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Results for “Prostatic Intraepithelial Neoplasia”

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PubMed2000

p53 mutations in prostatic intraepithelial neoplasia and concurrent carcinoma: analysis of laser capture microdissected specimens from non-transition and transition zones.

Prostatic intraepithelial neoplasia (PIN) is characterized by intraluminal proliferation of epithelial cells and is divided into high-grade (HGPIN) and low-grade (LGPIN) lesions. HGPIN is regarded as the most likely precursor of prostatic cancer (PCA). Microdissected DNA selectively extracted from paraffin-embedded sections of 27 cases with PCA were analyzed for p53 mutation in exons 5 - 8 by single-strand conformation polymorphism of polymerase chain reaction-amplified DNA fragments (PCR-SSCP) followed by direct sequencing. These patients received total prostatectomy (27 cases). After a review of histologic sections, DNA was extracted from 193 locations; 111 lesions from 27 cases with HGPIN (75 lesions from non-transition zone and 36 from transition zone), 55 lesions from 27 cases with PCA (30 lesions from non-transition zone and 25 from transition zone), and 27 from 27 benign glands. Analysis revealed 27 mutations of the p53 gene in 24 lesions from 12 cases. Benign glands adjoining PIN and / or PCA had no mutations. All mutations were point mutations: 17 missense, 7 silent, and 2 nonsense. Mutations were detected in 6 cases (22.2%) or 13 of 111 lesions (11.7%) with HGPIN and 8 cases (29.6%) or 11 of 55 lesions (20.0%) with PCA. In a given case, HGPIN and PCA lesions had different p53 mutations from each other, suggesting multiclonal development of prostatic precancerous lesions. The frequency of p53 mutation of PCA was significantly higher in the non-transition zone (33.3%) than in the transition zone (4%), and higher in the stage T3 cases (30.3%) than in the stage T2 cases (4.5%, 1 of 22 lesions) (both P < 0.05). Frequency of p53 mutation of PIN in the non-transition zone (14.7%) was higher than that in the transition zone (5.6%), although the difference was not significant. The frequency rate of p53 mutation in HGPIN close to PCA ( </= 2 mm) was significantly higher (24%) than that in HGPIN lesions > 2 mm from PCA (3%). All these findings indicate that the p53 gene mutations are involved in prostatic carcinogenesis and explain why the non-transition zone is the predominant site of PCA.

Genes, p53↗

PubMed1998

Statistical histometry of the basal cell/secretory cell bilayer in prostatic intraepithelial neoplasia.

OBJECTIVE: To delineate the sampling requirements for a histometric assessment of progression in low grade and high grade prostatic intraepithelial neoplasia (PIN) lesions. STUDY DESIGN: Images of whole glands from normal prostates, low grade PIN lesions and high grade PIN lesions were digitized. The images were processed by a machine vision system and automatically segmented, and a number of histometric characteristics descriptive of the disruption of the basal cell layer were extracted. Next, high-resolution images of secretory cell nuclei still facing or no longer facing intact segments of the basal cell layer were recorded and karyometrically analyzed. RESULTS: For the characterization of an individual lesion a minimum of 20-30 glands should be analyzed to provide an estimate of a progression index. Then, a change in progression, or due to regression, of approximately 16% can be documented. The disruption of the basal cell layer is accompanied by statistically highly significant changes in the chromatin texture and spatial distribution in secretory cell nuclei no longer facing an intact segment of that layer. CONCLUSION: Automated histometry by machine vision can provide valuable quantitative data for diagnostic assessment and for monitoring the efficacy of chemopreventive treatment.

Analysis of Variance↗

PubMed2006

Cytological features of prostatic intraepithelial neoplasia.

Fine-needle aspiration cytology (FNAC) is an acknowledged method for diagnosing prostate cancer. False-positive results are uncommon, but concerns have been raised that prostatic intraepithelial neoplasia (PIN) could be misinterpreted as carcinoma. Therefore, we attempted to describe cytological features of PIN. Cells were scraped from macroscopically normal areas of 177 radical prostatectomy specimens, smeared and Giemsa-stained. Histological slides from these areas were reviewed, and 17 samples with high-grade PIN and with no invasive cancer were selected. Smears from 17 invasive cancers were used for comparison. Cancer showed high cellularity and dissociation, while PIN smears only contained a few clusters of atypical cells. Pronounced nuclear atypia, prominent or multiple nucleoli and mucin were more common in cancer, while cytoplasmic granules, crystalloids and cluster size did not distinguish between PIN and cancer. In conclusion, PIN should not be diagnosed by FNAC alone. However, a highly cellular smear with pronounced atypia seems to preclude PIN.

Adenocarcinoma↗

PubMed2005

Decreased annexin I expression in prostatic adenocarcinoma and in high-grade prostatic intraepithelial neoplasia.

AIMS: To analyse annexin I expression in prostatic carcinoma. Annexin I belongs to a family of structurally related calcium and phospholipid-binding proteins implicated in signal transduction, DNA replication, cell proliferation and apoptosis. The decreased expression of annexin I, II and VII proteins has been reported in different types of cancer. METHODS AND RESULTS: Using immunohistochemistry, we analysed annexin I expression in 77 cases of prostatic adenocarcinoma (Gleason score 6, N = 40; Gleason scores 7-8, N = 27; and Gleason scores 9-10, N = 10) and high-grade prostatic intraepithelial neoplasia (PIN, N = 50). Immunoreactivity of annexin I in tumour cells was evaluated as negative (< 5% of cells), focally positive (5-25% of cells) or positive (> 25% of cells). In contrast to positive staining in adjacent benign prostatic epithelium, annexin I expression was decreased (focally positive) in 76% of cases of high-grade PIN (P < 0.0001) and was decreased or absent in 81% of prostatic adenocarcinomas (P < 0.0001). Annexin I expression in all higher grade tumours (Gleason scores 7-10) was only focally positive or absent. CONCLUSIONS: Expression of annexin I inversely correlates with the increasing histological grade of prostatic adenocarcinoma. By showing a progressive loss of annexin I expression in high-grade PIN, intermediate-grade and high-grade cancer, our findings suggest that the loss of annexin I expression occurs early in prostatic tumorigenesis and becomes more prominent throughout tumour progression. The loss of expression of annexin I may serve as a useful marker of prostate cancer development and progression.

Adenocarcinoma↗

PubMed1995

Prostatic intraepithelial neoplasia and well differentiated adenocarcinoma maintain an intact basement membrane.

The status of the basement membrane in prostatic intraepithelial neoplasia (PIN) and adenocarcinoma is unsettled. Previous studies using antibodies directed against Type IV collagen have been hindered by intense staining around the stromal smooth muscle fibers, making interpretation of acinar staining difficult. We employed a monoclonal antibody to heparan sulfate proteoglycan (HSPG) to overcome this problem, recognizing that HSPG is present in the basement membrane of epithelial and endothelial cells, but not stromal smooth muscle cells. In 22 totally-embedded whole mount radical prostatectomies for adenocarcinoma which contained PIN, intense HSPG immunoreactivity was observed in the basement membrane of all normal and hyperplastic acini, 98% of acini with high grade PIN, and 100% of acini of well differentiated (Gleason score 5) adenocarcinoma; vessels served as the internal positive control, with consistent staining throughout each specimen. The extent of HSPG immunoreactivity in cancer decreased with increasing Gleason grade (measured as percent of acini staining, in 10% increments; p = 0.002). These findings indicate that HSPG is a consistent component of the basement membrane of benign, hyperplastic, and early neoplastic prostatic acini, and, unlike other extracellular matrix proteins such as type IV collagen, is not hindered by background staining around stromal smooth muscle cells. High grade PIN and well differentiated adenocarcinoma usually maintain an intact basement membrane, and loss of the basement membrane occurs with histologic dedifferentiation.

Adenocarcinoma↗

PubMed2004

Analysis of alpha-methylacyl-CoA racemase (P504S) expression in high-grade prostatic intraepithelial neoplasia.

Alpha-methylacyl-CoA racemase (AMACR), also known as P504S, is a recently identified molecular marker for prostate cancer. The expression of AMACR/P504S has also been observed in high-grade prostatic intraepithelial neoplasia (PIN), a precursor lesion of prostate cancer. However, a detailed study focusing on the analysis of AMACR/P504S expression in high-grade PIN has not been performed. In this study, we analyzed AMACR/P504S expression by immunohistochemistry in 3954 prostatic ducts and acini with high-grade PIN from 140 prostatectomy specimens. AMACR/P504S immunoreactivity was measured as negative (0), weakly positive (+1), moderately positive (+2), and strongly positive (+3). AMACR/P504S immunoreactivity was detected in 90.0% (126/140) of high-grade PIN cases, although only 41.5% (1642/3954) of prostatic glands involved by PIN showed AMACR/P504S immunoreactivity. A significantly higher AMACR/P504S-positive rate (56.0%) was found in isolated high-grade PIN glands adjacent to cancer (distance less than 5 mm) compared with those away from cancer (distance more than 5 mm; 14%, P < 0.0001). High-grade PIN glands adjacent to cancer also showed a higher (P < 0.0004) AMACR/P504S intensity (1.62) than did those away from cancer (1.11). Our results suggest that PIN strongly positive for AMACR/P504S might be more closely associated with cancer than PIN negative or weakly positive for AMACR/P504S. This study provides additional evidence to link high-grade PIN as a precursor lesion to prostatic adenocarcinoma.

Adenocarcinoma↗

PubMed2003

Prevalence of prostate cancer and prostatic intraepithelial neoplasia in Caucasian Mediterranean males: an autopsy study.

BACKGROUND: The prevalence of carcinoma of the prostate gland (CaP) and high-grade prostatic intraepithelial neoplasia (HGPIN) was assessed in a Spanish population, representative of the Caucasian Mediterranean (CM) ethnic group. Data were compared with those described in populations from other geographical regions and in other ethnic groups. METHODS: CaP and HGPIN were evaluated in a consecutive series of prostatic glands collected at the post-mortem examination of 162 male patients born and living in Spain, aged 20-80 years, and dying from trauma. The glands were sliced every 2-3 mm. All slices were paraffin embedded and sectioned to obtain 5 microm whole-mount sections. To compare the prevalence rate in our series and in other Caucasian populations with that from other geographical areas and other ethnic groups, we used data from the autopsy study performed at the Wayne State University. RESULTS: Prevalence of CaP is 3.58, 8.82, 14.28, 23.80, 31.7, and 33.33% in the 3rd, 4th, 5th, 6th, 7th, and 8th decades, respectively. The rates of HGPIN were 7.14, 11.75, 35.71, 38.06, 45.40, and 48.15% at the 3rd, 4th, 5th, and 8th decades of life. Both CaP and HGPIN are located preferentially at the peripheral zone of the gland and in 21/27 cases (77.7%), an association between CaP and HGPIN was found. The prevalence of both lesions in CM males is significantly lower than in Caucasian American (CA) and Afro-American (AA) males in all the age groups evaluated. CONCLUSIONS: Microscopic foci of CaP and HGPIN can be documented in CM males from the 3rd decade of life onwards. The lesions become more frequent and extensive as age increases. The prevalence of both lesions seems to be significantly lower in the CM population than in CA and AA males in all the age groups evaluated.

Adenocarcinoma↗

PubMed1997

Incidence of high-grade prostatic intraepithelial neoplasia in sextant needle biopsy specimens.

OBJECTIVES: There is scant literature on the frequency of high-grade prostatic intraepithelial neoplasia (PIN) in needle biopsy specimens. These data have implications as to how often pathologists should be expected to diagnose these lesions on needle biopsy and impact on the feasibility of cancer chemoprevention trials for prostate cancer. METHODS: We reviewed 439 consecutive 18-gauge sextant needle biopsy specimens from the Johns Hopkins Hospital. RESULTS: Based on the pathology reports, high-grade PIN was recorded in 12 (2.7%) of the cases and was confirmed upon review. Following review of the slides, unequivocal high-grade PIN was found in an additional 6 cases. There were 6 other cases where the findings were borderline between high- and low-grade PIN, but which were believed to be more consistent with high-grade PIN. Considering these latter cases in conjunction with the unequivocal cases of high-grade PIN, the incidence of high-grade PIN was 5.5% (24 of 439). CONCLUSIONS: Recognizing that approximately 50% of men with high-grade PIN on needle biopsy will be found to have carcinoma on repeat biopsy, the management of high-grade PIN on biopsy will only apply to 50% of the men initially discovered with this finding. If only 2.75% of men who are biopsied eventually need therapy for high-grade PIN on needle biopsy, the number of cases needed to study the decrease of high-grade PIN following chemoprevention might be prohibitively high. If the incidence of high-grade PIN on needle biopsy requiring therapy is only 2.75%, it may also not be worthwhile developing large trials to investigate various treatment regimens for high-grade PIN found on biopsy.

Adult↗

PubMed1998

Telomerase activity, telomere length, and DNA ploidy in prostatic intraepithelial neoplasia (PIN).

PURPOSE: To investigate the relationship of telomerase activity, telomere length, and DNA ploidy in high grade prostatic intraepithelial neoplasia (PIN). MATERIALS AND METHODS: Tissue samples were carefully microdissected to obtain adenocarcinoma or PIN-containing tissue free of cancer. Telomerase activity was measured using the PCR-based telomeric repeat amplification protocol (TRAP). Telomere length was estimated from Southern blots of telomere restriction fragments (TRFs). DNA ploidy of PIN and carcinoma was determined by image analysis of adjacent Feulgen stained tissue sections. RESULTS: Telomerase activity was found in 4 of 25 samples (16%) of high grade PIN. All telomerase positive PIN foci had a diploid DNA content. Although 5 of 25 samples (25%) of high grade PIN foci analyzed were DNA aneuploid, none of these demonstrated telomerase activity. Telomerase positive foci of prostate carcinoma (69% of all cancer foci analyzed) displayed heterogeneity in TRF length, with a mean TRF length two kilobase pairs shorter than that of telomerase negative specimens. CONCLUSIONS: Telomerase activity is present in a low percentage of high-grade PIN foci, which are diploid by DNA content measurements.

Adenocarcinoma↗

PubMed1996

Biomarker expression in prostatic intraepithelial neoplasia.

OBJECTIVE: This study was conducted to gain a better understanding of the underlying cellular events involved in the development of prostatic intraepithelial neoplasia (PIN) and to clarify the relationship of PIN to invasive prostatic adenocarcinoma (PCa). METHOD: This article reviews previous studies from our laboratory and others of biomarker expression in PIN and PCa. RESULTS: The development of PIN is characterized by increased expression of several biomarkers which may influence the proliferative potential of the dysplastic cells. Increased expression of the growth factor receptors P185erbB-2, p180erbB-3, as well as the product of the c-met proto-oncogene is frequently detected in the dysplastic luminal cells as well as malignant cells of the prostate. Likewise, the expression of the nm-23H1 gene product is strongly expressed in dysplastic and malignant cells. Increased proliferative potential of the dysplastic cells is directly reflected by increased expression of PCNA. In contrast to the enhanced expression of the biomarkers associated with proliferation, decreased expression of prostate-specific antigen (PSA), prostatic acid phosphatase (PAP) and Leu 7 by dysplastic luminal cells is indicative of an impairment of the process of cellular differentiation. Aberrant glycosylation as well as the inappropriate expression of glycosylated tumor antigens is demonstrated by enhanced binding of the lectin Ulex europaeus and increased expression of tumor-associated glycoprotein 72 (TAG-72) and the Lewis Y antigen in dysplastic and malignant cells. Finally, enhanced expression of proteolytic enzymes such as cathepsin D and the 72-kD form of collagenase IV by dysplastic cells may represent an integral event in the development of invasive PCa. CONCLUSION: The studies described in this review clearly demonstrate phenotype similarities of PIN to invasive PCa and furthermore support the concept that PIN represents a preinvasive lesion.

Adenocarcinoma↗

PubMed2004

Predictors of prostate cancer on extended biopsy in patients with high-grade prostatic intraepithelial neoplasia: a multivariate analysis model.

OBJECTIVE: To define the importance of extended biopsy in patients with high-grade prostatic intraepithelial neoplasia (HGPIN) and to define predictors of cancer in extended biopsy in patients with HGPIN, using multivariate analysis. PATIENTS AND METHODS: In all, 83 patients with previous sextant biopsy of HGPIN had an extended 11-core biopsy taken. Patients with a negative biopsy for cancer were followed by serum prostate-specific antigen (PSA) and digital rectal examination (DRE) every 6 months. The extended biopsy was repeated in 21 patients. The criteria for second biopsy were an increase in PSA and/or abnormal changes on DRE. Overall, 49 patients had a transurethral resection of the prostate (TURP). The cancer-detection rate on extended biopsy was correlated with risk factors using the chi-square test and multivariate analysis. RESULTS: Extended biopsy detected prostate cancer in 30 of the 83 men (36%), with positive cores in only 20 sextant biopsy sites (67%), in only seven in additional sites (23%), and both in three (10%). Of the 21 patients who had repeat extended biopsy, four (19%) had cancers. There were two carcinomas in the 49 TURP specimens (4%). The PSA level, DRE and transrectal ultrasonography findings were not predictive of cancer in extended biopsies (chi-square test). Patient age, PSA density and the number of cores with HGPIN (all P < 0.001) had a significant effect on the cancer-detection rate, and multivariate analysis showed that all three were independent predictors of cancer. A logistic regression model was designed to predict the probability of cancer in extended biopsy, with an overall accuracy of 78%. CONCLUSION: Extended biopsy improved the cancer detection rate by 23% in patients with HGPIN. Patient age, PSA density and the number of cores with HGPIN were the only independent predictors of cancer.

Aged↗

PubMed1997

Detection of chromosomal anomalies and c-myc gene amplification in the cribriform pattern of prostatic intraepithelial neoplasia and carcinoma by fluorescence in situ hybridization.

Grading of the cribriform pattern of prostate cancer is controversial, and the genetic changes are largely unknown. Furthermore, the pathogenetic relationship between the cribriform pattern of high-grade prostatic intraepithelial neoplasia (PIN) and cribriform carcinoma is poorly understood. We used fluorescence in situ hybridization with centromere-specific probes for chromosomes 7, 8, 10, 12, and Y and a region-specific probe for c-myc to evaluate genetic changes in matched foci of high-grade PIN (48 foci) and prostatic carcinoma (71 foci) in 25 whole-mount radical prostatectomy specimens from patients with metastatic cancer. These cases included 10 foci of cribriform PIN and 10 foci of cribriform cancer. Numeric chromosomal anomalies were found in 67 and 68% of the high-grade PIN and carcinoma foci, respectively. Extra copies of the c-myc gene were identified in 52 and 44% of the high-grade PIN and carcinoma foci, respectively. The cribriform pattern of cancer had a higher percentage of foci with gain of chromosomes 7, 12, and Y, loss of chromosome 8, and extra copies of c-myc gene than other Gleason Primary Patterns 3 and 4; there was no difference, however, for all paired comparisons of genetic changes between the cribriform pattern of cancer and Gleason Primary Pattern 5 cancer. Cribriform PIN and cribriform cancer generally exhibited similar anomalies, although the percentage of foci with gain of chromosomes 10 and 12 was higher in cribriform cancer. Our results indicate that the cribriform pattern of prostate cancer shares genetic changes with Gleason Primary Pattern 5 and that both contain more genetic changes than the cribriform pattern of PIN. These findings suggest that the cribriform pattern of prostate cancer has biologic similarity with Gleason Pattern 5 carcinoma and that the cribriform pattern of PIN is closely associated with the cribriform pattern of prostatic carcinoma.

Adenocarcinoma↗

PubMed2003

Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia.

PURPOSE: One of the greatest concerns among clinicians regarding testosterone replacement therapy (TRT) is the fear of causing or promoting prostate cancer. We evaluated prostatic changes in hypogonadal men with and without high grade prostatic intraepithelial neoplasia (PIN), which is considered a prostatic precancerous lesion, after 1 year of TRT. MATERIALS AND METHODS: A total of 75 hypogonadal who completed 12 months of TRT were studied. All underwent prostate biopsy prior to initiating treatment. Of the men 55 had benign prostate biopsies (PIN-) and 20 had PIN without frank cancer (PIN+). All men with PIN underwent repeat biopsy to exclude cancer prior to the initiation of testosterone treatment. Prostate specific antigen (PSA), and total and free testosterone were determined prior to treatment and at 1 year. Repeat biopsy was performed for a change noted on digital rectal examination or for a PSA increase of 1 ng/l or greater. RESULTS: PSA was similar at baseline in men with and without PIN (1.49 +/- 1.1 and 1.53 +/- 1.6 ng/dl, p >0.05) and after 12 months of TRT (1.82 +/- 1.1 and 1.78 +/- 1.6 ng/dl, respectively, p >0.05). A slight, similar increase in mean PSA was noted in the PIN- and PIN+ groups (0.25 +/- 0.6 and 0.33 +/- 0.6 ng/dl, p >0.05). One man in the PIN+ group had cancer after biopsy was performed due to abnormal digital rectal examination. Four additional men in the PIN- group and 2 in the PIN+ group underwent re-biopsy for elevated PSA and none had cancer. No differences were noted between the PIN- and PIN+ groups with regard to total and free testosterone at baseline and at 1 year (p = 0.267). CONCLUSIONS: After 1 year of TRT men with PIN do not have a greater increase in PSA or a significantly increased risk of cancer than men without PIN. These results indicate that TRT is not contraindicated in men with a history of PIN.

Adult↗

PubMed2001

Overexpression of the cell cycle inhibitor p16INK4A in high-grade prostatic intraepithelial neoplasia predicts early relapse in prostate cancer patients.

Prostate cancer (PC) is the most commonly diagnosed male cancer in industrialized societies. No molecular markers of PC progression or outcome with proven clinical utility have been described. Because the loss of normal cell cycle control is an early event in the evolution of cancer, we sought to determine whether changes in expression of the cyclin-dependent kinase inhibitor, p16INK4A, predicted outcome in this disease. We screened a cohort of 206 patients with clinically localized PC treated with radical prostatectomy for overexpression of the INK4A gene, the product of which inactivates the G1-phase cyclin dependent kinases, Cdk4 and Cdk6. p16INK4A protein expression was evaluated by immunohistochemistry in areas of high-grade intraepithelial neoplasia (HGPIN), a precursor to invasive disease, and of cancer in the same specimen. Data were evaluated for disease relapse using the Kaplan-Meier method and in a Cox proportional hazards model by assessing p16INK4A status in areas of HGPIN and cancer with other variables of known clinical relevance. Overexpression of p16INK4A in HGPIN and cancer was correlated with, but independent of, pathological stage and was associated with early relapse in PC patients treated with radical prostatectomy (log-rank test, P < 0.001). In a multivariate model adjusted for Gleason grade, pretreatment prostate-specific antigen levels, pathological stage, and margin status, overexpression of p16INK4A in HGPIN was an independent predictor of disease relapse and increased the risk of recurrence 2.24-fold (95% confidence interval, 1.28-3.93). These data provide the first evidence for a prognostic marker in HGPIN. The clinical utility of p16INK4A status in stratifying patients for aggressive treatment very early in the disease process, potentially several years prior to the onset of invasive disease, requires further investigation.

Age Factors↗

PubMed1992

Localization of epidermal growth factor receptor by immunohistochemical methods in human prostatic carcinoma, prostatic intraepithelial neoplasia, and benign hyperplasia.

The epidermal growth factor receptor (EGFr) is a membrane-bound glycoprotein that is present in a wide variety of human normal and malignant tissues. In this study EGFr expression in frozen sections of prostate tissue obtained from 40 different surgical specimens was examined immunohistochemically with a well-characterized monoclonal antibody to EGFr, Ab-1 (Oncogene Science). Twenty cases of prostate adenocarcinoma and 20 cases of benign prostatic hyperplasia were studied. Six of the 20 cases of adenocarcinoma also contained prostatic intraepithelial neoplasia grade III (severe intraductal dysplasia). All of the cases containing benign glands showed strong immunostaining in a continuous or nearly continuous pattern, with staining restricted to the basal layer of the benign glands. Adenocarcinoma lacked immunostaining in 15 (75%) of 20 cases, while the remaining five cases (25%) showed diffuse cytoplasmic staining, which was weaker than that seen in the benign glands and that lacked basal accentuation. The six cases that contained prostatic intraepithelial neoplasia grade III showed a discontinuous basal pattern of staining, and the gaps in the staining appeared to correspond to areas of disruption of the basal cell layer. We conclude that the antigenic determinant recognized by this antibody to EGFr was detected preferentially in the basal layer in benign prostatic glands. In contrast, a minority of cases of adenocarcinoma expressed EGFr, as assessed by immunoreactivity with the Ab-1 monoclonal antibody. Prostatic intraepithelial neoplasia grade III expressed EGFr with a predominantly discontinuous basal pattern that corresponded to the disrupted basal cell layer typical of this process.

Adenocarcinoma↗

PubMed2004

Prostate intraepithelial neoplasia in Noble rats, a potential intermediate endpoint for chemoprevention studies.

In most prostate chemoprevention studies conducted with animal models, the incidence and multiplicity of tumours have been used as endpoints for efficacy. However, the latency of tumours is usually over 1 year, making these studies costly and time consuming. The main purpose of this study was to assess the utility of prostate intraepithelial neoplasia (PIN), induced in Noble rats by continuous testosterone + oestradiol (T + E) administration, as a potential intermediate endpoint biomarker of efficacy in chemoprevention studies. Noble rats at the age of 12 weeks were treated for 36 weeks with T + E given subcutaneously via Silastic capsules. The incidence and multiplicity of PIN were assessed in various prostate glands by serial sections generated at three separate tissue levels. The efficacy of dehydroepiandrosterone (DHEA) and DHEA 8354 (1000 and 2000 mg/kg diet), difluoromethylornithine (DFMO) (1000 and 2000 mg/kg diet) and oltipraz (125 and 250 mg/kg diet) to inhibit PIN was assessed in two independent sets of experiments. T + E induced multiple PIN in the dorsolateral prostate (DLP) of 80-100% of the animals. DHEA and DHEA 8354 did not affect the incidence but decreased the multiplicity of PIN in the DLP, from 3.2 +/- 1.0 in control group to 1.5 +/- 1.0 in the low-dose and to 1.6 +/- 0.6 in the high-dose group for DHEA (P<0.05 and P<0.02, respectively), and to 1.9 +/- 0.8 in the high-dose (P<0.05) DHEA 8354. Both agents did not affect PIN in anterior prostate, seminal vesicles or ventral prostate. In a second experiment, DFMO and oltipraz were found not effective in inhibiting PIN. In this study, we provide new evidence that PIN in Noble rats, induced by continuous T + E treatment, is a useful intermediate endpoint for determining the efficacy of DHEA and other potential chemopreventive agents. The hormonal pathogenesis, high multiplicity, short latency, preferential location in the DLP, similarity in morphology and biology to PIN of human prostate, and the sensitivity to agents that suppress prostate carcinogenesis, makes PIN in Noble rats a promising intermediate endpoint for chemoprevention studies.

Animals↗

PubMed1999

Membrane type 1-matrix metalloproteinase (MT1-MMP) and MMP-2 immunolocalization in human prostate: change in cellular localization associated with high-grade prostatic intraepithelial neoplasia.

Membrane type 1-matrix metalloproteinase (MT1-MMP) is a known activator of latent MMP-2 (pro-MMP-2), and increased MMP-2 expression has been associated with tumor aggressiveness in prostate cancer. However, expression of MT1-MMP in human prostate tissue has not been described. We investigated the expression and immunolocalization of MT1-MMP and MMP-2 in the epithelial components of benign prostate epithelium, high-grade prostatic intraepithelial neoplasia (HGPIN), and prostate cancer. Tissue sections from the peripheral zone of 50 prostates (radical prostatectomy specimens) were chosen based on their containing benign glands, HGPIN, and prostate cancer glands. All 50 sections were immunostained for MT1-MMP and MMP-2 and were evaluated for staining pattern, uniformity, and intensity. Western blotting and gelatin zymography were done to confirm expression of MT1-MMP and activity of MMP-2, respectively. Comparisons were made between benign epithelium, HGPIN, and cancer. In benign glands, basal cells (BCs) uniformly stained intensely for MT1-MMP, whereas secretory cells (SCs) were rarely positive (P < 0.0001). Conversely in HGPIN, SCs showed consistent cytoplasmic staining (P < 0.0001). In cancer cells, staining was heterogeneous and varied from no staining to very intense staining in select glands. MMP-2 in normal tissue stained both BCs and the apical region of SCs, whereas in HGPIN, staining was observed in the SC in a predominantly cytoplasmic pattern. Similar to MT1-MMP, staining in cancer tissue for MMP-2 was heterogeneous; however, there was a significant association between the pattern of MMP-2 and MT1-MMP staining within the epithelial components of the cancer glands in individual specimens (P < 0.001). Finally, MMP-2 and MT1-MMP were confirmed to be expressed in the prostate tissues by gelatin zymography and Western blotting. In conclusion, we found that consistent changes in localization and intracellular distribution of MMP-2 and MT1-MMP were associated with the transition from benign prostate epithelium to HGPIN, suggesting that regulation of these enzymes is altered during the earliest stages of prostate cancer.

Adult↗

PubMed2002

9-cis-retinoic acid but not 4-(hydroxyphenyl)retinamide inhibits prostate intraepithelial neoplasia in Noble rats.

In most previous studies, the incidence and multiplicity of chemically induced prostate tumors have been used as end points for assessing the efficacy of various chemopreventive agents. In this study, we used prostate intraepithelial neoplasia (PIN) in Noble rats as an intermediate end point to examine the chemopreventive efficacy of two retinoids, 9-cis-retinoic acid (9cRA) and 4-(hydroxyphenyl)retinamide, which in previous studies have shown promising inhibitory effects on various carcinogenesis models. We found that 80-100% of Noble rats treated for 36 weeks with testosterone + 17beta-estradiol developed multiple PIN lesions predominantly in the dorso-lateral prostate, which appears relevant to the place of origin of PIN and carcinoma in the human prostate. 9cRA at 50 or 100 mg/kg diet significantly decreased the multiplicity of PIN, whereas 4-(hydroxyphenyl) retinamide at 392 or 784 mg/kg diet, did not have an inhibitory effect on PIN. Thus, we provide for the first time evidence that the testosterone + 17beta-estradiol-induced PIN in Noble rats could be used as a potential intermediate end point in assessing the efficacy of retinoids and possibly of other agents on prostate carcinogenesis, and that 9cRA alone or in combination with other agents may have clinical promise in preventing the development of prostate cancer in men.

Alitretinoin↗