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PubMedDate not supplied

Tenascin-C expression in prostatic intraepithelial neoplasia (PIN): a marker of progression?

BACKGROUND: Tenascin (tenascin-C) has been suggested to be associated with active epithelial-stromal interactions. We evaluated tenascin expression in tissue remodelling processes presumably associated with PIN and prostate carcinoma (PCa). MATERIALS AND METHODS: Tenascin immunoreactivity was evaluated in 38 PIN lesions (low-grade = 5, high-grade = 33) from 27 paraffin-embedded PCa specimens, and compared with expression in pre-existent (normal) prostate, benign prostatic hyperplasia (BPH), and PCa. RESULTS: Periepithelial stromal tenascin expression was low in low-grade PIN, and similar to normal glands and BPH, whereas expression in high-grade PIN was high and partly overlapped that of well-/moderately differentiated PCa. High-grade PCa usually expressed little, if any tenascin. CONCLUSIONS: The variable periglandular tenascin expression in high-grade PIN may reflect the biologic behaviour of this lesion, and may be indicative of variable levels of tissue remodelling. In well/moderately differentiated PCa tenascin expression levels may be an indicator of tumour progression.

Biomarkers, Tumor↗
PubMedDate not supplied

The FAS-related apoptosis signaling pathway in the prostate intraepithelial neoplasia and cancer lesions.

An aim of the study was to determine the protein expression of the FAS-related apoptosis signaling pathway (FADD-FAS Associating Protein with Death Domain, PRO-CASPASE-8 and CASPASE-8), which are responsible for signal transduction to trigger programmed cell death (apoptosis) in cancer and Prostatic Intraepitelial Neoplasia (PIN). 20 specimens from prostate cancer patients treated with radical prostatectomy were inwestigated. 8 cancers were diagnosed as G-2 and 12 as G-3. 14 samples were described as poorly differentiated, high Gleason score (> or = 7). Control group consisted of prostate specimens from autopsy of 3 young men. Specimens were fixed in 10% buffered formaldehyde and immersed in paraffin. Haematoxylin and eosin staining was done. Monoclonal antibodies to FADD & CASPASE-8 (Novocastra, UK) were used to immunohistochemical study, according to streptavidine-biotin method. Semiquantitive method described protein expression. Expression index (EI) was calculated as a percent of positive FADD or CASPASE-8 cells to total cells in the specimen. Statistical analysis was performed with the Student t-test (p < 0.05). Normal prostate tissue was negative in both, FADD and CASPASE-8 immunohistochemistry staining. PIN & prostate cancer lesions were found to strongly express of FADD & CASPASE-8 proteins. Expression of FADD in cancer lesions was 66,5+/-27,8% and 59,8+/-19,0% vs. 56,8114,8% HGPIN and LGPIN, respectively. Expression of CASPASE-8 in cancer lesions was 64,1 + 23,4% and 61,5+/-15,0% vs. 48,0+/-17,6% HGPIN and LGPIN, respectively. PIN & prostate cancer lesions are characterized by similar high expression of proteins responsible for signal transduction to induce apoptosis. The mediators of apoptotic signal can be very important in prostate cancer prophylaxis and management.

Apoptosis↗
PubMed2004

mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways.

Loss of PTEN function leads to activation of phosphoinositide 3-kinase (PI3K) signaling and Akt. Clinical trials are now testing whether mammalian target of rapamycin (mTOR) inhibition is useful in treating PTEN-null cancers. Here, we report that mTOR inhibition induced apoptosis of epithelial cells and the complete reversal of a neoplastic phenotype in the prostate of mice expressing human AKT1 in the ventral prostate. Induction of cell death required the mitochondrial pathway, as prostate-specific coexpression of BCL2 blocked apoptosis. Thus, there is an mTOR-dependent survival signal required downstream of Akt. Bcl2 expression, however, only partially restored intraluminal cell growth in the setting of mTOR inhibition. Expression profiling showed that Hif-1 alpha targets, including genes encoding most glycolytic enzymes, constituted the dominant transcriptional response to AKT activation and mTOR inhibition. These data suggest that the expansion of AKT-driven prostate epithelial cells requires mTOR-dependent survival signaling and activation of HIF-1 alpha, and that clinical resistance to mTOR inhibitors may emerge through BCL2 expression and/or upregulation of HIF-1 alpha activity.

Animals↗
PubMed1989

Use of transrectal ultrasound and prostate-specific antigen in diagnosis of prostatic intraepithelial neoplasia.

1. PIN can present as a hypoechoic lesion on ultrasound. 2. Biopsy results prove a close relationship between PIN and cancer. 3. Measurements of age, lesion size, and PSA for diagnoses of PIN were intermediate values between non-cancer and cancer. 4. Sequential, precise transrectal ultrasound-guided biopsies of hypoechoic lesions are now possible, and close follow-up of patients with diagnoses of PIN is therefore possible.

Adult↗
PubMed1993

The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients.

The incidence of clinically detected prostate cancer is increasing with more frequent diagnosis in younger male patients. Whether this represents a genuine increase in incidence or earlier detection is not clear. To understand better the evolution and early changes of prostate cancer we evaluated 152 prostate glands from young male patients 10 to 49 years old. Of the prostates 98 were from African-Americans and 54 were from white patients. Prostatic intraepithelial neoplasia was identified in 0%, 9%, 20 and 44%, and small foci of histological cancer in 0%, 0%, 27% and 34% of the male patients in the second, third, fourth and fifth decades of age, respectively. The majority of the cases of prostatic intraepithelial neoplasia were of low grade. High grade prostatic intraepithelial neoplasia, found in 5 prostates, was first identified in the fifth decade. All 5 cases occurred in prostates containing histological carcinoma. Incidental carcinoma was detected with a similar frequency in white and black patients. The cancerous foci were of similar size with a tendency for cancer in black patients to be multifocal, particularly in those in the fifth decade. We conclude that prostatic intraepithelial neoplasia and histological cancers are surprisingly common in young male patients of both races. The evolution of prostatic intraepithelial neoplasia and focal histological cancers is not clear but it appears to present several decades earlier than clinically detected carcinoma. The natural history of prostate cancer must encompass many more years (decades) than has been previously realized. In addition, the initiating events leading to clinically relevant prostate cancers likely occur at a remarkably young age.

Adenocarcinoma↗
PubMedDate not supplied

The canine prostate is a spontaneous model of intraepithelial neoplasia and prostate cancer progression.

Increasing evidence suggests that high grade prostatic intraepithelial neoplasia (PIN) represents a precancerous stage in the morphologic continuum of progression from benign epithelium to carcinoma. In this report, we summarize our work characterizing the high grade PIN that occurs spontaneously in the canine prostate. The similarity between canine and human PIN for basal cell layer disruption, proliferative index, microvessel density, and its association with carcinoma suggest that the canine prostate may be a useful model for studying carcinogenesis and cancer progression.

Aging↗
PubMed2000

Kinetic profiles of intraepithelial and invasive prostatic neoplasias: the key role of down-regulated apoptosis in tumor progression.

The cell kinetic of prostatic intraepithelial neoplasia (PIN) is poorly understood. Herein we report the kinetic pattern of PIN, both not associated (primary) and associated (secondary) with coexistent invasive carcinoma (PCa). Surgical specimens collected in 20 cases of primary PIN, 20 of secondary PIN and 20 of PCa were studied by MIB-1 immunostaining, in situ end-labeling (ISEL) and DNA histogram analysis, and the cell density in each case was estimated using the formula N = (n pi/4)2. Fifty high-power fields (HPF), or the complete lesion if smaller, were screened in each lesion, and both mean and standard deviation were recorded. Statistical differences were studied by means of Fisher's exact test. ISEL indices were significantly (P < 0.0001) lower in PCa (0.1 +/- 0.3) than in primary PIN (0.5 +/- 0.3), while the MIB-I indices were similar in both conditions (P = 0.56). Statistically significant differences were also detected for both MIB-1 and ISEL indices when secondary PIN (MIB-1 1.9 +/- 0.7, ISEL 3.7 +/- 3.3) was compared with primary PIN (MIB-1 2.5 +/- 2.1, ISEL 0.5 +/- 0.3) and PCa (P < 0.0001). In terms of cellularity, primary PIN (26.3 +/- 7.1) revealed scores significantly lower (P < 0.0001) than those recorded in PCa (39.0 +/- 8.8) and secondary PIN (32.9 +/- 14.3). In conclusion, early prostatic tumor is mainly defined by down-regulated apoptosis rather than by increased proliferation. Secondary PIN displays unique kinetic features suggesting an evolved stage of primary PIN.

Aged↗
PubMed2004

Loss of 14-3-3sigma in prostate cancer and its precursors.

PURPOSE: The 14-3-3 family proteins are highly conserved over many mammalian species. The sigma isoform (also called HME-1 or stratifin) is expressed in epithelial cells. Loss of 14-3-3sigma is associated with failure to arrest the cell cycle at the G(2)-M phase checkpoint after DNA damage that leads to increased G(2)-type chromosomal aberrations. The role of 14-3-3sigma in prostatic carcinogenesis is uncertain. EXPERIMENTAL DESIGN: We studied one hundred and eleven specimens of invasive prostate adenocarcinoma with paired, adjacent high-grade prostatic intraepithelial neoplasia and normal prostate epithelium. Immunohistochemistry was used to detect the expression of 14-3-3sigma. The findings were correlated with various clinical pathological parameters. RESULTS: 14-3-3sigma is ubiquitously expressed at high levels in normal prostate epithelium. Its expression is significantly decreased in prostatic intraepithelial neoplasia and prostatic adenocarcinoma. Ninety percent of samples of prostatic intraepithelial neoplasia had no or low 14-3-3sigma expression. Ninety-seven percent of invasive adenocarcinomas had no or low 14-3-3sigma expression. In most specimens (90%), suppression of 14-3-3sigma expression occurred during the development of prostatic intraepithelial neoplasia from normal epithelium. CONCLUSIONS: Our data suggest that loss of 14-3-3sigma contributes to the development of prostate adenocarcinoma. 14-3-3sigma expression is significantly decreased during the progression of normal prostatic epithelium to prostatic intraepithelial neoplasia and invasive cancer.

14-3-3 Proteins↗
PubMed1999

Changes in the normal-looking epithelium in prostates with PIN or cancer.

BACKGROUND: In prostatic neoplasia, the time from tumour initiation and progression to invasive carcinoma often begins in men in the fourth and fifth decades of life and extends across decades. Until recently, the events initiating the process and the developments concomitant with the evolution towards invasive disease were largely unknown. METHODS: Quantitative and analytical methods are applied to provide insights into certain individual molecular events and their effects on the complex multiple feedback system of cellular metabolism and regulation in prostate neoplasia. RESULTS: Prostatic intraepithelial neoplasia (PIN) and prostate cancer (PCa) are associated with or possibly preceded by changes in the chromatin of secretory cell nuclei. The changes are detectable with a Bayesian belief network and quantifiable by computer image analysis in prostatic tissue that still appears histologically normal. In addition, normal looking prostate epithelium shows some molecular changes similar to those present in the associated preneoplastic and neoplastic lesions. Such changes are also occasionally present in normal prostate glands without PIN and cancer. CONCLUSIONS: The subtle morphological and molecular changes of normal looking epithelium might be seen as the onset of the development of prostatic neoplasia.

Adenocarcinoma↗
PubMed1997

Transurethral biopsy of the prostate for persistently elevated or increasing prostate specific antigen following multiple negative transrectal biopsies.

PURPOSE: Treatment of the patient with persistently elevated prostate specific antigen (PSA) levels after pathologically negative transrectal or manually directed prostate needle biopsy is unclear. We retrospectively evaluated the use of transurethral biopsy of the prostate as an adjunctive study for the diagnosis of prostate cancer in these patients. MATERIALS AND METHODS: From January 1993 through February 1996, 71 patients underwent transurethral biopsy in conjunction with repeat prostatic needle biopsy for a persistently elevated PSA (greater than 4 ng./ml.) after previously negative needle biopsy. All patients had at least 1 previous ultrasound guided sextant prostatic needle biopsy (mean 1.85, range 1 to 7) with or without manually directed biopsies. Following negative prostatic needle biopsy these patients subsequently underwent a minimum of a 4-quadrant transurethral sampling of the prostatic fossa followed by repeat sextant prostatic needle biopsy. A subset of patients underwent sampling of the anterior prostatic tissue or transition zone using transrectal ultrasound guided prostatic needle biopsy at transurethral biopsy. RESULTS: Of the 71 patients with elevated PSA (mean 16.2 ng./ml., range 4.2 to 171) 17 (24%) had prostate cancer on the repeat prostatic needle biopsy. Both patients who had prostate cancer on the transurethral biopsy specimens also had prostate cancer on the repeat prostatic needle biopsy specimens. A total of 68 patients had benign prostatic tissue and 1 had high grade prostatic intraepithelial neoplasia on transurethral biopsy specimens. Of 19 patients with high grade prostatic intraepithelial neoplasia on the initial prostatic needle biopsy, transurethral biopsy specimens revealed no prostate cancer or prostatic intraepithelial neoplasia. Repeat prostatic needle biopsy in these patients with high grade prostatic intraepithelial neoplasia revealed prostate cancer in 6 and high grade prostatic intraepithelial neoplasia in 4. CONCLUSIONS: In patients with persistently elevated or increasing serum PSA after a previously negative prostatic needle biopsy, transurethral biopsy is not a useful adjunct in diagnosing prostate cancer. In this high risk group of patients transurethral biopsy adds little or no diagnostic value to prostatic needle biopsy even in those with high grade prostatic intraepithelial neoplasia.

Adult↗
PubMed2000

Immunohistochemical staining for DNA topoisomerase II-alpha in benign, premalignant, and malignant lesions of the prostate.

BACKGROUND: The DNA topoisomerase II-alpha (topo II-alpha)-targeting drug etoposide was recently shown to be an active agent in the combined chemotherapy of hormone-insensitive prostatic carcinoma. Aside from being the molecular target of etoposide, topo II-alpha is also a cell proliferation marker. Much experimental data indicate that cells sensitive to topo II-targeting chemotherapeutic drugs are rapidly proliferating and show elevated topo II expression. There is little information concerning topo II expression in lesions of the prostate. METHODS: Paraffin blocks from cases of invasive prostatic carcinoma, prostatic intraepithelial neoplasia, and prostatic nodular hyperplasia were retrieved from the surgical pathology files at the University of Utah Health Sciences Center. Using a new immunohistochemical stain, specific for the alpha isoform of DNA topo II, enzyme expression was evaluated in 54 prostatic adenocarcinomas, 22 lesions of high-grade prostatic intraepithelial neoplasia (PIN), and 10 cases of benign prostatic nodular hyperplasia. Results were semiquantitated by determining for each case a topo II-alpha index, which represented the percent of positively staining cells. RESULTS: The average topo II-alpha index for well-differentiated prostatic adenocarcinomas (Gleason scores 2-4) was 1.5 +/- 0.9; for moderately differentiated tumors (Gleason scores 5-7), 3.1 +/- 2.4; and for poorly differentiated tumors (Gleason scores 8-10), 6.7 +/- 5.5. The average topo II-alpha index for all invasive prostatic adenocarcinomas was 4.0 (range, 0-19.0). Benign prostatic nodular hyperplasia had the lowest average topo II-alpha index, of 0.54 (range, 0.2-1.0). The average topo II-alpha index of 2.3 (range, 0-8.6) for high-grade prostatic intraepithelial neoplasia was intermediate between the invasive tumors and benign prostate. CONCLUSIONS: Topo II-alpha expression in carcinoma of the prostate correlates with Gleason score. The carcinomas with the highest expression of enzyme are more poorly differentiated and have the highest Gleason scores. Prostatic nodular hyperplasia shows little expression of topo II-alpha. Prostatic intraepithelial neoplasia has an average topo II-alpha index intermediate between nodular hyperplasia and carcinoma.

Adenocarcinoma↗
PubMed1999

Prostate-specific antigen expression and lipochrome pigment granules in the differential diagnosis of prostatic adenocarcinoma versus seminal vesicle-ejaculatory duct epithelium.

BACKGROUND: Lipochrome pigment granules (LPGs) and prostate-specific antigen (PSA) localization have been cited as helpful adjuncts in differentiating atypical histologic patterns of seminal vesicle-ejaculatory duct (SVED) from prostatic adenocarcinoma. However, LPGs have been described in both benign and neoplastic prostatic acini, and PSA expression within the intraprostatic SVED has not been fully explored. DESIGN: Fifty radical prostatectomy specimens were studied for LPGs and 9 cases for PSA expression. RESULTS: Two morphologic types of LPGs (type 1 and type 2) were observed. The reproducibility in classifying LPGs was evaluated by kappa statistics, which demonstrated a strong agreement between 4 observers. Type 1 was restricted to SVED in all 50 specimens. Type 2 was subclassified into 2A and 2B. Type 2 LPGs were observed in prostatic acini of different zones, high-grade prostatic intraepithelial neoplasia, prostatic adenocarcinoma, and occasionally with type 1 LPG in SVED. Focal reactivity for PSA in the distal portion of SVED near urethra was noted in 1 of 9 cases. CONCLUSION: Awareness about morphologic differences between the 2 types of LPGs could help to avoid a potential diagnostic pitfall of misinterpreting SVED epithelium for adenocarcinoma. Caution is recommended in interpreting PSA expression, since rare focal PSA reactivity was observed in the distal SVED.

Adenocarcinoma↗
PubMed2005

Elevated expression of angiogenin in prostate cancer and its precursors.

PURPOSE: Angiogenin is a polypeptide involved in the formation and establishment of new blood vessels necessary for growth and metastasis of numerous malignant neoplasms, including prostatic adenocarcinoma. Antiangiogenin therapy inhibits the establishment, growth, and metastasis of prostatic adenocarcinoma in animal studies. In this study, we have investigated the expression of angiogenin in prostatic adenocarcinoma, high-grade prostatic intraepithelial neoplasia, and adjacent benign prostatic epithelium in a large cohort of prostatectomy specimens. METHODS: We have studied the expression of angiogenin by immunohistochemistry in prostatic adenocarcinoma, high-grade prostatic intraepithelial neoplasia, and adjacent benign prostatic tissue in 107 human total prostatectomy specimens. RESULTS: The percentage of cells staining positively for angiogenin in benign prostatic glandular epithelium (mean = 17%) was significantly less than for high-grade prostatic intraepithelial neoplasia (mean = 58%, P < 0.001) and prostatic adenocarcinoma (mean = 60%, P < 0.001). Compared with adjacent benign prostatic epithelium, the staining intensity was significantly greater in high-grade prostatic intraepithelial neoplasia (P < 0.001) and prostatic adenocarcinoma (P < 0.001). Furthermore, staining intensity has significantly stronger in prostatic adenocarcinoma versus high-grade prostatic intraepithelial neoplasia (P = 0.0023). However, there was no correlation of angiogenin expression with various clinical and pathologic variables examined, including age at surgery, Gleason scores, pathologic stage, tumor extent, angiolymphatic invasion, extraprostatic extension, seminal vesical invasion, lymph node metastasis, surgical margin status, presence of prostatic intraepithelial neoplasia, and perineural invasion. CONCLUSION: Angiogenin expression in prostatic tissue increases as prostatic epithelial cells evolve from a benign to an invasive phenotype. The increasing expression of prostatic adenocarcinoma in the progression from benign prostate to high-grade prostatic intraepithelial neoplasia and ultimately to prostatic adenocarcinoma are consistent with previous studies showing the influential role that angiogenin plays in the growth, invasion, and metastasis of prostatic adenocarcinoma and many other malignant tumors.

Adenocarcinoma↗
PubMed2004

Up-regulation of hypoxia-inducible factor 1alpha is an early event in prostate carcinogenesis.

Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor (VEGF). HIF-1alpha is a major subunit of HIF-1 heterodimer. In this study, an immunohistochemical analysis of HIF-1alpha was focused on clinical specimens containing high-grade prostate intraepithelial neoplasia lesions since high-grade prostate intraepithelial neoplasia is considered the precursor of a majority of invasive prostate adenocarcinoma and presents the increased activity of angiogenesis. HIF-1alpha was up-regulated in 11 of 14 high-grade prostate intraepithelial neoplasia lesions identified in a total 10 prostate biopsies relative to the respective normal epithelium, stromal cells, and benign prostatic hyperplasia (BPH). Moreover, up-regulation of HIF-1alpha in adjacent prostate cancer lesions was more enhanced than in high-grade prostate intraepithelial neoplasia. The results suggest that up-regulation of HIF-1alpha is an early event in prostate carcinogenesis, and that HIF-1alpha may become a potential target for prostate cancer prevention and a surrogate biomarker for monitoring pre-malignant lesions of the prostate.

Biomarkers, Tumor↗
PubMed1998

CD34 immunohistochemical assessment of angiogenesis as a prognostic marker for prostate cancer recurrence after radical prostatectomy.

PURPOSE: We assess the neovascularity of clinically localized prostate cancer by immunohistochemistry using the monoclonal antibody CD34 in an attempt to identify associations between angiogenesis and disease progression following radical prostatectomy. MATERIALS AND METHODS: Microvascularity was evaluated using the CD34 monoclonal antibody in archival paraffin embedded radical prostatectomy specimens from 149 patients followed from 3 to 10 years (mean 6.6). Vessels were quantified by counting a minimum of 2 selected microscopic fields (200x, 0.754 mm.2) from each tumor, area of prostatic intraepithelial neoplasia and prostatic hyperplasia, and given a numerical value representing the microvessel density count. RESULTS: Mean microvessel density count did not vary significantly with age or race. There was a significant association between the count and nuclear grade, Gleason sum and pathological stage. Cox survival analysis shows that microvessel density is significantly related to time to recurrence when considered as a continuous variable (p=0.03) as well as dichotomous variable (p=0.007) (microvessel density count less than 90 and 90 or greater). The 5-year recurrence-free survival was significantly higher for patients with a count less than 90 (71%) than for those with a count 90 or greater (51%) (p=0.006). The 5-year recurrence-free survival was also significantly different when microvessel density was used as a continuous variable (p=0.02). Controlling for stage, Gleason sum, race and nuclear grade, microvessel density remained significant in predicting recurrence (p=0.03) but when pretreatment prostate specific antigen was included in the model the count was no longer significant. The microvessel density count in the tumor area significantly increased with increasing Gleason sum and nuclear grade but it did not increase significantly in the adjacent benign prostate or areas of prostatic intraepithelial neoplasia in the same specimen. CONCLUSIONS: Microvascularity or neovascularity as measured by the CD34 antigen may be a prognostic marker of recurrence for prostate cancer patients after radical prostatectomy but more study in prostate specific antigen era patients with sufficient followup is needed.

Age Factors↗