Journal Article

Targeting of Alpha-V Integrins Reduces Malignancy of Bladder Carcinoma

Lorenzon, Giocondo, Pelger, Rob C. M., van der Pluijm, Gabri, van der Horst, Geertje, Cheung, Henry, Clément-Lacroix, Philippe, Bos, Lieke, van der Mark, Maaike, Heckmann, Bertrand, Bevers, Rob F. M.

2014

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aldehyde dehydrogenase / Aldehyde Dehydrogenase - biosynthesis / Aldehyde Dehydrogenase - genetics / Angiogenesis / Animals / Biology and Life Sciences / Bioluminescence / Bladder / Bladder cancer / Breast cancer / Cancer / Cancer prevention / Carcinoma / Carcinoma, Transitional Cell - pathology / Cell Adhesion - drug effects / Cell Line, Tumor / Cell migration / Cell Movement - drug effects / Cell Self Renewal - drug effects / Dehydrogenase / E-cadherin / Epithelial-Mesenchymal Transition - drug effects / Female / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Genetic Vectors - pharmacology / Genotype & phenotype / Heart / Humans / Integrin alphaV - drug effects / Integrin alphaV - physiology / Integrins / Malignancy / Medicine and Health Sciences / Metastases / Metastasis / Mice / Mice, Inbred BALB C / Mice, Nude / Molecular Targeted Therapy / Neoplasm Invasiveness / Neoplasm Proteins - antagonists & inhibitors / Neoplasm Proteins - biosynthesis / Neoplasm Proteins - genetics / Neoplasm Transplantation - methods / Papilloma - pathology / Prostate cancer / Receptors, Vitronectin - antagonists & inhibitors / Receptors, Vitronectin - physiology / RNA Interference / RNA, Small Interfering - pharmacology / Snail protein / Stem cells / Survival / Tibia / Transcription factors / Transcription Factors - biosynthesis / Transcription Factors - genetics / Transduction, Genetic / Tumor cell lines / Tumor Stem Cell Assay / Tumors / Urinary bladder / Urinary Bladder Neoplasms - pathology / Urology / Xenograft Model Antitumor Assays