Somatic mutations of adenomatous polyposis coli gene and nuclear b‐catenin accumulation have prognostic significance in invasive urothelial carcinomas: Evidence for Wnt pathway implication

Kastritis, Efstathios; Murray, Samuel; Kyriakou, Fani; Horti, Maria; Tamvakis, N.; Kavantzas, N; Patsouris, Efstratios; Noni, Aphrodite; Legaki, Sofia; Dimopoulos, Meletios Α.; Bamias, Aristotle

doi:10.1002/ijc.23917

Cited by 57 publications

(45 citation statements)

References 40 publications

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“…Dysregulation of the Wnt/b-catenin signaling pathway has also been linked to bladder cancer growth (Bui et al 1998, Shiina et al 2002, Hsieh et al 2004, Stoehr et al 2004, Urakami et al 2006, Kastritis et al 2009, Hirata et al 2012). However, cross talk between the AR and Wnt/b-catenin pathways in bladder cancer cells remains unclear, although it has been well studied in prostate cancer (Chesire & Isaacs 2003, Wang et al 2008.…”

Section: Discussionmentioning

confidence: 99%

“…There are dissenting data as to the correlation of b-catenin staining in bladder cancer with tumor aggressiveness (Garcia del Muro et al 2000, Nakopoulou et al 2000, Zhu et al 2000, Stoehr et al 2002, Kastritis et al 2009). The discrepancy may have resulted from the use of different antibodies and methodologies.…”

Section: Discussionmentioning

confidence: 99%

“…Our current data also corroborated the demonstration that loss or reduced expression of membranous b-catenin was associated with worse outcome (Garcia del Muro et al 2000, Nakopoulou et al 2000. Nuclear accumulation of b-catenin, as a hallmark of Wnt/b-catenin activation (Chesire & Isaacs 2003), has been shown to correlate with lymph node involvement and poor prognosis (Kastritis et al 2009). Consistent with these findings, our data showed a trend to associate between nuclear b-catenin expression and a risk of tumor progression after cystectomy, while there was no relationship between lymph node metastases and the status of b-catenin expression in the nucleus as well as the membrane or cytoplasm, possibly due to relatively small number of cases.…”

Section: Discussionmentioning

confidence: 99%

“…Both downregulation of the Wnt antagonists (Hsieh et al 2004, Stoehr et al 2004 and upregulation of the Wnt target genes (Shiina et al 2002) have been observed in bladder cancer tissues. It has also been shown that nuclear accumulation of b-catenin correlates with worse outcomes in patients with bladder cancer (Kastritis et al 2009). These observations suggest that Wnt signaling is active in advanced urothelial tumors.…”

Section: Introductionmentioning

confidence: 99%

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Androgen activates β-catenin signaling in bladder cancer cells

Zheng

Izumi

et al. 2013

Endocrine-Related Cancer

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Androgen receptor (AR) signals have been implicated in bladder carcinogenesis and tumor progression. Activation of Wnt/b-catenin signaling has also been reported to correlate with bladder cancer progression and poor patients' outcomes. However, cross talk between AR and b-catenin pathways in bladder cancer remains uncharacterized. In radical cystectomy specimens, we immunohistochemically confirmed aberrant expression of b-catenin especially in aggressive tumors. There was a strong association between nuclear expressions of AR and b-catenin in bladder tumors (PZ0.0215). Kaplan-Meier and log-rank tests further revealed that reduced membranous b-catenin expression (PZ0.0276), nuclear b-catenin expression (PZ0.0802), and co-expression of nuclear AR and b-catenin (PZ0.0043) correlated with tumor progression after cystectomy. We then assessed the effects of androgen on b-catenin in AR-positive and AR-negative bladder cancer cell lines. A synthetic androgen R1881 increased the expression of an active form of b-catenin and its downstream target c-myc only in AR-positive lines. R1881 also enhanced the activity of b-catenin-mediated transcription, which was abolished by an AR antagonist hydroxyflutamide. Using western blotting and immunofluorescence, R1881 was found to induce nuclear translocation of b-catenin when co-localized with AR. Finally, co-immunoprecipitation revealed androgeninduced associations of AR with b-catenin or T-cell factor (TCF) in bladder cancer cells. Thus, it was likely that androgen was able to activate b-catenin signaling through the AR pathway in bladder cancer cells. Our results also suggest that activation of b-catenin signaling possibly via formation of AR/b-catenin/TCF complex contributes to the progression of bladder cancer, which may enhance the feasibility of androgen deprivation as a potential therapeutic approach.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Androgen activates β-catenin signaling in bladder cancer cells

Zheng

Izumi

et al. 2013

Endocrine-Related Cancer

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“…[18][19][20] Subsequently, evidence of missense (13%) and frameshift (3%) deletions in the APC protein adjacent to the b-catenin binding sites was reported. 24 Interestingly, the authors were able to demonstrate that either APC mutations or b-catenin accumulation was associated with shorter disease free interval and shorter disease specific survival in multivariate analysis. Earlier studies have demonstrated an upregulation of bcatenin by immunohistochemistry.…”

Section: Human Urothelial Cell Carcinomamentioning

confidence: 98%

The role of WNT signalling in urothelial cell carcinoma

Ahmad

2015

annals

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Urothelial cell carcinoma (UCC) of the bladder is one of the most common malignancies, causing considerable morbidity and mortality worldwide. It is unique among the epithelial carcinomas as two distinct pathways to tumourigenesis appear to exist: low grade, recurring papillary tumours usually contain oncogenic mutations in FGFR3 or HRAS whereas high grade, muscle invasive tumours with metastatic potential generally have defects in the pathways controlled by the tumour suppressors p53 and retinoblastoma. Over the last two decades, a number of transgenic mouse models of UCC, containing deletions or mutations of key tumour suppressor genes or oncogenes, have helped us understand the mechanisms behind tumour development. In this summary, I present my work investigating the role of the WNT signalling cascade in UCC. KEYWORDSUrothelial cell carcinoma -Bladder cancer -Mouse models -Transgenics -WNT Accepted 30 December 2014 CORRESPONDENCE TO Imran Ahmad, E: imran.ahmad@glasgow.ac.ukThe incidence of urothelial cell carcinoma (UCC) continues to rise, with significant implications for our healthcare systems. In the UK, it is the seventh most common cancer, accounting for 3% of all new cases, with an estimated 10,399 new cases diagnosed in the UK in 2011. 1UCCs are predominantly transitional cell carcinomas (TCCs), arising from the transitional epithelium that lines the bladder. Of these, 70-80% of cases are low grade (LG), papillary, non-invasive tumours that tend to recur in over 30% of patients despite local excision.2 There is controversy regarding whether these papillary tumours progress to invasive disease, with progression occurring in approximately 5% of cases.3 However, whether this is a true progression or development of de novo muscle invasive tumours remains unclear. Most morbidity and subsequent mortality secondary to UCC is due to the high grade (HG), non-papillary, muscle invasive form of the disease (20-30% of new TCC cases). 4 These invasive tumours penetrate through the muscularis of the bladder and 50% of patients relapse with tumours that metastasise to distant sites despite treatment. 5 The five-year survival rate for metastatic bladder cancer is approximately 7%. 6Clinical and pathological studies have found that these two forms of UCC arise through at least two separate mechanisms (Fig 1). 7,8 Recently, genomic profiling and expression studies have identified two separate signatures for different molecular subtypes of UCC that stratify into LG or HG disease and can independently predict the likelihood of development of metastasis and disease specific survival. 9-11Multiple transgenic murine models that attempt to recapitulate the different subtypes of UCC have been developed to better understand the disease process (Table 1). The role of WNT signalling in urothelial cell carcinoma Human urothelial cell carcinomaThe WNT pathway is conserved widely throughout many species including Caenorhabditis elegans, Drosophila, Xenopus and higher order mammals. It was discovered originally in Drosophila ...

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