Molecular pathways of urothelial development and bladder tumorigenesis

Bladder cancer is the fifth most common human malignancy and the second most frequently diagnosed genitourinary tumor after prostate cancer. The majority of malignant tumors arising in the urinary bladder are urothelial carcinomas. Clinically, superficial bladder tumors (stages Ta and Tis) account for 75% to 85% of neoplasms, while the remaining 15% to 25% are invasive (T1, T2-T4) or metastatic lesions at the time of initial presentation. Several studies have revealed that distinct genotypic and phenotypic patterns are associated with early vs. late stages of bladder cancer. Early superficial disease appears to segregate into 2 main pathways: (1) superficial papillary bladder tumors, which are characterized by gain-of-function mutations affecting oncogenes such as H-RAS, FGFR3, and PI3K, and deletions of the long arm of chromosome 9 (9q); (2) Carcinoma in situ, a "flat" high grade lesion considered to be a precursor of invasive cancer, is characterized by loss-of-function mutations affecting tumor suppressor genes, such as p53, RB, and PTEN. Based on these data, a model for bladder tumor progression has been proposed in which 2 separate genetic pathways characterize the evolution of early bladder neoplasms. Several molecular markers have been correlated with tumor stage, but the rationale for these 2 well-defined genetic pathways still remains unclear. Normal urothelium is a pseudo-stratified epithelium that coats the bladder, composed of 3 cell types: basal, intermediate, and superficial ("umbrella") cells. We have identified a series of markers that are differently expressed in these distinct cells types, and postulated a novel model for urothelium development and configuration. Briefly, it is our working hypothesis that 2 distinct progenitor cells are responsible for basal/intermediate cells and "umbrella" cells, respectively. Basal and intermediate cells are characterized by a p63 positive phenotype, as well as expression of high molecular weight cytokeratins (CKs), such as CK5, CK10, and CK14. On the contrary, "umbrella" cells display a p63 negative phenotype and are characterized by expression of 2 specific low molecular weight CKs: CK18 and CK20. Neither urothelial stem cells nor bladder cancer stem cells have been identified to date. In this review, we will further expand on the issues discussed above.