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

Oncogene. 2008 Nov 27;27(56):7118-30. doi: 10.1038/onc.2008.293. Epub 2008 Aug 25.

Abstract

Transforming growth factor (TGF)-beta is an important paracrine factor in tumorigenesis. Ligand binding of the type I and II TGF-beta receptors initiate downstream signaling. The role of stromal TGF-beta signaling in prostate cancer progression is unknown. In mice, the conditional stromal knockout of the TGF-beta type II receptor expression (Tgfbr2(fspKO)) resulted in the development of prostatic intraepithelial neoplasia and progression to adenocarcinoma within 7 months. Clinically, we observed a loss of TGF-beta receptor type II expression in 69% of human prostate cancer-associated stroma, compared to 15% of stroma associated with benign tissues (n=140, P-value <0.0001). To investigate the mechanism of paracrine TGF-beta signaling in prostate cancer progression, we compared the effect of the prostatic stromal cells from Tgfbr2(fspKO) and floxed TGF-beta type II receptor Tgfbr2(floxE2/floxE2) mice on LNCaP human prostate cancer cells in vitro and tissue recombination xenografts. Induction of LNCaP cell proliferation and tumorigenesis was observed by Tgfbr2(fspKO) prostate stroma as a result of elevated Wnt3a expression. Neutralizing antibodies to Wnt3a reversed LNCaP tumorigenesis. The TGF-beta inhibition of Wnt3a expression was in part through the suppression of Stat3 activity on the Wnt3a promoter. In conclusion, the frequent loss of stromal TGF-beta type II receptor expression in human prostate cancer can relieve the paracrine suppression of Wnt3a expression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma / metabolism
  • Animals
  • Disease Progression
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Ligands
  • Male
  • Mice
  • Mice, Knockout
  • Mice, SCID
  • Models, Biological
  • Neoplasm Transplantation
  • Paracrine Communication
  • Prostatic Neoplasms / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism*
  • Wnt Proteins / metabolism*
  • Wnt3 Protein
  • Wnt3A Protein

Substances

  • Ligands
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • WNT3A protein, human
  • Wnt Proteins
  • Wnt3 Protein
  • Wnt3A Protein
  • Wnt3a protein, mouse
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II