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

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

Research output: Contribution to journalArticle

50 Citations (Scopus)

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 wildtype 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.

Original languageEnglish
Pages (from-to)321-331
Number of pages11
JournalEndocrine-Related Cancer
Volume19
Issue number3
DOIs
StatePublished - Jun 2012

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Neuroendocrine Cells
Small Cell Carcinoma
Neuroendocrine Carcinoma
Adenocarcinoma
Prostate
Neuroendocrine Tumors
Interleukin-8
Mutation
Androgen Receptors
Therapeutic Uses
DNA Sequence Analysis
Prostatic Neoplasms
Therapeutics
Growth

ASJC Scopus subject areas

  • Endocrinology
  • Oncology
  • Cancer Research
  • Endocrinology, Diabetes and Metabolism

Cite this

Pathogenesis of prostatic small cell carcinoma involves the inactivation of the P53 pathway. / Chen, Hongbing; Sun, Yin; Wu, Chengyu; Magyar, Clara E.; Li, Xinmin; Cheng, Liang; Yao, Jorge L.; Shen, Steven; Osunkoya, Adeboye O.; Liang, Chaozhao; Huang, Jiaoti.

In: Endocrine-Related Cancer, Vol. 19, No. 3, 06.2012, p. 321-331.

Research output: Contribution to journalArticle

Chen, H, Sun, Y, Wu, C, Magyar, CE, Li, X, Cheng, L, Yao, JL, Shen, S, Osunkoya, AO, Liang, C & Huang, J 2012, 'Pathogenesis of prostatic small cell carcinoma involves the inactivation of the P53 pathway', Endocrine-Related Cancer, vol. 19, no. 3, pp. 321-331. https://doi.org/10.1530/ERC-11-0368
Chen, Hongbing ; Sun, Yin ; Wu, Chengyu ; Magyar, Clara E. ; Li, Xinmin ; Cheng, Liang ; Yao, Jorge L. ; Shen, Steven ; Osunkoya, Adeboye O. ; Liang, Chaozhao ; Huang, Jiaoti. / Pathogenesis of prostatic small cell carcinoma involves the inactivation of the P53 pathway. In: Endocrine-Related Cancer. 2012 ; Vol. 19, No. 3. pp. 321-331.
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