Neuroendocrine cells in human prostate over-express the anti-apoptosis protein survivin.

Department of Urology, Mayo Graduate School, Mayo Foundation, Rochester, Minnesota 55905, USA.
The Prostate (Impact Factor: 3.84). 07/2001; 48(1):7-15. DOI: 10.1002/pros.1076
Source: PubMed

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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abnormal expression of Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5, also called as survivin), a novel member of the inhibitor of apoptosis protein (IAP) family, has implications in many types of cancer and is considered as a new therapeutic target. We suppose that genetic variant rs9904341 in the 5[prime] UTR region of survivin gene may be associated with the development and progression of prostate cancer (PCa) in Chinese population. TaqMan assay method was used to genotype the polymorphism in the hospital-based case--control analysis of 665 patients with PCa and 710 age-matched cancer-free controls. The genetic associations with the occurrence and progression of PCa were calculated by logistic regression. Our results indicated that compared with GG genotypes, there was a statistically significant increased risk of PCa associated with those with CC genotypes [odds ratios (ORs) = 1.57, 95%confidence intervals (CIs) = 1.17-2.13, P = 0.004]. Moreover, stratification analysis revealed that the association was more pronounced in subgroups of nondrinkers, nonsmokers and those without a family history of cancer (all P < 0.05). In addition, we observed that PSA >= 20 was more frequent in patients carrying GC/CC genotypes than in those with a wild type genotype. The functional survivin rs9904341 genetic variant may have a substantial influence on the PCa susceptibility and evolution.
    BMC Cancer 07/2013; 13(1):356. · 3.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The human prostate is a gland composed of many types of cells and extracellular components with specific functions. The stromal compartment includes nerve tissue, fibroblasts, lymphocytes, macrophages, endothelial cells, and smooth muscular cells. The epithelial compartment is composed of luminal epithelial cells, basal cells, and a lesser number of neuroendocrine cells, which are transcendental in growth regulation, differentiation, and secretory function. In prostate cancer, neuroendocrine cells replicate especially in high grade and advanced stage, and hormonally treated tumoral cells adopt characteristics that make them resistant to hormonal deprivation. Androgen receptors have a crucial role in tumorigenesis of prostate adenocarcinoma. Deprivation hormone therapy blocks the expression of androgen receptors in the prostatic epithelial cells. Neuroendocrine cells lack androgen receptors; their growth is hormonally independent and that is why deprivation hormonal therapy does not eliminate the neoplasic neuroendocrine cells. In contrast, these types of cells proliferate after therapy and make a paracrine network, stimulating the proliferation of androgen-independent neoplastic cells, which finally lead to tumoral recurrence. In this work we describe the neuroendocrine function in normal tissue and in prostatic adenocarcinoma, including neoplasic proliferation stimulation, invasion, apoptosis resistance, and angiogenesis, and describe some molecular pathways involved in this neuroendocrine differentiation.
    Gaceta medica de Mexico 12/2013; 149(6):639-45. · 0.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.