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. av integrins are involved in essential processes for tumor growth and metastasis and targeting of av integrins has been shown to decrease angiogenesis, tumor growth and metastasis. In this study, the role of av integrin and its potential as a drug target in bladder cancer was investigated. Treatment with an av integrin antagonist as well as knockdown of av 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 av integrins resulted in decreased metastatic growth in preclinical in vivo models as assessed by bioluminescence imaging. In conclusion, we show that av integrins are involved in migration, EMT and maintenance of Aldehyde Dehydrogenase activity in bladder cancer cells. Targeting of av integrins might be a promising approach for treatment and/or prevention of metastatic bladder cancer.