Get access

Angiotensin-(1-7) attenuates metastatic prostate cancer and reduces osteoclastogenesis

Authors

  • Bhavani Krishnan,

    1. Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    2. Molecular Genetics & Genomics Program, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    Search for more papers by this author
  • Thomas L. Smith,

    1. Department of Orthopedic Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    Search for more papers by this author
  • Purnima Dubey,

    1. Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    Search for more papers by this author
  • Michael E. Zapadka,

    1. Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    Search for more papers by this author
  • Frank M. Torti,

    1. Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    Search for more papers by this author
  • Mark C. Willingham,

    1. Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    Search for more papers by this author
  • E. Ann Tallant,

    1. Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    2. Molecular Genetics & Genomics Program, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    Search for more papers by this author
  • Patricia E. Gallagher

    Corresponding author
    1. Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina
    • Hypertension and Vascular Research Center, Wake Forest School of Medicine, Medical Center Boulevard, Winston Salem, NC 27157.
    Search for more papers by this author

  • Conflict of interest: E.A. Tallant and P.E. Gallagher hold a patent for the treatment of cancer with Ang-(1-7). The other authors disclosed no potential conflict of interest.

Abstract

BACKGROUND

Angiotensin-(1-7) [Ang-(1-7)] is an endogenous, heptapeptide hormone with anti-proliferative and anti-angiogenic properties. The primary objective of this study was to determine whether Ang-(1-7) effectively reduces prostate cancer metastasis in mice.

METHODS

Human PC3 prostate cancer cells were injected into the aortic arch via the carotid artery of SCID mice pre-treated with Ang-(1-7) or injected into the tibia of athymic mice, administered Ang-(1-7) for 5 weeks beginning 2 weeks post-injection. Tumor growth and volume were determined by bioluminescent and magnetic resonance imaging. The presence of tumors was confirmed by hematoxylin and eosin staining; TRAP histochemistry was used to identify osteolytic lesions. The effect of Ang-(1-7) on osteoclastogenesis was assessed in differentiated bone marrow cells.

RESULTS

Pre-treatment with Ang-(1-7) prevented metastatic tumor formation following intra-aortic injection of PC3 cells, while 83% of untreated mice developed tumors in metastatic sites. Circulating VEGF was significantly higher in control mice compared to mice administered Ang-(1-7). A 5-week regimen of the heptapeptide hormone attenuated intra-tibial tumor growth; Ang-(1-7) was significantly higher in the tibia of treated mice than in control animals. Osteoclastogenesis was reduced by 50% in bone marrow cells differentiated in the presence of Ang-(1-7), suggesting that the heptapeptide hormone prevents the formation of osteolytic lesions to reduce tumor survival in the bone microenvironment.

CONCLUSIONS

These findings suggest that Ang-(1-7) may serve as an anti-angiogenic and anti-metastatic agent for advanced prostate cancer. By extension, the heptapeptide hormone may provide effective therapy for bone metastasis produced from primary tumors of the lung and breast. Prostate 73: 71–82, 2013. © 2012 Wiley Periodicals, Inc.

Get access to the full text of this article

Ancillary