Urothelial Cancer Stem Cells

Abstract

There is mounting evidence supporting the idea that tumors, similar to normal adult tissues, arise from a specific stem-like cell population, the cancer stem cells (CSCs), which are considered as the real driving force behind tumor growth, the ability to metastasize, as well as resistance to conventional antitumor therapy. The concept that cancer growth recapitulates normal proliferative and/or regenerative processes, even though in very dysfunctional ways, has tremendous implications for cancer therapy. The rapid development of the CSC field, shoulder to shoulder with powerful genome-wide screening techniques, has provided cause for optimism for the development of more reliable therapies in the future. However, several important issues still lie ahead. Recent identification of a highly tumorigenic stem-like compartment and existence of urothelial differentiation programs in urothelial cell carcinomas (UCCs) raised important questions about UCC initiation and development. This review examines the present knowledge on CSCs in UCCs regarding the similarities between CSCs and the adult urothelial stem cells, potential origin of urothelial CSCs, main regulatory pathways, surface markers expression, and the current state of CSC-targeting therapeutic strategies.

Stem-Like Signature Predicting Disease Progression in Early Stage Bladder Cancer. The Role of E2F3 and SOX4

“…The tissue-specific stem cells of the normal urothelium have been proposed to reside in the basal layer, responsible for the maintenance of tissue homeostasis and renewal. The basement membrane serves as a nidus for epithelial stromal interactions that are essential for stem cell preservation [ 4 ]. Alternatively, it has also been suggested that at least two independent pools of urothelial stem cells exist [ 1 ].…”

“…Several stem cell markers have been found to be linked to recurrence or progression. One example is the CD44v8-10-to-standard CD44-ratio (total ratio of all CD44 alternative splicing isoforms) in urothelial cancer that has been shown to be closely associated with tumor progression and aggressiveness [ 4 , 30 ]. ALDH1, has also been reported to be associated with BCSCs and a worse prognosis in a large number of studies [ 31 , 32 ].…”

“…For example, CBX7 that inversely correlated with the tumor stage and grade progression in BC, or EZH2 expression that showed a significant increase in UCC specimens and bladder cancer cell lines [ 69 , 70 ]. Interestingly, the Polycomb group of proteins are commonly abnormally overexpressed years prior to cancer pathology, making early targeted therapy an option to reverse tumor formation [ 4 , 71 ].…”

“…As an example, CD47 is highly expressed on UCC and functions as a ligand of the SIRP inhibitory molecule expressed on phagocytes. Blockade of CD47 by a monoclonal antibody resulted in efficient and specific macrophage engulfment of bladder cancer cells in vitro [ 4 ].…”

Immunohistochemical expression of cyclooxygenase-2 and CD44 (stem cell marker) in urinary bladder cancer

“…Adhesion molecules are cell surface glycoproteins mediating cellcell and cell-matrix interactions. CD44 positive cells are located in the basal layer of the normal urothelium as well as in urothelial cell carcinoma (Dimov et al, 2010). CD44 standard (CD44s) is a member of the immunoglobulin superfamily, involved in cell-cell and cell-matrix interactions.…”