Expression of c-kit and kit-ligand in benign and malignant prostatic tissues.

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.

Differential expression of interleukin-15, a pro-inflammatory cytokine and T-cell growth factor, and its receptor in human prostate.

BACKGROUND: Pro-inflammatory interleukin (IL)-15 plays a major role in host defense and chronic inflammation by stimulating T-lymphocyte recruitment and growth. Expression of IL-15 and IL-15 receptor (IL-15R) in human prostate was examined. METHODS: Normal and benign hyperplastic (BPH) prostate specimens (n = 23) were analyzed for IL-15 and IL-15Ralpha-chain expression by immunohistochemistry and Real-Time-PCR/RT-PCR. Regulation of prostatic stromal cell (PSC) IL-15 mRNA and effect of IL-15 on prostatic cell growth were analysed in vitro. RESULTS: In normal prostate, anti-IL-15 and anti-IL-15Ralpha-chain reactivity were restricted to smooth muscle and stromal cells. However, in BPH, in addition epithelial cells frequently exhibited discrete anti-IL-15R and often intense, membranous anti-IL-15 reactivity. IL-15/IL-15R mRNA were detected in all prostatic cells types. In BPH tissues, IL-15 mRNA content was variable (15-fold). IL-15 mRNA synthesis of PSC was significantly up-regulated by IFN-gamma. Furthermore IL-15 strongly stimulated the growth of BPH-T-lymphocytes and weakly that of carcinoma cell lines, but not of stromal cells. CONCLUSIONS: Overexpression of IL-15 and IL-15Ralpha-chain in BPH and massive proliferation of BPH-T-lymphocytes induced by IL-15 suggest a role for IL-15 in prostatic inflammation. Since IFN-gamma, a T-lymphocyte product, stimulates prostatic IL-15 production; chronic inflammation might be triggered by this paracrine loop.