Hyaluronic acid family in bladder cancer : potential prognostic biomarkers and therapeutic targets
Menée à partir de données du projet "The Cancer Genome Atlas" portant sur 407 patients atteints d'un cancer de la vessie et à l'aide de 70 échantillons de tissu sain ou cancéreux de la vessie puis de xénogreffes sur des modèles murins, cette étude analyse la possibilité d'utiliser comme biomarqueurs les niveaux d'expression intratumorale de l'acide hyaluronique synthétase, de la hyaluronidase et des récepteurs de l'acide hyaluronique, puis évalue l'efficacité de la 4-méthylumbelliférone, un inhibiteur de la synthèse de l'acide hyaluronique
Background : 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. Methods : 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. Results : 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. Conclusions
:
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.