Sox4 Expression Confers Bladder Cancer Stem Cell Properties and Predicts for Poor Patient Outcome

Shen, He; Blijlevens, Maxime; Yang, Nuo; Frangou, Costakis; Wilson, Kayla E.; Xu, Bo; Zhang, Yinglong; Zhang, Lirui; Morrison, Carl; Shepherd, Lori; Hu, Qiang; Zhu, Qianqian; Wang, Jianmin; Liu, Song; Zhang, Jianmin

doi:10.7150/ijbs.13240

Cited by 31 publications

(33 citation statements)

References 42 publications

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“…= 79, coverage = 7%). SOX4 overexpression has been studied experimentally and has been reported to be an important contributor in bladder cancer tumorigenesis [81,82]. The hypothesis that SOX4 cooperates with ARID1A and TP53 to initiate bladder carcinogenesis is novel and may merit further experimental investigation.…”

Section: Crso Identified a Novel 3-gene Combination In Bladder Cancermentioning

confidence: 99%

Identifying Modules of Cooperating Cancer Drivers

Klein

Cannataro

Townsend

et al. 2020

Preprint

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AbstractIdentifying cooperating modules of driver alterations can provide biological insights to cancer causation and would advance the development of effective personalized treatments. We present Cancer Rule-Set Optimization (CRSO) for inferring the combinations of alterations that cooperate to drive tumor formation in individual patients. Application to 19 TCGA cancer types found a mean of 11 core driver combinations per cancer, comprising 2-6 alterations per combination, and accounting for a mean of 70% of samples per cancer. CRSO departs from methods based on statistical cooccurrence, which we demonstrate is a suboptimal criterion for investigating driver cooperation. CRSO identified well-studied driver combinations that were not detected by other approaches and nominated novel combinations that correlate with clinical outcomes in multiple cancer types. Novel synergies were identified in NRAS-mutant melanomas that may be therapeutically relevant. Core driver combinations involving NFE2L2 mutations were identified in four cancer types, supporting the therapeutic potential of NRF2 pathway inhibition. CRSO is available at https://github.com/mikekleinsgit/CRSO/.

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Section: Crso Identified a Novel 3-gene Combination In Bladder Cancermentioning

confidence: 99%

Identifying Modules of Cooperating Cancer Drivers

Klein

Cannataro

Townsend

et al. 2020

Preprint

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“…ALDH is a polymorphic enzyme that is responsible for the oxidation of aldehydes to carboxylic acids, which could prevent cells from oxidative insult and facilitate their survival . The expression of ALDH genes, especially ALDH1, has been reported to be associated with UCSCs and a worse prognosis in a large number of previous studies . The functional role of ALDH1 has also been investigated.…”

Section: Aldh1mentioning

confidence: 99%

“…proved that the downregulation of SOX4 led to the inhibition of cell migration, colony formation, the EMT and reduced sphere formation, ALDH high SP, and tumor formation potential. They found that SOX4 regulates a wide range of genes related to the cell cycle, including CCND1, CDK1, FGFR1, FGFR3, MYB and MYC . In research on other tumors, Tiwari et al .…”

Section: Soxmentioning

confidence: 99%

“…Considering the morphological and antigenic similarities, many researchers believe that normal urothelial stem cell markers will be good candidates for the identification and characterization of UCSC populations . Thus, in addition to the markers that are discussed in the present review, functional assays including xenotransplantation experiments are necessary to identify and characterize UCSCs, as well as sphere formation, drug resistance, cell migration and colony formation, cell cycle progression, and other relevant features.…”

Section: Origin and Characteristics Of Ucscs: A Brief Introductionmentioning

confidence: 99%

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

Fang

Kitamura

2017

Int J of Urology

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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.

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“…The results of its knockdown include reduced sphere formation and enriched cell population with high levels of aldehyde dehydrogenase [ALDH (high)]; inhibition of cell migration, colony formation as well as MET; and decreased tumor formation potential of urothelial cancer cells [22] . The essential role of αv integrins has been shown in migration, EMT and maintenance of ALDH activity, tumor growth and metastasis.…”

Section: Therapeutic Implications and Challengesmentioning

confidence: 99%

Epithelial plasticity in urothelial carcinoma: Current advancements and future challenges

Garg¹

2016

WJSC

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Urothelial carcinoma (UC) of the bladder is characterized by high recurrence rate where a subset of these cells undergoes transition to deadly muscle invasive disease and later metastasizes. Urothelial cancer stem cells (UroCSCs), a tumor subpopulation derived from transformation of urothelial stem cells, are responsible for heterogeneous tumor formation and resistance to systemic treatment in UC of the bladder. Although the precise reason for pathophysiologic spread of tumor is not clear, transcriptome analysis of microdissected cancer cells expressing multiple progenitor/stem cell markers validates the upregulation of genes that derive epithelial-to-mesenchymal transition. Experimental studies on human bladder cancer xenografts describe the mechanistic functions and regulation of epithelial plasticity for its cancer-restraining effects. It has been further examined to be associated with the recruitment of a pool of UroCSCs into cell division in response to damages induced by adjuvant therapies. This paper also discusses the various probable therapeutic approaches to attenuate the progressive manifestation of chemoresistance by co-administration of inhibitors of epithelial plasticity and chemotherapeutic drugs by abrogating the early tumor repopulation as well as killing differentiated cancer cells. Core tip: A subset of bladder cancer cells, known as urothelial cancer stem cells, have abilities to self-renew, generate tumor heterogeneity via differentiation, and are actually responsible for tumor relapse and metastasis formation. Delineating the mechanistic complexity between epithelial plasticity and cancer stemness in malignant transformation of urothelial carcinoma provides the basis for designing rational therapies. Differentiation and elimination therapies targeting the potential biomarkers could prove to be clinically beneficial by suppressing the cancer stemness and inhibiting epithelial-to-mesenchymal transition phenotype and would provide novel opportunities for targeted therapeutic approaches in the clinical management of patients.

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Sox4 Expression Confers Bladder Cancer Stem Cell Properties and Predicts for Poor Patient Outcome

Cited by 31 publications

References 42 publications

Identifying Modules of Cooperating Cancer Drivers

Identifying Modules of Cooperating Cancer Drivers

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

Epithelial plasticity in urothelial carcinoma: Current advancements and future challenges

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