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: 5.01). 03/2009; 8(4):580-8. DOI: 10.4161/cc.8.4.7657
Source: PubMed

ABSTRACT 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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    • "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 01/2014; 7(4):1708-13. · 1.78 Impact Factor
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    • "Genetic events associated with human prostate cancer, the most common cancer and second leading cause of cancer death in American men (Jemal et al., 2010), include ETS family member translocation (Tomlins et al., 2005; Rubin, 2008) and (epi)genetic alterations of PTEN, p27 Kip1 , NKX3.1, c-MYC, FGFRs, EZH2/ MIR101, p53, SMAD4, among others (Li et al., 1997; Guo et al., 1997; Abate-Shen et al., 2008; Jenkins et al., 1997; Acevedo et al., 2009; Ding et al., 2011). Genomic analysis of human prostate cancers has revealed numerous recurrent amplifications and deletions (Taylor et al., 2010), pointing to the existence of many new prostate cancer-relevant genes. "
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    ABSTRACT: To determine the role of telomere dysfunction and telomerase reactivation in generating pro-oncogenic genomic events and in carcinoma progression, an inducible telomerase reverse transcriptase (mTert) allele was crossed onto a prostate cancer-prone mouse model null for Pten and p53 tumor suppressors. Constitutive telomerase deficiency and associated telomere dysfunction constrained cancer progression. In contrast, telomerase reactivation in the setting of telomere dysfunction alleviated intratumoral DNA-damage signaling and generated aggressive cancers with rearranged genomes and new tumor biological properties (bone metastases). Comparative oncogenomic analysis revealed numerous recurrent amplifications and deletions of relevance to human prostate cancer. Murine tumors show enrichment of the TGF-β/SMAD4 network, and genetic validation studies confirmed the cooperative roles of Pten, p53, and Smad4 deficiencies in prostate cancer progression, including skeletal metastases. Thus, telomerase reactivation in tumor cells experiencing telomere dysfunction enables full malignant progression and provides a mechanism for acquisition of cancer-relevant genomic events endowing new tumor biological capabilities.
    Cell 03/2012; 148(5):896-907. DOI:10.1016/j.cell.2012.01.039 · 33.12 Impact Factor
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    • "FGFs transduce signals through binding to transmembrane receptor tyrosine kinases, named FGF receptors (FGFR1-4), and also bind with lower affinity to heparin-like glycosaminoglycans of the extracellular matrix (McKeehan et al., 1998). After ligand binding, FGFRs activate major cellular growth and survival pathways including, for example, mitogen-activated protein kinase and phosphoinositide 3-kinase signal cascades (Acevedo et al., 2009). "
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    ABSTRACT: Cutaneous melanoma is a tumor with rising incidence and a very poor prognosis at the disseminated stage. Melanomas are characterized by frequent mutations in BRAF and also by overexpression of fibroblast growth factor 2 (FGF2), offering opportunities for therapeutic intervention. We investigated inhibition of FGF signaling and its combination with dacarbazine or BRAF inhibitors as an antitumor strategy in melanoma. The majority of melanoma cell lines displayed overexpression of FGF2 but also FGF5 and FGF18 together with different isoforms of FGF receptors (FGFRs) 1-4. Blockade of FGF signals with dominant-negative receptor constructs (dnFGFR1, 3, or 4) or small-molecule inhibitors (SU5402 and PD166866) reduced melanoma cell proliferation, colony formation, as well as anchorage-independent growth, and increased apoptosis. DnFGFR constructs also significantly inhibited tumor growth in vivo. Combination of FGF inhibitors with dacarbazine showed additive or antagonistic effects, whereas synergistic drug interaction was observed when combining FGFR inhibition with the multikinase/BRAF inhibitor sorafenib or the V600E mutant-specific BRAF inhibitor RG7204. In conclusion, FGFR inhibition has antitumor effects against melanoma cells in vitro and in vivo. Combination with BRAF inhibition offers a potential for synergistic antimelanoma effects and represents a promising therapeutic strategy against advanced melanoma.
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