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

Li X, Placencio V, Iturregui JM, Uwamariya C, Sharif-Afshar AR, Koyama T, Hayward SW, Bhowmick NA
Oncogene. 2008 27 (56): 7118-30

PMID: 18724388 · PMCID: PMC3222150 · DOI:10.1038/onc.2008.293

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.

MeSH Terms (22)

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

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