Oncogenic role of fibroblast growth factor receptor 3 in tumorigenesis of urinary bladder cancer

Pandith, Arshad A.; Shah, Zafar A.; Siddiqi, Mushtaq A.

doi:10.1016/j.urolonc.2010.07.014

Cited by 51 publications

(76 citation statements)

References 74 publications

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“…FGFR3 is a receptor tyrosine kinase implicated in the tumorigenesis of numerous types of myeloma, cervical cancer and urothelial carcinoma (13). There are two mechanisms that cause abnormal activation of FGFR3: Translocation of chromosome 4 to chromosome 14 (leading to overexpression) and activation of point mutations in the FGFR3 gene (11).…”

Section: Discussionmentioning

confidence: 99%

“…Low-grade noninvasive bladder tumors are characterized by gain-of-function mutations, which mainly affect classical oncogenes including fibroblast growth factor receptor 3 (FGFR3) and Harvey rat sarcoma viral oncogene homolog genes, whereas invasive tumors are characterized by loss-of-function mutations resulting in inactivation of tumor suppressors including p53, RB, and phosphate and tensin homolog (11,12). FGFR3 belongs to a family of structurally associated tyrosine kinase receptors that are involved in numerous aspects of embryogenesis and tissue homeostasis, as well as being implicated in the tumorigenesis of bladder and other urothelial types of cancer, multiple myeloma and cervical cancer (13)(14)(15). Mutated FGFR3 is constitutively activated and induces a number of oncogenic signaling pathways, including the RAS/mitogen activated protein kinases (MAPK), phospholipase Cc1 (PLCc1), phosphoinositide 3-kinase (PI3K) and signal transducer and activator of transcription (STAT) signaling pathways (11,(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

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Expression levels of FGFR3 as a prognostic marker for the progression of primary pT1 bladder cancer and its association with mutation status

et al. 2017

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Abstract. The present study examined the utility of fibroblast growth factor receptor 3 (FGFR3) mutation status and gene expression as a prognostic marker in primary pT1 bladder cancer (BC). A total of 120 patients with primary pT1 BC were enrolled. FGFR3 mutation status was determined by direct sequencing and FGFR3 mRNA expression level was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. The results were compared with the clinicopathological parameters, and the prognostic value of FGFR3 was evaluated by Kaplan-Meier analysis and a multivariate Cox regression test. FGFR3 mutations were identified in 48/120 (40.0%) patients with pT1 BC. FGFR3 mRNA expression level was significantly higher in those with BC harboring FGFR3 mutations (P<0.001). Low FGFR3 expression level was associated with high-grade tumors and cancer progression (P=0.006 and P=0.001), whereas FGFR3 mutation status was not associated with cancer progression. Kaplan-Meier analysis revealed a similar result (log-rank, P<0.001). Multivariate analysis identified low FGFR3 expression level (odds ratio, 3.300; 95% confidence interval, 1.310-8.313; P=0.011) as an independent predictor of cancer progression. Stratification by exon site of FGFR3 mutations yielded significant differences in mRNA expression level. None of the patients with BC harboring FGFR3 mutations in exon 9 demonstrated disease progression. The mRNA expression level of the FGFR3 gene may be used to precisely identify subsets of patients with pT1 BC that have a relatively better prognosis. The prognostic influences of FGFR3 mutations may be modulated by the exon site of FGFR3 mutations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression levels of FGFR3 as a prognostic marker for the progression of primary pT1 bladder cancer and its association with mutation status

et al. 2017

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“…28,29 Overexpression of FGFR3-TACC3 was found to induce cell proliferation in breast cancer, whereas an inhibitor of FGFR3 abolished the increased cell growth of FGFR3-TACC3-expressing cells. 21 These findings suggest that FGFR3 kinase activity plays an important role in the function of FGFR3-TACC3.…”

Section: Discussionmentioning

confidence: 99%

Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma

Li¹,

Liu²,

Lin

et al. 2014

Cancer Biology & Therapy

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These authors equally contributed to this work. Keywords: FGFR3-TACC3, fusion gene, NPC, proliferation, tumorigenesisAbbreviations: FGFR3, fibroblast growth factor receptor 3; TACC3, transforming acidic coiled-coil-containing protein 3; NPC, nasopharyngeal carcinoma; LTBR, lymphotoxin b receptor; CCND1, cyclin D1; RT-PCR, reverse transcription-PCR; FBS, fetal bovine serum; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide; SDS, sodium dodecyl sulfate; DTT, DL-dithiothreitol; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline; PI, propidium iodide.Nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies and exhibits regional differences in incidence. Because many fusion genes have been discovered in different types of tumors over the past few years, we aimed to investigate the existence of a fusion gene in primary NPC patients using RNA-seq. In this study, for the first time, we found that fibroblast growth factor receptor 3-transforming acidic coiled-coil-containing protein 3 (FGFR3-TACC3) fusion transcripts are recurrently detected in NPC. The presence of this fusion gene was also detected in head and neck cancer, esophageal squamous cell carcinoma (ESCC), and lung cancer. Furthermore, we found certain new isoforms of the FGFR3-TACC3 fusion transcripts, such as a gene fusion between exon 18 of FGFR3 and exon 6 or exon 14 of TACC3 and agene fusion between exon 19 of FGFR3 and exon 11 of TACC3. In addition, we showed that the FGFR3-TACC3 fusion gene promotes cell proliferation, colony formation, and transforming ability in vitro, whereas the FGFR3-TACC3 K508M mutant or treatment with the FGFR inhibitor PD173074 abrogates these effects, suggesting that FGFR3-TACC3 most likely exerts its effects through activation of FGFR kinase activity. This activation likely leads to the development of NPC. Additionally, FGFR3-TACC3 could trigger activation of the ERK and Akt signaling pathways, whereas FGFR3-TACC3 K508M mutant could not, suggesting that these 2 signaling pathways might be involved in the function of FGFR3-TACC3. Taken together, our data demonstrated the oncogenic role of FGFR3-TACC3 in vitro, indicating that FGFR3-TACC3 may be useful as a diagnostic marker and therapeutic target in cancers.

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“…FGFR3 mutations are one of the most frequent FGFR alterations found in bladder cancer, interestingly it is more present in low-grade urothelial tumors than in the high-grade tumors (Pandith et al, 2008).…”

Section: Gene Mutationmentioning

confidence: 99%

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

177

162

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Introduction The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. Areas Covered This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Expert opinion Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations

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Oncogenic role of fibroblast growth factor receptor 3 in tumorigenesis of urinary bladder cancer

Cited by 51 publications

References 74 publications

Expression levels of FGFR3 as a prognostic marker for the progression of primary pT1 bladder cancer and its association with mutation status

Expression levels of FGFR3 as a prognostic marker for the progression of primary pT1 bladder cancer and its association with mutation status

Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma

FGFR a promising druggable target in cancer: Molecular biology and new drugs

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