The role of WNT signalling in urothelial cell carcinoma

Abstract

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 ...

Wnt/β-Catenin Signaling and Immunotherapy Resistance: Lessons for the Treatment of Urothelial Carcinoma

“…For instance, The Cancer Genome Atlas (TCGA) Research Network detected Wnt signaling alterations in 73% of UCC tumors [ 35 ]. However, Ahmad et al noted Wnt signaling in only 33% of their clinical UCC samples [ 36 , 37 , 38 ]. The discrepancy could most likely be due to comparisons using different methods and patient populations.…”

“…For example, one Ahmad et al study used a tissue microarray array with core biopsy samples, whereas a TCGA study detected aberrations in Wnt signaling through genomics using RNA-seq and whole exome sequencing [ 35 , 36 , 37 , 38 ]. Also there was a difference in sample size with TCGA and Ahmad et al studies using 131 and 60 patient samples respectively [ 35 , 36 , 37 , 38 ]. Additionally it was noted that β-catenin expression’s correlation to tumor grade and muscle invasion has been inconsistent [ 39 ].…”

Suppression of LETM1 by siRNA inhibits cell proliferation and invasion of bladder cancer cells

“…Knockdown of LETM1 inhibits the activation of the Wnt/β-catenin pathway. Some evidence has indicated that the Wnt/β-catenin pathway plays a critical role in the tumor progression and metastasis of human bladder cancer cells (11,12). To further explore the effects of si-LETM1 on the Wnt/β-catenin signaling pathway in human bladder cancer cells, we determined the protein expression of β-catenin, cyclin D1 and c-Myc when knocking down LETM1.…”

Evolution of Network Biomarkers from Early to Late Stage Bladder Cancer Samples

“…Therefore, the Wnt signaling pathway participates in each of the stages of malignant cancer development and clearly contributes to human tumor progression. Much research has been reported on the relationship between Wnt signaling pathways and urological cancers (including bladder cancer) [ 37 , 38 ].…”