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Expression of c-kit and kit-ligand in benign and malignant
prostatic tissues
R. Simak1, P. Capodieci1, D.W. Cohen1, W.R.
Fair1, H. Scher3, J. Melamed2,
M. Drobnjak2, W.D. Heston1, U. Stix4, G. Steiner4 and C. Cordon-Cardo2
1Urology Service, Department of Surgery, 2Department
of Pathology, 3Division of Solid Tumor Oncology, Department of
Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA
and 4Department of Urology, University of Vienna Medical School,
Austria
Offprint requests to: Dr.
Carlos Cordon-Cardo, MD, PhD, Department of Pathology, Memorial
Sloan-Kettering Cancer Center, 1275 York Avenue New York, NY 10021,
USA. Fax: 212-794-3186. e-mail: cordon-c@mskcc.org
Summary. The
tyrosine kinase receptor c-kit and its ligand [kit ligand (KL)
or stem cell factor (SCF)] exert a broad range of biological activities
during organogenesis and normal cell development. Recent studies
have revealed that altered c-kit levels occur in a variety of
malignancies and cancer cell lines. KL has also been shown to
stimulate the growth of malignant cells, as well as to promote
chemotaxis. We had previously reported expression of KL in stroma
cells of normal human prostate.
The present study was undertaken in order to analyze the patterns
of expression of c-kit and KL in a well characterized set of prostatic
tissues, including normal prostate (n=4), benign prostatic hyperplasia
(BPH) (n=53) and adenocarcinoma (n=46) samples. The distribution
of c-kit and KL proteins was studied by immunohistochemical analyses,
while transcript levels were determined by in situ hybridization
with specific RNA probes on a subset of the benign and malignant
tissues referred above. In addition, reverse-transcriptase polymerase
chain reaction (RT-PCR) was performed to determine levels of c-kit
and KL expression in cultures of epithelial and stroma cells,
as well as in the prostate cancer cell lines LNCaP, DU145 and
PC3.
c-kit protein in normal prostate was exclusively detected in mast
cells by immunohistochemistry and in situ hybridization. However,
c-kit transcripts, but not c-kit protein, were detected in low
levels and with an heterogeneous pattern in basal epithelial cells
of ducts and acini. c-kit in BPH was detected in epithelial cells
in 9 of 53 (17%) specimens. c-kit protein expression in malignant
epithelial cells was identified in 1 of 46 (2%) tumors. However,
c-kit transcripts were detected in low levels by in situ hybridization
in most of the tumors analyzed.
KL protein and transcripts in normal prostate were detected in
high levels in stroma cells. However, epithelial cells were unreactive
for anti-KL antibody, but showed low levels of KL transcripts
mainly in cells of the basal layer. Basal epithelial cells in
hyperplastic glands showed KL expression in 13 of 53 (24%) specimens.
KL protein in tumor cells was noted in 18 of 46 (39%) cases.
c-kit transcripts were not found in normal prostate and in the
3 cancer cell lines analyzed by RT-PCR, however, it was present
in cultured epithelial cells of BPH, and in cultures of stroma
cells from both normal and BPH. The majority of cultured cell
lines of epithelial and stromal origin displayed considerable
levels of KL. In addition all prostate cell lines studied showed
significant levels of KL transcripts.
In summary, co-expression of c-kit and KL in a subset of BPH cases
may suggest an autocrine mode of signaling. Data from this study
reveals that altered patterns of c-kit and KL expression are associated
with BPH and adenocarcinoma of prostate. It appears that KL induces
mast cells proliferation and maturation and enhances their release
of protease. This could explain the accumulation of mast cells
at tumor sites, a phenomenon that was not observed in normal prostate
or BPH samples. Histol. Histopathol. 15, 365-374 (2000)
Key words: c-Kit,
Kit ligand, Benign prostatic hyperplasia, Prostate neoplasms,
Immunohistochemistry
DOI: 10.14670/HH-15.365
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