Paths of FGFR-driven tumorigenesis

Program in Cell and Molecular Biology, Department of Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 03/2009; 8(4):580-8. DOI: 10.4161/cc.8.4.7657
Source: PubMed


Fibroblast growth factor receptors (FGFRs) comprise a subfamily of receptor tyrosine kinases (RTKs) that are master regulators of a broad spectrum of cellular and developmental processes, including apoptosis, proliferation, migration and angiogenesis. Due to their broad impact, FGFRs and other RTKs are highly regulated and normally only basally active. Deregulation of FGFR signaling by activating mutations or ligand/receptor overexpression could allow these receptors to become constitutively active, leading to cancer development, including both hematopoietic and solid tumors, such as breast, bladder and prostate carcinomas. In this review, we focus on potential modes of FGFR-mediated tumorigenesis, in particular, the role of FGFR1 during prostate cancer progression.

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    • "Figure 4D shows decreased expression of phosphorylated FGFR1 in the group both treated with in Aea4 and Aea25 compared to that of the untreated group, suggesting that Aea4 and Aea25 have a significant inhibitory activity against FGFR1. FGFR1 activation leads to the phosphorylation of ERK and Akt which are considered to be downstream signaling pathway of FGFR1, plays important role in the important roles in the proliferation and survival of cancer cells [25]. Thus the inhibition of phosphorylation of Erk and Akt in tumor samples was tested by immunohistochemistry. Similarly these compounds inhibited FGFR1 downstream ERK and Akt phosphorylation (Figure 4E). "
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    ABSTRACT: Accumulating evidence suggests that high expression of FGFR1 is closely related to the development of lung cancer especially in non-small cell lung cancers (NSCLC), to which non-ATP competitive inhibitors represent an effective therapeutical approach due to their good specificity. Herein, a series of NDGA analogues with the framework of bisaryl-1,4-dien-3-one as novel FGFR1 inhibitors have been designed and screened. Among them Aea4 and Aea25 showed strong FGFR1`inhibition and high selectivity over other receptor kinases. The kinase inhibitory assay in different ATP concentrations and computer-assistant molecular docking showed that the FGFR1 inhibition mode of both Aea4 and Aea25 was non-ATP-competitive. The in vitro and in vivo study on anticancer efficacy of Aea4 and Aea25 against non-small cell lung cancer involves inhibition of cell proliferation, apoptosis induction and cell cycle arrest with no toxicity. Thus, these two novel non-ATP competitive inhibitors derived from NDGA may have a great therapeutic potential in the treatment of NSCLC. This work also provides a structural lead for the design of new non-ATP-competitive FGFR1 inhibitors.
    Oncotarget 06/2014; 5(12). DOI:10.18632/oncotarget.2122 · 6.36 Impact Factor
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    • "lying molecular mechanisms still remain unclear . Recently, constitutively activated fusion genes generated via chromosomal re-arrangements were identified as a new mechanism of uncontrolled FGFR3 activation [1] [7]. "
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    ABSTRACT: The FGF/FGFR-system plays an important role in embryogenesis, tissue homeostasis and carcinogenesis. Mutational activation of FGFR2 resulting in aberrant FGFR2 signaling activation is known from both hereditary germ line alterations and somatic mutations in various malignancies (e.g. breast, gastric or ovarian cancer). FGFR2 mutations are mainly located within the hinge between Ig-like domains (exon 7), around the 3rd Ig-like domains and within the kinase domain. For bladder cancer only sparse data on FGFR2 mutations are available. Most interestingly a case of early-onset papillary carcinoma of the bladder showing a FGFR2 p.Pro253Arg mutation in exon 7 in a patient with Apert Syndrome was reported recently. To further evaluate the importance of FGFR2 exon 7 alterations in bladder cancer a cohort of 254 bladder tumors (cohort 1: unselected cases: n=139; cohort 2: early-onset bladder cancer cases (age at time of diagnosis ≤45 years): n=115) was analyzed. Sections from formalin-fixed, paraffin-embedded bladder tumors were used for DNA isolation. After precise microdissection exon 7 of the FGFR2 gene was analyzed by direct Sanger sequencing. All cases could be analyzed successfully. Mutations in exon 7 of FGFR2 could not be detected in any of the cases. All tumors showed wild type sequence. Our data demonstrate that the recently reported association between early-onset papillary carcinoma of the bladder with germ line FGFR2 p.Pro253Arg mutation could not be found in our cohorts of sporadic bladder tumors. These results indicate that FGFR2 gene mutations might only play a minor role in bladder carcinogenesis.
    International journal of clinical and experimental pathology 05/2014; 7(4):1708-13. · 1.89 Impact Factor
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    • "Among the 18 FGF ligands, FGF19 binds preferentially FGFR4 [24], although it binds also FGFR1. Binding occurs in a complex comprising heparin, FGFR4 and two FGF molecules, which triggers FGFR dimerization, leading to autophosphorylation of multiple tyrosine residues in the intracellular tyrosine kinase domain [3], [25]. FGF19-FGFR4 has been proposed to play a role in the induction of hepatocyte proliferation and carcinogenesis [26]. "
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    ABSTRACT: Fibroblast growth factor receptor 4 (FGFR4) is vital in early development and tissue repair. FGFR4 expression levels are very restricted in adult tissues, except in several solid tumors including colorectal cancer, which showed overexpression of FGFR4. Here, FGFR4 mutation analysis discarded the presence of activating mutations, other than Arg(388), in different colorectal cancer cell lines and tumoral samples. Stable shRNA FGFR4-silencing in SW480 and SW48 cell lines resulted in a significant decrease in cell proliferation, adhesion, cell migration and invasion. This decrease in the tumorigenic and invasive capabilities of colorectal cancer cells was accompanied by a decrease of Snail, Twist and TGFβ gene expression levels and an increase of E-cadherin, causing a reversion to a more epithelial phenotype, in three different cell lines. In addition, FGFR4-signaling activated the oncogenic SRC, ERK1/2 and AKT pathways in colon cancer cells and promoted an increase in cell survival. The relevance of FGFR4 in tumor growth was supported by two different strategies. Kinase inhibitors abrogated FGFR4-related cell growth and signaling pathways at the same extent than FGFR4-silenced cells. Specific FGFR4-targeting using antibodies provoked a similar reduction in cell growth. Moreover, FGFR4 knock-down cells displayed a reduced capacity for in vivo tumor formation and angiogenesis in nude mice. Collectively, our data support a crucial role for FGFR4 in tumorigenesis, invasion and survival in colorectal cancer. In addition, FGFR4 targeting demonstrated its applicability for colorectal cancer therapy.
    PLoS ONE 05/2013; 8(5):e63695. DOI:10.1371/journal.pone.0063695 · 3.23 Impact Factor
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