The loss of TGF-beta signaling promotes prostate cancer metastasis.
In breast and colon cancers, transforming growth factor (TGF)-beta signaling initially has an antineoplastic effect, inhibiting tumor growth, but eventually exerts a proneoplastic effect, increasing motility and cancer spread. In prostate cancer, studies using human samples have correlated the loss of the TGF-beta type II receptor (T beta R II) with higher tumor grade. To determine the effect of an inhibited TGF-beta pathway on prostate cancer, we bred transgenic mice expressing the tumorigenic SV40 large T antigen in the prostate with transgenic mice expressing a dominant negative T beta R II mutant (DN II R) in the prostate. Transgene(s) and TGF-beta 1 expression were identified in the prostate and decreased protein levels of plasminogen activator inhibitor type I, as a marker for TGF-beta signaling, correlated with expression of the DN II R. Although the sizes of the neoplastic prostates were not enlarged, increased amounts of metastasis were observed in mice expressing both transgenes compared to age-matched control mice expressing only the large T antigen transgene. Our study demonstrates for the first time that a disruption of TGF-beta signaling in prostate cancer plays a causal role in promoting tumor metastasis.
Tu
William H
WH
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA. william.tu@vanderbilt.edu
Thomas
Tania Z
TZ
Masumori
Naoya
N
Bhowmick
Neil A
NA
Gorska
Agnieszka E
AE
Shyr
Yu
Y
Kasper
Susan
S
Case
Tom
T
Roberts
Richard L
RL
Shappell
Scott B
SB
Moses
Harold L
HL
Matusik
Robert J
RJ
D000818:Animals; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009362:Neoplasm Metastasis; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II