Overexpression of ELAV-like protein HuR is associated with increased COX-2 expression in atrophy, high-grade prostatic intraepithelial neoplasia, and incidental prostate cancer in cystoprostatectomies

Background

The human ELAV-like protein HuR regulates the stability of several mRNA targets, including that of cyclooygenase-2 (COX-2). Their expression in prostatic carcinogenesis is uncertain.

Objective

To analyze HuR and COX-2 expression in cystoprostatectomies (CyPs) with incidental prostate cancer and compare their expression with those in radical prostatectomies (RPs) with clinically detected cancer.

Design, setting, and participants

HuR and COX-2 were immunohistochemically evaluated in normal-looking epithelium (NEp), atrophy, high-grade prostatic intraepithelial neoplasia (HGPIN), and prostate carcinoma (PCa) in 20 CyPs and 20 RPs, both types of specimens with pT2a Gleason score 6 PCa.

Measurements

At least 1000 cells were counted in contiguous 400X microscopic fields in each case, separately for NEp, atrophy, HGPIN, and PCa.

Results and limitations

There was an increase in the percentage of secretory cells with cytoplasmic HuR staining from NEp to atrophy, HGPIN, and PCa. The mean percentages in NEp, atrophy, and HGPIN adjacent to PCa were greater than away from cancer, both in the CyP and RPs. There was a trend towards a reduced nuclear HuR expression in atrophy, HGPIN, and PCa, compared to NEp. COX-2 staining was seen in the cytoplasm of the basal and secretory cells. There was a reduction in the mean proportion of positive basal cells and progressive increase in the percentage of positive secretory cells from atrophy to HGPIN and PCa, compared to NEp. Cytoplasmic HuR overexpression was correlated with COX-2 expression. There was no difference in HuR and COX-2 expression between cancers with tumour volume <0.5 ccm or >0.5 ccm.The limitations of this study were the small number of cases investigated and lack of a control group without cancer.

Conclusions

The secretory cells showed shift in HuR staining from nuclear in NEp to cytoplasmic in PCa. This is associated with a parallel shift in COX-2 expression from basal to secretory cells.     

The possibility of ''de novo'' cancer in the prostate

BACKGROUND: To investigate the possibility of 'de novo' prostate cancer by analyzing the relationship between high grade prostatic intraepithelial neoplasia (HGPIN) and latent prostate cancer. MATERIALS AND METHODS: Latent prostate cancers found at autopsy were examined and 55 cancer foci with a poorly (Gleason grade 4 and 5) or moderately (Gleason grade 3) differentiated component were selected. The 55 foci were separated into two groups: (i) foci with either a poorly or moderately differentiated component only (single differentiation group, SDG); and (ii) mixed foci with two or more types of differentiation components (mixed differentiation group, MDG). High grade intraepithelial neoplasia was defined as positive if it was observed within 2 mm from the edge of the cancer focus and the relationship between HGPIN and the two groups was investigated. RESULTS: The MDG had 39 cancer foci (71.0%) and there were 16 in the SDG (29.0%). There were 31 foci that were small-volume cancers (<0.2 mL). In the MDG, 13 small-volume cancer foci were HGPIN positive, but in the SDG, none of the small-volume cancers were HGPIN positive. CONCLUSIONS: Small-volume cancer foci without HGPIN in the SDG may be candidates for de novo prostate cancers.     

Allelotyping analysis at chromosome 13q of high-grade prostatic intraepithelial neoplasia and clinically insignificant and significant prostate cancers

BACKGROUND: Loss of heterozygosity (LOH) at 13q is one of the most common chromosomal alterations in high-stage prostate cancer, yet little is known about genetic changes in earlier-stage prostate cancer. METHODS: We used five microsatellite markers at 13q14, 21, and 33 to compare LOH frequencies in 51 lesions of high-grade prostatic intraepithelial neoplasia (HGPIN), 21 cases of incidental prostate cancers (IPCs), 31 cases of latent prostate cancers (LPCs), and 102 cases of clinical prostate cancers (CPCs). RESULTS: The frequency of LOH at 13q with at least 1 marker was 0%, 38%, 56%, and 49% in HGPIN, IPCs, LPCs, and CPCs, respectively. No statistically significant difference was found between the types of prostate cancer. Allelic loss at 13q14 was significantly more frequent in pT4 tumors than in earlier-stage tumors (P=0.011). CONCLUSIONS: Allelic loss at 13q is not only an important event in the metastasis of prostate cancer, but also associated with the initiation of the tumor.     

Endothelin-1 production by prostate cancer cell lines is up-regulated by factors involved in cancer progression and down-regulated by androgens.

BACKGROUND: Recent data demonstrate that endothelin-1 (ET-1) concentration increases in plasma of men with advanced, hormone-refractory prostate adenocarcinoma. In addition, ET-1 is involved in osteblastic remodelling and new bone formation, suggesting a role for this vasoactive peptide in the metastatic progression of prostate cancer to the bone. METHODS: We investigated the regulation of ET-1 expression in androgen-sensitive and insensitive prostate cancer cell lines by androgens and several factors involved in progression of prostate cancer (EGF) and bone remodelling (TGFbeta-1, IL1-alpha and IGF-1). RESULTS: Northern analysis and radio immunoassay demonstrated that all the ET-1 pathways are tuned off in the androgen-sensitive LNCaP cell line when compared to the androgen-insensitive PC-3 and DU145. In PC-3 cells transfected with a full-length androgen receptor expression vector (PC-3-AR), treatment with androgens reduced gene expression and secretion of ET-1 without affecting the gene expression of ET-3. Collectively, these data support a role for androgens in the regulation of ET-1 production by prostate adenocarcinoma cells. In PC-3 and DU145 cells, ET-1 gene expression and secretion were up-regulated by TGFbeta-1, EGF and IL1-alpha, whereas IGF-1 was ineffective. Conversely, none of the treatments affected ECE-1 or ET-3 gene expression. CONCLUSIONS: In conclusion, ET-1 production by prostate adenocarcinoma cells is down-regulated by androgens and up-regulated by factors involved in tumour progression indicating a role for this peptide in the biology of prostate cancer. In view of the role exerted by ET-1 in the process of bone metastasis, our data suggest the use of ET-1 receptor antagonists in the treatment of advanced prostate cancer.     

前列腺癌患者血浆内皮素-1的检测及其意义

目的:探讨内皮素-1(Endothelin-1,ET-1)与前列腺癌(PCa)的关系及其临床意义。方法:应用放射免疫分析法对31例PCa患者血浆中ET-1水平进行检测,其中新发PCa且对内分泌治疗敏感者(non-HRPC)23例,激素难治性PCa(HRPC)8例;以26例良性前列腺增生(BPH)患者作为对照,并作对比分析。结果:血浆ET-1水平在BPH组、未经治疗的PCa组及对雄激素治疗不敏感PCa组3组之间相互比较,差异均无显著性(P>0.05);在高、中分化PCa中血浆ET-1水平差异无显著性(P>0.05),但显著高于低分化PCa(P<0.05);在骨转移癌和非骨转移癌之间差异无显著性;在PSA各分组之间的ET-1水平,差异无显著性(P>0.05)。结论:血浆ET-1水平检测,未能反映PCa的发生发展和预后。     

Renin-angiotensin system is an important factor in hormone refractory prostate cancer

BACKGROUND: The aim of this study was to perform a comprehensive evaluation of the renin-angiotensin system (RAS) in prostate cancer. METHODS: We investigated the expression of RAS components in prostate cancer cells treated with hormonal agents. Real-time PCR data showed the expression of the AT1 receptor, angiotensin I converting enzyme (ACE), and angiotensin I/II (Ang-I/II) precursor in all 87 prostate tissue samples. RESULTS: Expression of these genes in hormone refractory prostate cancer (HRPC) was significantly higher than that in normal prostate tissue and untreated prostate cancer tissue. Western blot showed that protein expression of the AT1 receptor and Ang-I/II was enhanced in LNCaP cells cultivated in steroid-free medium. When LNCaP cells were stimulated with dihydrotestosterone (DHT), estradiol (E2), dexamethasone (DEX), or anti-androgen drugs, protein expression of the AT1 receptor and Ang-I/II was augmented. CONCLUSIONS: The present data suggest that prostatic RAS is overexpressed in HRPC tissue, and expression of its components is influenced by several kinds of hormonal stimulation.     

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.     

Apolipoprotein-D: a novel cellular marker for HGPIN and prostate cancer

BACKGROUND: High grade prostatic intraepithelial neoplasia (HGPIN) is a putative pre-malignant lesion of the prostate. While apolipoprotein-D (Apo-D), an androgen-regulated hydrophobic transporter protein, is expressed in prostate tumors, its expression in HGPIN is unknown. METHODS: Immunoreactivity for Apo-D and another androgen-regulated protein, prostate specific antigen (PSA), was investigated in 64 radical prostatectomy tissues by video image analysis. RESULTS: Eighty two percent of prostatectomy specimens demonstrated moderate to strong Apo-D immunoreactivity in areas of HGPIN. In comparison, weak Apo-D immunoreactivity was observed in non-malignant areas in only 24% of specimens. The median (range) percentage cellular area of HGPIN immunopositive for Apo-D (9.7%, 0-42.9), and the cellular concentration of Apo-D (MIOD 3.1, 0-13.3), were intermediate between that of normal (area 0%, 0-53.5%, MIOD 0, 0-12.6) and early stage prostate cancer tissues (area 29.2%, 0-90.8%, MIOD 6.7, 0-28.1). This increase in Apo-D expression from non-malignant, through HGPIN to prostate cancer was statistically significant (P < 0.001), and contrasted with the decrease observed in PSA staining between adjacent areas of normal glands, HGPIN, and cancer (P = 0.026). CONCLUSIONS: The presence of high levels of immunoreactive Apo-D in HGPIN and prostate cancer, but not in non-malignant epithelial cells, is consistent with HGPIN being an intermediate lesion in the transition to prostate cancer, and suggests that cellular Apo-D expression is a marker of malignant transformation of the prostate.     

Lycopene as a chemopreventive agent in the treatment of high-grade prostate intraepithelial neoplasia

OBJECTIVE: Because of its long latency, slow growing nature, and high prevalence, prostate cancer is the best model for chemoprevention. High-grade prostate intraepithelial neoplasia (HGPIN) is a precursor of prostate cancer. Chemoprevention with lycopene has shown definite results in prostate cancer. We undertook a study to use lycopene as a chemopreventive agent in the treatment of HGPIN for preventing prostate cancer from developing in this vulnerable group of patients. MATERIALS AND METHODS: A total of 40 patients with HGPIN were randomized into 2 groups: one received 4 mg lycopene twice a day for one year, and the other was periodically followed up. Total follow-up was one year. RESULTS: Our results show that lycopene can delay or prevent HGPIN from developing into occult prostate cancer, and there exists an inverse relationship between lycopene and prostate-specific antigen. Being a vegetable carotenoid, lycopene is a safe drug to be used for a longer period without any adverse reaction. CONCLUSION: Lycopene is an effective chemopreventive agent in the treatment of HGPIN, with no toxicity and good patient tolerance.     

Fluorodeoxyglucose positron emission tomography studies in the diagnosis and staging of clinically advanced prostate cancer

OBJECTIVE: To determine the value of 18F-fluoro-2-deoxyglucose (FDG) positron-emission tomography (PET) studies in evaluating patients with advanced prostate cancer. PATIENTS AND METHODS: FDG-PET scans were taken in 30 patients with advanced prostate cancer 1 h after an injection with 555 MBq of FDG. Patients were scanned from the base of the skull to the inguinal region (including the pelvis). They were also assessed by computed tomography (CT) of the abdomen and pelvis, and bone scintigraphy, to evaluate them for metastases. RESULTS: Thirteen patients had locally extensive prostate cancer and 17 had metastatic disease. Twenty of the 30 patients were positive for radioisotope uptake in the prostate or extraprostatically. The patients with PET-detected prostate cancer were untreated (seven), treated hormonally while they had rising PSA levels (eight), or treated hormonally with a detectable but stable PSA (five). The remaining 10 patients were negative for FDG uptake in the prostate or any metastatic sites; these 10 patients were receiving hormone therapy, with undetectable PSA levels. CONCLUSION: FDG-PET imaging is not a useful test in evaluating advanced prostate cancer in patients being treated and who have an undetectable PSA level. Staging of advanced prostate cancer may be enhanced by FDG-PET imaging in patients who are untreated, who have had an incomplete response to therapy, or who have a rising PSA level despite treatment.     

Tumour markers for managing men who present with metastatic prostate cancer and serum prostate-specific antigen levels of <10 ng/mL

OBJECTIVE: To define immunohistochemical features of the primary cancers that might help in the differential diagnosis and monitoring of treatment in men presenting with metastatic prostate cancer and low serum levels of prostate-specific antigen (PSA), who can be difficult to diagnose and manage. PATIENTS AND METHODS: Paraffin blocks of prostate biopsies were obtained for 33 patients presenting with untreated metastatic prostate cancer and serum PSA levels of <10 ng/mL. Sections were immunostained for PSA, prostatic acid phosphatase (PAP), prostate-specific membrane antigen (PSMA), androgen receptor (AR), chromogranin A and CD 56. RESULTS: The combined Gleason scores were 8-10 in 25 men (76%) and 6 or 7 in the other eight (24%). Morphologically, there were no neuroendocrine features. PSA immunostaining was equivocal in 12 (36%) cases and in a further 19 (58%) was strong but focal and could be missed on biopsy sampling. PSMA was expressed in 90% of cases, and staining was widely distributed in nine of the 12 in which PSA staining was equivocal. There was strong AR expression in 30 (91%) cases and it was present in areas where PSA was absent. CONCLUSION: In this patient group, immunohistochemical assessments of PSMA and AR are potentially useful as diagnostic markers.     

Pathological changes of high-grade prostatic intraepithelial neoplasia and prostate cancer after monotherapy with bicalutamide 150 mg

OBJECTIVES:To evaluate the morphological changes induced by a 3-month course of neoadjuvant bicalutamide 150 mg/day before radical prostatectomy (RP) on prostatic adenocarcinoma and high-grade prostatic intraepithelial neoplasia (HGPIN). PATIENTS AND METHODS: In all, 90 patients with cT1-T2 prostate cancer and HGPIN on prostatic biopsy were randomized to receive bicalutamide (150 mg/day for 3 months) before RP, or to have immediate surgery. Surgical specimens were assessed for the histopathological features of cancer, HGPIN and benign epithelium in a blinded manner. The volumes of prostate cancer and HGPIN were evaluated using a stereological (i.e. grid) method. RESULTS: Compared with the bicalutamide-treated group, the ratio of stroma to epithelium, evaluated by visual microscopic assessment in the normal epithelium of the three prostate zones, was significantly lower in the control group, at 2.27 (sd 1.13), than in the treated group, at 1.87 (sd 0.72) (P = 0.048). The mean (sd) tumour volume was significantly lower in the bicalutamide-treated than in the control group, at 0.914 (0.13) vs 1.47 (0.24) mL (P = 0.044). Similarly, the mean (sd) volume of HGPIN was significantly lower in the bicalutamide-treated than in the control group, at 0.34 (0.06) vs 0.62 (0.07) mL (P = 0.003). At RP, specimen Gleason scores in the bicalutamide-treated group were similar to those in the control group, and were no different from the biopsy Gleason scores. CONCLUSIONS: Involution and epithelial shrinkage of prostate cancer and HGPIN were evident after neoadjuvant treatment with bicalutamide 150 mg. There was no evidence of the emergence of higher-grade cancer after treatment.     

Contrast‐enhanced colour Doppler‐targeted vs a 10‐core systematic repeat biopsy strategy in patients with previous high‐grade prostatic intraepithelial neoplasia

Study Type – Diagnosis (case series)
Level of Evidence 4

OBJECTIVE

To compare the results of contrast‐enhanced colour Doppler (CECD)‐targeted prostate biopsy with a systematic 10‐core grey‐scale biopsy scheme in patients initially diagnosed with high‐grade prostatic intraepithelial neoplasia (HGPIN), as although HGPIN is thought to be a precursor to invasive adenocarcinoma, its diagnosis is no longer considered an indication for repeat prostate biopsy and patients should be followed by prostate‐specific antigen levels and a digital rectal examination.

PATIENTS AND METHODS

In all, 104 patients (aged 45–78 years) diagnosed with HGPIN on initial prostate needle biopsy were referred for a repeat biopsy within 6 months. Two independent examiners evaluated each patient; one used CECD‐targeted biopsy (up to five cores) into hypervascular regions in the peripheral zone only, and subsequently the second took a systematic 10‐core grey‐scale biopsy. Cancer detection rates of both techniques were compared.

RESULTS

Overall, 26 of the 104 men (25%) had prostate cancer in the repeated biopsy. Using the CECD technique cancer was detected in 21% (22 of 104). The positive re‐biopsy rate using the systematic technique was 9.6% (10 of 104; P < 0.001). The total incidence of HGPIN with no evidence of tumour on re‐biopsy was 8.7% (nine of 104). The Gleason score in all 22 cancers detected with the CECD technique varied between 6 and 8. The systematic technique detected cancers with Gleason scores of 6 or 7. There were no adverse events or complications.

CONCLUSION

CECD increased the detection rate of prostate cancer, and using fewer biopsy cores than the systematic biopsy technique in patients previously diagnosed with HGPIN.     

Lesions missed on prostate biopsies in cases sent in for consultation

BACKGROUND: There are no reports on how often lesions are missed on prostate needle biopsies. METHODS: Over a 10-month period, 8/99 to 5/00, 3,251 prostate biopsy cases were seen in consultation. RESULTS: We identified 87 (2.7%) patients with missed lesions (n = 9 academic hospitals; n = 44 community hospitals; n = 34 commercial labs). Overall, 119 lesions were missed in 87 patients. Missed lesions were as follows: small atypical glands suspicious for cancer (41 lesions in 35 patients), prostatic adenocarcinoma (39 cancers in 32 patients), high grade prostatic intraepithelial neoplasia (HGPIN) (34 lesions in 30 patients), and HGPIN with adjacent small atypical glands (five lesions in five patients)--some men with more than one type of missed lesion. Detection of the missed lesions would have resulted in either: a definite change in care in 15 of 3,251 (0.5%) patients or a possible change in care (bilateral cancer vs. unilateral cancer; HGPIN vs. atypical) in 17 (0.5%) patients. In 21 (24%) of the cases, the slides were seen by at least two pathologists prior to consultation at our hospital. CONCLUSIONS: Although the number of prostate biopsies with missed lesions in a consult-based population of prostate biopsies appears relatively high (2.7%), the detection of the missed lesions would have only effected a definite change in care in 0.5% of all patients or a possible change in care in another 0.5% of patients. Our data underestimates missed lesions, as the entire specimen was not submitted for review in 41% of cases. Although our incidence of missed lesions gives some indication as to the magnitude of the problem, it cannot be equated with the risk of missing lesions in unselected cases.     

Canine prostatic intraepithelial neoplasia: Is the comparative model relevant?

BACKGROUND: Histologic sections from an archival collection of a veterinary teaching hospital were examined to determine the likelihood of detection of canine high-grade prostatic intraepithelial neoplasms (HGPIN), as a prelude to use of the canine model of prostatic carcinogenesis for chemopreventive strategies. METHODS: Tissue specimens representing clinically healthy (normal) prostate glands, benign prostatic hyperplasia, and prostatic carcinoma were examined in one tissue plane for histological evidence of HGPIN. RESULTS: No histological evidence of HGPIN was detected in 20 normal prostate glands or 95 prostate glands with benign prostatic hyperplasia. Seven of 20 prostatic carcinomas had synchronous HGPIN. CONCLUSIONS: Histological evidence of HGPIN is unlikely to be detected in the healthy or hyperplastic canine prostate gland with the clinically-procured biopsy. This might diminish the usefulness of canine HGPIN in temporal studies of chemoprevention of prostate cancer. HGPIN was found simultaneously with prostatic carcinoma in more than one-third of the carcinomas examined.     

Role of endothelin axis in progression to aggressive phenotype of prostate adenocarcinoma

BACKGROUND: Mitogenic and anti-apoptotic actions of endothelin-1 (ET-1) are mediated through endothelin A (ET(A)) receptors. We investigated endothelin receptor expression in increasingly aggressive phenotype and in vivo effects of combination therapy using ET(A) antagonist with paclitaxel. METHODS: Dunning prostate cancer cells ranged in aggressiveness from non-tumorigenic G, to tumorigenic, non-metastatic AT-1, and to tumorigenic and metastatic MLL. Binding assays were performed alongside Q-PCR to assess receptor density. MLL xenografts were treated with vehicle, atrasentan, paclitaxel, and paclitaxel+atrasentan. RESULTS: Saturation binding assays demonstrated endothelin receptor density of MLL and AT-1 cells seven- and threefold higher than G cells, respectively. Q-PCR showed 9- and 4.5-fold greater ET(A) mRNA expression in MLL and AT-1 than G cells, respectively and no endothelin receptor B (ET(B)) expression. Combination therapy had significant effect on reduction of tumor volume than paclitaxel or atrasentan alone. CONCLUSIONS: ET(A) expression increases in aggressive prostate carcinoma. ET(A) blockade combined with paclitaxel may reduce tumor growth in advanced prostate carcinoma.