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 K. Terris, Vinata B. Lokeshwar

Research output: Contribution to journalArticle

10 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
Externally publishedYes

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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 K.; 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 K. ; 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 K.

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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