Figure 5.

Divergent molecular pathways of urothleial tumorigenesis. Transgenic mouse models recapitulate the two main phenotypes of urothelial carcinomas. Whereas urothelial expression of SV40 large T antigen elicits exclusively high-grade, flat urothelial lesions (a) bearing strong resemblance to carcinoma in situ of the human counterparts, urothelial expression of activated Ha-ras induces exclusively low-grade, non-invasive superficial papillary urothelial tumors (b). (c) Dosage-dependence of ras activation in triggering urothelial tumorigenesis. While low-level ras activation activates the MAPK pathway resulting in urothelial hyperplasia, it is insufficient to induce tumorigenesis. Hyperactivation of ras can, however, activate the PI3K/AKT and STAT3/5 pathways, leading to nodular urothelial hyperplasia and low-grade, superficial papillary tumors. The activation of these two pathways may also be facilitated by the functional inactivation of PTEN via its C-terminal hyper-phosphorylation. FGFR3, whose mutations occur in up to 80% of the low-grade, superficial papillary tumors in humans, may trigger this urothelial tumor variant through similar signal mechanisms (adapted from Ref. 130).