Urothelial carcinoma: stem cells on the edge

Abstract

Tumors are heterogeneous collections of cells with highly variable abilities to survive, grow, and metastasize. This variability likely stems from epigenetic and genetic influences, either stochastic or hardwired by cell type-specific lineage programs. That differentiation underlies tumor cell heterogeneity was elegantly demonstrated in hematopoietic tumors, in which rare primitive cells (cancer stem cells (CSCs)) resembling normal hematopoietic stem cells are ultimately responsible for tumor growth and viability. Because of the compelling clinical implications CSCs pose--across the entire spectrum of cancers--investigators applied the CSC model to cancers arising in tissues with crudely understood differentiation programs. Instead of relying on differentiation, these studies used empirically selected markers and statistical arguments to identify CSCs. The empirical approach has stimulated important questions about "stemness" in cancer cells as well as the validity and stoichiometry of CSC assays. The recent identification of urothelial differentiation programs in urothelial carcinomas (UroCas) supports the idea that solid epithelial cancers (carcinomas) develop and differentiate analogously to normal epithelia and provides new insights about the spatial localization and molecular makeup of carcinoma CSCs. Importantly, CSCs from invasive UroCas (UroCSCs) appear well situated to exchange important signals with adjacent stroma, to escape immune surveillance, and to survive cytotoxic therapy. These signals have potential roles in treatment resistance and many participate in druggable cellular pathways. In this review, we discuss the implications of these findings in understanding CSCs and in better understanding how UroCas form, progress, and should be treated.

Fig. 1

Development of low-grade papillary versus high-grade muscle-invasive UroCa. The bladder consists of a stratified polarized epithelium. a The urothelial lining of the bladder originates with basal cells (B) located next to the stroma (S). The basal cells give rise to transient amplifying intermediate cells (I), which in turn differentiate into superficial umbrella cells (U). Umbrella cells form the barrier that prevents urinary solutes from re-entering the bloodstream. b Genetic and/or epigenetic changes leading to malignant transformation of intermediate cells by FGFR3 lead to hyperplasia and low-grade papillary tumors. c Malignant transformation of basal stem cells through modification of p53, retinoblastoma, and Pten genes lead to CIS and high-grade muscle (M) invasive UC. High-grade UC can also be initiated, or propagated, by inflammation or other stromal factors

Fig. 2

CSCs drug resistance methodology. Cancer stem cells have developed multiple mechanisms to resist chemo- and radiotherapy. The nuclei of CSCs retain lower levels of reactive oxygen species, resulting in less DNA damage. The DNA damage response pathway is preferentially activated allowing for increased DNA repair capacity. A modified epigenetic signature can prevent CSCs from undergoing apoptosis through repression of retinoblastoma (Rb) protein activity. ATP-binding cassette (ABC) transporters efficiently pump chemotherapeutic drugs out of the cell. The ALDH1 enzyme can effectively oxidize and inactivate certain bioactive metabolic drugs. IAP proteins block the function of death caspases preempting cell death. UroCa stem cells upregulate the expression of CD47 to prevent phagocytosis by macrophages