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. 2012 May 24;19(3):321-31.
doi: 10.1530/ERC-11-0368. Print 2012 Jun.

Pathogenesis of prostatic small cell carcinoma involves the inactivation of the P53 pathway

Hongbing Chen  1 , Yin Sun, Chengyu Wu, Clara E Magyar, Xinmin Li, Liang Cheng, Jorge L Yao, Steven Shen, Adeboye O Osunkoya, Chaozhao Liang, Jiaoti Huang
Affiliations

Pathogenesis of prostatic small cell carcinoma involves the inactivation of the P53 pathway

Hongbing Chen et al. Endocr Relat Cancer. .

Abstract

Small cell neuroendocrine carcinoma (SCNC) of the prostate is a variant form of prostate cancer that occurs de novo or as a recurrent tumor in patients who received hormonal therapy for prostatic adenocarcinoma. It is composed of pure neuroendocrine (NE) tumor cells, but unlike the scattered NE cells in benign prostate and adenocarcinoma that are quiescent, the NE cells in SCNC are highly proliferative and aggressive, causing death in months. In this study, we provide evidence that interleukin 8 (IL8)-CXCR2-P53 (TP53) signaling pathway keeps the NE cells of benign prostate and adenocarcinoma in a quiescent state normally. While P53 appears to be wild-type in the NE cells of benign prostate and adenocarcinoma, immunohistochemical studies show that the majority of the NE tumor cells in SCNC are positive for nuclear p53, suggesting that the p53 is mutated. This observation is confirmed by sequencing of genomic DNA showing p53 mutation in five of seven cases of SCNC. Our results support the hypothesis that p53 mutation leads to inactivation of the IL8-CXCR2-p53 signaling pathway, resulting in the loss of an important growth inhibitory mechanism and the hyper-proliferation of NE cells in SCNC. Therefore, we have identified potential cells of origin and a molecular target for prostatic SCNC that are very different from those of conventional adenocarcinoma, which explains SCNC's distinct biology and the clinical observation that it does not respond to hormonal therapy targeting androgen receptor signaling, which produces short-term therapeutic effects in nearly all patients with prostatic adenocarcinoma.

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Conflict of interest statement

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Figures

Figure 1
Figure 1
Activation of CXCR2 by IL8 inhibits cell proliferation and induces changes in gene expression profile. LNCaP cells were stably transfected with a plasmid-expressing CXCR2, a receptor for IL8. Real-time PCR (A), western blot (B), and flow cytometry (C) analyses show that CXCR2 is not expressed in the parental LNCaP cells but highly overexpressed in the stable cell line. (D) LNCaP cells transfected with vector control or CXCR2 were cultured in the absence or presence of IL8. IL8 significantly inhibits the proliferation of LNCaP cells expressing CXCR2. (E) Microarray analysis shows that IL8 stimulation of LNCaP/CXCR2 cells results in significant changes of gene expression profile. Similar changes were observed at 1 and 12 h after IL8 treatment.
Figure 2
Figure 2
p53 is important for mediating IL8 activity in LNCAP and PC3 cells. (A) Knocking down endogenous p53 in CXCR2-expressing LNCaP cells leads to increase in cell proliferation in response to IL8 treatment. (B) Expression of p53 renders PC3 cells responsive to growth inhibition of IL8. GFP-positive cells were counted using laser microplate cytometer as equivalent to p53 expression in PC3 cells. The ratio of the number of cells in the presence or absence of IL8 was tabulated.
Figure 3
Figure 3
NE cells in benign and adenocarcinoma of prostate are negative for nuclear P53 staining. (A) Adjacent sections of benign prostate were stained with anti-CgA and anti-P53 antibodies respectively. The upper panel shows that NE cells (CgA+, arrows) are negative for nuclear P53. The lower panel shows that the scattered P53+ cells (arrows) were not NE cells (CgA−). (B) Adjacent sections of prostate adenocarcinoma were stained with anti-CgA and anti-P53 antibodies respectively. The upper panel shows that NE cells (CgA+, arrows) are negative for nuclear P53. The lower panel shows that the scattered P53+ cells (arrows) were not NE cells (CgA−). (C) Sections of benign prostate and prostate adenocarcinoma were doubly stained for CgA (cytoplasmic, red, thick arrow) and P53 (nuclear, brown, thin arrow). The pictures on the left show benign prostate with NE cells (thick arrow, top), P53+ cells (thin arrow, middle), and both (lower). The right panel shows the same in adenocarcinoma. Importantly, cytoplasmic CgA staining and nuclear P53 staining do not occur in the same cells.
Figure 4
Figure 4
SCNC shows diffuse nuclear P53 staining and contains P53 mutation. (A) H&E slide of SCNC composed of pure NE tumor cells with characteristic morphological features including scant cytoplasm, fine nuclear chromatin pattern, and nuclear molding. (B) Immunohistochemistry shows diffuse nuclear P53 staining in SCNC. (C) Sequencing data from SCNC. The two examples in the top and middle panels show p53 mutation in exon 5 resulting in replacement of aspartic acid at position 184 by asparagine. The bottom panel shows wild-type P53 sequence in the same region.
Figure 5
Figure 5
The function of IL8–CXCR2–p53 pathway in controlling the proliferation of NE cells in benign prostate, adenocarcinoma, and SCNC. The model on the left suggests that autocrine activation of CXCR2 by IL8 activates the p53 pathway, which keeps NE cells of benign prostate and prostate adrenocarcinoma in a quiescent state. The model on the right suggests that p53 mutation inactivates the IL8–CXCR2–p53 pathway, leading to rapid proliferation and aggressive biological behavior of NE tumor cells in SCNC.
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