p53 Pathway Is Involved in the Pathogenesis of Small Cell Carcinoma of the Prostate
JL Clebanoff, C Magyar, JL Yao, PA di Sant'Agnese, L Cheng, Q Yang, X Li, J Huang. David Geffen School of Medicine at UCLA, Los Angeles, CA; University of Rochester Medical Center, Rochester, NY; Indiana University School of Medicine, Indianapolis, IN
Background: Benign prostate and prostate adenocarcinoma (PCa) contain rare neuroendocrine (NE) cells while prostatic small cell neuroendocrine carcinomas (SCNC) consist of pure NE cells. Unlike the quiescent NE cells in benign prostate and PCa, those in SCNC are highly proliferative and cause death in months. NE cells of prostate express interleukin-8 (IL-8) and its receptor CXCR2. It was recently reported that CXCR2 induces cell senescence mediated by p53. Thus, we hypothesize that the IL-8-CXCR2-p53 pathway maintains the NE cells in a quiescent state. We further hypothesize that p53 mutation, the most common genetic change in human tumors, leads to hyper-proliferation and expansion of NE cells, resulting in SCNC.
Design: 1. Two TMAs were prepared from 75 prostatectomies, one containing tumor and the other benign prostate. Adjacent sections of the TMAs, containing essentially the same cells, were stained for chromogranin A (CgA) and p53 respectively, scanned and analyzed using the Ariol SL-50 scanner with thresholds applied for RGB algorithms, shapes and size, to determine if nuclear staining of p53 which indicates p53 mutation, occurs in CgA+ (NE) cells. 2. LNCaP cells were transfected to express CXCR2 and treated with IL-8. mRNAs were prepared and microarray analysis performed to determine if CXCR2 activation induces a p53 gene signature. 3. Tissue sections from 31 prostatic SCNC were stained for p53.
Results: 1. Benign cores of the TMAs contained 1353 NE cells (0.33% of total cells) and 3297 p53+ cells (0.84%); cancer cores had 1331 NE cells (0.23%) and 4646 p53+ cells (0.9%). The two types of cells did not overlap. 2. Microarray analysis showed that CXCR2 activation induced a p53 gene signature. 3. All prostatic SCNCs were p53+, with 74% (23/31) showing positivity in 50-100% cells and the remaining 26% (8/31) being positive in 5-50% cells.
Conclusions: 1. In normal prostate and PCa, activation of CXCR2 by IL-8 activates p53 pathway in NE cells, maintaining them in a quiescent state. 2. In prostatic SCNC, p53 mutation results in inactivation of the IL-8-CXCR2-p53 pathway and hyperproliferation and aggressive behavior of the NE cells. 3. In contrast to PCa, hormonal therapy targeting androgen receptor will not be effective for SCNC while therapies that restore p53 pathway may be useful.
Category: Genitourinary (including renal tumors)
Monday, March 22, 2010 1:00 PM
Poster Session II # 112, Monday Afternoon