Insulin-like growth factor (IgF)-I,IgF binding protein-3, and prostate cancer: correlation with gleason score

Introduction

Non-androgenic growth factors are involved in the growth regulation of prostate cancer (PCa).

Objective

This is the first Brazilian study to correlate, in a population of patients operated for PCa, PSA, total testosterone, insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) with Gleason score and to compare with a control group with benign prostate hyperplasia (BPH).

Materials and Methods

This retrospective single-center study included 49 men with previously diagnosed PCa and 45 with previously diagnosed BPH. PSA, testosterone, IGF-I, IGFBP-3 were determined in both groups.

Results

PSA and IGFBP-3 levels were significantly higher in the PCa group as compared to the BPH group (p<0.001 and p=0.004, respectively). There was a significant difference when we compared the PSA before surgery (p<0.001) and at the inclusion in the study (p<0.001) and IGFBP3 (0.016) among patients with Gleason <7, ≥7 and BPH. In the PCa group, PSA, testosterone, IGF-I and IGFBP-3 levels were comparable between Gleason <7 and ≥7.

Conclusions

Our data suggest that in localized PCa, the quantification of PSA and, not of IGF-1, may provide independent significant information in the aggressiveness. IGFBP-3 could be a biochemical marker of disease control in PCa patients.     

Insulin-like growth factors and their binding proteins in prostate cancer: Cause or consequence?☆

Insulin-like growth factors (IGFs) promote growth and survival of many types of tumor cells. Epidemiologic studies have implicated carcinogenesis with high levels of IGFs in circulation or in tissues. The levels of IGF binding proteins (IGFBPs) have been associated with reduced risk for prostate and other cancers. Experimental studies have implicated high levels of IGF-I directly and IGFBP-3 inversely in prostate cancer growth, survival, and progression. However, recent evidence suggests a much weaker association of IGF-I with prostate cancer development and a stronger antagonistic association of IGFBP-3 with prostate cancer progression. Considering the clonal heterogeneity and unpredictable progression pattern of prostate cancer, the role of any single growth factor or its regulator (IGFBP) as a single determining factor is limited. This review is a critical appraisal of the role of IGFs, IGFBP, and IGF-I receptor (the IGF axis) in both experimental and clinical prostate cancer genesis and progression.     

Concordance of tumor differentiation among brothers with prostate cancer

Background

Genetic factors seem to be of greater importance in prostate cancer than in other forms of cancer. Studies have suggested familial concordance in survival, but the extent to which that is due to tumor characteristics is not known.

Objective

We hypothesized that a brother of an index case with prostate cancer is at particularly increased risk of prostate cancer with the same tumor differentiation as the index case.

Design, setting and participants

We identified 21 930 brothers of index cases with prostate cancer in the Prostate Cancer Data Base Sweden and followed them up for incidence of prostate cancer.

Outcome measurements and statistical analysis

The relative risk of Gleason score–specific prostate cancer in the cohort of brothers was estimated by using the standardized incidence ratio (SIR) stratified by Gleason score of the index case. We estimated 95% confidence intervals (CIs) assuming a Poisson distribution.

Results and limitations

Among brothers of index cases with Gleason score 8–10 cancer, the SIR was 2.53 (95% CI, 1.97–3.21) for a Gleason score 2–6 cancer and 4.00 (95% CI, 2.63–5.82) for a Gleason score 8–10 cancer. SIR for Gleason score 2–6 cancer among brothers decreased with time since the date of the index cases’ diagnoses, whereas the risk of Gleason 8–10 cancer increased over time for brothers of index cases with Gleason 8–10 cancer (p for trend = 0.009).

Conclusions

Brothers of men with high-grade prostate cancer are at particularly increased risk of high-grade prostate cancer. Likewise, there is a concordance of less malignant prostate cancers within families. These findings may have direct clinical relevance for counseling men with a family history of prostate cancer.     

Expression of the tumour antigen T21 is up-regulated in prostate cancer and is associated with tumour stage

What's known on the subject? and What does the study add? T21 is an immunogenic prostate‐associated tumor antigen identified by SEREX expression cloning and shown to have a highly restricted mRNA expression profile. This study shows the expression of T21 at the protein level in a panel of tissues and cell lines and demonstrates increasing levels of T21 protein expression in patients with more advanced stage prostate cancer.

OBJECTIVES

• ? To define the expression pattern of the tumour antigen T21 at the protein level in prostate tissues, prostate cell lines and a panel of normal tissues.
• ? To correlate the expression pattern of T21 in prostate cancer with clinical parameters.

PATIENTS AND METHODS

• ? Tissue samples were collected from 79 patients presenting at clinic with either prostate cancer (63 patients) or benign prostatic hyperplasia (BPH, 16 patients).
• ? A tissue microarray (TMA) was constructed from 44 of the prostate cancer tissues and areas of benign disease (43 patients) from these tissues were also included on the TMA. The remaining tissues (prostate cancer 19 patients and BPH 16 patients) were mounted fresh frozen onto cork boards and sectioned.
• ? Full ethical approval was granted for all aspects of the study and informed patient consent was taken before tissue collection.
• ? Immunohistochemistry was used on the prostate tumour TMA, the normal tissue TMA and the fresh‐frozen prostate tissues. Fluorescent microscopy and flow cytometry was performed on prostate cell lines.

RESULTS

• ? Expression of T21 was highly restricted within normal tissues with only the stomach, ovary, breast and prostate having detectable T21 expression.
• ? T21 was significantly over‐expressed in prostate cancer glands compared with benign tissue and was present in >80% of the malignant specimens analysed.
• ? Increased expression was positively correlated to pathological stage of prostate tumours.
• ? Additionally, T21 was associated with Gleason grade and prostate‐specific antigen recurrence, although statistical significance was not reached in this restricted cohort of patients.

CONCLUSION

• ? Taken together these results show that T21 is a potential new biomarker for advanced disease and that elevated levels of T21 appear relevant to prostate cancer development.

     

XPA-210: a new proliferation marker determines locally advanced prostate cancer and is a predictor of biochemical recurrence

Purpose

XPA-210 is a proliferation marker derived from Thymidine kinase-1. It is of clinical significance in kidney, breast, and bladder cancer. There are no data available for XPA-210 in prostate cancer (PC). Herein, we aim to determine the clinical usefulness of XPA-210 in PC.

Materials and methods

In a retrospective study, cancer and benign tissue samples of 103 patients (median age 65?years, median PSA 9.04?ng/ml, median Gleason score 6) who underwent prostatectomy were constructed to a tissue micro array and stained for XPA-210. Semi-quantitative results were correlated with pathological and clinical data by Wilcoxon–Kruskall–Wallis and linear regression analysis. Expression levels in PC were correlated between the time of biochemical recurrence and the time to development of metastasis by the Kaplan–Meier method. Multivariate analysis was done to correlate those with the resection status.

Results

Mean staining score was 0.51–0.14 for tumor and benign tissue (P?P?2 (P?=?0.0007). When dividing the tumor score by the mean value, higher expression of XPA-210 was associated with a shorter time to biochemical recurrence (P?=?0.003) and time to development of metastasis (P?=?0.0061). Tumor staining (P?=?0.0371) was an independent prognostic factor for biochemical relapse regardless of resection status.

Conclusions

XPA-210 is a new tissue-based prognostic marker for prostate cancer histopathology. It reliably differentiates tumor and normal prostatic tissue predicting biochemical relapse and onset of metastatic disease. XPA-210 might be clinically useful for individual decision-making in PC-treatment.     

Objektivierung des Tumorgradings bei Prostatakarzinomen anhand der fraktalen Dimensionen

Background

Significant intra- and interobserver variability ranging between 40 and 80% is observed in tumor grading of prostate carcinoma. By combining geometric and statistical methods, an objective system of grading can be designed.

Material and methods

The distributions of cell nuclei in two-dimensional patterns of prostate cancer classified subjectively as Gleason score 3+3, 3+4, 4+3, 4+4, 4+5, 5+4, and 5+5 were analyzed with algorithms measuring the global fractal dimensions of the Rényi family and with the algorithm for the local connected fractal dimension (LCFD).

Results

The dimensions for global fractal capacity, information, and correlation (standard deviation) were 1.470 (045), 1.528 (046), and 1.582 (099) for homogenous Gleason grade 3 (n = 16), 1.642 (034), 1.678 (041), and 1.673 (084) for homogenous Gleason grade 4 (n=18), and 1.797 (042), 1.791 (026), and 1.854 (031) for homogenous Gleason grade 5 (n=12), respectively. The LCFD algorithm can be used to distinguish both qualitatively and quantitatively between mixed and heterogeneous patterns, such as Gleason score 3+4=7a (intermediate risk cancer) and Gleason score 4+3=7b (high-risk cancer). Sensitivity of the method is 89.3%, and specificity 84.3%.

Conclusion

The method of fractal geometry enables both an objective and quantitative grading of prostate cancer.     

ID4 is frequently downregulated and partially hypermethylated in prostate cancer

Purpose

The candidate tumor suppressor ID4 is downregulated in various cancers by DNA hypermethylation. We have performed the first systematic analysis of ID4 expression and methylation in prostate cancer.

Methods

ID4 mRNA expression was analyzed by quantitative RT-PCR in 47 carcinoma and 13 benign prostatic tissues obtained by prostatectomy. Methylation was analyzed in an extended series of samples by methylation-specific MS-PCR and pyrosequencing, controlled by bisulfite sequencing.

Results

ID4 expression was significantly decreased in prostate cancers, especially in cases with adverse clinical and histopathological features and earlier recurrence. Hypermethylation in carcinomas was detected by MS-PCR and pyrosequencing, but the results of the two techniques were not fully concordant. The difference was created by generally partial and heterogeneous methylation. Weak methylation was also detected in benign prostatic tissue samples.

Conclusions

ID4 downregulation may contribute to prostate cancer pathogenesis and is often accompanied by DNA hypermethylation. The case of ID4 illustrates exemplarily the limits and pitfalls of techniques for the detection of methylation changes in prostate cancer tissues.     

Serial analysis of resected prostate cancer suggests up‐regulation of type 1 IGF receptor with disease progression

What’s known on the subject? and What does the study add? In a previous study of diagnostic prostate biopsies, we showed that the insulin‐like growth factor (IGF) receptor is up‐regulated in primary prostate cancers. In this study we identified prostate cancer cases in which multiple transurethral resections had been performed, and showed that IGF receptor expression increased or remained high with disease progression. Thus, the IGF receptor is an attractive therapeutic target for patients with advanced prostate cancer.

OBJECTIVE

• ? To compare immunostaining protocols using different antibodies for the type 1 insulin‐like growth factor receptor (IGF‐1R) in channel transurethal resection of the prostate (chTURP) chips, and to investigate how IGF‐1R expression varies with time in serial prostate cancer specimens from individual patients.

METHODS

• ? We studied IGF‐1R expression in 44 prostate cancer specimens from 18 patients who had undergone serial chTURP at least 3 months apart.
• ? Retrospective analysis of the hospital notes was undertaken to obtain clinical information, including age, Gleason score, prostate‐specific antigen (PSA) level, hormone treatment and metastatic disease status at the time of each operation.
• ? After an optimization process using three commercially‐available IGF‐1R antibodies, we used two antibodies for semiquantititve immunostaining of serial chTURP chips.

RESULTS

• ? Santa Cruz antibody sc713 gave positive staining in IGF‐1R null R– cells, and was not used further. Antibodies from Cell Signaling Technology (Beverly, MA, USA) (CS) and NeoMarkers Inc. (Fremont, CA, USA) (NM) did not stain R– cells and, in prostate tissue, showed staining of the glandular epithelium, with negligible stromal staining. All 44 chTURP samples contained identifiable malignant tissue and, of these, 73% and 64% scored moderately or strongly (score 3 or 4) with the CS and NM antibodies respectively.
• ? There was significant correlation of IGF‐1R scores of malignant tissue between the two antibodies (P < 0.001). By contrast, staining of benign glands showed poor correlation between antibodies: CS gave significantly weaker staining than malignant epithelium in the same sections (P < 0.001), whereas NM showed poor discrimination between malignant and benign glands. IGF‐1R staining scores generated by the CS antibody were used to analyze the clinical data.
• ? Most patients (six of seven) with falling IGF‐1R staining scores were responding to androgen deprivation therapy (confirmed by PSA response) between operations. Conversely, in seven of eight patients who had progression to androgen‐independence between procedures, IGF‐1R levels increased or remained high. Finally, seven of 11 patients who developed radiologically confirmed metastases between procedures showed stable or increasing IGF‐1R staining scores.

CONCLUSION

• ? The present study is the first to assess changes in IGF‐1R expression in serial prostate cancer samples. The results obtained indicate that IGF‐1R expression usually remains high throughout the course of histologically‐proven disease progression in serial specimens, suggesting that the IGF‐1R remains a valid treatment target for advanced prostate cancer.

     

Down-regulation of protein kinase,DNA-activated,catalytic polypeptide attenuates tumor progression and is an independent prognostic predictor of survival in prostate cancer

Objective

Protein kinase, DNA-activated, catalytic polypeptide (PRKDC) is a critical component of DNA repair machinery and its dysregulated expression has been observed in various cancer types or premalignant cells. However, its role in prostate cancer (PCa) development and its prognostic significance in PCa is unknown.

Immunohistochemical Localization of Metallothionein in Human Prostate Cancer

Purpose

We investigated the expression of metallothionein in human prostate cancer.

Materials and Methods

Formalin fixed and paraffin embedded tissue specimens from 45 patients with primary prostate cancer were stained for metallothionein using a standard immunohistochemical technique.

Results

Metallothionein was detected in 15 of 45 prostate cancers (33.3 percent). Cytoplasmic and nuclear staining occurred in most cells. Additionally, metallothionein was found in basement membrane surrounding the cancer cells in 2 cases with metallothionein expression, and in secretory products of the lumen in a few cases. Statistical analysis for metallothionein expression related to tumor grade revealed a significant difference between high (7 to 10) and low (2 to 4) Gleason scores (p less than 0.001), as well as between middle (5 and 6) and low scores (p less than 0.05). However, no relationship was found with clinical stage.

Conclusions

Our data suggest a close correlation of metallothionein expression with tumor grade and a wide range of metallothionein expression in prostate cancer.     

THE VALUE OF THE RATIO OF FREE-TO-TOTAL PROSTATE SPECIFIC ANTIGEN FOR STAGING PURPOSES IN PREVIOUSLY UNTREATED PROSTATE CANCER

Purpose

We analyzed the use of the ratio of free-to-total prostate specific antigen (PSA), also termed percentage of the free PSA, for predicting tumor stage, volume and grade in patients with clinically localized prostate cancer.

Materials and Methods

A total of 515 consecutive patients underwent further prostate evaluation due to elevated PSA (greater than 4.0 ng./ml.) or abnormal digital rectal examination. Prostate cancer was diagnosed in 307 patients (59.6%), including 170 (55.4%) who underwent radical retropubic prostatectomy. Data on pathological stage, Gleason grade, and total and Gleason grade 4 cancer volume were available in all patients. In the remaining 208 men (40.4%) benign prostate hyperplasia was diagnosed. Total and free PSA was measured in preoperative serum.

Results

Total PSA was significantly higher (p <0.0001) in the 71 men with stage pT3 tumors than in the 91 with pT2 disease. Eight patients had stage pT4 tumors. Cancer volume correlated well with advancing pathological stage (p <0.0001) and total PSA (p <0.0001). The free-to-total PSA ratio was not significantly different (p = 0.93) in stages pT2 and pT3 tumors, and it did not correlate with total (p = 0.71) or pure Gleason grade 4 (p = 0.94) cancer volume. However, the ratio of free-to-total PSA tended to decrease (p = 0.07) in tumors of increasing Gleason grade.

Conclusions

The ratio of free-to-total PSA does not help in the preoperative prediction of final tumor stage and volume. However, disease grading may alter the free-to-total PSA ratio.     

Observed correlation between the expression levels of catalytic subunit,Cβ2, of cyclic adenosine monophosphate–dependent protein kinase and prostate cancer aggressiveness

Background

Today overtreatment of indolent prostate cancers and undertreatment of aggressive prostate cancer are a major concern for patients, their families, and the health care system. New biomarkers distinguishing indolent and aggressive prostate cancer are needed to improve precision medicine. In prostate cancer, protein kinase A (PKA) is known to activate the androgen receptor and published data indicate that PKA subunits can act as predictive markers for response to radiation and chemotherapy. We have previously shown that the catalytic subunit, Cβ2, of PKA is up-regulated in prostate cancer and we would in this study investigate the potential of Cβ2 to become a prognostic biomarker in prostate cancer.

CXCR4 is highly expressed at the tumor front but not in the center of prostate cancers

Objective

To evaluate the expression of CXCR4, its ligand SDF-1, β-catenin and E-cadherin throughout the local tumor microenvironment of prostate cancer.

Patients and methods

A total of 64 prostate cancer specimens, 24 frozen and 40 paraffin-embedded sections, were obtained from patients treated with radical prostatectomy for clinically localized cancer. Real-time RT-PCR was used for mRNA quantification of CXCR4 and SDF-1 in the tumor center (T), tumor front (F) and distant peritumoral tissue (D). Immunohistochemical analysis was used to investigate the expression patterns of CXCR4, E-cadherin and β-catenin. Clinical records of these patients were studied for follow-up data, and the prognostic value of these molecules’ expression was statistically assessed.

Results

CXCR4 mRNA and protein were significantly increased at the tumor front as compared to distant tissue or tumor center. In comparison, SDF-1 mRNA level gradually increased from the tumor center to the distant peritumoral tissue. High CXCR4 at the tumor front was associated with high Gleason score. Low SDF-1 at the tumor front was associated with locally advanced cancer and disease recurrence. Moreover, high CXCR4 staining at the tumor front and increased cytosolic E-cadherin expression in the same location was associated with locally advanced disease.

Conclusions

CXCR4 seems overexpressed at the tumor front of prostate tumors, where it potentially promotes cell migration toward the SDF-1 centrifugal attracting gradient, as well as epithelial–mesenchymal transition. High CXCR4 and low SDF-1 levels at tumor front were both associated with adverse histological features.

     

Impalpable Invisible Stage T1c Prostate Cancer: Characteristics and Clinical Relevance in 100 Radical Prostatectomy Specimens-A Different View

Purpose

We analyzed 100 consecutive radical prostatectomy specimens to evaluate the extent and clinical relevance of the stage T1c cancers discovered.

Materials and Methods

All cases were diagnosed by systematic prostatic puncture biopsies because of abnormal prostate specific antigen (PSA) or PSA density. Surgical specimens were examined with the whole organ multiple step-section technique (4 mm.) to identify primary tumor location (peripheral or transition zone cancer), tumor volume, tumor volume divided by prostate volume (percent tumor volume), Gleason score, pathological T stage and positive surgical margins. Tumors smaller than 0.5 cm.³ and without unfavorable pathology (Gleason score 7 or more, or positive surgical margins) were considered insignificant.

Results

Median patient age, PSA, tumor volume and Gleason score were 64 years, 8.8 micro g./l., 1.6 cm.³ and 6, respectively. Of the specimens 46 (46%) had transition zone cancer that was clinically undetectable due to anterior location, while peripheral zone cancers were small, diffuse, anterolateral or in large glands with low percent tumor volume. Transition zone cancer showed greater PSA, PSA density, tumor volume and percent tumor volume than peripheral zone cancer (p = 0.08, 0.03, 0.0002 and 0.0004, respectively), yet with similar Gleason score (p = 0.4). Of the tumors 34 (34%) were locally advanced (stage pT3 and/or positive surgical margins, mostly anterior in 16 transition zone cancers, and apical or posterolateral in 18 peripheral zone cancers), whereas 22 were insignificant (6 transition and 16 peripheral zone cancers). Prostatic puncture biopsies with a core cancer length of less than 3 mm. could have predicted 18 of 19 insignificant tumors but underestimated 13 (33%) and 6 (17%) significant transition and peripheral zone cancers.

Conclusions

The majority of our stage T1c tumors were significant with a distinguished high incidence of transition zone cancer. Therefore, they were large but occult. Transition zone cancer behaved differently than peripheral zone cancer, and warranted considerations during treatment of stage T1c prostate carcinoma.     

Characterization of insulin-like growth factors and their binding proteins in peritoneal dialysate

.Serum insulin-like growth factors (IGFs), which circulate bound to specific IGF binding proteins (IGFBPs), must exit the intravascular space before acting on target tissues. Little is known about the nature of IGF/IGFBPs in extravascular fluids of patients with chronic renal failure (CRF). Peritoneal dialysate (PD) was studied since, after a short incubation, PD contains proteins which have entered an extravascular space; thus, IGF/IGFBP forms in PD are more likely than serum forms to interact with target tissues. IGF-I and IGF-II, and IGFBPs 1 – 4, were readily identified by specific immunoassays and/or ¹²⁵iodine-IGF ligand blotting of simultaneously obtained PD and serum samples from seven CRF children; IGFBP-3 was a major IGFBP in PD as in serum. Where quantitated, IGF and IGFBP levels in PD were approximately 10% of serum concentrations. After separation of PD and serum by size-exclusion chromatography, serum had more IGFBP-3 in 150-kilodalton (kDa) than 35-kDa fractions, while PD had far less IGFBP-3 in 150-kDa than 35-kDa fractions. Immunoblot studies revealed a major 29-kDa IGFBP-3 fragment, in addition to intact 41- and 38-kDa IGFBP-3 forms, in PD and CRF serum; the 29-kDa form predominated in the 35-kDa PD fractions. These data suggest that the 29-kDa fragment is the IGFBP-3 form most likely to modulate IGF effects on target tissues of CRF individuals. Received: April 17, 1995; received in revised form September 19, 1995; accepted October 12, 1995     

DIFFERENTIAL NUCLEAR MATRIX PROTEIN EXPRESSION IN PROSTATE CANCERS: CORRELATION WITH PATHOLOGIC STAGE

Purpose

Nuclear Matrix Proteins (NMP) have been shown to be tissue and cell-type specific. Several unique NMPs have been investigated in various cancerous tissues, including prostate, bladder and kidney, and some are presently utilized as tumor markers. This study was aimed at characterizing the differential NMP expression in the pathologically more aggressive prostate cancers.

Methods

High resolution two-dimensional gel electrophoresis and silver staining was used to elucidate the NMP distribution of fresh prostate cancer nuclei, obtained from 39 radical prostatectomy specimens, surgically removed from men with clinically localized prostate cancer. Based on the final pathological grading, specimens were grouped according to predicted prognosis: poor-with seminal vesicle (SV) or lymph node (LN) involvement or established capsular penetration (ECP) with gleason score >7; intermediate-organ confined (OC) or focal capsular penetration (FCP) with gleason score 7 or ECP with gleason score 6; and good-with OC or FCP and gleason score <7.

Results

A specific charged protein (YL-1) of molecular weight 76 kD and isoelectric range 6.0-6.6 was found to be consistently present in 19 of 19 aggressive cancers. It was present only in 1 of 10 in the group with good prognosis and weakly positive in 9 of 10 in the intermediate group.

Conclusions

Within this preliminary study, the expression of YL-1 appears to be related to aggressive prostate cancer, suggesting a potential marker of poor prognosis for clinically localized prostate cancer. Further characterization of the identity and function of this NMP is needed to fully ascertain its clinical potential.     

Role of insulin-like growth factor binding proteins in 1alpha,25-dihydroxyvitamin D(3)-induced growth inhibition of human prostate cancer cells

BACKGROUND: The mechanisms underlying 1alpha,25-dihydroxyvitamin D(3) (1,25D)-induced growth inhibition of human prostate cancer cells have not been fully elucidated. To determine whether alterations in the insulin-like growth factor (IGF) signaling axis are associated with 1,25D-induced growth inhibition, we examined the ability of 1,25D to regulate expression of IGF binding proteins (IGFBPs) in human prostate cancer cell lines. METHODS: Northern and Western blot analyses were used to detect 1,25D-induced alterations in IGFBP expression. Additional in vitro studies were performed to determine the role of IGFBP-3 in 1,25D-induced growth inhibition. RESULTS: 1,25D decreased mRNA levels of the growth stimulatory IGFBP-2 and induced IGFBP-3 mRNA in LNCaP and C4-2 cells. 1,25D treatment also increased secreted IGFBP-3 protein levels in prostate cancer cell lines sensitive to 1,25D growth inhibition but had little effect on IGFBP-3 expression in 1,25D-resistant DU145 cells. However, recombinant IGFBP-3 had only a minor effect on LNCaP cell growth in the presence of serum. Furthermore, siRNA duplexes that reduced IGFBP-3 expression did not alter 1,25D growth inhibition in either LNCaP or PC-3 cell lines grown in serum-containing media. CONCLUSIONS: Our studies indicate 1,25D-induced up-regulation of IGFBP-3 is not required for the growth inhibitory effects of 1,25D in prostate cancer cells grown in serum-containing media.     

Expression and prognostic relevance of annexin A3 in prostate cancer

Objectives

By differential quantitative protein expression, it has previously been shown that annexin A3 (ANXA3) expression is associated with prostate cancer. However little is known about the role and biology of ANXA3 in the human prostate. The aim of this study was to thoroughly analyze ANXA3 expression patterns and its potential as a prognostic marker in a large set of benign, preneoplastic, and neoplastic prostate tissue samples.

Methods

Immunohistochemistry-based ANXA3 protein expression was analyzed for 1589 prostate cancers as well as smaller subsets of benign epithelium and high-grade prostatic intraepithelial neoplasia (PIN) in a tissue microarray format.

Results

All samples of benign prostatic epithelium and PIN showed ANXA3 protein expression, with PIN lesions showing a decreased staining intensity compared with benign epithelium (p < 0.0001). In cancer, ANXA3 protein expression was essentially reduced, resulting in a negative staining rate of 27.2%, which correlated with increasing pT stage and Gleason score (p < 0.0001). ANXA3 status in cancer was shown to be an independent adverse prognostic factor and enabled substratification of the large group of intermediate-risk patients (n = 969) into high- and low-risk subgroups.

Conclusions

ANXA3 represents a promising candidate tissue marker, and when combined with the standard prognostic parameters, is suggested to provide a more precise prediction of prognosis in the individual patient, therefore harboring the potential to contribute to future patient management.     

RANKL/RANK/OPG cytokine receptor system: mRNA expression pattern in BPH,primary and metastatic prostate cancer disease

Background

The cytokine system RANKL (receptor activator of NF-κB ligand), its receptor RANK and the antagonist OPG (osteoprotegerin) play a critical role in bone turnover. Our investigation was conducted to describe the gene expression at primary tumour site in prostate cancer patients and correlate the results with Gleason Score and PSA level.

Methods

Seventy-one samples were obtained from prostate cancer patients at the time of radical prostatectomy and palliative prostate resection (n = 71). Patients with benign prostate hyperplasia served as controls (n = 60). We performed real-time RT-PCR after microdissection of the samples.

Results

The mRNA expression of RANK was highest in tumour tissue from patients with bone metastases (p < 0.001) as compared to BPH or locally confined tumours, also shown in clinical subgroups distinguished by Gleason Score (< 7 or ≥ 7, p = 0.028) or PSA level (< 10 or ≥ 10 µg/l, p = 0.004). RANKL and OPG mRNA expression was higher in tumour tissue from patients with metastatic compared to local disease. The RANKL/OPG ratio was low in normal prostate tissue and high tumours with bone metastases (p < 0.05). Expression of all three cytokines was high in BPH tissue but did not exceed as much as in the tumour tissue.

Conclusion

We demonstrated that RANK, RANKL and OPG are directly expressed by prostate cancer cells at the primary tumour site and showed a clear correlation with Gleason Score, serum PSA level and advanced disease. In BPH, mRNA expression is also detectable, but RANK expression does not exceed as much as compared to tumour tissue.