title: Functional and molecular characterization of cancer stem-like cells in bladder cancer: a potential signature for muscle-invasive tumors.
abstract: Striking evidence associates cancer stem cells (CSCs) to the high recurrence rates and poor survival of patients with muscle-invasive bladder cancer (BC). However, the prognostic implication of those cells in risk stratification is not firmly established, mainly due to the functional and phenotypic heterogeneity of CSCs populations, as well as, to the conflicting data regarding their identification based on a single specific marker. This emphasizes the need to exploit putative CSC-related molecular markers with potential prognostic significance in BC patients.This study aimed to isolate and characterize bladder CSCs making use of different functional and molecular approaches. The data obtained provide strong evidence that muscle-invasive BC is enriched with a heterogeneous stem-like population characterized by enhanced chemoresistance and tumor initiating properties, able to recapitulate the heterogeneity of the original tumor. Additionally, a logistic regression analysis identified a 2-gene stem-like signature (SOX2 and ALDH2) that allows a 93% accurate discrimination between non-muscle-invasive and invasive tumors.Our findings suggest that a stemness-related gene signature, combined with a cluster of markers to more narrowly refine the CSC phenotype, could better identify BC patients that would benefit from a more aggressive therapeutic intervention targeting CSCs population.
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|CNC.IBILI, University of Coimbra, Coimbra, Portugal.
authors.forename: Margarida
authors.initials: M
authors.lastname: Ferreira-Teixeira
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|Urology and Renal Transplantation Department, Coimbra University Hospital Centre (CHUC), Coimbra, Portugal.
authors.forename: Belmiro
authors.initials: B
authors.lastname: Parada
authors.affiliation: Immunology and Oncology Laboratory, Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal.|Institute of Immunology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Rodrigues-Santos
authors.affiliation: Institute of Immunology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Vera
authors.initials: V
authors.lastname: Alves
authors.affiliation: CEDOC, Faculty of Medical Sciences, New University of Lisbon, Lisbon, Portugal.
authors.forename: José S
authors.initials: JS
authors.lastname: Ramalho
authors.affiliation: Laboratory of Biostatistics and Medical Informatics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Francisco
authors.initials: F
authors.lastname: Caramelo
authors.affiliation: Institute of Anatomical and Molecular Pathology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|Service of Anatomical Pathology, Coimbra University Hospital Centre (CHUC), Coimbra, Portugal.
authors.forename: Vitor
authors.initials: V
authors.lastname: Sousa
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|CNC.IBILI, University of Coimbra, Coimbra, Portugal.|Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Flávio
authors.initials: F
authors.lastname: Reis
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|CNC.IBILI, University of Coimbra, Coimbra, Portugal.|Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Célia M
authors.initials: CM
authors.lastname: Gomes
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology*
keywords: ALDH; bladder cancer; cancer stem cells; chemoresistance; stemness markers