Targeted expression of a human pituitary tumor–derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis

Ezzat, Shereen; Zheng, Lei; Zhu, Xian-Feng; Wu, Gillian E.; Sylvia, L.

doi:10.1172/jci14036

Cited by 162 publications

(96 citation statements)

References 31 publications

(21 reference statements)

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“…It is, however, not uncommon for the first published studies to report over-inflated estimates of effects, which subsequent larger studies cannot replicate. Studies that have examined the role of FGFR4 in the carcinogenesis provide evidence for the complexity of the FGF/ FGFR signalling pathway in different tumour types (Olson et al, 1998;Cavallaro et al, 2001;Ezzat et al, 2002;Shah et al, 2002). It therefore seems unlikely a priori that a single SNP, albeit one with functional effects, will impart substantial differences in cancer prognosis independently.…”

Section: Discussionmentioning

confidence: 99%

Further observations on the relationship between the FGFR4 Gly388Arg polymorphism and lung cancer prognosis

et al. 2007

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The Gly388Arg polymorphism in the fibroblast growth factor receptor 4 (FGFR4) gene has been reported to influence prognosis in a wide variety of cancer types. To determine whether Gly388Arg is a marker for lung cancer prognosis, we genotyped 619 lung cancer patients with incident disease and examined the relationship between genotype and overall survival. While we employed a comprehensive set of statistical tests, including those sensitive to the detection of differences in early survival, our data provide little evidence to support the tenet that the FGFR4 Gly388Arg polymorphism is a clinically useful marker for lung cancer prognosis. British Journal of Cancer (2007Cancer ( ) 96, 1904Cancer ( -1907 (Parkin et al, 2005). Despite recent improvements in treatment, the prognosis has only marginally improved and 5-year survival rates from both small-(SCLC) and non-small-cell lung cancer (NSCLC) are generally no better than 15% (Cancer Research UK). While the major prognostic determinant is stage at presentation, there is variability in survival for patients with same-stage disease, making it highly advantageous to identify further prognostic markers, which may predict patients likely to benefit from treatment. Furthermore, detecting genes with prognostic relevance has the potential to aid the identification of pathways that may be targeted for therapeutic interventions.The FGF/FGFR receptor (FGFR) signalling pathway plays a pivotal role in cellular biology, being involved in differentiation, angiogenesis and motility (reviewed in Powers et al (2000)). Dysregulation of this pathway is a feature of a number of tumours and allelic imbalance at several FGF/FGFR loci is common in lung cancer. Correlations between such changes and lymph node status in cancer has been reported (Beau-Faller et al, 2003), implying that FGF/FGFR signalling may play an important role in the growth and survival of cancer cells.A specific role for FGFR4 in cancer is not well established, but altered expression has been documented in breast, lung, pancreatic and prostate cancers (Bange et al, 2002;Shah et al, 2002;Nakamura et al, 2004;Wang et al, 2004). Recently, a common polymorphism in the transmembrane domain of the FGFR4 gene, Gly388Arg, has been reported to correlate with tumour aggressiveness (lymph node metastasis, advanced stage at presentation and reduced survival in several cancer types, including breast, sarcoma, lung and prostate (Bange et al, 2002;Morimoto et al, 2003;Nakamura et al, 2004;Wang et al, 2004;Spinola et al, 2005a)). Some of these studies were, however, conducted on relatively small sample sizes and subsequent studies of breast, colon, head and neck, and bladder cancers (Becker et al, 2003;Jezequel et al, 2004;Streit et al, 2004;Spinola et al, 2005b;Yang et al, 2006), have provided little support for an association between FGFR4 Gly388Arg genotype and prognosis.To evaluate the prognostic significance of the FGFR4 Gly388Arg polymorphism in lung cancer, we analysed a cohort of 619 lung cancer patients. We employed a compr...

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Section: Discussionmentioning

confidence: 99%

Further observations on the relationship between the FGFR4 Gly388Arg polymorphism and lung cancer prognosis

et al. 2007

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“…The FGFR consists of four receptors and mRNA for prototypic isoforms of FGFR1, FGFR2, and FGFR3 are present in the normal pituitary (Abbass et al 1997). A common alteration in the FGFR that promote PA is the presence of an N-terminally truncated variant of FGFR4 called pituitary tumor-derived FGFR4 (ptd-FGFR4; Ezzat et al 2002). N-terminal truncation of FGFR4 results in a constitutively activated protein that is localized to the cytoplasm where it promotes PA oncogenic transformation in vitro and in vivo.…”

Section: Analysis Of the Rtk/pi3k/akt/mtor Pathways In Pamentioning

confidence: 99%

The PI3K/AKT/mTOR pathway in the pathophysiology and treatment of pituitary adenomas

Monsalves¹,

Juraschka²,

Tateno³

et al. 2014

Endocrine-Related Cancer

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Pituitary adenomas are common intracranial neoplasms. Patients with these tumors exhibit a wide range of clinically challenging problems, stemming either from results of sellar mass effect in pituitary macroadenoma or the diverse effects of aberrant hormone production by adenoma cells. While some patients are cured/controlled by surgical resection and/or medical therapy, a proportion of patients exhibit tumors that are refractory to current modalities. New therapeutic approaches are needed for these patients. Activation of the AKT/phophotidylinositide-3-kinase pathway, including mTOR activation, is common in human neoplasia, and a number of therapeutic approaches are being employed to neutralize activation of this pathway in human cancer. This review examines the role of this pathway in pituitary tumors with respect to tumor biology and its potential role as a therapeutic target.

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“…Several reports have indicated different oncogenic potential of the various isoforms of the FGFRs (64)(65)(66)(67)(68). A shift in splicing generating the more oncogenic isoforms during carcinogenesis could thus promote tumor growth.…”

Section: Switching Between Alternatively Spliced Isoformsmentioning

confidence: 99%

Roles of Fibroblast Growth Factor Receptors in Carcinogenesis

Haugsten

Wiedlocha

Olsnes

et al. 2010

Molecular Cancer Research

274

226

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The fibroblast growth factor receptors (FGFR) play essential roles both during development and in the adult. Upon ligand binding, FGFRs induce intracellular signaling networks that tightly regulate key biological processes, such as cell proliferation, survival, migration, and differentiation. Deregulation of FGFR signaling can thus alter tissue homeostasis and has been associated with several developmental syndromes as well as with many types of cancer. In human cancer, FGFRs have been found to be deregulated by multiple mechanisms, including aberrant expression, mutations, chromosomal rearrangements, and amplifications. In this review, we will give an overview of the main FGFR alterations described in human cancer to date and discuss their contribution to cancer progression.

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Targeted expression of a human pituitary tumor–derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis

Cited by 162 publications

References 31 publications

Further observations on the relationship between the FGFR4 Gly388Arg polymorphism and lung cancer prognosis

Further observations on the relationship between the FGFR4 Gly388Arg polymorphism and lung cancer prognosis

The PI3K/AKT/mTOR pathway in the pathophysiology and treatment of pituitary adenomas

Roles of Fibroblast Growth Factor Receptors in Carcinogenesis

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