Neuroendocrine cells in human prostate over-express the anti-apoptosis protein survivin.
ABSTRACT Neuroendocrine (NE) differentiation may be related to the growth and progression of prostate cancer, especially androgen-insensitive tumors. Recently the over-expression of a new anti-apoptosis protein, survivin, has attracted attention for its potential implication in many human cancers. The fact that NE cells in prostate are bcl-2 negative prompted us to investigate if the prostatic NE cells over-express survivin.
Double immunohistochemical staining and immunofluorescence of chromogranin A (CgA) and survivin were performed in 57 patients with localized prostate cancer who underwent radical prostatectomy. The terminal deoxynucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick end-labeling (TUNEL) method was used for apoptosis detection in three prostate cancer specimens with NE differentiation. The relationship between NE differentiation and clinicopathological characteristics, disease progression as well as patient survival, were analyzed retrospectively.
It was found that NE cells in both benign and malignant prostate tissues over-expressed the anti-apoptosis protein survivin. While apoptosis was detected in non-NE epithelial cells, all NE cells were negative for apoptosis detection. During the period of follow-up, 17 (63%) of 27 patients with NE differentiation had prostate cancer progression, while 12 (40%) of 30 patients without NE differentiation had systemic prostate cancer progression. 10 (37%) of 27 patients with NE differentiation died from prostate cancer during the period of follow up, while 6 (20%) of 30 patients without NE differentiation died from prostate cancer. However, none of these characteristics reached statistical significance, probably because of the small number of cases enrolled.
This study discovers that all the prostatic NE cells express the new anti-apoptosis protein survivin. This provides a strong molecular basis for the hypothesis that NE cells may endure stressful conditions and escape from apoptosis. While our results suggest a trend of NE differentiation with poorer prognosis, the prognosis implication cannot be concluded due to our small sample size.
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ABSTRACT: On July 31, 2013, the Prostate Cancer Foundation assembled a working committee on the molecular biology and pathologic classification of neuroendocrine (NE) differentiation in prostate cancer. New clinical and molecular data emerging from prostate cancers treated by contemporary androgen deprivation therapies, as well as primary lesions, have highlighted the need for refinement of diagnostic terminology to encompass the full spectrum of NE differentiation. The classification system consists of: Usual prostate adenocarcinoma with NE differentiation; 2) Adenocarcinoma with Paneth cell NE differentiation; 3) Carcinoid tumor; 4) Small cell carcinoma; 5) Large cell NE carcinoma; and 5) Mixed NE carcinoma - acinar adenocarcinoma. The article also highlights "prostate carcinoma with overlapping features of small cell carcinoma and acinar adenocarcinoma" and "castrate-resistant prostate cancer with small cell cancer-like clinical presentation". It is envisioned that specific criteria associated with the refined diagnostic terminology will lead to clinically relevant pathologic diagnoses that will stimulate further clinical and molecular investigation and identification of appropriate targeted therapies.The American journal of surgical pathology 04/2014; · 4.59 Impact Factor
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ABSTRACT: In normal prostate, neuroendocrine (NE) cells are rare and interspersed among the epithelium. These cells are believed to provide trophic signals to epithelial cell populations through the secretion of an abundance of neuropeptides that can diffuse to influence surrounding cells. In the setting of prostate cancer (PC), NE cells can also stimulate surrounding prostate adenocarcinoma cell growth, but in some cases adenocarcinoma cells themselves acquire NE characteristics. This epithelial plasticity is associated with decreased androgen receptor (AR) signaling and the accumulation of neuronal and stem cell characteristics. Transformation to an NE phenotype is one proposed mechanism of resistance to contemporary AR-targeted treatments, is associated with poor prognosis, and thought to represent up to 25% of lethal PCs. Importantly, the advent of high-throughput technologies has started to provide clues for understanding the complex molecular profiles of tumors exhibiting NE differentiation. Here, we discuss these recent advances, the multifaceted manner by which an NE-like state may arise during the different stages of disease progression, and the potential benefit of this knowledge for the management of patients with advanced PC.Frontiers in Oncology 01/2014; 4:60.
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ABSTRACT: Neuroendocrine differentiation (NED) is a process by which prostate cancer cells transdifferentiate into neuroendocrine-like (NE-like) cancer cells. Accumulated evidence suggests that NED is associated with disease progression and therapy resistance in prostate cancer patients. We previously reported that by mimicking a clinical radiotherapy protocol, fractionated ionizing radiation (FIR) induces NED in prostate cancer cells. Interestingly, FIR-induced NED constitutes two distinct phases: a radioresistance phase in which a fraction of cells selectively survive during the first two week irradiation, and a neuroendocrine differentiation phase in which surviving cells differenti-ate into NE-like cancer cells during the second two week irradiation. We have also observed increased activation of the transcription factor cAMP response element binding (CREB) protein during the course of FIR-induced NED. To determine whether targeting NED can be explored as a radiosensitization approach, we employed two CREB target-ing strategies, CREB knockdown and overexpression of ACREB, a dominant-negative mutant of CREB, to target both phases. Our results showed that ACREB expression increased FIR-induced cell death and sensitized prostate cancer cells to radiation. Consistent with this, knockdown of CREB also inhibited FIR-induced NED and sensitized prostate cancer cells to radiation. Molecular analysis suggests that CREB targeting primarily increases radiation-induced pre-mitotic apoptosis. Taken together, our results suggest that targeting NED could be developed as a radiosensitization approach for prostate cancer radiotherapy.American Journal of Cancer Research 11/2014; 4(6):850-861. · 3.97 Impact Factor