Br J Cancer. 2017 Nov 7;117(10):1507-1517. doi: 10.1038/bjc.2017.318. Epub 2017 Oct 3.

Hyaluronic acid family in bladder cancer: potential prognostic biomarkers and therapeutic targets.

Morera DS¹, Hennig MS², Talukder A³, Lokeshwar SD⁴, Wang J¹, Garcia-Roig M⁵, Ortiz N⁵, Yates TJ⁶, Lopez LE¹, Kallifatidis G⁷, Kramer MW², Jordan AR^1,6, Merseburger AS², Manoharan M⁸, Soloway MS⁹, Terris MK¹⁰, Lokeshwar VB¹.

Abstract

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.