Active sonic hedgehog signaling between androgen independent human prostate cancer cells and normal/benign but not cancer-associated prostate stromal cells

Authors

  • Katsumi Shigemura,

    1. Molecular Urology and Therapeutics Program, Department of Urology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
    2. Division of Urology, Department of Organ Therapeutics, Faculty of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
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  • Wen-Chin Huang,

    1. Molecular Urology and Therapeutics Program, Department of Urology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
    2. Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
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  • Xiangyan Li,

    1. Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
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  • Haiyen E. Zhau,

    1. Molecular Urology and Therapeutics Program, Department of Urology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
    2. Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
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  • Guodong Zhu,

    1. Molecular Urology and Therapeutics Program, Department of Urology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
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  • Akinobu Gotoh,

    1. Laboratory of Cell and Gene Therapy Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan
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  • Masato Fujisawa,

    1. Division of Urology, Department of Organ Therapeutics, Faculty of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
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  • Jingwu Xie,

    1. Department of Pharmacology and Toxicology, Sealy Center for Cancer Cell Biology, University of Texas at Galveston, Galveston, Texas
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  • Fray F. Marshall,

    1. Molecular Urology and Therapeutics Program, Department of Urology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
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  • Leland W. K. Chung

    Corresponding author
    1. Molecular Urology and Therapeutics Program, Department of Urology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
    2. Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
    • Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, 8750, Beverly Blvd., Atrium 103, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
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  • This article was published online on 25 April 2011. Errors were subsequently identified on pages 2,4,5,6 and 10. This notice is included in the online version to indicate that these have been corrected 21 May 2011.

Abstract

BACKGROUND

Sonic hedgehog (Shh) signaling plays a pivotal role in stromal–epithelial interaction during normal development but its role in tumor–stromal interaction during carcinogenic progression is less well defined. Since hormone refractory prostate cancer with bone metastasis is difficult to treat, it is crucial to investigate how androgen independent (AI) human prostate cancer cells communicate with their associated stroma.

METHODS

Shh and its target transcription factor, Gli1 mRNA, were assessed by RT-PCR and/or quantitative RT-PCR in co-cultured cell recombinants comprised of AI C4–2 either with NPF (prostate fibroblasts from normal/benign prostate gland) or CPF (cancer-associated stromal fibroblasts) under Shh/cyclopamine (a hedgehog signaling inhibitor) treatment. Human bone marrow stromal (HS27A) cells were used as controls. In vivo investigation was performed by checking serum PSA and immunohistochemical staining for the apoptosis-associated M30 gene in mice bearing chimeric C4–2/NPF tumors.

RESULTS

We found that (1) Shh has minimal growth-stimulating effects on prostate cancer cells, but it stimulated the growth of NPF but not CPF; (2) active Shh signaling was found between AI C4–2 cells and NPF but not CPF; and (3) osteonectin (ON) is a Gli1 target gene in NPF and not in CPF, and ON up-regulation in NPF can be blocked by cyclopamine

CONCLUSIONS

Based on co-culture and chimeric tumor models, active Shh-mediated signaling was demonstrated between AI prostate cancer and NPF in a paracrine- and tumor progression-dependent manner. Our study suggests that drugs like cyclopamine that interfere with Shh signaling could be beneficial in preventing AI progression in prostate cancer cells. Prostate 71:1711–1722, 2011. © 2011 Wiley Periodicals, Inc.

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