Hyaluronic acid family in bladder cancer

Potential prognostic biomarkers and therapeutic targets

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 Kennedy Terris, Vinata B Lokeshwar

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1507-1517
Number of pages11
JournalBritish Journal of Cancer
Volume117
Issue number10
DOIs
StatePublished - Nov 7 2017

Fingerprint

Hyaluronic Acid
Urinary Bladder Neoplasms
Hymecromone
Biomarkers
Atlases
Therapeutics
Hyaluronoglucosaminidase
Genome
Neoplasms
Phosphatidylinositol 3-Kinase
Catenins
Epithelial-Mesenchymal Transition
Snails
Cadherins
Tumor Biomarkers
Heterografts
Oral Administration
Urinary Bladder
Apoptosis
Neoplasm Metastasis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Morera, D. S., Hennig, M. S., Talukder, A., Lokeshwar, S. D., Wang, J., Garcia-Roig, M., ... Lokeshwar, V. B. (2017). Hyaluronic acid family in bladder cancer: Potential prognostic biomarkers and therapeutic targets. British Journal of Cancer, 117(10), 1507-1517. https://doi.org/10.1038/bjc.2017.318

Hyaluronic acid family in bladder cancer : Potential prognostic biomarkers and therapeutic targets. / Morera, Daley S.; Hennig, Martin S.; Talukder, Asif; Lokeshwar, Soum D.; Wang, Jiaojiao; Garcia-Roig, Michael; Ortiz, Nicolas; Yates, Travis J.; Lopez, Luis E.; Kallifatidis, Georgios; Kramer, Mario W.; Jordan, Andre R.; Merseburger, Axel S.; Manoharan, Murugesan; Soloway, Mark S.; Terris, Martha Kennedy; Lokeshwar, Vinata B.

In: British Journal of Cancer, Vol. 117, No. 10, 07.11.2017, p. 1507-1517.

Research output: Contribution to journalArticle

Morera, DS, Hennig, MS, Talukder, A, Lokeshwar, SD, Wang, J, Garcia-Roig, M, Ortiz, N, Yates, TJ, Lopez, LE, Kallifatidis, G, Kramer, MW, Jordan, AR, Merseburger, AS, Manoharan, M, Soloway, MS, Terris, MK & Lokeshwar, VB 2017, 'Hyaluronic acid family in bladder cancer: Potential prognostic biomarkers and therapeutic targets', British Journal of Cancer, vol. 117, no. 10, pp. 1507-1517. https://doi.org/10.1038/bjc.2017.318
Morera DS, Hennig MS, Talukder A, Lokeshwar SD, Wang J, Garcia-Roig M et al. Hyaluronic acid family in bladder cancer: Potential prognostic biomarkers and therapeutic targets. British Journal of Cancer. 2017 Nov 7;117(10):1507-1517. https://doi.org/10.1038/bjc.2017.318
Morera, Daley S. ; Hennig, Martin S. ; Talukder, Asif ; Lokeshwar, Soum D. ; Wang, Jiaojiao ; Garcia-Roig, Michael ; Ortiz, Nicolas ; Yates, Travis J. ; Lopez, Luis E. ; Kallifatidis, Georgios ; Kramer, Mario W. ; Jordan, Andre R. ; Merseburger, Axel S. ; Manoharan, Murugesan ; Soloway, Mark S. ; Terris, Martha Kennedy ; Lokeshwar, Vinata B. / Hyaluronic acid family in bladder cancer : Potential prognostic biomarkers and therapeutic targets. In: British Journal of Cancer. 2017 ; Vol. 117, No. 10. pp. 1507-1517.
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AU - Hennig, Martin S.

AU - Talukder, Asif

AU - Lokeshwar, Soum D.

AU - Wang, Jiaojiao

AU - Garcia-Roig, Michael

AU - Ortiz, Nicolas

AU - Yates, Travis J.

AU - Lopez, Luis E.

AU - Kallifatidis, Georgios

AU - Kramer, Mario W.

AU - Jordan, Andre R.

AU - Merseburger, Axel S.

AU - Manoharan, Murugesan

AU - Soloway, Mark S.

AU - Terris, Martha Kennedy

AU - Lokeshwar, Vinata B

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N2 - 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.

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