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1.  Role of IAPs in prostate cancer progression: immunohistochemical study in normal and pathological (benign hyperplastic, prostatic intraepithelial neoplasia and cancer) human prostate 
BMC Cancer  2010;10:18.
Background
In this study was investigate IAPs in normal human prostate (NP), benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN) and prostatic carcinoma (PC), and their involvement in apoptosis/proliferation via NF-kB (TNF-α, IL-1) stimulation.
Methods
Immunohistochemical and Western blot analyses were performed in 10 samples of normal prostates, 35 samples of BPH, 27 samples diagnosis of PIN (with low-grade PIN or high-grade PIN) and 95 samples of PC (with low, medium or high Gleason grades).
Results
In NP, cytoplasm of epithelial cells were positive to c-IAP1/2 (80% of samples), c-IAP-2 (60%), ILP (20%), XIAP (20%); negative to NAIP and survivin. In BPH, epithelial cells were immunostained to c-IAP1/2 (57.57%), c-IAP-2 (57.57%), ILP (66.6%), NAIP (60.6%), XIAP (27.27%), survivin (9.1%). Whereas low-grade PIN showed intermediate results between NP and BPH; results in high-grade PIN were similar to those found in PC. In PC, epithelial cells were immunostained to c-IAP1/2, c-IAP-2, ILP, NAIP, XIAP (no Gleason variation) and survivin (increasing with Gleason).
Conclusions
IAPs could be involved in prostate disorder (BPH, PIN and PC) development since might be provoke inhibition of apoptosis and subsequently cell proliferation. At the same time, different transduction pathway such as IL-1/NIK/NF-kB or TNF/NF-kB (NIK or p38) also promotes proliferation. Inhibitions of IAPs, IL-1α and TNFα might be a possible target for PC treatment since IAPs are the proteins that inhibited apoptosis (favour proliferation) and IL-1α and TNFα would affect all the transduction pathway involucrate in the activation of transcription factors related to survival or proliferation (NF-kB, Elk-1 or ATF-2).
doi:10.1186/1471-2407-10-18
PMCID: PMC2838819  PMID: 20078866
2.  Immunohistochemical profiles of claudin-3 in primary and metastatic prostatic adenocarcinoma 
Diagnostic Pathology  2011;6:12.
Background
Claudins are integral membrane proteins that are involved in forming cellular tight junctions. One member of the claudin family, claudin-3, has been shown to be overexpressed in breast, ovarian, and pancreatic cancer. Here we use immunohistochemistry to evaluate its expression in benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), normal tissue adjacent to prostatic adenocarcinoma (NAC), primary prostatic adenocarcinoma (PCa), and metastatic prostatic adenocarcinoma (Mets).
Methods
Tissue microarrays were immunohistochemically stained for claudin-3, with the staining intensities subsequently quantified and statistically analyzed using a one-way ANOVA with subsequent Tukey tests for multiple comparisons or a nonparametric equivalent. Fifty-three cases of NAC, 17 cases of BPH, 35 cases of PIN, 107 cases of PCa, and 55 cases of Mets were analyzed in the microarrays.
Results
PCa and Mets had the highest absolute staining for claudin-3. Both had significantly higher staining than BPH (p < 0.05 in both cases) and NAC (p < 0.05 in both cases). PIN had a lower, but non-significant, staining score than PCa and Mets, but a statistically higher score than both BPH and NAC (p < 0.05 for both cases). No significant differences were observed between PCa, Mets, and PIN.
Conclusions
To our knowledge, this represents one of the first studies comparing the immunohistochemical profiles of claudin-3 in PCa and NAC to specimens of PIN, BPH, and Mets. These findings provide further evidence that claudin-3 may serve as an important biomarker for prostate cancer, both primary and metastatic, but does not provide evidence that claudin-3 can be used to predict risk of metastasis.
doi:10.1186/1746-1596-6-12
PMCID: PMC3033791  PMID: 21255442
3.  Organ-wide Telomeric Status in Diseased and Disease-free Prostatic Tissues 
The Prostate  2010;70(13):1471-1479.
BACKGROUND
Telomere attrition occurs early in the development of prostatic adenocarcinoma. However, little is known about either telomere status in benign prostatic hyperplasia (BPH), or the spatial and organ-wide distribution of potential telomere aberrations throughout all areas of prostatic glands affected by cancer or BPH.
METHODS
Slot blot titration assay was used to determine telomere DNA content (TC), a proxy for telomere length, in macrodissected tissue consisting of 54 normal samples from 5 disease-free prostates, 128 BPH samples from 4 non-cancerous prostates, and 45 tumor, 73 BPH, and 4 prostatic intraepithelial neoplasia (PIN) samples from 5 cancerous prostates.
RESULTS
Compared to TC in normal prostate samples (n=54; TC mean=0.98), tumor samples displayed telomere attrition (n=45; TC mean=0.67). TC in PIN samples was similar to tumors. BPH samples from cancerous prostates were similar to TC in tumors and also displayed telomere shortening (n=73; TC mean=0.76), whereas BPH samples from non-cancerous prostates displayed longer telomeres (n=128; TC mean=1.06). In prostates affected by adenocarcinoma, areas of potential telomere attrition occurred in histologically normal tissues through the entire gland. However, three-dimensional zoning revealed a pattern of increasing TC as a function of distance from the primary (index) tumor.
CONCLUSIONS
Spatial distributions of TC in prostate specimens indicate a complex “field effect” with varying contributions from both cancer and BPH. The observation that telomere length variations occur in fields of histologically normal tissues surrounding the tumor is of clinical importance, as it may have implications for the diagnosis and focal therapy of prostate cancer.
doi:10.1002/pros.21182
PMCID: PMC3920907  PMID: 20687220
Telomere alterations; prostate cancer; benign prostatic hyperplasia; field cancerization
4.  BAX-INTERACTING FACTOR-1 (BIF-1) EXPRESSION IN PROSTATE CANCER 
Clinical genitourinary cancer  2008;6(2):117-121.
Background
Bif-1 protein is a member of the endophilin B family that binds to and activates the pro-apoptotic Bax protein in response to apoptotic signals. Loss of Bif-1 suppresses the intrinsic pathway of apoptosis and promotes tumorigenesis. We examined the expression levels of Bif-1 protein in human prostate cancer.
Methods
Thirty-nine archival tissues specimens of human prostate cancer, and a human prostate cancer tissue microarray containing 19 samples of normal prostate (NR), 26 samples of benign prostatic hyperplasias (BPH), 30 samples of high grade prostatic intraepithelial neoplasia (PIN), and 153 samples of prostate cancer (CA), were selected for immuno-histochemical staining with Bif-1 antibody. The slides were scored by two independent observers.
Results
Non TMA samples: moderate to strong Bif-1 staining was identified in 38 of 39 CA. In 32 cases foci of PIN were identified adjacent to CA. Of these, twenty-nine (91%) showed strong and diffuse Bif-1 staining. BPH, identified in 27 cases, was weakly Bif-1 positive in 89% of cases. TMA samples: 38.6% (59/153) of CA showed moderate-strong Bif-1 expression, and 21.5% (33/153) were Bif-1 negative. Bif-1 expression was moderate-strong in 76.6% (23/30) of PIN. Bif-1 was weak-moderate in 53.8% (14/26) of BPH and negative in 46.1% (12/26) of them. Low-moderate Bif-1 was seen in 89.5% of NR.
Conclusions
The loss of Bif-1 expression in a subset of CAs is in agreement with the proapoptotic function of Bif-1. The significance of the increased Bif-1 in a subgroup of CA and in PIN remains to be determined. It seems that Bif-1 has a role in prostate cancer, providing the rationale for using Bif-1 as a target for prostate anticancer therapy.
doi:10.3816/CGC.2008.n.018
PMCID: PMC2626142  PMID: 18824435
Bif-1; prostate adenocarcinoma; PIN; immunohistochemistry
5.  Overexpression of Pim‐1 during progression of prostatic adenocarcinoma 
Journal of Clinical Pathology  2006;59(3):285-288.
Aims
Pim‐1 is a serine/threonine kinase that has been shown to play an integral role in the development of a number of human cancers, such as haematolymphoid malignancies. Recently, evidence has shown Pim‐1 to be important in prostatic carcinogenesis. In order to further our understanding of its role in prostate cancer, we investigated Pim‐1 expression in normal, premalignant, and malignant prostate tissue.
Methods
Using immunohistochemistry, Pim‐1 expression was analysed in prostate tissue from 120 radical prostatectomy specimens. In each case, Pim‐1 staining was evaluated in benign prostatic epithelium, high grade prostatic intraepithelial neoplasia (PIN), and prostatic adenocarcinoma. The number of positively staining cells was estimated, and the intensity of staining was scored on a scale of 0 to 3+.
Results
Pim‐1 immunoreactivity was identified in 120 cases (100%) of adenocarcinoma, 120 cases (100%) of high grade PIN, and 62 cases (52%) of benign glands. The number of cells staining in benign epithelium (mean 34%) was much lower than that in high grade PIN (mean 80%; p<0.0001) or adenocarcinoma (mean, 84%; p<0.0001). There was no significant difference between high grade PIN and adenocarcinoma in the percentage of cells staining positively for Pim‐1 (p = 0.34). The staining intensity for Pim‐1 was significantly lower in benign prostatic epithelium than in PIN and adenocarcinoma (p<0.001). There was no statistically significant correlation between the level of Pim‐1 expression and Gleason score, patient age, tumour stage, lymph node metastasis, perineural invasion, vascular invasion, surgical margin status, extraprostatic extension, or seminal vesicle invasion.
Conclusions
Pim‐1 expression is elevated in PIN and prostatic adenocarcinoma compared with benign prostatic epithelium. This finding suggests that upregulation of Pim‐1 may play a role in prostatic neoplasia.
doi:10.1136/jcp.2005.027672
PMCID: PMC1860332  PMID: 16505280
prostate; prostatic intraepithelial neoplasia; adenocarcinoma; Pim‐1; biomarkers; progression; carcinogenesis
6.  Unique Expression Pattern of the α6β4 Integrin and Laminin-5 in Human Prostate Carcinoma 
The Prostate  2001;46(3):240-248.
BACKGROUND
The α6β4 integrin and its ligand, laminin-5, are essential gene products for the maintenance and remodeling of a stratified epithelium. Apparent loss of polarized α6β4 integrin and laminin-5 protein expression in invasive prostate cancer as compared to normal prostate glands is known to occur. It is unknown whether these alterations occur in prostatic intraepithelial neoplasia (PIN) lesions and whether this combined defect occurs in other epithelial cancers.
METHODS
Human prostate tissues containing both normal, PIN, and cancerous regions and normal and cancer tissue from breast and colon were obtained at surgery and examined for β4 integrin and laminin-5 using standard immunofluorescence staining methods.
RESULTS
Both normal prostate glands and PIN lesions contain β4 integrin and laminin-5. Prostate carcinoma was unique in that both β4 integrin and laminin-5 expression was uniformly absent. In contrast, the β4 integrin and its ligand, laminin-5 were detected in all of the colon carcinoma cases and in 60% of the breast carcinomas.
CONCLUSIONS
The β4 integrin and its ligand, laminin-5 are altered during the transition of PIN lesions to invasive prostate carcinoma. These data suggest the loss of these proteins during cancer progression. In both prostate and breast carcinoma, the normal expression pattern of the β4 integrin and laminin-5 is interrupted, in contrast to the persistent β4 integrin and laminin-5 expression detected in colon carcinoma.
PMCID: PMC2824426  PMID: 11170153
integrin; prostate; epithelial; laminin; carcinoma; α6β4; colon; breast; tissue
7.  Protein expressions and genetic variations of SLC5A8 in prostate cancer risk and aggressiveness 
Urology  2011;78(4):971.e1-971.e9.
OBJECTIVES
Previous studies suggest that SLC5A8 may function as a tumor suppressor gene whose silencing by epigenetic changes may contribute to carcinogenesis. To understand a role in prostate cancer risk and aggressiveness, we investigated expression in prostate tumor and single nucleotide polymorphisms (SNPs) of SLC5A8.
METHODS
We constructed tissue microarrays (TMAs) from 183 prostate tumor tissues, 43 adjacent non-neoplastic tissues from the same prostate cancer patients, and 13 tissues from patients with benign prostatic hyperplasia (BPH) or prostate intraepithelial neoplasia (PIN). A semi-quantitative assessment of SLC5A8 protein expression was determined as the product of immuno-stain intensity and percentage of cells stained. In addition, we compared the frequencies of four SNPs (rs164365, rs1709189, rs1399236, and rs1681096) in SLC5A8 between 668 prostate cancer cases and 385 controls.
RESULTS
SLC5A8 expression was significantly higher in tumor tissues than in paired non-neoplastic tissues (p<0.0001). In the Moffitt samples, we observed a borderline moderate risk increase in individuals with a genotype containing at least one ‘A’ allele of rs164365 (OR=1.35, 95%=1.00–1.80), especially among tall individuals (≥70 inches) (OR=1.80, 95%=1.20–2.68). However, these results were not confirmed in the CGEMS population.
Conclusions
These data suggest that expression pattern of SLC5A8 may be used as a diagnostic biomarker, and a larger study is required to assess the importance of SLC5A8 SNPs in prostate cancer.
doi:10.1016/j.urology.2011.04.055
PMCID: PMC3190039  PMID: 21802122
Prostate cancer; SLC5A8; tissue microarray; polymorphism
8.  Leukocytic Promotion of Prostate Cellular Proliferation 
The Prostate  2010;70(4):377-389.
BACKGROUND
Histological evidence of pervasive inflammatory infiltrate has been noted in both benign prostatic hyperplasia/hypertrophy (BPH) and prostate cancer (PCa). Cytokines known to attract particular leukocyte subsets are secreted from prostatic stroma consequent to aging and also from malignant prostate epithelium. Therefore, we hypothesized that leukocytes associated with either acute or chronic inflammation attracted to the prostate consequent to aging or tumorigenesis may promote the abnormal cellular proliferation associated with BPH and PCa.
METHODS
An in vitro system designed to mimic the human prostatic microenvironment incorporating prostatic stroma (primary and immortalized prostate stromal fibroblasts), epithelium (N15C6, BPH-1, LNCaP, and PC3 cells), and inflammatory infiltrate (HL-60 cells, HH, and Molt-3 T-lymphocytes) was developed. Modified Boyden chamber assays were used to test the ability of prostate stromal and epithelial cells to attract leukocytes and to test the effect of leukocytes on prostate cellular proliferation. Antibody arrays were used to identify leukocyte-secreted cytokines mediating prostate cellular proliferation.
RESULTS
Leukocytic cells migrated towards both prostate stromal and epithelial cells. CD4+ T-lymphocytes promoted the proliferation of both transformed and non-transformed prostate epithelial cell lines tested, whereas CD8+ T-lymphocytes as well as dHL-60M macrophagic and dHL-60N neutrophilic cells selectively promoted the proliferation of PCa cells.
CONCLUSIONS
The results of these studies show that inflammatory cells can be attracted to the prostate tissue microenvironment and can selectively promote the proliferation of non-transformed or transformed prostate epithelial cells, and are consistent with differential role(s) for inflammatory infiltrate in the etiologies of benign and malignant proliferative disease in the prostate.
doi:10.1002/pros.21071
PMCID: PMC3167472  PMID: 19866464
BPH; PCa; immune; inflammatory infiltrate; chemokine; microenvironment
9.  Immunohistochemical Staining of Slit2 in Primary and Metastatic Prostatic Adenocarcinoma1 
Translational Oncology  2011;4(5):314-320.
BACKGROUND: Conflicting roles for Slit2, a protein involved in mediating the processes of cell migration and chemotactic response, have been previously described in prostate cancer. Here we use immunohistochemistry to evaluate the expression of Slit2 in normal donor prostate (NDP), benign prostatic hyperplasia (BPH), high-grade prostatic intraepithelial neoplasia (HGPIN), normal tissue adjacent to prostatic adenocarcinoma (NAC), primary prostatic adenocarcinoma (PCa), and metastatic prostatic adenocarcinoma (Mets). METHODS: Tissue microarrays were immunostained for Slit2. The staining intensities were quantified using automated image analysis software. The data was statistically analyzed using one-way analysis of variance with subsequent Tukey tests for multiple comparisons or a nonparametric equivalent. Eleven cases of NDP, 35 cases of NAC, 15 cases of BPH, 35 cases of HGPIN, 106 cases of PCa, and 37 cases of Mets were analyzed. RESULTS: Specimens of PCa and HGPIN had the highest absolute staining for Slit2. Significant differences were seen between PCa and NDP (P < .05), PCa and NAC (P < .05), HGPIN and NDP (P < .05), and HGPIN and NAC (P < .05). Whereas the average Mets staining was not significantly different from NDP or NAC, several individual Mets cases featured intense staining. CONCLUSIONS: To our knowledge, this represents the first study comparing the immunohistochemical profiles of Slit2 in PCa and Mets to specimens of HGPIN, BPH, NDP, and NAC. These findings suggest that Slit2 expression can be increased in HGPIN, PCa, and Mets, making it a potentially important biomarker for prostate cancer.
PMCID: PMC3162306  PMID: 21966548
10.  Primary Cilia Are Lost in Preinvasive and Invasive Prostate Cancer 
PLoS ONE  2013;8(7):e68521.
Prostate cancer is the second most commonly diagnosed cancer in men worldwide. Little is known about the role of primary cilia in preinvasive and invasive prostate cancer. However, reduced cilia expression has been observed in human cancers including pancreatic cancer, renal cell carcinoma, breast cancer, cholangiocarcinoma, and melanoma. The aim of this study was to characterize primary cilia expression in preinvasive and invasive human prostate cancer, and to investigate the correlation between primary cilia and the Wnt signaling pathway. Human prostate tissues representative of stages of prostate cancer formation (normal prostate, prostatic intraepithelial neoplasia (PIN), and invasive prostate cancer (including perineural invasion)) were stained for ciliary proteins. The frequency of primary cilia was determined. A decrease in the percentage of ciliated cells in PIN, invasive cancer and perineural invasion lesions was observed when compared to normal. Cilia lengths were also measured to indirectly test functionality. Cilia were shorter in PIN, cancer, and perineural invasion lesions, suggesting dysfunction. Primary cilia have been shown to suppress the Wnt pathway. Increased Wnt signaling has been implicated in prostate cancer. Therefore, we investigated a correlation between loss of primary cilia and increased Wnt signaling in normal prostate and in preinvasive and invasive prostate cancer. To investigate Wnt signaling in our cohort, serial tissue sections were stained for β-catenin as a measure of Wnt signaling. Nuclear β-catenin was analyzed and Wnt signaling was found to be higher in un-ciliated cells in the normal prostate, PIN, a subset of invasive cancers, and perineural invasion. Our results suggest that cilia normally function to suppress the Wnt signaling pathway in epithelial cells and that cilia loss may play a role in increased Wnt signaling in some prostate cancers. These results suggest that cilia are dysfunctional in human prostate cancer, and increase Wnt signaling occurs in a subset of cancers.
doi:10.1371/journal.pone.0068521
PMCID: PMC3699526  PMID: 23844214
11.  Prostate stem cell antigen (PSCA) expression in human prostate cancer tissues and its potential role in prostate carcinogenesis and progression of prostate cancer 
Background
Prostate stem cell antigen (PSCA) is a recently defined homologue of the Thy-1/Ly-6 family of glycosylphosphatidylinositol (GPI)-anchored cell surface antigens. The purpose of the present study was to examine the expression status of PSCA protein and mRNA in clinical specimens of human prostate cancer (Pca) and to validate it as a potential molecular target for diagnosis and treatment of Pca.
Materials and Methods
Immunohistochemical (IHC) and in situ hybridization (ISH) analyses of PSCA expression were simultaneously performed on paraffin-embedded sections from 20 benign prostatic hyperplasia (BPH), 20 prostatic intraepithelial neoplasm (PIN) and 48 prostate cancer (Pca) tissues, including 9 androgen-independent prostate cancers. The level of PSCA expression was semiquantitatively scored by assessing both the percentage and intensity of PSCA-positive staining cells in the specimens. Then compared PSCA expression between BPH, PIN and Pca tissues and analysed the correlations of PSCA expression level with pathological grade, clinical stage and progression to androgen-independence in Pca.
Results
In BPH and low grade PIN, PSCA protein and mRNA staining were weak or negative and less intense and uniform than that seen in HGPIN and Pca. There were moderate to strong PSCA protein and mRNA expression in 8 of 11 (72.7%) HGPIN and in 40 of 48 (83.4%) Pca specimens examined by IHC and ISH analyses, with statistical significance compared with BPH (20%) and low grade PIN (22.2%) samples (p < 0.05, respectively). The expression level of PSCA increased with high Gleason grade, advanced stage and progression to androgen-independence (p < 0.05, respectively). In addition, IHC and ISH staining showed a high degree of correlation between PSCA protein and mRNA overexpression.
Conclusions
Our data demonstrate that PSCA as a new cell surface marker is overexpressed by a majority of human Pca. PSCA expression correlates positively with adverse tumor characteristics, such as increasing pathological grade (poor cell differentiation), worsening clinical stage and androgen-independence, and speculatively with prostate carcinogenesis. PSCA protein overexpression results from upregulated transcription of PSCA mRNA. PSCA may have prognostic utility and may be a promising molecular target for diagnosis and treatment of Pca.
doi:10.1186/1477-7819-2-13
PMCID: PMC420493  PMID: 15132743
Prostate; Neoplasm; Prostate stem cell antigen (PSCA)
12.  Role of the TMPRSS2-ERG Gene Fusion in Prostate Cancer123 
Neoplasia (New York, N.Y.)  2008;10(2):177-188.
TMPRSS2-ERG gene fusions are the predominant molecular subtype of prostate cancer. Here, we explored the role of TMPRSS2-ERG gene fusion product using in vitro and in vivo model systems. Transgenic mice expressing the ERG gene fusion product under androgen-regulation develop mouse prostatic intraepithelial neoplasia (PIN), a precursor lesion of prostate cancer. Introduction of the ERG gene fusion product into primary or immortalized benign prostate epithelial cells induced an invasion-associated transcriptional program but did not increase cellular proliferation or anchorage-independent growth. These results suggest that TMPRSS2-ERG may not be sufficient for transformation in the absence of secondary molecular lesions. Transcriptional profiling of ERG knockdown in the TMPPRSS2-ERG-positive prostate cancer cell line VCaP revealed decreased expression of genes over-expressed in prostate cancer versus PIN and genes overexpressed in ETS-positive versus -negative prostate cancers in addition to inhibiting invasion. ERG knockdown in VCaP cells also induced a transcriptional program consistent with prostate differentiation. Importantly, VCaP cells and benign prostate cells overexpressing ERG directly engage components of the plasminogen activation pathway to mediate cellular invasion, potentially representing a downstream ETS target susceptible to therapeutic intervention. Our results support previous work suggesting that TMPRSS2-ERG fusions mediate invasion, consistent with the defining histologic distinction between PIN and prostate cancer.
PMCID: PMC2244693  PMID: 18283340
13.  Immunohistochemical staining of radixin and moesin in prostatic adenocarcinoma 
Background
Some members of the Protein 4.1 superfamily are believed to be involved in cell proliferation and growth, or in the regulation of these processes. While the expression levels of two members of this family, radixin and moesin, have been studied in many tumor types, to our knowledge they have not been investigated in prostate cancer.
Methods
Tissue microarrays were immunohistochemically stained for either radixin or moesin, with the staining intensities subsequently quantified and statistically analyzed using One-Way ANOVA or nonparametric equivalent with subsequent Student-Newman-Keuls tests for multiple comparisons. There were 11 cases of normal donor prostates (NDP), 14 cases of benign prostatic hyperplasia (BPH), 23 cases of high-grade prostatic intraepithelial neoplasia (HGPIN), 88 cases of prostatic adenocarcinoma (PCa), and 25 cases of normal tissue adjacent to adenocarcinoma (NAC) analyzed in the microarrays.
Results
NDP, BPH, and HGPIN had higher absolute staining scores for radixin than PCa and NAC, but with a significant difference observed between only HGPIN and PCa (p = < 0.001) and HGPIN and NAC (p = 0.001). In the moesin-stained specimens, PCa, NAC, HGPIN, and BPH all received absolute higher staining scores than NDP, but the differences were not significant. Stage 4 moesin-stained PCa had a significantly reduced staining intensity compared to Stage 2 (p = 0.003).
Conclusions
To our knowledge, these studies represent the first reports on the expression profiles of radixin and moesin in prostatic adenocarcinoma. The current study has shown that there were statistically significant differences observed between HGPIN and PCa and HGPIN and NAC in terms of radixin expression. The differences in the moesin profiles by tissue type were not statistically significant. Additional larger studies with these markers may further elucidate their potential roles in prostatic neoplasia progression.
doi:10.1186/1472-6890-11-1
PMCID: PMC3029218  PMID: 21235778
14.  Morphological identification of the patterns of prostatic intraepithelial neoplasia and their importance 
Journal of Clinical Pathology  2000;53(9):655-665.
High grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of prostatic carcinoma. PIN has a high predictive value as a marker for carcinoma, and its identification in biopsy specimens warrants repeat biopsy for concurrent or subsequent carcinoma. The only methods of detection are biopsy and transurethral resection; PIN does not greatly raise the concentration of serum prostate specific antigen (PSA) or its derivatives, does not induce a palpable mass, and cannot be detected by ultrasound. Androgen deprivation decreases the prevalence and extent of PIN, suggesting that this form of treatment might play a role in chemoprevention. Radiotherapy is also associated with a decreased incidence of PIN.
Key Words: prostate • prostatic intraepithelial neoplasia • intraductal dysplasia • intraductal carcinoma • atypical adenomatous hyperplasia • prostatic adenocarcinoma • chemoprevention
doi:10.1136/jcp.53.9.655
PMCID: PMC1731241  PMID: 11041054
15.  Interleukin-6 and oncostatin-M synergize with the PI3K/AKT pathway to promote aggressive prostate malignancy in mouse and human tissues 
Molecular cancer research : MCR  2013;11(10):1159-1165.
Chronic inflammation has been proposed as an etiological and progression factor in prostate cancer. In this study, we used a dissociated prostate tissue recombination system to interrogate the role of interleukin 6 (IL6) and the related cytokine oncostatin M (OSM) in the initiation and progression of prostate cancer. We identified that prostatic intraepithelial neoplasia (PIN) lesions induced by PTEN loss of function (PTENLOF) progress to invasive adenocarcinoma following paracrine expression of either cytokine. Increased expression of OSM was also able to drive progression of benign human epithelium when combined with constitutively activated AKT. Malignant progression in the mouse was associated with invasion into the surrounding mesenchyme and increased activation of STAT3 in PTENLOF grafts expressing IL6 or OSM. Collectively, our work indicates that pro-inflammatory cytokines such as IL6 or OSM could activate pathways associated with prostate cancer progression and synergize with cell autonomous oncogenic events to promote aggressive malignancy.
doi:10.1158/1541-7786.MCR-13-0238
PMCID: PMC3800471  PMID: 23867565
Prostate carcinoma; PTEN; AKT; Interleukin 6; Oncostatin M
16.  Sex steroid receptor expression and localization in benign prostatic hyperplasia varies with tissue compartment 
Androgens and estrogens, acting via their respective receptors, are important in benign prostatic hyperplasia (BPH). The goal of this study was to quantitatively characterize the tissue distribution and staining intensity of androgen receptor (AR) and estrogen receptor-alpha (ERα), and assess cells expressing both AR and ERα, in human BPH compared to normal prostate. A tissue microarray composed of normal prostate and BPH tissue was used and multiplexed immunohistochemistry was performed to detect AR and ERα. We used a multispectral imaging platform for automated scanning, tissue and cell segmentation and marker quantification. BPH specimens had an increased number of epithelial and stromal cells and increased percentage of epithelium. In both stroma and epithelium, the mean nuclear area was decreased in BPH relative to normal prostate. AR expression and staining intensity in epithelial and stromal cells was significantly increased in BPH compared to normal prostate. ERα expression was increased in BPH epithelium. However, stromal ERα expression and staining intensity was decreased in BPH compared to normal prostate. Double positive (AR & ERα) epithelial cells were more prevalent in BPH, and fewer double negative (AR & ERα) stromal and epithelial negative cells were observed in BPH. These data underscore the importance of tissue layer localization and expression of steroid hormone receptors in the prostate. Understanding the tissue-specific hormone action of androgens and estrogens will lead to a better understanding of mechanisms of pathogenesis in the prostate and may lead to better treatment for BPH.
doi:10.1016/j.diff.2013.02.006
PMCID: PMC3729928  PMID: 23792768
Benign Prostatic Hyperplasia; Androgen Receptor; Estrogen Receptor alpha
17.  Immunohistochemical analysis of ezrin-radixin-moesin-binding phosphoprotein 50 in prostatic adenocarcinoma 
BMC Urology  2011;11:12.
Background
Ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is an adapter protein which has been shown to play an active role in a wide variety of cellular processes, including interactions with proteins related to both tumor suppression and oncogenesis. Here we use immunohistochemistry to evaluate EBP50's expression in normal donor prostate (NDP), benign prostatic hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN), normal tissue adjacent to prostatic adenocarcinoma (NAC), primary prostatic adenocarcinoma (PCa), and metastatic prostatic adenocarcinoma (Mets).
Methods
Tissue microarrays were immunohistochemically stained for EBP50, with the staining intensities quantified using automated image analysis software. The data were statistically analyzed using one-way ANOVA with subsequent Tukey tests for multiple comparisons. Eleven cases of NDP, 37 cases of NAC, 15 cases of BPH, 35 cases of HGPIN, 103 cases of PCa, and 36 cases of Mets were analyzed in the microarrays.
Results
Specimens of PCa and Mets had the lowest absolute staining for EBP50. Mets staining was significantly lower than NDP (p = 0.027), BPH (p = 0.012), NAC (p < 0.001), HGPIN (p < 0.001), and PCa (p = 0.006). Additionally, HGPIN staining was significantly higher than NAC (p < 0.009) and PCa (p < 0.001).
Conclusions
To our knowledge, this represents the first study comparing the immunohistochemical profiles of EBP50 in PCa and Mets to specimens of HGPIN, BPH, NDP, and NAC and suggests that EBP50 expression is decreased in Mets. Given that PCa also had significantly higher expression than Mets, future studies are warranted to assess EBP50's potential as a prognostic biomarker for prostate cancer.
doi:10.1186/1471-2490-11-12
PMCID: PMC3132203  PMID: 21672215
18.  Prognostic relevance of Tiam1 protein expression in prostate carcinomas 
British Journal of Cancer  2006;95(8):1081-1086.
The Rac-specific guanine nucleotide exchange factor, Tiam1, plays a major role in oncogenicity, tumour invasion and metastasis but its usefulness as a prognostic marker in human cancer has not been tested yet. In the present study, Tiam1 expression was analysed in benign secretory epithelium, pre-neoplastic high-grade prostatic intraepithelium neoplasia (HG-PIN) and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochemistry. Tiam1 proved significantly overexpressed in both HG-PIN (P<0.001) and prostate carcinomas (P<0.001) when compared to benign secretory epithelium. Strong Tiam1 overexpression (i.e. ⩾3.5-fold) in prostate carcinomas relative to the respective benign prostatic epithelium was statistically significantly associated with disease recurrence (P=0.016), the presence of lymph vessel invasion (P=0.031) and high Gleason scores (GS) (i.e. ⩾7) (P=0.044). Univariate analysis showed a statistically significant association of strong Tiam1 overexpression with decreased disease-free survival (DFS) (P=0.03). This prognostic effect of strong Tiam1 overexpression remained significant in multivariate analysis including preoperative prostate-specific antigen levels, pT stage, and GS (relative risk= 3.75, 95% confidence interval=1.06–13.16; P=0.04). Together, our data suggest that strong Tiam1 overexpression relative to the corresponding benign epithelial cells is a new and independent predictor of decreased DFS for patients with prostate cancer.
doi:10.1038/sj.bjc.6603385
PMCID: PMC2360703  PMID: 17003780
Tiam1; Rac; prognosis; prostate cancer; proliferation
19.  Transgenic overexpression of PKCε in the mouse prostate induces preneoplastic lesions 
Cell Cycle  2011;10(2):268-277.
It is well established that protein kinase C (PKC) isozymes play distinctive roles in mitogenic and survival signaling as well as in cancer progression. PKCε, the product of the PRKCE gene, is upregulated in various types of cancers including prostate, lung and breast cancer. To address a potential role for PKCs in prostate cancer progression we generated three mouse transgenic lines expressing PKCα, PKCδ or PKCε in the prostate epithelium under the control of the rat probasin (PB) promoter. Whereas PB-PKCα and PB-PKCδ mice did not show any evident phenotype, PB-PKCε mice developed prostate hyperplasia as well as prostate intraepithelial neoplasia (PIN) that displayed enhanced phospho-Akt, phospho-S6 and phospho-Stat3 levels, as well as enhanced resistance to apoptotic stimuli. PKCε overexpression was insufficient to drive neoplastic changes in the mouse prostate. Notably, overexpression of PKCε by adenoviral means in normal immortalized RWPE-1 prostate cells confers a growth advantage and hyperactivation of Erk and Akt. Our results argue for a causal link between PKCε overexpression and prostate cancer development.
doi:10.4161/cc.10.2.14469
PMCID: PMC3048798  PMID: 21224724
PKCε; transgenic mice; prostate; preneoplastic lesions; cell survival; Akt
20.  Zinc status of patients with benign prostatic hyperplasia and prostate carcinoma 
Objectives:
The exact cause of benign prostatic hyperplasia (BPH) and prostatic carcinoma is unknown. Changes in the level of the trace element zinc (Zn) are known to be associated with the functioning of different organs (breast, colon, stomach, liver, kidney, prostate, and muscle). This study is aimed at estimating and comparing the zinc levels in the prostate tissue, plasma, and urine obtained from patients diagnosed with BPH or prostatic carcinoma.
Materials and Methods:
The prostate tissue zinc, plasma zinc, and urine zinc/creatinine ratio in BPH, prostate cancer, and normal subjects were measured by atomic absorption spectrophotometry.
Results:
In prostate carcinoma, the mean tissue zinc was decreased by 83% as compared to normal tissue and in BPH, there was a 61% decrease in mean tissue zinc as compared to normal tissues. Both these values were statistically significant. The plasma zinc in prostate cancer patients showed a 27% decrease (P < 0.01) as compared to controls and 18% decrease (P < 0.01) as compared to BPH. The urine zinc/creatinine (ratio) was significantly increased to 53% in prostate cancer patients, and a 20% significant increase was observed in BPH as compared to normal subjects.
Conclusions:
It is evident from this study that BPH or prostate carcinoma may be associated with a reduction in the levels of tissue zinc, plasma zinc, and an increase in urine zinc/creatinine.
doi:10.4103/0970-1591.78405
PMCID: PMC3114577  PMID: 21716879
Benign prostatic hyperplasia; plasma zinc; prostate cancer; tissue zinc; urine zinc/creatinine
21.  The Effects of Aging on the Molecular and Cellular Composition of the Prostate Microenvironment 
PLoS ONE  2010;5(9):e12501.
Background
Advancing age is associated with substantial increases in the incidence rates of common diseases affecting the prostate gland including benign prostatic hyperplasia (BPH) and prostate carcinoma. The prostate is comprised of a functional secretory epithelium, a basal epithelium, and a supporting stroma comprised of structural elements, and a spectrum of cell types that includes smooth muscle cells, fibroblasts, and inflammatory cells. As reciprocal interactions between epithelium and stromal constituents are essential for normal organogenesis and serve to maintain normal functions, discordance within the stroma could permit or promote disease processes. In this study we sought to identify aging-associated alterations in the mouse prostate microenvironment that could influence pathology.
Methodology/Principal Findings
We quantitated transcript levels in microdissected glandular-adjacent stroma from young (age 4 months) and old (age 20–24 months) C57BL/6 mice, and identified a significant change in the expression of 1259 genes (p<0.05). These included increases in transcripts encoding proteins associated with inflammation (e.g., Ccl8, Ccl12), genotoxic/oxidative stress (e.g., Apod, Serpinb5) and other paracrine-acting effects (e.g., Cyr61). The expression of several collagen genes (e.g., Col1a1 and Col3a1) exhibited age-associated declines. By histology, immunofluorescence, and electron microscopy we determined that the collagen matrix is abundant and disorganized, smooth muscle cell orientation is disordered, and inflammatory infiltrates are significantly increased, and are comprised of macrophages, T cells and, to a lesser extent, B cells.
Conclusion/Significance
These findings demonstrate that during normal aging the prostate stroma exhibits phenotypic and molecular characteristics plausibly contributing to the striking age associated pathologies affecting the prostate.
doi:10.1371/journal.pone.0012501
PMCID: PMC2931699  PMID: 20824135
22.  Loss of stromal androgen receptor leads to suppressed prostate tumourigenesis via modulation of pro-inflammatory cytokines/chemokines 
EMBO Molecular Medicine  2012;4(8):791-807.
Stromal–epithelial interaction is crucial to mediate normal prostate and prostate cancer (PCa) development. The indispensable roles of mesenchymal/stromal androgen receptor (AR) for the prostate organogenesis have been demonstrated by using tissue recombination from wild-type and testicular feminized mice. However, the stromal AR functions in the tumour microenvironment and the underlying mechanisms governing the interactions between the epithelium and stroma are not completely understood. Here, we have established the first animal model with AR deletion in stromal fibromuscular cells (dARKO, AR knockout in fibroblasts and smooth muscle cells) in the Pten+/− mouse model that can spontaneously develop prostatic intraepithelial neoplasia (PIN). We found that loss of stromal fibromuscular AR led to suppression of PIN lesion development with alleviation of epithelium proliferation and tumour-promoting microenvironments, including extracellular matrix (ECM) remodelling, immune cell infiltration and neovasculature formation due, in part, to the modulation of pro-inflammatory cytokines/chemokines. Finally, targeting stromal fibromuscular AR with the AR degradation enhancer, ASC-J9®, resulted in the reduction of PIN development/progression, which might provide a new approach to suppress PIN development.
doi:10.1002/emmm.201101140
PMCID: PMC3494077  PMID: 22745041
androgen receptor; PIN; prostate stroma; PTEN; tumour microenvironment
23.  Periostin: a promising target of therapeutical intervention for prostate cancer 
Background
In our recent study, Periostin was up-regulated in prostate cancer(PCa) compared with benign prostate hyperplasia (BPH) by proteomics analysis of prostate biopsies. We investigated the effect of sliencing Periostin by RNA interference (RNAi) on the proliferation and migration of PCa LNCap cell line.
Methods
All the prostate biopsies from PCa, BPH and BPH with local prostatic intraepithelial neoplasm(PIN) were analyzed by iTRAQ(Isobaric tags for relative and absolute quantification) technology. Western blotting and immunohistochemical staining were used to verify Periostin expression in the tissues of PCa. Periostin expression in different PCa cell lines was determined by immunofluorescence staining, western blotting and reverse transcription PCR(RT-PCR). The LNCap cells with Periostin expression were used for transfecting shRNA-Periostin lentiviral particles. The efficancy of transfecting shRNA lentiviral particles was evaluated by immunofluorescence, western blotting and Real-time PCR. The effect of silencing Periostin expression by RNAi on proliferation of LNCap cells was determined by MTT assay and tumor xenografts. The tissue slices from theses xenografts were analyzed by hematoxylin and eosin(HE) staining. The expression of Periostin in the xenografts was deteminned by Immunohistochemical staining and western blotting. The migration of LNCap cells after silencing Periostin gene expression were analyzed in vitro.
Results
Periostin as the protein of interest was shown 9.12 fold up-regulation in PCa compared with BPH. The overexpression of Periostin in the stroma of PCa was confirmed by western blotting and immunohistochemical staining. Periostin was only expressed in PCa LNCap cell line. Our results indicated that the transfection ratio was more than 90%. As was expected, both the protein level and mRNA level of Periostin in the stably expressing shRNA-Periostin LNCap cells were significantly reduced. The stably expressing shRNA-Periostin LNCap cells growed slowly in vitro and in vivo. The tissues of xenografts as PCa were verificated by HE staining. Additionally, the weak positive Periostin expressed tumor cells could be seen in the tissues of 6 xenografts from the group of down-regulated Periostin LNCap cells which had a significant decrease of the amount of Periostin compared to the other two group. Furthermore, our results demonstrated that sliencing Periostin could inhibit migration of LNCap cells in vitro.
Conclusions
Our data indicates that Periostin as an up-regulated protein in PCa may be a promising target of therapeutical intervention for PCa in future.
doi:10.1186/1479-5876-9-99
PMCID: PMC3146429  PMID: 21714934
Periostin; Prostate cancer; RNAi; Proliferation; Migration
24.  Serum CXCL13 positively correlates with prostatic disease, prostate-specific antigen and mediates prostate cancer cell invasion, integrin clustering and cell adhesion 
Cancer letters  2009;283(1):29-35.
Chemokines and corresponding receptor interactions have been shown to be involved in prostate cancer (PCa) progression and organ-specific metastasis. We have recently shown that PCa cell lines and primary prostate tumors express CXCR5, which correlates with PCa grade. In this study, we present the first evidence that CXCL13, the only ligand for CXCR5, and IL-6 were significantly elevated in PCa patient serum compared to serum from subjects with benign prostatic hyperplasia (BPH), or high-grade prostatic intraepithelial neoplasia (HGPIN) as well as normal healthy donors (NHD). Serum CXCL13 levels significantly (p < 0.0001) correlated with serum prostate-specific antigen (PSA), whereas serum IL-6 levels significantly (p < 0.0003) correlated with CXCL13 serum levels. CXCL13 was found to be a better predictor of PCa than PSA. In addition, CXCL13 was highly expressed by human bone marrow endothelial (HBME) cells and osteoblasts (OBs), but not osteoclasts (OCs), following treatment with physiologically relevant levels of interleukin-6 (IL-6). We further demonstrate that CXCL13, produced by IL-6-treated HBME cells, was able to induce PCa cell invasion in a CXCR5-dependent manner. CXCL13-mediated PCa cell αvβ3-integrin clustering and adhesion to HBME cells was abrogated by CXCR5 blockade. These results demonstrate that the CXCL13-CXCR5 axis is significantly associated with PCa progression.
doi:10.1016/j.canlet.2009.03.022
PMCID: PMC3600557  PMID: 19375853
chemokine; prostate; integrin; adhesion; invasion
25.  Metallothionein isoform II expression in hyperplastic, dysplastic and neoplastic prostatic lesions 
Journal of Clinical Pathology  2006;59(11):1171-1174.
Background
Metallothionein is a low‐molecular‐weight cysteine‐rich protein that has the ability to bind and sequestrate heavy metal ions. It is associated with metalloregulatory functions such as cell proliferation, growth and differentiation.
Aims
To investigate the expression of metallothionein in hyperplastic, dysplastic and neoplastic prostatic lesions and to correlate its expression with histological grade of prostatic carcinoma.
Method
The study was carried out on formalin‐fixed and paraffin‐wax‐embedded tissue blocks from 8 patients with benign prostatic hyperplasia, 6 patients with prostatic intraepithelial neoplasia (PIN) and 30 patients with prostatic carcinoma, using the streptavidin–biotin technique. The histological grade was defined and the carcinomas were divided into low‐grade (Gleason Score 2–4), 12 moderate grade (Gleason Score 5–6) and 10 high‐grade (Gleason Score 7–10) carcinomas.
Results
Patchy metallothionein staining of epithelial cells was observed in normal and benign prostatic tissues. All cases of PIN and 20 of 30 patients with prostatic carcinoma showed positive staining for metallothionein. Metallothionein expression considerably increased from low‐grade to high‐grade tumours. The proportion of cells staining positively for metallothionein was directly correlated with histological grade of prostatic carcinoma. The epithelial cells lack uniformity in staining intensity, but the percentage of strongly positive cells increased with the histological grade of prostatic carcinoma.
Conclusions
The high incidence of metallothionein expression in PIN in our study suggests that it is associated with early prostate tumorigenesis. Also, metallothionein expression was directly correlated with the histological grade of prostatic carcinoma, suggesting that metallothionein may be a useful marker for predicting the prognosis of prostate cancer.
doi:10.1136/jcp.2005.033746
PMCID: PMC1860510  PMID: 16574721

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