TY - JOUR
TI - Integrated Hedgehog signaling is induced following castration in human
and murine prostate cancers
AU - Efstathiou, Eleni
AU - Karlou, Maria
AU - Wen, Sijin
AU - Hoang, Anh and
AU - Pettaway, Curtis A.
AU - Pisters, Louis L.
AU - Maity, Sankar and
AU - Troncoso, Patricia
AU - Logothetis, Christopher J.
JO - Prostate Cancer and Prostatic Diseases
PY - 2013
VL - 73
TODO - 2
SP - 153-161
PB - Wiley-Blackwell
SN - 1365-7852, 1476-5608
TODO - 10.1002/pros.22550
TODO - prostate cancer; preoperative treatment; Hedgehog signaling; resistance
to treatment; androgen ablation
TODO - BACKGROUND The interplay between androgen and Hedgehog (Hh) signaling
pathways may be associated with prostate cancer progression and
resistance to therapy.
METHODS Tissue microarrays from prostatectomy specimens were derived
from 53 patients treated preoperatively with androgen ablation (AA) with
or without chemotherapy, and from 26 stage- and grade-matched controls.
A previously characterized androgen-regulated human prostate cancer
xenograft was used to conduct parallel murine studies. Expression of
markers of interest was determined on both untreated and castrated
tumors.
RESULTS Four-month exposure to AA or AA with chemotherapy led to a
uniform increase in Hh signaling as compared to controls, paired with an
inverse trend of androgen receptor (AR) and CYP17 expression in
clinically derived specimens. Changes in the expression profiles of Hh
signaling were observed in the epithelium and stroma, in response to
genotoxic stress of androgen ablation and chemotherapy. A reduced
expression of KI67 and increased bcl2 expression was observed in the
malignant epithelial compartment.
CONCLUSION To our knowledge, this is the first clinical evidence that Hh
signaling is induced by AA or the combination of AA and chemotherapy
and, by inference, contributes to castrate-resistant progression of
prostate cancer as supported by parallel human and murine studies. These
data are in agreement with previous reports that implicate Hh signaling
in castrate-resistant progression of prostate cancer. Based on these
findings, we are pursuing parallel clinical and murine investigations to
determine if Hh signaling inhibition combined with AA will be more
effective than AA alone. Prostate 73: 153161, 2013. (c) 2012 Wiley
Periodicals, Inc.
ER -