β-Catenin activation synergizes with PTEN loss to cause bladder cancer formation

Abstract

Although deregulation of the Wnt signalling pathway has been implicated in urothelial cell carcinoma (UCC), the functional significance is unknown. To test its importance, we have targeted expression of an activated form of β-catenin to the urothelium of transgenic mice using Cre-Lox technology (UroIICRE+ β-cateninexon3/+). Expression of this activated form of β-catenin led to the formation of localised hyperproliferative lesions by 3 months, which did not progress to malignancy. These lesions were characterised by a marked increase of the PTEN tumour suppressor protein. This appears to be a direct consequence of activating Wnt signalling in the bladder as conditional deletion of the Apc (Adenomatous Polyposis coli) gene within the adult bladder led rapidly to coincident β-catenin and PTEN expression. This PTEN expression blocked proliferation. Next, we combined PTEN deficiency with β-catenin activation and found this caused papillary UCC. These tumours had increased pAKT signalling and were dependent on mTOR. Importantly in human UCC, there was a significant correlation between high levels of β-catenin and pAKT (and low levels of PTEN). Taken together these data definitively show that deregulated Wnt signalling plays a critical role in driving UCC, and suggests that human UCC which have high levels of Wnt and PI3 kinase signalling may be responsive to mTOR inhibition.

Does Wnt/β-catenin pathway contribute to the stability of DNMT1 expression in urological cancer cell lines?

“…18 Activation of the Wnt signaling pathway in the bladder of mice fails to drive urothelial cell carcinoma; however, it strongly cooperates with PTEN loss to drive tumourigenesis. 19 Since APC and -catenin mutations are rare in urological tumors, epigenetic regulators might be common traits of urological neoplasms. 20 Epigenetics is one of the mechanisms that could play a major role in the activation of Wnt/b-catenin signaling pathway.…”

The role of WNT signalling in urothelial cell carcinoma

“…33 Indeed, in our own studies, we have demonstrated that WNT signalling is activated in approximately a third of clinical UCC samples. 34,35 A significant correlation was observed between activation of the WNT pathway and either phosphoinositide 3-kinase (PI3K) or mitogen activated protein kinase (MAPK) activation. Interestingly, both groups were mutually exclusive with almost no overlap between the WNT/PI3K and the WNT/MAPK tumours (p<0.0001), suggesting a different molecular basis for each tumour subtype.…”

Imaging molecular dynamics in vivo – from cell biology to animal models

“…1). This approach is generally non-invasive and can be repeated many times on the same animal, which facilitates longitudinal studies of tumor growth or senescence, metastatic progression and response to therapy (Ahmad et al, 2011;Morton et al, 2010). Basic systems provide qualitative information about the size and location of fluorescent tumors on the basis of epi-fluorescent illumination, a macroscopic lens and sensitive detection using cooled CCD cameras.…”

“…Increasingly, fluorescent protein expression has been incorporated to enable the study of cellular dynamics within these tumor models. Murine models of human cancers that use the Cre-Lox technology to target expression of known oncogenes and/or tumor suppressors in parallel with fluorescent proteins to specific tissues have recently facilitated the study of pancreatic, bladder, renal and colon cancer (Ahmad et al, 2011;Cole et al, 2010;Doyle et al, 2010;Morton et al, 2010). The use of intermediate systems described above combined with in vivo work can substantially improve our insight into cell behavior in the given disease state.…”