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

SUBMITTER: van der Horst G

PROVIDER: S-EPMC4172769 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Targeting of alpha-v integrins reduces malignancy of bladder carcinoma.

van der Horst Geertje G Bos Lieke L van der Mark Maaike M Cheung Henry H Heckmann Bertrand B Clément-Lacroix Philippe P Lorenzon Giocondo G Pelger Rob C M RC Bevers Rob F M RF van der Pluijm Gabri G

PloS one 20140923 9

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 bladd ...[more]

PMID: 25247809

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Project description:Integrins mediate adhesive interactions between cells and their environment, including neighboring cells and extracellular matrix (ECM). These heterodimeric transmembrane receptors bind extracellular ligands with their globular head domains and connect to the cytoskeleton through multi-protein interactions at their cytoplasmic tails. Integrin containing cell-matrix adhesions are dynamic force-responsive protein complexes that allow bidirectional mechanical coupling of cells with their environment. This allows cells to sense and modulate tissue mechanics and regulates intracellular signaling impacting on cell faith, survival, proliferation, and differentiation programs. Dysregulation of these functions has been extensively reported in cancer and associated with tumor growth, invasion, angiogenesis, metastasis, and therapy resistance. This central role in multiple hallmarks of cancer and their localization on the cell surface makes integrins attractive targets for cancer therapy. However, despite a wealth of highly encouraging preclinical data, targeting integrin adhesion complexes in clinical trials has thus far failed to meet expectations. Contributing factors to therapeutic failure are 1) variable integrin expression, 2) redundancy in integrin function, 3) distinct roles of integrins at various disease stages, and 4) sequestering of therapeutics by integrin-containing tumor-derived extracellular vesicles. Despite disappointing clinical results, new promising approaches are being investigated that highlight the potential of integrins as targets or prognostic biomarkers. Improvement of therapeutic delivery at the tumor site via integrin binding ligands is emerging as another successful approach that may enhance both efficacy and safety of conventional therapeutics. In this review we provide an overview of recent encouraging preclinical findings, we discuss the apparent disagreement between preclinical and clinical results, and we consider new opportunities to exploit the potential of integrin adhesion complexes as targets for cancer therapy.

Dataset Information

Targeting of alpha-v integrins reduces malignancy of bladder carcinoma.

Publications

Targeting of alpha-v integrins reduces malignancy of bladder carcinoma.

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