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

Department of Urology, The Geriatrics Research Institute, First Affiliated Hospital of Anhui Medical University, Anhui, China.
Endocrine Related Cancer (Impact Factor: 4.81). 03/2012; 19(3):321-31. DOI: 10.1530/ERC-11-0368
Source: PubMed


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.

Download full-text


Available from: Clara E Magyar,
  • Source
    • "Tan et al. reported that loss of RB1 by deletion is a common event in PSCC, similar to small cell carcinoma of the lung (Tan et al., 2014). Chen et al. found that TP53 mutation inactivates the IL8- CXCR2 pathway, leading to increased proliferation and invasive biological behavior of neuroendocrine tumor cells of PSCC in response to chemokine release from stromal macrophages and endothelial cells (Chen et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Small cell carcinoma of the prostate (PSCC) is a rare and highly aggressive malignancy with a dismal prognosis. Most patients present with advanced disease, including metastases to bone, viscera, and the central nervous system. Histologically, PSCC is indistinguishable from its pulmonary counterpart. Although PSCC may occur in pure form, as in small cell lung carcinoma, it also occurs in conjunction with conventional glandular prostate carcinoma, and may evolve from conventional adenocarcinoma during the course of hormonal therapy. Immunohistochemical staining is extremely helpful in establishing the diagnosis, a prerequisite, as in small cell lung cancer, for optimal therapeutic strategy. Currently, combinations of surgical resection, chemotherapy, and radiation therapy represent the main treatment options. Improvement in survival may depend upon the identification of new molecular markers to facilitate earlier diagnosis and the development of novel targeted therapies. This review will discuss general aspects of PSCC, focusing on ways in which our understanding of PSCC has been advanced by studies of the histopathologic, immunohistochemical and molecular alterations in this disease.
    Histology and histopathology 11/2014; 30(4). DOI:10.14670/HH-30.413 · 2.10 Impact Factor
  • Source
    • "Significant progress has been made in understanding the molecular mechanism of SCNC development. We reported that in benign prostate and adenocarcinoma, the IL-8-CXCR2-P53 pathway provides a strong growth inhibitory signal that keeps NE cells quiescent.1725 P53 mutation, likely a result of environmental pressure from hormonal therapy, inactivates this pathway and leads to hyperproliferation and aggressive behavior of the NE cells, resulting in the development of SCNC.17 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Most prostate cancers (PCas) are classified as acinar type (conventional) adenocarcinoma which are composed of tumor cells with luminal differentiation including the expression of androgen receptor (AR) and prostate-specific antigen (PSA). There are also scattered neuroendocrine (NE) cells in every case of adenocarcinoma. The NE cells are quiesecent, do not express AR or PSA, and their function remains unclear. We have demonstrated that IL8-CXCR2-P53 pathway provides a growth-inhibitory signal and keeps the NE cells in benign prostate and adenocarcinoma quiescent. Interestingly, some patients with a history of adenocarcinoma recur with small cell neuroendocrine carcinoma (SCNC) after hormonal therapy, and such tumors are composed of pure NE cells that are highly proliferative and aggressive, due to P53 mutation and inactivation of the IL8-CXCR2-P53 pathway. The incidence of SCNC will likely increase due to the widespread use of novel drugs that further inhibit AR function or intratumoral androgen synthesis. A phase II trial has demonstrated that platinum-based chemotherapy may be useful for such therapy-induced tumors.
    Asian Journal of Andrology 02/2014; 16(4). DOI:10.4103/1008-682X.123669 · 2.60 Impact Factor
  • Source
    • "Importantly, while neuroendocrine cells in benign prostate and adenocarcinoma express wild-type p53, IHC analysis of SCNC samples revealed that the majority of the NE tumor cells in SCNC display strong and diffuse nuclear p53 staining, suggesting that p53 is frequently mutated in SCNC [62]. Furthermore, targeted sequencing of exons 5–10 of TP53 gene showed that five of seven cases of SCNC harbor a recurrent p53 mutation (D184N) [62], supporting the notion that p53 missense mutation in neuroendocrine cells could be the critical genetic event in the development of prostate SCNC. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer is a common malignancy among men in Western countries. Recently the morbidity and mortality of prostate cancer increase dramatically in several oriental countries including China. Rapidly evolving technology in molecular biology such as high-throughput sequencing and integrative analysis of genomic and transcriptomic landscapes have enabled the identification of key oncogenic events for prostate cancer initiation, progression and resistance to hormonal therapy. These surging data of prostate cancer genome also provide insights on ethnic variation and the differences in histological subtype of this disease. In this review, differences in the incidence of prostate cancer and the prevalence of main genetic alterations between Asian and Western populations are discussed. We also review the recent findings on the mechanisms underlying neuroendocrine differentiation of prostate cancer and the development of small cell neuroendocrine carcinoma after androgen deprivation therapy.
    Science China. Life sciences 07/2013; 56(9). DOI:10.1007/s11427-013-4522-0 · 1.69 Impact Factor
Show more