When urothelial differentiation pathways go wrong: implications for bladder cancer development and progression

Abstract

Differentiation is defined as the ability of a cell to acquire full functional behavior. For instance, the function of bladder urothelium is to act as a barrier to the diffusion of solutes into or out of the urine after excretion by the kidney. The urothelium also serves to protect the detrusor muscle from toxins present in stored urine. A major event in the initiation and progression of bladder cancer is loss of urothelial differentiation. This is important because less differentiated urothelial tumors (higher histologic tumor grade) are typically associated with increased biologic and clinical aggressiveness. The differentiation status of urothelial carcinomas can be assessed by histopathologic examination and is reflected in the assignment of a histologic grade (low-grade or high-grade). Although typically limited to morphologic evaluation in most routine diagnostic practices, tumor grade can also be assessed using biochemical markers. Indeed, current pathological analysis of tumor specimens is increasingly reliant on molecular phenotyping. Thus, high priorities for bladder cancer research include identification of (1) biomarkers that will enable the identification of high grade T1 tumors that pose the most threat and require the most aggressive treatment; (2) biomarkers that predict the likelihood that a low grade, American Joint Committee on Cancer stage pTa bladder tumor will progress into an invasive carcinoma with metastatic potential; (3) biomarkers that indicate which pTa tumors are most likely to recur, thus enabling clinicians to prospectively identify patients who require aggressive treatment; and (4) how these markers might contribute to biological processes that underlie tumor progression and metastasis, potentially through loss of terminal differentiation. This review will discuss the proteins associated with urothelial cell differentiation, with a focus on those implicated in bladder cancer, and other proteins that may be involved in neoplastic progression. It is hoped that ongoing discoveries associated with the study of these differentiation-promoting proteins can be translated into the clinic to positively impact patient care.

Keywords: Bladder cancer; Differentiation; FOXA1; PPARγ; Retinoic acid; Transcription factors.

Figure 1

Normal bladder urothelium displays a spectrum of protein markers identifying subpopulations of specific cell types. Although the pathways required for urothelial differentiation are not completely understood, it is theorized that differentiation of cytokeratin (CK) 14 and CK10 basal cells results in an intermediate, CK5 positive cell population. Presence of uroplakin (UP) and cytokeratin 18/20 positive cells, as well as absence of p63 expression indicates the presence of superficial “umbrella cells” which are often lost early in bladder cancer progression.

Figure 2

Pathways implicated in both urothelial differentiation and neoplastic progression. Biochemical crosstalk between the urothelium and bladder smooth muscle during development and in the mature organ maintains the differentiated phenotype. As discussed in the text, Shh signaling between urothelium and smooth muscle tissue compartments is important in this regard. EGFR and FGFR families and associated ligands have been reported to drive proliferation and inhibit differentiation. Emerging evidence indicates steroid receptor family members, namely RAR, RXR, and PPARγ steroid receptors activate the expression of intermediate transcription factors, including FOXA1 and KLF4. In turn, these factors appear to be important for the activation of gene networks/circuits. It is these networks/circuits that drive and/or maintain urothelial differentiation.