Relationship between E-cadherin and fibroblast growth factor receptor 2b expression in bladder carcinomas

Medina, Sixtina Gil-Diez de; Popov, Z̆.; Chopin, Dominique; Southgate, Jennifer; Tucker, Gordon C.; Delouvée, Annie; Thiery, Jean Paul; Radvanyi, François

doi:10.1038/sj.onc.1202958

Cited by 24 publications

(13 citation statements)

References 15 publications

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“…E-cadherin has been proposed to act as a`master gene' that activates and regulates the expression of other genes that are required for epithelial di erentiation. In bladder cancer, expression of E-cadherin and FGF receptor 2-IIIb are closely related (Diez de Medina et al, 1999). Although the numbers were small (n=20), our study suggests that Ecadherin and expression of FGF receptor 2-IIIb mRNA are also related in ovarian cancer; the EOCs expressing the highest levels of E-cadherin protein expressed FGF receptor 2-IIIb mRNA.…”

Section: Discussionmentioning

confidence: 75%

Induction of FGF receptor 2-IIIb expression and response to its ligands in epithelial ovarian cancer

et al. 2001

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Epithelial ovarian cancers (EOCs) arise in the Ovarian Surface Epithelium (OSE). This tissue is a simple, poorly committed mesothelium which exhibits characteristics of epithelial and mesenchymal cells when grown in culture. In contrast, EOCs frequently exhibit properties of complex epithelial tissues of the female reproductive tract, such as oviductal, endometrial and cervical epithelia, and show induction of expression of epithelial markers such as E-cadherin. Fibroblast Growth Factor Receptor 2 isoform IIIb (FGF receptor 2-IIIb) is a spliced variant of FGF receptor 2 that binds the ligands FGF-1 and FGF-7 with high a nity, and is expressed exclusively by epithelial cells. We have studied the expression of FGF receptor 2-IIIb and its ligands in primary cultures of normal human OSE, EOC cell lines and snap frozen tissue from EOCs. Expression of FGF receptor 2-IIIb mRNA is undetectable in normal OSE, but is expressed in 16/20 (80%) of EOCs. FGFs 1 and 7 mRNAs are expressed in normal OSE, whilst only 4/20 (20%) and 12/20 (60%) of EOCs demonstrated expression for these ligands respectively. However, FGF-7 protein was detected in 70% (mean level=0.7 ng/ml) of ascitic¯uids obtained from patients with EOC. FGFs 1 and 7 stimulate DNA synthesis in EOC cell lines that express FGF receptor 2-IIIb. Moreover, DNA synthesis in these cell lines can be partially blocked by blocking antisera to FGFs 1 and 7. It is suggested that induction of expression of FGF receptor 2-IIIb may play a role in the development of EOCs by rendering the OSE susceptible to paracrine and/or autocrine stimulation by its requisite FGF ligands. Oncogene (2001) 20, 5878 ± 5887.

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Section: Discussionmentioning

confidence: 75%

Induction of FGF receptor 2-IIIb expression and response to its ligands in epithelial ovarian cancer

et al. 2001

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“…FGFR2IIIb is expressed in normal urothelium and is down-regulated in bladder transitional cell carcinoma. Furthermore, loss of this receptor is accompanied by a loss of E-cadherin and the epithelial phenotype, along with a gain in migratory and invasive potential in bladder carcinoma (34). In models of bladder carcinoma, an FGF2 or FGF1 ligand-receptor autocrine loop elicits profound effects on cellular phenotype reminiscent of EMT, and these effects are associated with an increase in matrix metalloproteinase and urokinase activity, resulting in increased invasive potential and tumor volume following s.c. inoculation (35,36).…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal-to-Epithelial Transition Facilitates Bladder Cancer Metastasis: Role of Fibroblast Growth Factor Receptor-2

et al. 2006

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Epithelial-to-mesenchymal transition (EMT) increases cell migration and invasion, and facilitates metastasis in multiple carcinoma types, but belies epithelial similarities between primary and secondary tumors. This study addresses the importance of mesenchymal-to-epithelial transition (MET) in the formation of clinically significant metastasis. The previously described bladder carcinoma TSU-Pr1 (T24) progression series of cell lines selected in vivo for increasing metastatic ability following systemic seeding was used in this study. It was found that the more metastatic sublines had acquired epithelial characteristics. Epithelial and mesenchymal phenotypes were confirmed in the TSU-Pr1 series by cytoskeletal and morphologic analysis, and by performance in a panel of in vitro assays. Metastatic ability was examined following inoculation at various sites. Epithelial characteristics associated with dramatically increased bone and soft tissue colonization after intracardiac or intratibial injection. In contrast, the more epithelial sublines showed decreased lung metastases following orthotopic inoculation, supporting the concept that EMT is important for the escape of tumor cells from the primary tumor. We confirmed the overexpression of the IIIc subtype of multiple fibroblast growth factor receptors (FGFR) through the TSU-Pr1 series, and targeted abrogation of FGFR2IIIc reversed the MET and associated functionality in this system and increased survival following in vivo inoculation in severe combined immunodeficient mice. This model is the first to specifically model steps of the latter part of the metastatic cascade in isogenic cell lines, and confirms the suspected role of MET in secondary tumor growth. (Cancer Res 2006; 66(23): 11271-8)

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“…In an animal model of bladder cancer metastasis using an FGFR1-dependent cell line, FGFR inhibition reduced the development of circulating tumour cells and metastasis but not primary tumour growth 69 . Interestingly, although FGFR2 shows reduced expression in MI disease 164 , cells selected for enhanced metastatic capability were found to be dependent on FGFR2 isoform IIIc for this phenotype, which was associated with a mesenchymal-epithelial transition (MET) 165 . Thus, FGFRs are implicated in both the EMT required early in the process of metastasis and in the MET required to recapitulate the epithelial phenotype at the metastatic site.…”

Section: Emt and Metastasismentioning

confidence: 99%

Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

2014

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Correspondence to M.A.K. m.a.knowles@leeds.ac.uk 2 Preface Urothelial carcinoma of the bladder comprises two long-recognised disease entities with distinct molecular features and clinical outcome. Low-grade, non-muscle-invasive tumours recur frequently but rarely progress to muscle invasion, whereas muscle invasive tumours are usually diagnosed de novo and frequently metastasize. Recent genome-wide expression and sequencing studies identify genes and pathways that are key drivers of urothelial cancer and reveal a more complex picture with multiple molecular subclasses that cut across conventional grade and stage groupings. This improved understanding of molecular features, disease pathogenesis and heterogeneity provides new opportunities for prognostic application, disease monitoring and personalised therapy.Bladder cancer is the most common cancer of the urinary tract with approximately 380,000 new cases and 150,000 deaths per year worldwide 1 . It ranks fifth among cancers in men in Western countries.Epidemiological studies identify a range of environmental risk factors, many of which reflect exposure to excreted carcinogenic molecules (BOX 1). Recent genome-wide association studies have also identified germline variants that contribute to risk 2 .In Europe and North America, more than 90% of bladder cancers are urothelial carcinoma. These tumours are staged using the Tumour Nodes Metastasis (TNM) system 3 , which describes the extent of invasion (Tis-T4), and graded according to their cellular characteristics. Two classification systems are in current use 4, 5 .At diagnosis the majority of bladder cancers (~ 60%) are non-muscle-invasive (NMIBC) (stage Ta) NMIBCs frequently recur (50-70%) but infrequently progress to invasion (10-15%) 6 and five-year survival is ~90%. These patients are monitored by cystoscopy and may have multiple resections over many years.Improved monitoring is needed, ideally via urine analysis, which could reduce the morbidity and costs associated with cystoscopy. Although risk tables provide a prognostic tool 7 , no molecular biomarkers accurately predict disease progression. For these patients, localised therapies to remove residual neoplastic and preneoplastic cells post-resection may have major impacts on both quality of life and in health economic terms. MIBCs (>stage T2) have less favourable prognosis with five-year survival <50% and common progression to metastasis (BOX1). Treatment has not advanced for several decades and new approaches to systemic therapy are needed 8 .Improved treatment requires detailed understanding of urothelial carcinoma pathogenesis and molecular biology. A model has evolved, taking into account both histopathological and molecular features. This socalled 'two-pathway' model proposes that papillary NMIBC develops via epithelial hyperplasia and recruitment of a branching vasculature. MIBCs are proposed to develop via flat dysplasia and carcinoma in situ (CIS). The molecular characteristics of MIBC and NMIBC are highly distinct (Tables 1 and 2). Whilst 3 m...

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Relationship between E-cadherin and fibroblast growth factor receptor 2b expression in bladder carcinomas

Cited by 24 publications

References 15 publications

Induction of FGF receptor 2-IIIb expression and response to its ligands in epithelial ovarian cancer

Induction of FGF receptor 2-IIIb expression and response to its ligands in epithelial ovarian cancer

Mesenchymal-to-Epithelial Transition Facilitates Bladder Cancer Metastasis: Role of Fibroblast Growth Factor Receptor-2

Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

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