C35: A new prognostic tool and potential target in prostate cancer.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 212-212
Author(s):  
Deepak Kilari ◽  
Jorge Yao ◽  
Emelian Scosyrev ◽  
Elizabeth E. Evans ◽  
Deepak M. Sahasrabudhe
Keyword(s):  
Prostate Cancer ◽  
Tissue Microarrays ◽  
Normal Prostate ◽  
Tissue Samples ◽  
Over Expression ◽  
Potential Target ◽  
Prostate Cells ◽  
Primary Prostate Cancer ◽  
Prostate Cancers ◽  
Metastatic Sites

212 Background: Identification and validation of biomarkers can help prognosticate patients and potentially serve as therapeutic targets. C35, a protein encoded by novel gene C17orf37 is located on 17q12 “the hotspot of cancer”. Dasgupta et al. (Oncogene 2009) noted higher expression of C35 in prostate cancer cell lines as compared to minimal expression in normal prostate cells. Furthermore, over expression of C35 enhanced motility and invasion. We hypothesized that C35 expression would correlate with other markers of aggressive clinical behavior and tested this by studying C35 expression in tissue microarrays (TMAs). Methods: TMAs were constructed using tissue samples obtained from normal organs including prostate, primary prostate cancers and prostate cancer from various metastatic sites. The TMAs had triplicates of each specimen which was then stained with rabbit polyclonal anti -C35 antibody. Each sample was scored based on the product of intensity (0-3) and distribution (0-4) of staining, with the maximum score being 12. A blinded review of the final scores and Gleason’s sum were independently conducted by a pathologist. Results: The C35 expression scores were higher in primary prostate cancer compared to benign prostate tissue. The average expression scores increased with increasing Gleason sum. Prostate cancer specimens from the metastatic sites had significantly lower expression scores when compared with the primary prostate cancer specimens. There was minimal to no expression in other normal organs. All these differences were statistically significant (p<0.001). The protein was predominantly cytosolic with membrane localization. Distributions of expression scores according to specimen type are summarized below. Conclusions: C35 expression directly correlates with Gleason sum, a validated prognostic marker. C35 may be a potential target for therapeutic agents. Further studies are needed to determine if increased expression of C35 in normal prostate can predict future development of prostate cancer. [Table: see text]

scholarly journals HERV-K Gag RNA and Protein Levels Are Elevated in Malignant Regions of the Prostate in Males with Prostate Cancer

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 449
Author(s):  
Simin D. Rezaei ◽  
Joshua A. Hayward ◽  
Sam Norden ◽  
John Pedersen ◽  
John Mills ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Normal Prostate ◽  
Tissue Samples ◽  
Gag Protein ◽  
Protein Levels ◽  
Prostate Epithelial Cells ◽  
Prostate Cancers

Heightened expression of human endogenous retrovirus (HERV) sequences has been associated with a range of malignancies, including prostate cancer, suggesting that they may serve as useful diagnostic or prognostic cancer biomarkers. We analysed the expression of HERV-K (Gag and Env/Np9 regions), HERV-E 4.1 (Pol and Env regions), HERV-H (Pol) and HERV-W (Gag) sequences in prostate cancer cells lines and normal prostate epithelial cells using qRT-PCR. HERV expression was also analysed in matched malignant and benign prostate tissue samples from men with prostate cancer (n = 27, median age 65.2 years (range 47–70)) and compared to prostate cancer-free male controls (n = 11). Prostate cancer epithelial cell lines exhibited a signature of HERV RNA overexpression, with all HERVs analysed, except HERV-E Pol, showing heightened expression in at least two, but more commonly all, cell lines analysed. Analysis of primary prostate material indicated increased expression of HERV-E Pol but decreased expression of HERV-E Env in both malignant and benign regions of the prostate in men with prostate cancer as compared to those without. Expression of HERV-K Gag was significantly higher in malignant regions of the prostate in men with prostate cancer as compared to matched benign regions and prostate cancer-free men (p < 0.001 for both), with 85.2% of prostate cancers donors showing malignancy-associated upregulation of HERV-K Gag RNA. HERV-K Gag protein was detected in 12/18 (66.7%) malignant tissues using immunohistochemistry, but only 1/18 (5.6%) benign tissue sections. Heightened expression of HERV-K Gag RNA and protein appears to be a sensitive and specific biomarker of prostate malignancy in this cohort of men with prostate carcinoma, supporting its potential utility as a non-invasive, adjunct clinical biomarker.

scholarly journals Neurotensin Receptor-1 Expression in Human Prostate Cancer: A Pilot Study on Primary Tumors and Lymph Node Metastases

2019 ◽  
Vol 20 (7) ◽  
pp. 1721 ◽  
Author(s):  
Clément Morgat ◽  
Adrien Chastel ◽  
Vincent Molinie ◽  
Romain Schollhammer ◽  
Gaétan Macgrogan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lymph Nodes ◽  
Distant Metastases ◽  
Human Prostate ◽  
Normal Prostate ◽  
Tissue Samples ◽  
Primary Tumors ◽  
Metastatic Lymph Nodes ◽  
Metastatic Lymph ◽  
Prostate Cancers

Neurotensin and its high-affinity receptor, NTR1, are involved in the growth of various tumors. Few data are available regarding NTR1 expression in normal and tumoral human prostate tissue samples. NTR1 expression was assessed using immunohistochemistry in 12 normal prostate tissues, 11 benign prostatic hyperplasia (BPH), 44 prostate cancers, and 15 related metastatic lymph nodes (one per patient, when available). NTR1-staining was negative in normal prostate and BPH samples. NTR1 was overexpressed in four out of 44 (9.1%) primary tumors. There was no clear association between NTR1 overexpression and age, PSA-values, Gleason score, pT-status, nodal-status, or margin. NTR1 was expressed at a high level of five out of 15 (33.3%) metastatic lymph nodes. NTR1 overexpression was thus more frequent in metastatic lymph nodes than in primary tumors (p = 0.038). In this limited series of samples, NTR1 overexpression was observed in few primary prostate cancers. Upregulation was more frequent in related lymph nodes. The presence of this target in metastatic lymph nodes may open new perspectives for imaging and radionuclide therapy of prostate cancer. Factors driving NTR1 expression in primary prostate cancer and in nodal and distant metastases still need to be characterized.

ATM loss in primary prostate cancer: Analysis of >1000 cases using a validated clinical-grade immunohistochemistry (IHC) assay.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5069-5069 ◽  
Author(s):  
Emmanuel S. Antonarakis ◽  
Harsimar B Kaur ◽  
Jessica Hicks ◽  
Colin C. Pritchard ◽  
Angelo M De Marzo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tissue Microarrays ◽  
Early Event ◽  
High Grade ◽  
Clinical Grade ◽  
Protein Loss ◽  
Gleason Pattern ◽  
Primary Prostate Cancer ◽  
Atm Protein ◽  
Prostate Cancers

5069 Background: ATM is a protein kinase acting as the main signal transducer of double-strand DNA break repair, in addition to mediating other cellular functions. Germline and somatic pathogenic mutations in ATM occur in a significant fraction of prostate cancers, and targeted therapies for ATM-deficient tumors ( e.g. ATR inhibitors) appear promising. Because DNA sequencing assays frequently cannot distinguish mono-allelic from bi-allelic ATM alterations, a clinical-grade protein IHC assay for ATM loss is needed to select men for these trials and better characterize ATM-deficient tumors. Methods: We validated an automated dichotomously-scored IHC assay to detect ATM protein loss in primary prostate cancer using prostate cancer cell lines with and without bi-allelic ATM inactivation and 49 high-grade (primary Gleason pattern 5) prostate tumors with known ATM genomic status. We then examined the frequency of ATM loss among 23 tumors with pathogenic germline ATM mutations, as well as > 1000 additional primary prostate carcinomas using tissue microarrays (TMA). Results: ATM loss by IHC was found in 14% (7/49) of primary Gleason pattern 5 (5+4 = 9 and 5+5 = 10) tumors. Of these, all cases with adequate tumor content and DNA yield had underlying pathogenic ATM mutations. Of the remaining 42 cases without ATM protein loss, none had ATM alterations. Among men with pathogenic germline ATM mutations, 74% (17/23) had ATM loss by IHC. Of these, 76% (13/17) had homogeneous loss of ATM protein in all tumor cells within a dominant tumor nodule, suggesting that ATM loss was an early clonal event. On TMA analysis, 90% (944/1044) of tumors were evaluable for ATM status by IHC. Among these, ATM loss was seen in 3.3% (31/944), and was significantly more common in tumors with Gleason scores 9-10 (20/198; 10.1%) than in those of all other Gleason grades (11/746; 1.5%) ( P< 0.0001). Conclusions: Validated ATM IHC is a sensitive assay for detecting underlying genomic ATM alterations. ATM protein loss appears to be an early event occurring in the majority of tumors with underlying germline pathogenic ATM mutations, and is significantly enriched in high-grade prostate cancers (especially Gleason grades 9-10).

AS1 expression in prostate cancer and its effects on proliferation and invasion of prostate cancer cells

2021 ◽  
pp. 1-9
Author(s):  
Yuxin Li ◽  
Xiaohong Zhuang ◽  
Li Zhuang ◽  
Hongjian Liu
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Related Protein ◽  
Prostate Cancer Cells ◽  
Blank Group ◽  
Normal Prostate ◽  
Cell Cycles ◽  
Prostate Cells ◽  
Proliferation And Invasion

This paper aimed at investigating AS1 expression in prostate cancer (PCa) and its effects on the proliferation and invasion of prostate cancer cells (PCCs). The prostate tissues and the matched adjacent normal prostate tissues excised and preserved during radical prostatectomy in our hospital were collected. The LncRNA NCK1-AS1 expression was detected. PCa patients were followed up for three years to analyze their prognosis. The correlation of LncRNA NCK1-AS1 expression with clinicopathological features was analyzed. Human normal prostate cells and human PCCs were selected, in which LncRNA NCK1-AS1 expression was tested to screen and then transfect the cells. Cell proliferation, invasion and migration were detected. Cell cycles and apoptosis were analyzed. Compared with the adjacent normal tissues, LncRNA NCK1-AS1 was highly expressed in the prostate cancer tissues. Its expression was remarkably different in those with different stages of TNM and with lymphatic metastasis or not. The prognosis of patients with high LncRNA NCK1-AS1 expression was remarkably poorer than that of those with low expression. Compared with the human normal prostate cells, LncRNA NCK1-AS1 expression in the human PCCs remarkably rose, with the greatest difference in 22Rv1 cells. Compared with the Blank group, cell proliferation and the number of plate cloned cells remarkably reduced in the sh-NCK1-AS1 group. Additionally, in this group, the number of invasive and migratory cells remarkably reduced; the expression of invasion-related protein E-cadherin remarkably rose but that of MMP-2 remarkably reduced; cell cycles were arrested and the expression of cycle-related proteins (CDK4, CDK6, cyclin D1) remarkably reduced; the apoptotic rate and the expression of apoptosis-related protein Bax remarkably rose. LncRNA NCK1-AS1 is highly expressed in PCa, so its down-regulation can inhibit PCCs from proliferating and reduce the number of invasive cells.

scholarly journals Prostate Stem Cells in the Development of Benign Prostate Hyperplasia and Prostate Cancer: Emerging Role and Concepts

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Akhilesh Prajapati ◽  
Sharad Gupta ◽  
Bhavesh Mistry ◽  
Sarita Gupta
Keyword(s):  
Prostate Cancer ◽  
Stem Cells ◽  
Benign Prostate Hyperplasia ◽  
Normal Prostate ◽  
Prostate Hyperplasia ◽  
Regulatory Factors ◽  
Prostate Cells ◽  
Hormonal Imbalance ◽  
Benign Prostate ◽  
Insight Into

Benign Prostate hyperplasia (BPH) and prostate cancer (PCa) are the most common prostatic disorders affecting elderly men. Multiple factors including hormonal imbalance, disruption of cell proliferation, apoptosis, chronic inflammation, and aging are thought to be responsible for the pathophysiology of these diseases. Both BPH and PCa are considered to be arisen from aberrant proliferation of prostate stem cells. Recent studies on BPH and PCa have provided significant evidence for the origin of these diseases from stem cells that share characteristics with normal prostate stem cells. Aberrant changes in prostate stem cell regulatory factors may contribute to the development of BPH or PCa. Understanding these regulatory factors may provide insight into the mechanisms that convert quiescent adult prostate cells into proliferating compartments and lead to BPH or carcinoma. Ultimately, the knowledge of the unique prostate stem or stem-like cells in the pathogenesis and development of hyperplasia will facilitate the development of new therapeutic targets for BPH and PCa. In this review, we address recent progress towards understanding the putative role and complexities of stem cells in the development of BPH and PCa.

scholarly journals Interfocal heterogeneity challenges the clinical usefulness of molecular classification of primary prostate cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kristina Totland Carm ◽  
Andreas M. Hoff ◽  
Anne Cathrine Bakken ◽  
Ulrika Axcrona ◽  
Karol Axcrona ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Classification ◽  
Primary Diagnosis ◽  
The Cancer Genome Atlas ◽  
Clinical Usefulness ◽  
Whole Exome ◽  
Primary Prostate Cancer ◽  
Cancer Genome Atlas ◽  
Prostate Cancers

Abstract Prostate cancer is a highly heterogeneous disease and typically multiple distinct cancer foci are present at primary diagnosis. Molecular classification of prostate cancer can potentially aid the precision of diagnosis and treatment. A promising genomic classifier was published by The Cancer Genome Atlas (TCGA), successfully classifying 74% of primary prostate cancers into seven groups based on one cancer sample per patient. Here, we explore the clinical usefulness of this classification by testing the classifier’s performance in a multifocal context. We analyzed 106 cancer samples from 85 distinct cancer foci within 39 patients. By somatic mutation data from whole-exome sequencing and targeted qualitative and quantitative gene expression assays, 31% of the patients were uniquely classified into one of the seven TCGA classes. Further, different samples from the same focus had conflicting classification in 12% of the foci. In conclusion, the level of both intra- and interfocal heterogeneity is extensive and must be taken into consideration in the development of clinically useful molecular classification of primary prostate cancer.

scholarly journals Cytochrome P450 3A5 is highly expressed in normal prostate cells but absent in prostate cancer

2007 ◽  
Vol 14 (3) ◽  
pp. 645-654 ◽  
Author(s):  
S Leskelä ◽  
E Honrado ◽  
C Montero-Conde ◽  
I Landa ◽  
A Cascón ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cytochrome P450 ◽  
Prostate Cancer Risk ◽  
Cytochrome P450 3A ◽  
Active Metabolites ◽  
Normal Prostate ◽  
Prostate Cells ◽  
Mrna Content ◽  
Luminal Cells ◽  
And Function

Testosterone is essential for the growth and function of the luminal prostate cells, but it is also critical for the development of prostate cancer, which in the majority of the cases derives from luminal cells. Cytochrome P450 3A (CYP3A) enzymes hydroxylate testosterone and dehydroepiandrosterone to less active metabolites, which might be the basis for the association between CYP3A polymorphisms and prostate cancer. However, it is unknown whether the CYP3A enzymes are expressed at relevant levels in the prostate and which polymorphisms could affect this tissue-specific CYP3A activity. Thus, we measured CYP3A4, CYP3A5, CYP3A7, and CYP3A43 mRNA in 14 benign prostatic hyperplasias and ten matched non-tumoral/tumoral prostate samples. We found that CYP3A5 mRNA in non-tumoral prostate tissue was 10% of the average amount of liver samples, whereas the expression of the other CYP3A genes was much lower. Similarly to liver, CYP3A5*3 polymorphism decreased CYP3A5 mRNA content 13-fold. CYP3A5 protein was detected in non-tumoral prostate microsomes by western blot, and immunohistochemistry (IHC) localized CYP3A5 exclusively in the basolateral prostate cells. In contrast to the normal tissue, IHC and RT-PCR showed that tumoral tissue lacked CYP3A5 expression. In conclusion, prostate basolateral cells express high levels of CYP3A5 which dramatically decrease in tumoral tissue. This finding supports an endogenous function of CYP3A5 related to the metabolism of intra-prostatic androgens and cell growth, and that polymorphisms affecting CYP3A5 activity may result in altered prostate cancer risk and aggressiveness.

scholarly journals Analysis of androgen and anti-androgen regulation of KLK-related peptidase 2, 3, and 4 alternative transcripts in prostate cancer

2014 ◽  
Vol 395 (9) ◽  
pp. 1127-1132 ◽  
Author(s):  
John Lai ◽  
Jiyuan An ◽  
Colleen C. Nelson ◽  
Melanie L. Lehman ◽  
Jyotsna Batra ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Treatment Resistance ◽  
Cancer Genes ◽  
Lncap Cells ◽  
Normal Prostate ◽  
Alternative Transcripts ◽  
Androgen Regulation ◽  
Prostate Cancers

Abstract We assessed whether alternative transcripts (using KLK2, KLK3 and KLK4 as models) are differentially regulated by androgens and anti-androgens as an indicator of prostate cancers as they acquire treatment resistance. Using RNAseq of LNCaP cells treated with dihydrotestosterone, bicalutamide and enzalutamide, we show that the expression of variant KLK transcripts is markedly different to other variant transcripts at those loci. We also reveal that KLK variants are also over 2-fold more highly expressed in prostate cancers compared to their corresponding normal prostate. We propose that androgens and anti-androgens can activate specific variant transcripts of critical prostate cancer genes during treatment resistance.

scholarly journals Oncogenic Gene Fusions in Non-Neoplastic Precursors as Evidence that Bacterial Infection Initiates Prostate Cancer

2020 ◽  
Author(s):  
Eva Shrestha ◽  
Jonathan B. Coulter ◽  
William Guzman ◽  
Busra Ozbek ◽  
Luke Mummert ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bacterial Infections ◽  
Precancerous Lesions ◽  
Driver Gene ◽  
Gene Fusions ◽  
Precursor Lesions ◽  
Dna Breaks ◽  
Prostate Cells ◽  
Prostate Cancers ◽  
Carcinogenic Process

AbstractProstate adenocarcinoma is the second most commonly diagnosed cancer in men worldwide and the initiating factors are unknown. Oncogenic TMPRSS2:ERG (ERG+) gene fusions are facilitated by DNA breaks and occur in up to 50% of prostate cancers1,2. Infection-driven inflammation is implicated in the formation of ERG+ fusions3, and we hypothesized that these fusions initiate in early inflammation-associated prostate cancer precursor lesions, such as proliferative inflammatory atrophy (PIA), prior to cancer development. We investigated whether bacterial prostatitis is associated with ERG+ precancerous lesions in unique cases with active bacterial infections at time of radical prostatectomy. We identified a high frequency of ERG+ non-neoplastic-appearing glands in these cases, including ERG+ PIA transitioning to early invasive cancer. We verified TMPRSS2:ERG genomic rearrangements in precursor lesions using tri-color fluorescence in situ hybridization. Identification of rearrangement patterns combined with whole prostate mapping in 3 dimensions confirmed multiple (up to 8) distinct ERG+ precancerous lesions in infected cases. Finally, we identified the pathogen-derived genotoxin colibactin as a potential source of DNA breaks in clinical cases as well as cultured prostate cells. Overall, we provide evidence that bacterial infections initiate driver gene alterations in prostate cancer. Furthermore, infection-induced ERG+ fusions are an early alteration in the carcinogenic process and PIA may serve as a direct precursor to prostate cancer.

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