signaling molecules implicated in the growth and survival signals in normal and tumor cells,[77] angiogenesis, and inflammation[78] Signaling of FGF through FGFR is believed to be through paracrine and autocrine loops resulting in tumor blood vessel proliferation and survival as well as potential resistance mechanisms with Vascular endothelial growth factor (VEGF) and EGFR.[7679–81] Gly388ARG polymorphism is associated with a poor prognosis.[82–84] "
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