Molecular markers of clinical outcome may aid in designing targeted treatments for bladder cancer. However, only a few bladder cancer biomarkers have been examined as therapeutic targets.
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Data from The Cancer Genome Atlas (TCGA) and bladder specimens were evaluated to determine the biomarker potential of the hyaluronic acid (HA) family of molecules - HA synthases, HA receptors and hyaluronidase. The therapeutic efficacy of 4-methylumbelliferone (4MU), a HA synthesis inhibitor, was evaluated in vitro and in xenograft models.
In clinical specimens and TCGA data sets, HA synthases and hyaluronidase-1 levels significantly predicted metastasis and poor survival. 4-Methylumbelliferone inhibited proliferation and motility/invasion and induced apoptosis in bladder cancer cells. Oral administration of 4MU both prevented and inhibited tumour growth, without dose-related toxicity. Effects of 4MU were mediated through the inhibition of CD44/RHAMM and phosphatidylinositol 3-kinase/AKT axis, and of epithelial-mesenchymal transition determinants. These were attenuated by HA, suggesting that 4MU targets oncogenic HA signalling. In tumour specimens and the TCGA data set, HA family expression correlated positively with β-catenin, Twist and Snail expression, but negatively with E-cadherin expression.
This study demonstrates that the HA family can be exploited for developing a biomarker-driven, targeted treatment for bladder cancer, and 4MU, a non-toxic oral HA synthesis inhibitor, is one such candidate.British Journal of Cancer advance online publication 3 October 2017; doi:10.1038/bjc.2017.318 www.bjcancer.com.
British journal of cancer. 2017 Oct 03 [Epub ahead of print]
Daley S Morera, Martin S Hennig, Asif Talukder, Soum D Lokeshwar, Jiaojiao Wang, Michael Garcia-Roig, Nicolas Ortiz, Travis J Yates, Luis E Lopez, Georgios Kallifatidis, Mario W Kramer, Andre R Jordan, Axel S Merseburger, Murugesan Manoharan, Mark S Soloway, Martha K Terris, Vinata B Lokeshwar
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Room CN 1177A, Augusta, GA 30912-2100, USA., Department of Urology, University Hospital Schleswig-Holstein, Kiel, Lübeck 23538, Germany., Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA., Honors Program in Medical Education, University of Miami-Miller School of Medicine, 1600 NW 10th Avenue, Miami, FL 33136, USA., Department of Urology, University of Miami-Miller School of Medicine, 1600 NW 10th Avenue, Miami, FL 33136, USA., Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center, University of Miami-Miller School of Medicine, 1600 NW 10th Avenue, Miami, FL 33136, USA., Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA., Miami Cancer Institute, Baptist Health South Florida, 8900 N Kendall, Miami, FL 33176, USA., Memorial Healthcare System, 20801 Biscayne Blvd Ste 203, Aventura, FL 33180, USA., Department of Surgery, Division of Urology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.