Suppression of DHT-induced paracrine stimulation of endothelial cell growth by estrogens via prostate cancer cells

Authors

  • Juan Wen,

    1. Department of Medicine/Endocrinology, Weill Cornell Medical College, New York, New York
    2. The Center of Clinical Pharmacology, Central South University, Changsha, China
    Search for more papers by this author
  • Yuan Zhao,

    1. Department of Medicine/Endocrinology, Weill Cornell Medical College, New York, New York
    Current affiliation:
    1. A visiting fellow from the Department of Cardiovascular Surgery of the Second Xiangya Hospital, Central South University, Changsha, China.
    Search for more papers by this author
  • Jinghe Li,

    1. Department of Medicine/Endocrinology, Weill Cornell Medical College, New York, New York
    Search for more papers by this author
  • Chunyan Weng,

    1. Department of Medicine/Endocrinology, Weill Cornell Medical College, New York, New York
    2. The Center of Clinical Pharmacology, Central South University, Changsha, China
    Search for more papers by this author
  • Jingjing Cai,

    1. Department of Medicine/Endocrinology, Weill Cornell Medical College, New York, New York
    2. The Center of Clinical Pharmacology, Central South University, Changsha, China
    Search for more papers by this author
  • Kan Yang,

    1. Department of Cardiology of the Third Xiangya Hospital, Central South University, Changsha, China
    Search for more papers by this author
  • Hong Yuan,

    1. The Center of Clinical Pharmacology, Central South University, Changsha, China
    Search for more papers by this author
  • Julianne Imperato-McGinley,

    1. Department of Medicine/Endocrinology, Weill Cornell Medical College, New York, New York
    Search for more papers by this author
  • Yuan-Shan Zhu

    Corresponding author
    1. Department of Medicine/Endocrinology, Weill Cornell Medical College, New York, New York
    2. The Institute of Clinical Pharmacology, Central South University, Changsha, China
    • Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 149, New York, NY 10065.
    Search for more papers by this author

Abstract

BACKGROUND

Androgen modulation of angiogenesis in prostate cancer may be not directly mediated by androgen receptor (AR) as AR is not detected in the prostatic endothelial cells.

METHODS

We examined the paracrine stimulation of cell proliferation by prostate tumor cells and its modulation by androgen and estrogens in a murine endothelial cell line (MEC) that does not express AR.

RESULTS

Tumor cell conditioned media (TCM) collected from LAPC-4 or LNCaP prostatic tumor cells produced a time- and concentration-dependent induction of cell growth in MECs, which was parallel to the VEGF concentration in the TCM. This TCM-induced cell growth in MECs was enhanced by the treatment of prostatic tumor cells with dihydrotestosterone (DHT). Both the TCM-stimulation and DHT-enhancement effects in MECs were completely blocked by SU5416, a specific VEGF receptor antagonist. Co-administration of 17α-estradiol or 17β-estradiol with DHT in prostatic tumor cells completely inhibited the DHT-enhancement effect while treatment with DHT, 17α-estradiol or 17β-estradiol did not produce any significant direct effect in MECs. Moreover, administration of 17α-estradiol or 17β-estradiol in xenograft animals with LAPC-4 or LNCaP prostate tumor significantly decreased the microvessel number in the tumor tissues.

CONCLUSIONS

Our study indicated that prostate tumor cells regulate endothelial cell growth through a paracrine mechanism, which is mainly mediated by VEGF; and DHT is able to modulate endothelial cell growth via tumor cells, which is inhibited by 17α-estradiol and 17β-estradiol. Thus, both17α-estradiol and 17β-estradiol are potential agents for anti-angiogenesis therapy in androgen-responsive prostate cancer. Prostate 73: 1069–1081, 2013. © 2013 Wiley Periodicals, Inc.

Ancillary