Urothelial tumorigenesis: a tale of divergent pathways

Key Points Urothelial tumours arise and evolve through divergent phenotypic pathways. Some tumours progress from urothelial hyperplasia to low-grade non-invasive superficial papillary tumours. More aggressive variants arise either from flat, high-grade carcinoma in situ and progress to invasive tumours, or they arise de novo as invasive tumours. These two important phenotypic variants of urothelial tumours exhibit drastically different biological behaviours and prognoses. The low-grade papillary variant is often multifocal and tends to recur, but it infrequently progresses to muscle invasive stages, whereas most of the invasive variants develop into incurable metastases despite radical cystectomy. It is becoming clear that the two urothelial tumour variants harbour distinctive genetic defects: the low-grade non-invasive papillary tumours are characterized by activating mutations in the HRAS gene and fibroblast growth factor receptor 3 gene; and the high-grade invasive tumours are characterized by structural and functional defects in the p53 and retinoblastoma protein (RB) tumour-suppressor pathways. The deletion of both arms of chromosome 9 is prevalent in urothelial carcinomas and occurs during the earliest stages of tumorigenesis. However, these chromosomal aberrations do not seem to distinguish between the two tumour development pathways. Tumour invasion and progression in the bladder seems to be a multifactorial process, promoted by microenvironmental changes that include the upregulation of N-cadherin, the downregulation of E-cadherin, the overexpression of matrix metalloproteinases 2 and 9, an imbalance between angiogenic and anti-angiogenic factors, and increased synthesis of prostaglandin. Urothelial carcinomas are particularly amenable to pathway- and target-based therapies. The low-grade non-invasive papillary tumours could benefit tremendously from receptor tyrosine kinase (RTK)–Ras pathway inhibition by means such as small molecule inhibitors, monoclonal antibodies, farnesyl and geranylgeranyl inhibitors, and RAF and mitogen-activated protein kinase kinase (MEK) inhibitors. The invasive tumours, on the other hand, could benefit from replacement therapies that restore the functions of p53 and RB. The intravesical (within the bladder) route of drug delivery provides a unique advantage because it locally enriches the drug while preventing systemic toxicity in urothelial carcinoma treatment. The identification of specific carcinogens that precipita