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An Orthotopic Murine Model of Human Prostate Cancer Metastasis

Published on: September 18, 2013

Prostate tumor progression is mediated by a paracrine TGF-beta/Wnt3a signaling axis

X Li1, V Placencio, J M Iturregui

  • 1Department of Urologic Surgery, The Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

Oncogene
|August 30, 2008
PubMed

Insights

Loss of transforming growth factor (TGF)-beta type II receptor in prostate cancer stroma promotes tumor growth by increasing Wnt3a expression. This finding reveals a new mechanism in prostate cancer progression.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Transforming growth factor (TGF)-beta is a key paracrine factor in tumorigenesis.
  • The role of stromal TGF-beta signaling in prostate cancer progression remains unclear.
  • TGF-beta exerts its effects through binding to type I and II receptors, initiating downstream signaling.

Purpose of the Study:

  • To investigate the mechanism of paracrine TGF-beta signaling in prostate cancer progression.
  • To determine the role of stromal TGF-beta type II receptor in prostate cancer development.
  • To elucidate the relationship between stromal TGF-beta signaling and Wnt3a expression in prostate cancer.

Main Methods:

  • Generated a conditional stromal knockout mouse model (Tgfbr2(fspKO)) for TGF-beta type II receptor.
  • Utilized in vitro and tissue recombination xenograft models with LNCaP human prostate cancer cells.
  • Analyzed Wnt3a expression and Stat3 activity on the Wnt3a promoter.

Main Results:

  • Stromal knockout of TGF-beta type II receptor in mice led to prostatic intraepithelial neoplasia and adenocarcinoma.
  • A significant loss of TGF-beta receptor type II expression was observed in human prostate cancer stroma (69%) compared to benign tissues (15%).
  • Prostatic stromal cells lacking TGF-beta type II receptor induced LNCaP cell proliferation and tumorigenesis via elevated Wnt3a expression, which was reversed by Wnt3a neutralizing antibodies.

Conclusions:

  • Frequent loss of stromal TGF-beta type II receptor expression in human prostate cancer relieves paracrine suppression of Wnt3a.
  • TGF-beta signaling suppresses Wnt3a expression, in part, by inhibiting Stat3 activity on the Wnt3a promoter.
  • Stromal TGF-beta type II receptor loss is a critical event in prostate cancer progression, mediated by Wnt3a upregulation.

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