Cancer stem cells and epithelial–mesenchymal transition in urothelial carcinoma: Possible pathways and potential therapeutic approaches

Abstract

Abbreviations & Acronyms ALDH = aldehyde dehydrogenase AR = androgen receptor BCG = bacillus Calmette-Gu erin CD = cluster of differentiation COX-2 = cyclooxygenase-2 CSC = cancer stem cell CT = cancer testis EMT = epithelial-mesenchymal transition JAK2 = Janus kinase 2 MAGE = melanoma-associated antigen malat1 = metastasis-associated lung adenocarcinoma transcript 1 MAPK = mitogen-activated protein kinase MC-A = myrtucommulone-A MIBC = muscle-invasive bladder cancer miRNA = micro-ribonucleic acid OCT = octamer-binding transcription factor PD-1 = programmed cell death protein 1 PGE2 = prostaglandin E2 PI3K = phosphatidylinositol-3-kinase PRC = polycomb repressive complex Shh = sonic hedgehog SOX = sex-determining region of the Y chromosome-related high mobility group box SP = side population STAT3 = signal transducer and activator of transcription 3 TGF = transforming growth factor UCSC = urothelial cancer stem cell UTUC = upper tract urothelial carcinoma Abstract: There is growing evidence of the presence of cancer stem cells in urothelial carcinoma. Cancer stem cells have the ability to self-renew and to differentiate into all cell types of the original heterogeneous tumor. A panel of diverse cancer stem cell markers might be suitable for simulation studies of urothelial cancer stem cells and for the development of optimized treatment protocols. The present review focuses on the advances in recognizing the markers of urothelial cancer stem cells and possible therapeutic targets. The commonly reported markers and pathways that were evaluated include CD44, CD133, ALDH1, SOX2 & SOX4, BMI1, EZH1, PD-L1, MAGE-A3, COX2/PGE2/ STAT3, AR, and autophagy. Studies on the epithelial-mesenchymal transition-related pathways (Shh, Wnt/b-catenin, Notch, PI3K/Akt, TGF-b, miRNA) are also reviewed. Most of these markers were recognized through the expression patterns of cancer stem cell-rich side populations. Their regulative role in the development and differentiation of urothelial cancer stem cells was confirmed in vitro by functional analyses (e.g. cell migration, colony formation, sphere formation), and in vivo in xenograft experiments. Although a small number of these pathways are targeted by currently available drugs or drugs that are the currently being tested in clinical trials, a clear treatment approach has not been developed for most pathways. A greater understanding of the mechanisms that control the proliferation and differentiation of cancer stem cells is expected to lead to improvements in targeted therapy.

Emerging Roles of Cancer Stem Cells in Bladder Cancer Progression, Tumorigenesis, and Resistance to Chemotherapy: A Potential Therapeutic Target for Bladder Cancer

“…Several CSC surface markers have been identified as responsible for BC development, progression, maintenance of stemness, metastasis, and recurrence [21]. Among them are CD44, CD67LR, EMA, CD133, SOX2, SOX4, ALDH1A1, EZH1, BMI1, MAGE-A3, PD-L1, YAP1, and COX2/PGE2/STAT3, as well as the molecules related to hedgehog, phosphoinositide 3-kinase (PI3K)/AKT, Wnt/β-catenin, Notch [21,22], and c-Myc signaling pathways [23,24].…”

“…Understanding the role of CSCs in BC and their regulatory mechanisms may facilitate therapy and provide a better prognosis. In addition, pathways related to EMT (such as Wnt/β-catenin, Notch, and transforming growth factor-beta (TGF-β) [22]), the sonic hedgehog signaling pathway [69,70], the PI3K/AKT pathway [22], MAPKs [71,72], and the JAK-STAT pathway have been implicated in the development and progression of bladder CSCs [73] (Figure 2).…”

“…The tested small molecules, GSIs104 and 105 in the clinical trials to inhibit NOTCH signaling [89] showed the disruption of CD44, ERBB4, and cadherin-mediated pathways, leading to varied and unpredictable effects. Due to these opposing roles of NOTCH and the challenges for avoiding side effects in other organs, more evidence will be needed to support the development of NOTCH-targeting therapy in cancer [22].…”

Linking NRP2 With EMT and Chemoradioresistance in Bladder Cancer

“…qPCR of CDH1 (E-Cadherin) confirmed that this change did not arise from altered transcript levels ( Supplementary Figure 7). Because EMT-related signaling pathways are involved in the regulation of cancer stem cell (CSC) phenotype and properties in urothelial carcinoma including BCa, we analyzed if the absence of NRP2 has an impact on the CSC-related properties (24). Sphere forming assays revealed that the number of spheres formed by KO cells was significantly reduced (Supplementary Figure 8A).…”

High‐dimensional single‐cell proteomics analysis reveals the landscape of immune cells and stem‐like cells in renal tumors

“…Overcoming the heterogeneity of CSCs is also the key to treat renal tumors, and these cells can be identified through the expression of cell surface markers or functional markers. Several of these types of markers are derived from the markers that have been established in studies with normal hematopoietic stem cells or embryonic stem cells, such as CD133 and CD44 molecules . We studied the expression of 21 stem‐like cell‐centric markers using antibodies in renal tumors using MC.…”