Molecular characterization of prostatic small‐cell neuroendocrine carcinoma

Clegg, Nigel; Ferguson, Camari; True, Lawrence D.; Arnold, Hugh; Moorman, Alec J.; Quinn, Janna E.; Vessella, Robert L.; Nelson, Peter S.

doi:10.1002/pros.10217

Cited by 68 publications

(45 citation statements)

References 49 publications

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“…To this end, in a previous study, we developed patient prostate tumor-derived xenografts (PDX) of AR-negative SCPC (AR ¡ SCPC) and compared the AR ¡ SCPC gene expression profiles to those of AR-positive adenocarcinomas (AR C ADENO) derived from men with CRPC. 7,8 In line with the findings of others, 9,10 we found that AR ¡ SCPC is characterized by a loss of prostate luminal epithelial markers and a gain of neural progenitor/stem cell markers. Because DNA methylation profiles reflect cellular differentiation, 11 we hypothesized that the DNA methylation profiles of AR ¡ and AR C are distinct and that specific DNA methylation markers might be used to detect AR ¡ disease, which is of therapeutic relevance.…”

Section: Introductionsupporting

confidence: 78%

Differentially methylated genes and androgen receptor re-expression in small cell prostate carcinomas

et al. 2016

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(2016) Differentially methylated genes and androgen receptor re-expression in small cell prostate carcinomas, Epigenetics, 11:3, 184-193, DOI: 10.1080/15592294.2016 ABSTRACTSmall cell prostate carcinoma (SCPC) morphology is rare at initial diagnosis but often emerges during prostate cancer progression and portends a dismal prognosis. It does not express androgen receptor (AR) or respond to hormonal therapies. Clinically applicable markers for its early detection and treatment with effective chemotherapy are needed. Our studies in patient tumor-derived xenografts (PDX) revealed that AR-negative SCPC (AR ¡ SCPC) expresses neural development genes instead of the prostate luminal epithelial genes characteristic of AR-positive castration-resistant adenocarcinomas (AR C ADENO). We hypothesized that the differences in cellular lineage programs are reflected in distinct epigenetic profiles. To address this hypothesis, we compared the DNA methylation profiles of AR ¡ and AR C PDX using methylated CpG island amplification and microarray (MCAM) analysis and identified a set of differentially methylated promoters, validated in PDX and corresponding donor patient samples. We used the Illumina 450K platform to examine additional regions of the genome and the correlation between the DNA methylation profiles of the PDX and their corresponding patient tumors. Struck by the low frequency of AR promoter methylation in the AR ¡ SCPC, we investigated this region's specific histone modification patterns by chromatin immunoprecipitation. We found that the AR promoter was enriched in silencing histone modifications (H3K27me3 and H3K9me2) and that EZH2 inhibition with 3-deazaneplanocin A (DZNep) resulted in AR expression and growth inhibition in AR ¡ SCPC cell lines. We conclude that the epigenome of AR ¡ is distinct from that of AR C castration-resistant prostate carcinomas, and that the AR ¡ phenotype can be reversed with epigenetic drugs.

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Section: Introductionsupporting

confidence: 78%

Differentially methylated genes and androgen receptor re-expression in small cell prostate carcinomas

et al. 2016

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“…SV2 is known to participate in the regulation of calcium-mediated synaptic transmission and to play a role in vesicle trafficking by binding to other cell surface proteins [42]. Although SV2 was originally reported to be specifically expressed in the central nervous system, recent studies have shown that it is also distributed in other organs [43,44]. SV2B is reported to be expressed in the microvesicles of pinealocytes, which are rich in process terminals [45].…”

Section: Synaptic Vesicle Protein 2b (Sv2b)mentioning

confidence: 97%

Slit diaphragm dysfunction in proteinuric states: identification of novel therapeutic targets for nephrotic syndrome

et al. 2009

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Several recent studies have demonstrated that the slit diaphragm of the glomerular epithelial cell (podocyte) is the structure likely to be the principal barrier in the glomerular capillary wall. Nephrin identified as a gene product mutated in congenital nephrotic syndrome located at the outer leaflet of plasma membranes of the slit diaphragm. The anti-nephrin antibody is capable of inducing massive proteinuria, which indicates that nephrin is a key functional molecule in the slit diaphragm. Expression of nephrin was reduced in glomeruli of minimal change nephrotic syndrome. Some recent studies demonstrated that podocin, CD2-associated protein and NEPH1 are also functional molecules in the slit diaphragm, and their expressions are altered in membranous nephropathy and also in focal glomerulosclerosis. These observations suggested that the alteration of the molecular arrangement in the slit diaphragm is involved in the development of proteinuria in several kinds of glomerular diseases. Recent studies of our group have demonstrated that type 1 receptor-mediated angiotensin II action reduced the expression of the slit diaphragm-associated molecules and that type 1 receptor blockade ameliorated proteinuria by preventing the function of angiotensin II on the slit diaphragm. By the subtraction hybridization techniques using glomerular cDNA of normal and proteinuric rats, we detected that synaptic vesicle protein 2B and ephrin B1 are involved in the maintenance of the barrier function of the slit diaphragm.

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“…9 In biology, they have aggressive properties with increased expression of genes involved in cellular proliferation, the cell cycle, antiapoptosis, and mitosis. 10,11 A recent study used nextgeneration sequencing for molecular characterization of NE tumors of the prostate. 12 The cell cycle kinase AURKA (aurora kinase A) and MYCN are overexpressed and amplified in NE tumors.…”

mentioning

confidence: 99%

The potential of neurotensin secreted from neuroendocrine tumor cells to promote gelsolin-mediated invasiveness of prostate adenocarcinoma cells

Hashimoto

Kyoda

Tanaka

et al. 2015

Laboratory Investigation

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Neuroendocrine (NE) cells in prostate cancer have been shown to be associated with the progression of prostate cancer. However, little is known about the molecular basis of this association. We have previously demonstrated that NE cells promote metastasis of a human prostate cancer cell line (LNCaP) with overexpression of the gelsolin gene. The purpose of this study was to investigate the interactions between NE cells and LNCaP cells and the involvement of gelsolin in contributing to the invasive potential of LNCaP cells. In addition, we examined whether neurotensin induced gelsolin-mediated invasion. We used the NE cell line NE-CS that was established from the prostate of the LPB-Tag 12T-10 transgenic mouse. Small interfering RNA (siRNA) targeting gelsolin or not targeting it was transfected into LNCaP cells.

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Molecular characterization of prostatic small‐cell neuroendocrine carcinoma

Cited by 68 publications

References 49 publications

Differentially methylated genes and androgen receptor re-expression in small cell prostate carcinomas

Differentially methylated genes and androgen receptor re-expression in small cell prostate carcinomas

Slit diaphragm dysfunction in proteinuric states: identification of novel therapeutic targets for nephrotic syndrome

The potential of neurotensin secreted from neuroendocrine tumor cells to promote gelsolin-mediated invasiveness of prostate adenocarcinoma cells

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