Up-regulation of MKK4, MKK6 and MKK7 during prostate cancer progression: an important role for SAPK signalling in prostatic neoplasia

Identification of the signalling cascades that are differentially activated during prostatic tumourigenesis is a crucial step in the search for future molecular targets in this disease. The stress-activated protein kinase (SAPK) signalling cascade culminates in the phosphorylation of the JNK and p38 mitogen-activated protein kinases (MAPKs). Recently, the upstream activators of these proteins, the MAPK kinases (MKKs), have been implicated as inhibitors of tumour progression in a variety of clinical and experimental tumour models. This study evaluates MKK4, MKK6 and MKK7 expression during prostate cancer progression in humans and in the transgenic adenocarcinoma of a mouse prostate (TRAMP) model of prostate tumourigenesis. Benign prostate, prostatic intraepithelial neoplasia (PIN) lesions and tumour tissues were collected from 37 TRAMP mice. Additionally, six tissue microarrays were constructed with tumours from a matched group of 102 men who underwent radical prostatectomy. Tissues from 20 patients with extensive high-grade prostatic intraepithelial neoplasia (HGPIN) were also analysed. For all samples, immunohistochemical staining for MKK4, MKK6 and MKK7 was scored in normal and neoplastic glands. Staining intensities of MKK4, MKK6 and MKK7 were significantly increased in HGPIN and prostate cancer compared to surrounding normal glands in both the TRAMP and human samples (p < 0.0001 for all markers). Increased levels of MKK4 or MKK7 correlated with higher pathological stage at prostatectomy (p = 0.01 and p = 0.04). Using multivariate analysis, there was no association between protein levels and time to biochemical recurrence in the human samples. The up-regulation of MKK4, MKK6 and MKK7 during prostate cancer progression in both TRAMP and human tissues highlights an important role for the SAPK signalling cascade in prostatic neoplasia. The finding that higher MKK4 and MKK7 expression is associated with higher-stage prostatic tumours underscores the dynamic regulation of these proteins during prostatic tumourigenesis.     

Peripheral T cell tolerance occurs early during spontaneous prostate cancer development and can be rescued by dendritic cell immunization

In the tumor-prone transgenic adenocarcinoma mouse prostate (TRAMP) mouse model we followed the fate of the immune response against the SV40 large T antigen (Tag) selectively expressed in the prostate epithelium during the endogenous transformation from normal cells to tumors. Young (5-7-week-old) male TRAMP mice, despite a dim and patchy expression of Tag overlapping foci of mouse prostate intraepithelial neoplasia, displayed a strong Tag-specific cytotoxic T lymphocyte (CTL) response after an intradermal injection of peptide-pulsed dendritic cells (DC). This response was weaker than the one found in vaccinated wild-type littermates, and was characterized by a reduced frequency and avidity of Tag-specific CTL. Early DC vaccination also subverted the profound state of peripheral tolerance typically found in TRAMP mice older than 9-10 weeks. The DC-induced CTL response indeed was still detectable in TRAMP mice of 16 weeks, and was associated with histology evidence of reduced disease progression. Our findings suggest that tumor antigens are handled as self antigens, and peripheral tolerance is associated with in situ antigen overexpression and cancer progression. Our data also support a relevant role for DC-based vaccines in controlling the induction of peripheral tolerance to tumor antigens.     

Androgen-dependent prostate epithelial cell selection by targeting ARR(2)PBneo to the LPB-Tag model of prostate cancer

Cell cultures representing different stages of prostatic carcinoma will be a useful tool allowing a more complete understanding of the role of individual genes in tumorigenesis. We used the androgen-regulated probasin promoter linked to the neomycin phosphotransferase (Neo) gene, to generate the ARR(2)PBneo transgenic mouse model. Development was normal and all six ARR(2)PBneo transgenic founder lines expressed the Neo gene in a prostate-specific manner. Line C, which expressed high levels of neo, was crossbred to LPB-Tag 12T-7f transgenic mice (in which the SV40 large T antigen (Tag) was targeted to the prostate by the large probasin (LPB) promoter). Three bigenic males (carrying both Neo and Tag transgenes) were identified. Prostatic lesions developed in these mice in a predictable and heritable manner, indicating that Neo did not alter Tag-induced prostate tumor development and progression. Three separate NeoTag epithelial cell strains were established from three bigenic mice. G418 selection was used to obtain immortalized epithelial cells in culture. Selected cells expressed the Neo and Tag transgenes, cytokeratins 8 and 18, and were androgen responsive for growth. To determine if these NeoTag cells maintained a similar in vivo phenotype to the 12T-7f transgenic line, tissue recombinations were made with rat urogenital sinus mesenchyme (rUGM) and grafted under the renal capsule of male nude mouse hosts. In recombinants, the three NeoTag strains developed PIN lesions and/or more extensive adenocarcinoma than seen in the 12T-7f mouse. Androgen ablation demonstrated that the grafts were androgen responsive. NeoTag cells grafted without rUGM developed undifferentiated adenocarcinoma demonstrating that prostatic stroma dictates the glandular architecture seen in the well-differentiated adenocarcinoma.     

Inactivation of LGI1 expression accompanies early stage hyperplasia of prostate epithelium in the TRAMP murine model of prostate cancer

The LGI1 gene has been implicated in tumor cell invasion through regulation of the ERK pathway. To determine whether human prostate cancer cells (PC3, 22RV, Du145) are similarly affected by exposure to LGI1, we conducted scratch wound assays and demonstrated that the secreted LGI1 protein can reduce cell motility, an essential component of invasion and metastasis. These studies have now been extended to an in vivo mouse model of prostate cancer. Using a BAC transgenic mouse expressing a GFP reporter gene under the control of cis regulatory elements, we demonstrated that LGI1 is highly expressed in the normal prostate epithelium. To determine whether loss of LGI1 expression is associated with development and progression of murine prostate cancer, we bred the GFP reporter BAC transgenic mice with TRAMP mice which undergo early hyperplasia and progressive stages of prostate cancer. In the F1 animals, although the surrounding normal prostate epithelium expressed high levels of LGI1 in the double transgenic mice, the LGI1 gene had been inactivated even at the earliest stages of hyperplasia. This observation supports the suggestion that inactivation of LGI1 in certain cell types is related to tumor progression. Taken together these results suggest that LGI1 may be an important molecule for the arrest of prostate cancer cell invasion and possibly as a biomarker for early detection of prostate hyperplasia.     

Use of tissue recombination to predict phenotypes of transgenic mouse models of prostate carcinoma

Transgenic mouse models of cancer represent a powerful approach for exploring disease processes and testing potential therapeutic interventions. Currently, it is difficult to predict if a specific genetic manipulation will result in a desirable phenotype. The present study tests the idea that tissue recombinants recapitulate the pathologic features of the neoplastic prostate seen in transgenic mice, and would thus be suitable predictive models for new mouse design. The large probasin-large T-antigen (LPB-Tag) transgenic lines 12T-7f and 12T-10 were used as a basis for this study. Tissue recombinants of bladder epithelium (BlE) and urogenital sinus mesenchyme (UGM) were implanted under the renal capsule of athymic mice. Recombinants composed of BlE from 12T-10 LPB-Tag and wild-type (wt) UGM faithfully recapitulated the histopathologic and temporal features of intact transgenic mice of this line. Tissue recombinants using BlE from 12T-7f mice and wt UGM developed epithelial proliferation with atypia that lacked the associated hypercellular stroma seen in the intact 12T-7f line. Recombinants using 12T-7f UGM demonstrated that the hypercellular stroma results from stromal cell expression of the SV40 large T antigen. Corresponding to the recombinant phenotypes, stromal Tag immunostaining was observed in prostate tissues from intact 12T-7f but not 12T-10 mice. Similar stromal expression of Tag was also noted in the hypercellular TRAMP prostatic stroma. Further analysis revealed a previously unreported pattern of SV40T expression in the LADY and TRAMP models including ductus deferens and seminal vesicle stroma as well as region and cell type-specific patterns in the epididymis. The present study demonstrates the utility of using tissue recombination to explore organ-specific phenotypes. Recombination strategies should enable quick and cost-effective screening for likely phenotypes in transgenic animals. This comparison of tissue recombination to existing models shows that this approach can elicit new information on well-characterized models.     

A review of the existing grading schemes and a proposal for a modified grading scheme for prostatic lesions in TRAMP mice

The transgenic adenocarcinoma of the mouse prostate (TRAMP) model is well established and offers several advantages for the study of chemopreventive agents, including its well-defined course of disease progression and high incidence of poorly differentiated carcinomas within a relatively short length of time. However, there is no consensus on the grading of prostatic lesions in these mice. In particular, agreement is lacking on the criteria for differentiating prostatic intraepithelial neoplasia (PIN) from well-differentiated adenocarcinoma, specifically as it relates to evidence of invasion. This differentiation is critical for evaluating the effects of putative chemopreventive agents on progression to neoplasia. Moreover, only one of the published grading schemes assigns numerical grades to prostatic lesions, which facilitate statistical analysis. Here, we review five currently available grading schemes and propose a refined scheme that provides a useful definition of invasion for the differentiation of PIN from well-differentiated adenocarcinoma and includes a numerical scoring system that accounts for both the most severe and most common histopathological lesions in each of the lobes of the prostate and their distributions. We expect that researchers will find this refined grading scheme to be useful for chemoprevention studies in TRAMP mice.     

An investigation of the effects of late-onset dietary restriction on prostate cancer development in the TRAMP mouse

In our previous work we showed that dietary restriction initiated at puberty reduced prostate cancer development in the TRAMP mouse model. The current study was conducted to ascertain whether a dietary restriction regime would similarly reduce lesion development if imposed once tumor development was well established. Male TRAMP mice were maintained on an ad libitum diet until 20 weeks of age when proliferative prostate lesions are clearly evident. Mice were then subjected to a 20% restriction in dietary calories compared to matched controls, which were continued on ad libitum feeding. Mice were sacrificed at 20, 24, 32, and 39 weeks of age and proliferative epithelial lesions of the prostate were assessed using an established grading scheme. In this study, although dietary restriction reduced mean sex pluck weight (prostate and seminal vesicles), and mean grade of epithelial proliferative lesions in the dorsal and lateral lobes of the prostate, the effect was not as pronounced as was the case with dietary restriction from puberty. There was no relationship between serum insulin like growth factor (IGF-1) and prostate lesion grade. Additionally, we also report the relationship between lobe specific lesion development and SV40 immunostaining and, the occurance of neuroendocrine tumors (NETs) in the ventral prostate and urethra of the TRAMP mouse. NETs stained with high specificity and sensitivity for the neuroendocrine markers, synaptophysin and neuron-specific enolase (NSE), less for serotonin, but not for chromogranin A. NETs did not stain for cyclo-oxygenase-2 (COX-2) nor androgen receptor (AR). SV40 positive tubulo-acinar tumors seen occasionally in the kidney, did not stain for synaptophysin nor NSE.     

Age-related histopathological lesions in the Mongolian gerbil ventral prostate as a good model for studies of spontaneous hormone-related disorders

The Meriones unguiculatus (Mongolian) gerbil has demonstrated significant prostatic responses to hormonal treatments, and to drugs against human prostatic hyperplasia Spontaneous neoplasia develops in the older animals. Thirty gerbils (age 18 months) were divided into non-affected and prostatic lesion bearers and the prostate lesions were evaluated morphologically, immunohistochemically and quantitatively. The most frequent changes were in epithelial sites and, namely prostatic intraepithelial neoplasias, microinvasive carcinomas and adenocarcinomas. In the stromal compartment, cellular hyperplasia, when verified, was always associated with the sites of anomalous epithelium. Additionally, larger deposition of collagen fibrils, generating stromal fibrosis, was found in all the old gerbils analysed. The quantitative analysis showed that prostatic tissue proportions differed in altered areas, being specific for each lesion type. Isolated nuclear and nucleolar parameters were not effective in diagnosing the malign potential of lesions. However, the cellular proliferation and death indexes indicated larger cellular turnover in invasive lesions such as carcinomas. With these analyses, it could be verified that old gerbils present high propensity to develop spontaneous prostate changes and this may aid in a better understanding of the biological behaviour of human prostate cancer.     

Diagnostic utility of a p63/alpha-methyl-CoA-racemase (p504s) cocktail in atypical foci in the prostate.

Prostatic needle biopsy is the preferred method for diagnosing early prostate cancer, providing specific information. In cases of histological cancer mimics, a diagnosis of atypical small acinar proliferation suspected of but not diagnosed as malignancy can be made. In such cases, and in small focus carcinomas, pathologists use 34betaE12, cytokeratin (CK) 5/6 or p63 immunostaining to label basal cells, and alpha-methylacyl-CoA racemase (AMACR/p504s) immunostaining as a positive prostate cancer marker on two distinct slides. However, in cases of small foci, ambiguous lesions might disappear. The purpose of our study was to improve the sensitivity of a cocktail of two antibodies (p63/p504s) with a sample incubation on 260 prostatic specimens, in order to help make a decision in conjunction with standard histology and CK 5/6 immunostaining. We tested 101 small focus prostatic cancers, 104 atypical small acinar proliferation, 19 high-grade prostatic intraepithelial neoplasia, two atypical adenomatous hyperplasia and 34 benign mimics of cancer. After p63/p504s immunostaining, the final diagnoses retained were as follows: 154 prostatic cancers, 14 atypical small acinar proliferation, 30 high-grade prostatic intraepithelial neoplasia, three atypical adenomatous hyperplasia and 62 benign mimics of cancer. To differentiate malignant from benign lesions, we used the criteria of greater sensitivity to p504s/p63 (95%) than to CK 5/6 (57%) or p63 (86%), and higher specificity for p504s/p63 (95%) than for CK 5/6 (88%) or p63 (81%). With the p504s/p63 cocktail, 89% of the ambiguous lesions were classified vs 53% for CK 5/6. Combined use of the two antibodies, one (p504s) as a positive marker and the other (p63) as a negative marker, with a simple immunostaining procedure, may improve diagnostic performance, sensitivity and specificity, leading to a reduction in the risk of false negatives; this technique in cases of atypical small acinar proliferation should reduce the percentage of residual ambiguous lesions and the need for additional biopsies.     

The biological significance of atypical hyperplasia of the prostate

Summary In tissue biopsies and resection material (TUR) of the prostate a high coincidence (49.4%) was found between atypical primary hyperplasia with atypical-dysplastic microglandular, adenomatous and cribriform structures on the one hand and carcinomas on the other. The frequency of atypical hyperplasia in prostatic tissue without carcinoma was 2.8%. Microglandular pattern predominates in atypical hyperplasia combined with differentiated adenocarcinomas. A high coincidence between cribriformly structured glands of atypical primary hyperplasia and solid anaplastic — cribriform carcinomas can be observed.Autoradiographically the labeling index of atypical hyperplasia was three times as high as that of simple hyperplasia. The mean labeling index of atypical hyperplasia, however, was similar to that of poorly differentiated adenocarcinomas and cribriform carcinomas. The similar proliferation pattern of atypical hyperplasia and carcinomas as well as the high coincidence between both indicate that severe atypical primary hyperplasia is a precancerous lesion.Therefore, those patients with primary atypical hyperplasia with distinct cellular and structural atypia but without manifest carcinomas in prostatic biopsy or resection material should be followed up at short intervals.Supported by Landesamt für Forschung, Minister für Wissenschaft und Forschung des Landes Nordrhein-Westfalen, Düsseldorf     

The spectrum of morphology in non-neoplastic prostate including cancer mimics

The spectrum of morphology in non-neoplastic prostate includes lesions of prostatic epithelial origin, the most common being atrophy, including partial atrophy, adenosis (atypical adenomatous hyperplasia), basal cell hyperplasia and crowded benign glands, as well as those of non-prostatic origin, such as seminal vesicle epithelium. These lesions often mimic lower-grade prostatic adenocarcinoma whereas others, such as granulomatous prostatitis, for example, are in the differential diagnosis of adenocarcinoma, Gleason grades 4 or 5. Diagnostic awareness of the salient histomorphological and relevant immunohistochemical features of these prostatic pseudoneoplasms is critical to avoid rendering false positive diagnoses of malignancy.     

High-grade prostatic intraepithelial neoplasia: the only accepted prostate cancer precursor lesion

For many tumors the early detection of precursor lesions of invasive cancer has an impact on the clinical course. The high-grade prostatic intraepithelial neoplasia (HG-PIN) is the only accepted facultative precursor lesion for acinar prostate cancer. While HG-PIN shows many similarities to prostate cancer it is most probably not a precursor of every prostate cancer variant. However, the detection of HG-PIN in needle biopsies is a significant risk factor for the subsequent diagnosis of invasive prostate cancer. Low-grade PIN (LG-PIN), proliferative inflammatory atrophy (PIA), and atypical adenomatous hyperplasia are no longer considered to be true precursor lesions.     

Differential diagnosis of glandular proliferations in the prostate

 A variety of small acinar lesions of the prostate can mimic prostate cancer in punch biopsies and in transurethral resection material. The first part of this review deals with differential diagnostic problems of the central and transition zone, including atypical adenomatous hyperplasia of the prostate, atrophic processes, sclerosing adenosis, basal cell hyperplasia, and low-grade adenocarcinoma. The second part deals with differential diagnostic problems in the peripheral zone: prostatic intraepithelial neoplasia, postatrophic hyperplasia, Cowper’s glands, seminal vesicles, and ductal and intraductal carcinoma. Finally, atypical and small acinar proliferations are described. Diagnostic perspectives are discussed. Received: 23 June 1998 / Accepted: 13 August 1998     

CD44 expression is a feature of prostatic small cell carcinoma and distinguishes it from its mimickers

Small cell neuroendocrine carcinoma of the prostate is a rare variant of prostatic cancer that shares morphologic similarity with prostatic adenocarcinoma of Gleason 5 pattern. It has also been considered morphologically and immunohistochemically indistinguishable from small cell neuroendocrine carcinomas of other origins. CD44 is a cell-surface molecule proposed to identify cancer stem/progenitor cells in prostate cancer. We performed immunohistochemical study for CD44 expression in 11 cases of prostatic small cell neuroendocrine carcinoma and compared its patterns of expression with 73 cases of prostatic adenocarcinoma and 47 cases of small cell neuroendocrine carcinomas of other organs. Strong and diffuse membrane staining for CD44 was observed in 100% of the prostatic small cell neuroendocrine carcinomas. In conventional adenocarcinomas of the prostate, positive staining was only seen in rare, scattered tumor cells; and CD44 staining was negative in most of the small cell neuroendocrine carcinomas of nonprostate origin. The difference in CD44 expression between small cell neuroendocrine carcinomas of the prostate and those of other organs are statistically significant (P < .001). Our study demonstrates the utility of immunohistochemical staining for CD44 in distinguishing prostatic small cell neuroendocrine carcinoma from its mimickers including prostatic adenocarcinoma of Gleason 5 pattern and small cell neuroendocrine carcinomas of other organs. CD44 is the first marker that shows a high degree of tissue/organ specificity for small cell neuroendocrine carcinomas. Because CD44 is a putative marker of prostate cancer stem cells, the strong and diffuse expression of CD44 and the lack of expression of prostate luminal differentiation markers androgen receptor and prostatic specific antigen in prostatic small cell neuroendocrine carcinomas suggest that the tumor cells may retain cancer stem cell features.     

A human prostatic bacterial isolate alters the prostatic microenvironment and accelerates prostate cancer progression

Inflammation is associated with several diseases of the prostate including benign enlargement and cancer, but a causal relationship has not been established. Our objective was to characterize the prostate inflammatory microenvironment after infection with a human prostate‐derived bacterial strain and to determine the effect of inflammation on prostate cancer progression. To this end, we mimicked typical human prostate infection with retrograde urethral instillation of CP1, a human prostatic isolate of Escherichia coli. CP1 bacteria were tropic for the accessory sex glands and induced acute inflammation in the prostate and seminal vesicles, with chronic inflammation lasting at least 1 year. Compared to controls, infection induced both acute and chronic inflammation with epithelial hyperplasia, stromal hyperplasia, and inflammatory cell infiltrates. In areas of inflammation, epithelial proliferation and hyperplasia often persist, despite decreased expression of androgen receptor (AR). Inflammatory cells in the prostates of CP1‐infected mice were characterized at 8 weeks post‐infection by flow cytometry, which showed an increase in macrophages and lymphocytes, particularly Th17 cells. Inflammation was additionally assessed in the context of carcinogenesis. Multiplex cytokine profiles of inflamed prostates showed that distinct inflammatory cytokines were expressed during prostate inflammation and cancer, with a subset of cytokines synergistically increased during concurrent inflammation and cancer. Furthermore, CP1 infection in the Hi‐Myc mouse model of prostate cancer accelerated the development of invasive prostate adenocarcinoma, with 70% more mice developing cancer by 4.5 months of age. This study provides direct evidence that prostate inflammation accelerates prostate cancer progression and gives insight into the microenvironment changes induced by inflammation that may accelerate tumour initiation or progression. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Cytokeratin immunohistochemistry as a diagnostic tool for distinguishing malignant from benign epithelial lesions of the prostate.

The basal cell layer (BCL) is believed to be absent in malignant but present in nonmalignant epithelial lesions of the prostate. Using the avidin-biotin-peroxidase complex (ABC) immunoperoxidase method, we examined the value of the monoclonal antibody cocktail MA-903, which stains selectively the prostatic BCL layer, in the distinction between benign and malignant epithelial lesions of the prostate. We immunostained histologic sections of 63 prostates, containing 235 morphologic appearances: normal prostate glands, 43; benign prostate hyperplasia (BPH), 59; basal cell hyperplasia (BCH), 24; adenosis, seven; prostatic intraductal neoplasia (PIN 1), 21; PIN 2, 25; PIN 3, 16; and cancer, 40. Some degree (continuous, continuous with focal disruption, and disrupted patterns) of basal cell staining was demonstrable in all normal and BPH, BCH, and PIN 1 lesions, but was absent in 39 of 40 cancers. However, not every gland in benign lesions stained positively. Further, two of 25 PIN 2 and six of 16 PIN 3 lesions failed to reveal BCL. Our results suggest that the presence or absence of BCL, predicated on cytokeratin MA-903 immunoreactivity, may be a useful indicator in the distinction between benign and malignant epithelial lesions of the prostate.     

Common benign mimics of prostate cancer

A challenge in the diagnosis of prostate pathology is the numerous benign mimics of prostatic adenocarcinoma. Most of these lesions have no clinical significance but may be misinterpreted as cancer in biopsy specimens. In this review we describe the features of some of the more common benign mimics and discuss how they can be distinguished from carcinoma. The diagnostic entities most commonly associated with a false positive diagnosis of cancer are the atrophic group of lesions that include simple atrophy, partial atrophy and post-atrophic hyperplasia. Benign proliferations exhibit architectural atypia, often with closely packed small glands, but with no or little nuclear atypia. The most common diagnostic pitfall of this group is adenosis, which may have an even more atypical architecture than some cancers. A common denominator of atrophy and benign proliferations is that they consist of small glands that may have a patchy or absent basal cell layer, which adds to the diagnostic difficulties. Amongst hyperplastic and metaplastic lesions, basal cell hyperplasia may be misinterpreted as cancer because of its dark basophilic glands that sometimes display a certain degree of nuclear atypia and occasionally exhibit a pseudoinfiltrative pattern. The most important extraprostatic anatomical structure causing diagnostic difficulties is the seminal vesicle. The closely clustered small glands and often strikingly atypical nuclei of seminal vesicle epithelium may be misinterpreted as cancer. Awareness of these mimics is of paramount importance for the practicing pathologist as a false positive diagnosis of prostate cancer may lead to unnecessary radical therapy.     

Spontaneous lesions in control B6C3F1 mice and recommended sectioning of male accessory sex organs

Because sampling of the paired lobes (ventral, dorsal, lateral, and anterior) of the mouse prostate has often been inconsistent, comparisons among different investigations have lacked validity. The absence of site identification for prostatic lesions has made reported incidences relatively nonspecific. We present here the lobe-specific incidences and degree of severity of spontaneous lesions in prostate, coagulating gland (anterior prostatic lobe), seminal vesicles, and ampullary glands in 612 control B6C3F1 mice from 12 recent National Toxicology Program 2-year carcinogenicity and toxicity studies conducted in 1 of 4 different laboratories. Lymphocytic infiltration, inflammation, epithelial hyperplasia, mucinous cyst, and mucinous metaplasia were observed in the dorsolateral lobes. Lymphocytic infiltration, inflammation, epithelial hyperplasia, and edema were present in the ventral lobes. Lymphocytic infiltration, acinar dilatation, inflammation, epithelial hyperplasia, and atrophy occurred in the coagulating glands. No neoplastic lesions were observed in the prostate or coagulating gland. Lymphocytic infiltration, acinar dilatation, inflammation, atrophy, adenoma, adenocarcinoma, and a granular cell tumor were observed in the seminal vesicles. Lymphocytic infiltration was also present in the ampullary glands. The results of our survey indicate that the amounts of glandular tissues were not present consistently in slides from the different laboratories. Landmarks for uniform tissue trimming are needed. We therefore suggest an optimal trimming and embedding method for mouse prostate and seminal vesicles to ensure adequate, consistent sampling.     

Augmented expression of chromogranin A and serotonin in peri-malignant benign prostate epithelium as compared to adenocarcinoma

There is a growing body of evidence that the occurrence of neuroendocrine (NE) differentiation in prostate carcinoma correlates with poor prognosis, tumor progression, and androgen-independence. In the present study, the expression of common NE markers, i.e., chromogranin A (ChGA), serotonin (5HT), neuron-specific enolase (NSE) and adrenomedullin (AM), was retrospectively examined in formalin-fixed, paraffin-embedded prostate tissue samples obtained from patients with adenocarcinoma and from patients with nodular hyperplasia of the prostatic gland (NHPG) (33 and 28, respectively). The statistical analysis of the results (tested the equality of matched pairs of observations using the Wilcoxon matched-pairs signed ranks test) revealed a more prominent expression of ChGA in benign epithelial cells adjacent to adenocarcinomatic lesions (Peri-PAC) than in the adenocarcinoma (PAC) (p = 0.0049). A similar pattern of expression was detected for 5HT (p = 0.000). When comparing the expression of ChGA and 5HT in tissue samples originating in cancer patients with those obtained from NHPG samples, more ChGA and 5HT were expressed in Peri-PAC than in NHPG (p = 0.0004 and 0.002, respectively). The results obtained raise the possibility that adenocarcinoma cells urge some adjacent benign epithelial cells to differentiate into NE cells, which, in turn, may promote tumor growth and invasion.