Elevated hyaluronan and hyaluronan-mediated motility receptor are associated with biochemical failure in patients with intermediate-grade prostate tumors

Authors

  • Anthony E. Rizzardi BS,

    1. Department of Pathology, University of Washington, Seattle, Washington
    2. Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
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  • Rachel Isaksson Vogel MS,

    1. Biostatistics and Bioinformatics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
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  • Joseph S. Koopmeiners PhD,

    1. Biostatistics and Bioinformatics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
    2. Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
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  • Colleen L. Forster BS,

    1. BioNet, Academic Health Center, University of Minnesota, Minneapolis, Minnesota
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  • Lauren O. Marston BS,

    1. Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
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  • Nikolaus K. Rosener BS,

    1. Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
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  • Natalia Akentieva PhD,

    1. Department of Biochemistry, London Health Sciences Center, University of Western Ontario, London, Ontario, Canada
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  • Matthew A. Price BS,

    1. Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
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  • Gregory J. Metzger PhD,

    1. Department of Radiology, University of Minnesota, Minneapolis, Minnesota
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  • Christopher A. Warlick MD, PhD,

    1. Department of Urology, University of Minnesota, Minneapolis, Minnesota
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  • Jonathan C. Henriksen,

    1. Department of Pathology, University of Washington, Seattle, Washington
    2. Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
    3. BioNet, Academic Health Center, University of Minnesota, Minneapolis, Minnesota
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  • Eva A. Turley PhD,

    1. Department of Biochemistry, London Health Sciences Center, University of Western Ontario, London, Ontario, Canada
    2. Department of Oncology, London Health Sciences Center, University of Western Ontario, London, Ontario, Canada
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    • The last 3 authors are equal coauthors.

  • James B. McCarthy PhD,

    1. Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
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    • The last 3 authors are equal coauthors.

  • Stephen C. Schmechel MD, PhD

    Corresponding author
    1. Department of Pathology, University of Washington, Seattle, Washington
    2. Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
    3. BioNet, Academic Health Center, University of Minnesota, Minneapolis, Minnesota
    • Corresponding author: Stephen C. Schmechel, MD, PhD, Department of Pathology, University of Washington, Mailcode 359791, 908 Jefferson Street, Seattle, WA 98104; Fax: (206) 744-8240; sschmech@uw.edu

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    • The last 3 authors are equal coauthors.


  • The authors thank Dr. Timothy Schacker (supported by NIH grants P01-AI074340, R01-AI093319) for providing computer resources used in this study.

Abstract

BACKGROUND

The clinical course of prostate cancer (PCa) measured by biochemical failure (BF) after prostatectomy remains unpredictable in many patients, particularly in intermediate Gleason score (GS) 7 tumors, suggesting that identification of molecular mechanisms associated with aggressive PCa biology may be exploited for improved prognostication or therapy. Hyaluronan (HA) is a high molecular weight polyanionic carbohydrate produced by synthases (HAS1 through HAS3) and fragmented by oxidative/nitrosative stress and hyaluronidases (HYAL1 through HYAL4, SPAM1) common in PCa microenvironments. HA and HA fragments interact with receptors CD44 and hyaluronan-mediated motility receptor (HMMR), resulting in increased tumor aggressiveness in experimental PCa models. This study evaluated the association of HA-related molecules with BF after prostatectomy in GS7 tumors.

METHODS

Tissue microarrays were constructed from a 96-patient cohort. HA histochemistry and HAS2, HYAL1, CD44, CD44v6, and HMMR immunohistochemistry were quantified using digital pathology techniques.

RESULTS

HA in tumor-associated stroma and HMMR in malignant epithelium were significantly and marginally significantly associated with time to BF in univariate analysis, respectively. After adjusting for clinicopathologic features, both HA in tumor-associated stroma and HMMR in malignant epithelium were significantly associated with time to BF. Although not significantly associated with BF, HAS2 and HYAL1 positively correlated with HMMR in malignant epithelium. Cell culture assays demonstrated that HMMR bound native and fragmented HA, promoted HA uptake, and was required for a promigratory response to fragmented HA.

CONCLUSIONS

HA and HMMR are factors associated with time to BF in GS7 tumors, suggesting that increased HA synthesis and fragmentation within the tumor microenvironment stimulates aggressive PCa behavior through HA-HMMR signaling. Cancer 2014;120:1800–1809. © 2014 American Cancer Society.

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