title: Targeting of alpha-v integrins reduces malignancy of bladder carcinoma.
abstract: Low survival rates of metastatic cancers emphasize the need for a drug that can prevent and/or treat metastatic cancer. αv integrins are involved in essential processes for tumor growth and metastasis and targeting of αv integrins has been shown to decrease angiogenesis, tumor growth and metastasis. In this study, the role of αv integrin and its potential as a drug target in bladder cancer was investigated. Treatment with an αv integrin antagonist as well as knockdown of αv integrin in the bladder carcinoma cell lines, resulted in reduced malignancy in vitro, as illustrated by decreased proliferative, migratory and clonogenic capacity. The CDH1/CDH2 ratio increased, indicating a shift towards a more epithelial phenotype. This shift appeared to be associated with downregulation of EMT-inducing transcription factors including SNAI2. The expression levels of the self-renewal genes NANOG and BMI1 decreased as well as the number of cells with high Aldehyde Dehydrogenase activity. In addition, self-renewal ability decreased as measured with the urosphere assay. In line with these observations, knockdown or treatment of αv integrins resulted in decreased metastatic growth in preclinical in vivo models as assessed by bioluminescence imaging. In conclusion, we show that αv integrins are involved in migration, EMT and maintenance of Aldehyde Dehydrogenase activity in bladder cancer cells. Targeting of αv integrins might be a promising approach for treatment and/or prevention of metastatic bladder cancer.
authors.affiliation: Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Geertje
authors.initials: G
authors.lastname: van der Horst
authors.affiliation: Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Lieke
authors.initials: L
authors.lastname: Bos
authors.affiliation: Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: van der Mark
authors.affiliation: Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Henry
authors.initials: H
authors.lastname: Cheung
authors.affiliation: Galapagos SASU, Romainville, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Heckmann
authors.affiliation: Galapagos SASU, Romainville, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Clément-Lacroix
authors.affiliation: Galapagos SASU, Romainville, France.
authors.forename: Giocondo
authors.initials: G
authors.lastname: Lorenzon
authors.affiliation: Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Rob C M
authors.initials: RC
authors.lastname: Pelger
authors.affiliation: Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Rob F M
authors.initials: RF
authors.lastname: Bevers
authors.affiliation: Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Gabri
authors.initials: G
authors.lastname: van der Pluijm
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005822:Genetic Vectors / Q000494:pharmacology*; D006321:Heart; D006801:Humans; D039564:Integrin alphaV / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation / Q000379:methods; D010212:Papilloma / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology*; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000502:physiology; D013977:Tibia; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014161:Transduction, Genetic; D014410:Tumor Stem Cell Assay; D001749:Urinary Bladder Neoplasms / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D039564:Integrin alphaV; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D019030:Receptors, Vitronectin; D014157:Transcription Factors; C064660:integrin alphaVbeta5; D000444:Aldehyde Dehydrogenase