Biomedical subjects

Rainer Kuefer

Publications and source records attributed to Rainer Kuefer.

At least 19 recordsLinked to original sources

PubMed2006

Elevated E2F1 inhibits transcription of the androgen receptor in metastatic hormone-resistant prostate cancer.

Activation of E2F transcription factors, through disruption of the retinoblastoma (Rb) tumor-suppressor gene, is a key event in the development of many human cancers. Previously, we showed that homozygous deletion of Rb in a prostate tissue recombination model exhibits increased E2F activity, activation of E2F-target genes, and increased susceptibility to hormonal carcinogenesis. In this study, we examined the expression of E2F1 in 667 prostate tissue cores and compared it with the expression of the androgen receptor (AR), a marker of prostate epithelial differentiation, using tissue microarray analysis. We show that E2F1 expression is low in benign and localized prostate cancer, modestly elevated in metastatic lymph nodes from hormone-naïve patients, and significantly elevated in metastatic tissues from hormone-resistant prostate cancer patients (P = 0.0006). In contrast, strong AR expression was detected in benign prostate (83%), localized prostate cancer (100%), and lymph node metastasis (80%), but decreased to 40% in metastatic hormone-resistant prostate cancer (P = 0.004). Semiquantitative reverse transcription-PCR analysis showed elevated E2F1 mRNA levels and increased levels of the E2F-target genes dihyrofolate reductase and proliferating cell nuclear antigen in metastatic hormone-independent prostate cancer cases compared with benign tissues. To identify a role of E2F1 in hormone-independent prostate cancer, we examined whether E2F1 can regulate AR expression. We show that exogenous expression of E2F1 significantly inhibited AR mRNA and AR protein levels in prostate epithelial cells. E2F1 also inhibited an AR promoter-luciferase construct that was dependent on the transactivation domain of E2F1. Furthermore, using chromatin immunoprecipitation assays, we show that E2F1 and the pocket protein family members p107 and p130 bind to the AR promoter in vivo. Taken together, these results show that elevated E2F1, through its ability to repress AR transcription, may contribute to the progression of hormone-independent prostate cancer.

Autopsy↗

PubMed2006

TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer.

Prostate cancer is a common and clinically heterogeneous disease with marked variability in progression. The recent identification of gene fusions of the 5'-untranslated region of TMPRSS2 (21q22.3) with the ETS transcription factor family members, either ERG (21q22.2), ETV1 (7p21.2), or ETV4 (17q21), suggests a mechanism for overexpression of the ETS genes in the majority of prostate cancers. In the current study using fluorescence in situ hybridization (FISH), we identified the TMPRSS2:ERG rearrangements in 49.2% of 118 primary prostate cancers and 41.2% of 18 hormone-naive lymph node metastases. The FISH assay detected intronic deletions between ERG and TMPRSS2 resulting in TMPRSS2:ERG fusion in 60.3% (35 of 58) of the primary TMPRSS2:ERG prostate cancers and 42.9% (3 of 7) of the TMPRSS2:ERG hormone-naive lymph node metastases. A significant association was observed between TMPRSS2:ERG rearranged tumors through deletions and higher tumor stage and the presence of metastatic disease involving pelvic lymph nodes. Using 100K oligonucleotide single nucleotide polymorphism arrays, a homogeneous deletion site between ERG and TMPRSS2 on chromosome 21q22.2-3 was identified with two distinct subclasses distinguished by the start point of the deletion at either 38.765 or 38.911 Mb. This study confirms that TMPRSS2:ERG is fused in approximately half of the prostate cancers through deletion of genomic DNA between ERG and TMPRSS2. The deletion as cause of TMPRSS2:ERG fusion is associated with clinical features for prostate cancer progression compared with tumors that lack the TMPRSS2:ERG rearrangement.

5' Untranslated Regions↗

PubMed2006

Hydronephrosis as a prognostic marker in bladder cancer in a cystectomy-only series.

OBJECTIVES: Hydronephrosis in patients with bladder cancer is caused by tumour at the ureteral orifice, secondary ureteral tumours, intramural or extravesical tumour infiltration, or compression of the ureter. This study investigated the prognostic impact of hydronephrosis in bladder cancer. METHODS: A series of 788 patients were treated with radical cystectomy with curative intent for transitional cell carcinoma of the bladder without neoadjuvant/adjuvant radiotherapy/chemotherapy between January 1986 and September 2003. All patients had a complete follow-up until death or until the study's end date. Survival rates were calculated using the Kaplan-Meier method. A multivariate analysis with a Cox regression model was performed with respect to potential influencing factors. RESULTS: A total of 108 patients (13.7%) had unilateral and 25 patients (3.2%) had bilateral hydronephrosis. The rate of organ-confined tumours was significantly higher in patients without hydronephrosis (67.9% vs. 37.6%; p<0.001). Forty-three (32.3%) of the 133 hydronephrotic patients had a tumour involving the ureteral orifice. In this group the rate of organ-confined tumours was significantly higher than in the other patients with hydronephrosis (53.5% vs. 30.0%; p=0.009). In the multivariate analysis, preoperative hydronephrosis was determined as an independent prognostic marker for recurrence-free survival besides the pT classification and lymph node status (p=0.0015). The etiology of hydronephrosis did not affect the tumour-specific survival. CONCLUSIONS: Hydronephrosis at the time of diagnosis of bladder cancer is associated with a high probability of advanced tumours. It is an independent prognostic factor for recurrence-free survival.

Adult↗

PubMed2006

Prognostic factors in lymph node-positive prostate cancer.

OBJECTIVES: To characterize lymph node metastasis of prostate cancer (PCa) and identify the parameters associated with patient outcome. The incidence of clinically localized PCa with concurrent lymph node metastasis has decreased to less than 1% in the United States but is between 10% and 15% in other countries. METHODS: Our study cohort of 1148 patients underwent radical prostatectomy in Ulm, Germany, between 1986 and 2002, and 201 (18%) had lymph node-positive PCa. RESULTS: The metastases showed growth architecture resembling primary PCa. We assigned a Gleason pattern and evaluated for size, extranodal extension, and lymphovascular invasion (LVI). Of 201 patients, 155 had original pathology slides available; 36 of the 155 were excluded because of preoperative hormonal ablation therapy. Of the remaining 119 patients, 22 (19%) were assigned Gleason pattern 3, 93 (78%) Gleason pattern 4, and 4 (3%) Gleason pattern 5. Extranodal extension was present in 66 (55%) of 119 patients and LVI in 29 (25%). An increased risk of prostate-specific antigen (PSA) recurrence was found for Gleason pattern 4/5 (hazard ratio [HR] 2.5, P = 0.038), LVI in the lymph nodes (HR 1.9, P = 0.038), and nuclear grade of the primary tumor (HR 2, P = 0.025). Independent predictors of PSA recurrence included LVI and nuclear grade (HR 1.9, P = 0.03 and HR 2, P = 0.03, respectively). CONCLUSIONS: Lymph node metastases of PCa are heterogeneous and have a close relation to the corresponding primary tumor. Most patients with lymph node-positive PCa remained disease free for up to 13 years after radical prostatectomy. Independent predictors of PSA recurrence among those with lymph node-positive PCa included LVI in the lymph nodes and the nuclear grade of the primary tumor. These parameters may be useful in predicting PSA recurrence in lymph node-positive PCa and could be included in patient follow-up.

Aged↗

PubMed2006

Defining aggressive prostate cancer using a 12-gene model.

The critical clinical question in prostate cancer research is: How do we develop means of distinguishing aggressive disease from indolent disease? Using a combination of proteomic and expression array data, we identified a set of 36 genes with concordant dysregulation of protein products that could be evaluated in situ by quantitative immunohistochemistry. Another five prostate cancer biomarkers were included using linear discriminant analysis, we determined that the optimal model used to predict prostate cancer progression consisted of 12 proteins. Using a separate patient population, transcriptional levels of the 12 genes encoding for these proteins predicted prostate-specific antigen failure in 79 men following surgery for clinically localized prostate cancer (P = .0015). This study demonstrates that cross-platform models can lead to predictive models with the possible advantage of being more robust through this selection process.

Biomarkers, Tumor↗

PubMed2006

ADAM15 disintegrin is associated with aggressive prostate and breast cancer disease.

The aim of the current study was to evaluate the expression of ADAM15 disintegrin (ADAM15) in a broad spectrum of human tumors. The transcript for ADAM15 was found to be highly upregulated in a variety of tumor cDNA expression arrays. ADAM15 protein expression was examined in tissue microarrays (TMAs) consisting of 638 tissue cores. TMA analysis revealed that ADAM15 protein was significantly increased in multiple types of adenocarcinoma, specifically in prostate and breast cancer specimens. Statistical association was observed with disease progression within clinical parameters of predictive outcome for both prostate and breast cancers, pertaining to Gleason sum and angioinvasion, respectively. In this report, we also present data from a cDNA microarray of prostate cancer (PCa), where we compared transfected LNCaP cells that overexpress ADAM15 to vector control cells. In these experiments, we found that ADAM15 expression was associated with the induction of specific proteases and protease inhibitors, particularly tissue inhibitor of metalloproteinase 2, as validated in a separate PCa TMA. These results suggest that ADAM15 is generally overexpressed in adenocarcinoma and is highly associated with metastatic progression of prostate and breast cancers.

ADAM Proteins↗

PubMed2006

Genomic profiling of hormone-naïve lymph node metastases in patients with prostate cancer.

The progression of organ-confined prostate cancer to metastatic cancer is inevitably fatal. Consequently, identification of structural changes in the genome and associated transcriptional responses that drive this progression is critical to understanding the disease process and the development of biomarkers and therapeutic targets. In this study, whole genome copy number changes in genomes of hormone-naïve lymph node metastases were profiled using array comparative genomic hybridization, and matched primaries were included for a subset. Matched primaries and lymph node metastases showed very similar copy number profiles that are distinct from primary tumors that fail to metastasize.

Biomarkers, Tumor↗

PubMed2005

Effect of a pT0 cystectomy specimen without neoadjuvant therapy on survival.

BACKGROUND: In some cases of radical cystectomy for bladder cancer, no residual tumor is found in the cystectomy specimen (the pT0 classification). The aim of this study was to evaluate the outcome of such patients in a large cystectomy series. METHODS: All 900 patients with radical cystectomy and pelvic lymphadenectomy for TCC of the bladder in the period January 1986 to September 2003 who received no neoadjuvant therapy were included. Cystectomy specimens from 181 (20.1%) patients were graded as pT0. Complete follow-up was obtained in all cases. Tumor-specific survival (pT0 vs. pT+) was calculated with the Kaplan-Meier method and compared with the log-rank test. RESULTS: The rate of lymph node metastases in the pT0 group was 6.6%. pT0 status was found with Ta/is/1 in 36.8%, T2a in 41.8%, and T2b in 10.9%. The 169 patients with pT0pN0 tumors had 10-year tumor-specific survival rates of 91.0. There was no statistically significant survival benefit for pT0pN0 tumors compared with pT+pN0 tumors for maximal tumor classifications of pTa/pTis/pT1 and pT2b, but patients with a pT0T2apN0 tumor had a statistically significantly better tumor-specific survival than those with a pT2apN0 tumor (P = 0.002). No patient with a pT0pN0 tumor had a local recurrence. The rate of incidental second primary malignancies in a specimen was 15.5%. CONCLUSIONS: A pT0pN0 cystectomy specimen indicates a curative therapy, but there is a substantial risk of tumor recurrence. In the group of tumors with a maximal classification of pT2a, the pT0 tumors constitute a subgroup with a significantly higher likelihood of survival.

Combined Modality Therapy↗

PubMed2005

Mutation screen and association study of EZH2 as a susceptibility gene for aggressive prostate cancer.

BACKGROUND: Several linkage studies have provided evidence for a prostate cancer aggressiveness gene on chromosome 7q. This report details the results of the first mutation screen and association study of EZH2 (located at 7q35) as a potential candidate gene for the development of aggressive prostate cancer. METHODS: In 10 families with linkage of chromosome 7q31-33 to aggressive prostate cancer, we sequenced the promoter region and all 20 exons of EZH2. We genotyped 11 variants in 287 prostate cancer probands and 96 controls. Association between the disease and the variants/haplotypes was evaluated taking into account clinical data and disease recurrence. RESULTS: The individual variation sites did not show significant differences in the allele frequencies between cases and controls. In contrast, one haplotype had a higher frequency in controls, and another haplotype was significantly more frequent in cases with low grade tumors (GI/II) and progression free survival (NED). CONCLUSION: We have possibly identified haplotypes which mark alleles that have a beneficial effect on the development of prostate cancer. Moreover, our results suggest that genetic variations of the EZH2 gene are not responsible for the linkage of 7q to aggressive prostate cancer.

Adult↗

PubMed2005

Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer.

Recurrent chromosomal rearrangements have not been well characterized in common carcinomas. We used a bioinformatics approach to discover candidate oncogenic chromosomal aberrations on the basis of outlier gene expression. Two ETS transcription factors, ERG and ETV1, were identified as outliers in prostate cancer. We identified recurrent gene fusions of the 5' untranslated region of TMPRSS2 to ERG or ETV1 in prostate cancer tissues with outlier expression. By using fluorescence in situ hybridization, we demonstrated that 23 of 29 prostate cancer samples harbor rearrangements in ERG or ETV1. Cell line experiments suggest that the androgen-responsive promoter elements of TMPRSS2 mediate the overexpression of ETS family members in prostate cancer. These results have implications in the development of carcinomas and the molecular diagnosis and treatment of prostate cancer.

Androgens↗

PubMed2005

Influence of nitrate levels in drinking water on urological malignancies: a community-based cohort study.

OBJECTIVE: To evaluate the effect of nitrate levels in the drinking water on the incidence of urological malignancies in a German community. PATIENTS AND METHODS: For 28 years (1957-86) the community of Bocholt, Germany (70,000 inhabitants) had a drinking water supply with different nitrate levels, i.e. 60 mg/L in group A (57,253 inhabitants) and 10 mg/L in group B (10,037 inhabitants). All newly diagnosed cases of urological malignancies were registered from 1986 to 1997. The incidence was calculated using an age standardization based on the German population. RESULTS: In all, there were 527 urological malignancies recorded (urothelial cancer 39.8%, renal cell carcinoma 10.8%, testicular tumours 8.0%, penile carcinoma 1.7%, prostate cancer 39.7%). The incidence per 100,000 inhabitants/year of urinary tract tumours was 33.8 in group A and only 17.1 in group B (relative risk, RR 1.98, 95% confidence interval, CI, 1.10-3.54). The RR was 0.87 (0.34-2.22) for renal tumours, 0.66 (0.14-2.88) for penile cancer and 1.06 (0.76-1.48) for prostate cancer. For testicular tumours there was an inverse association with nitrate level, with a RR of 0.43 (0.21-0.90). CONCLUSION: This study showed an association of nitrate load in drinking water and the incidence of urothelial cancer in both genders, with an inverse correlation to testicular tumours and no correlation with renal, penile and prostatic tumours.

Adolescent↗

PubMed2004

Cleavage of beta-catenin by calpain in prostate and mammary tumor cells.

Mutations in the NH(2)-terminal regulatory domain of the beta-catenin gene lead to aberrant stabilization and accumulation of the protein and increased TCF/LEF-dependent transcription. Although these mutations are common in some cancers, they are infrequent in prostate and breast cancer. We have found that metastatic prostate cancer specimens, obtained through a rapid autopsy tissue procurement program, expressed a novel M(r) 75,000 proteolytic fragment of beta-catenin (beta-cat(75)). beta-Cat(75) was also expressed in multiple prostate and breast cancer cell lines and was closely associated with the activity of the calcium-dependent protease, calpain. In a prostate cancer cDNA microarray, m-calpain RNA levels were found to be significantly increased in metastatic disease compared with normal prostate. We showed calpain-dependent generation of beta-cat(75) in cell culture and in vitro. Molecular mapping revealed that calpain cleavage removed the NH(2)-terminal regulatory domain of the beta-catenin protein. Treatment of MCF-7 cells with ionomycin led to increased accumulation of beta-cat(75) in the nucleus and TCF-dependent transcriptional activity. Overexpression of a similar beta-catenin fragment that lacks the NH(2)-terminal 132 amino acids and has transforming potential activated TCF-dependent transcription. Given the low frequency of mutation-induced activation of beta-catenin in prostate and breast cancers, proteolytic cleavage of beta-catenin by calpain may represent a novel mechanism by which the protein is activated during tumorigenesis.

Breast Neoplasms↗

PubMed2004

High-flow priapism: colour-Doppler ultrasound-guided supraselective embolization therapy.

High flow priapism is mainly caused by traumatic arteriocavernous fistulas. The standard therapy is a transcatheter embolization of the fistula. This study analyzes the combined approach of arteriography and color Doppler ultrasound during the embolization procedure. During the arteriography procedure, a perineal color Doppler ultrasound examination of the fistula was performed to achieve an optimal positioning of the catheter tip in the fistula with a minimum of radiation exposure. To visualize the correct localization, ultrasound contrast medium or saline solution was injected through the catheter. The flow-pattern of the contrast medium allowed evaluation of the successful occlusion of the fistula and preservation of the unaffected penile arteries. In six patients (unilateral fistula: three, bilateral fistulas: three) with a posttraumatic high-flow priapism, this technique was performed for embolization of the fistulas. A total of nine embolization sessions were performed. Only one case required a second session due to dislocation of a microcoil. In all cases, the priapism disappeared immediately after the final session while erectile function was restored within 4 weeks after embolization. The combined approach of x-ray and ultrasound imaging facilitates the supraselective embolization of the arteriocavernous fistula, leading to an optimal success rate, while reducing the radiation exposure and the applied dose of contrast medium.

Embolization, Therapeutic↗

PubMed2004

Overexpression, amplification, and androgen regulation of TPD52 in prostate cancer.

Gains in the long arm of chromosome 8 (8q) are believed to be associated with poor outcome and the development of hormone-refractory prostate cancer. Based on a meta-analysis of gene expression microarray data from multiple prostate cancer studies (D. R. Rhodes et al., Cancer Res 2002;62:4427-33), a candidate oncogene, Tumor Protein D52 (TPD52), was identified in the 8q21 amplicon. TPD52 is a coiled-coil motif-bearing protein, potentially involved in vesicle trafficking. Both mRNA and protein levels of TPD52 were highly elevated in prostate cancer tissues. Array comparative genomic hybridization and amplification analysis using single nucleotide polymorphism arrays demonstrated increased DNA copy number in the region encompassing TPD52. Fluorescence in situ hybridization on tissue microarrays confirmed TPD52 amplification in prostate cancer epithelia. Furthermore, our studies suggest that TPD52 protein levels may be regulated by androgens, consistent with the presence of androgen response elements in the upstream promoter of TPD52. In summary, these findings suggest that dysregulation of TPD52 by genomic amplification and androgen induction may play a role in prostate cancer progression.

Adult↗

PubMed2004

The role of metastasis-associated protein 1 in prostate cancer progression.

Distinguishing aggressive prostate cancer from indolent disease represents an important clinical challenge, as current therapy requires over treating men with prostate cancer to prevent the progression of a few cases. Expression of the metastasis-associated protein 1 (MTA1) has previously been found to be associated with progression to the metastatic state in various cancers. Analyzing DNA microarray data, we found MTA1 to be selectively overexpressed in metastatic prostate cancer compared with clinically localized prostate cancer and benign prostate tissue. These results were validated by demonstrating overexpression of MTA1 in metastatic prostate cancer by immunoblot analysis. MTA1 protein expression was evaluated by immunohistochemistry in a broad spectrum of prostate tumors with tissue microarrays containing 1940 tissue cores from 300 cases. Metastatic prostate cancer demonstrated significantly higher mean MTA1 protein expression intensity (score = 3.4/4) and percentage of tissue cores staining positive for MTA1 (83%) compared with clinically localized prostate cancer (score = 2.8/4, 63% positive cores) or benign prostate tissue (score = 1.5/4, 25% positive cores) with a mean difference of 0.54 and 1.84, respectively (P < 0.00001 for both). Paradoxically, for localized disease, higher MTA1 protein expression was associated with lower rates of prostate specific antigen recurrence after radical prostatectomy for localized disease. In summary, this study identified an association of MTA1 expression and prostate cancer progression.

Adult↗

PubMed2004

Pathological T0 prostate cancer without neoadjuvant therapy: clinical presentation and follow-up.

INTRODUCTION AND OBJECTIVES: Radical prostatectomy is a standard therapy for patients with prostate cancer diagnosed by prostatic needle biopsy, prostate cytology, transurethral resection of the prostate or prostatectomy. In a small group of patients no tumour can be found in the radical prostatectomy specimen. These cases are classified as stage pT0. The aim of this study was to evaluate the clinical presentation of this entity and their prognosis. MATERIAL AND METHODS: In a nation-wide database the clinical data of 3609 patients with prostate cancer were collected. 28 patients (0.8%) were staged as pT0 in the radical prostatectomy specimen. The data included age, prostate specific antigen (PSA), and pathological report at diagnosis, histology of the radical prostatectomy specimen and follow-up data. RESULTS: The diagnosis was made by TURP (transurethral resection of the prostate) in 15, prostatectomy in 2, needle biopsy in 11, and cytology in 2 patients. For patients who underwent TURP or prostatectomy the preoperative staging was T1a in 10 and T1b in 5 cases. 12 patients diagnosed by biopsy or cytology were classified T2a and one patient after biopsy as T2b. 9 patients had a GI- and 19 a GII-tumour, GIII-pattern was not represented. The mean age at diagnosis was 64.7 years (range 53-79 years). The PSA at the time of diagnosis was <4ng/ml in 8 cases; 4-10ng/ml in 16 cases and >10ng/ml in 4 patients. One patient presented with a micrometastasis in a single lymph node. Median follow-up was 62 months (19-150). All patients had undetectable PSA levels following surgery. No patient presented with clinical or biochemical progression. One patient died with no evidence of disease at 133 months after radical prostatectomy. CONCLUSIONS: None of the clinical parameters had a strong association with a pathologically proven T0 situation after radical prostatectomy in this setting. Interestingly no patient had a high-grade tumour. None of the patients classified as pT0 had a biochemical or clinical relapse during follow-up.

Adult↗

PubMed2004

Quantitative determination of expression of the prostate cancer protein alpha-methylacyl-CoA racemase using automated quantitative analysis (AQUA): a novel paradigm for automated and continuous biomarker measurements.

Despite years of discovery and attempts at validation, few molecular biomarkers achieve acceptance in the clinical setting. Tissue-based markers evaluated by immunohistochemistry suffer from a high degree of inter- and intraobserver variability. One recent advance in this field that promises to automate this process is the development of AQUA, a molecular-based method of quantitative assessment of protein expression. This system integrates a set of algorithms that allows for the rapid, automated, continuous, and quantitative analysis of tissue samples, including the separation of tumor from stromal elements and the subcellular localization of signals. This study uses the AQUA system to assess a recently described prostate cancer biomarker, alpha-methylacyl-CoA-racemase (AMACR), and to determine the effectiveness of the quantitative measurement of this marker as a means for making the diagnosis of prostate cancer. Using a prostate cancer progression tissue microarray containing a wide range of prostate tissues, AQUA was directly compared to standard immunohistochemical evaluation for AMACR protein expression using the p504s monoclonal antibody. Both methods produced similar results showing AMACR protein expression to be strongest in the clinically localized prostate cancer, followed by the metastatic tumor samples. Benign prostate tissue was categorized as negative for most tissue samples by immunohistochemistry. However, AMACR was detectable using the AQUA system at low levels using the standard 1:25 dilution but also at 1:250 dilution, which is not detectable by light microscopy. The AQUA system was also able to discriminate foamy gland prostate cancers, which are known to have a lower AMACR expression than typical acinar prostate cancers, from benign prostate tissue samples. Finally, a receiver-operating-characteristic curve was plotted to determine the specificity of the AMACR AQUA Z-score (normalized AQUA score) to predict that a given tissue microarray sample contains cancer. The area under the curve was calculated at 0.90 (P < 0.00001; 95% CI, 0.84 to 0.95). At an AMACR AQUA Z-score score of -0.3, 91% of the 70 samples classified as prostate cancer were correctly categorized without the intervention of a pathologist reviewing the tissue microarray slide. In conclusion, the AQUA system provides a continuous measurement of AMACR on a wide range of prostate tissue samples. In the future, the AMACR AQUA Z-score may be useful in the automated screening and evaluation of prostate tissue biomarkers.

Biomarkers, Tumor↗

PubMed2003

The role of an 80 kDa fragment of E-cadherin in the metastatic progression of prostate cancer.

PURPOSE: The purpose of this study was to evaluate an 80 kDa proteolytic fragment of E-cadherin as a potential biomarker for prostate cancer progression and to identify putative proteases that are responsible for the cleavage of E-cadherin. EXPERIMENTAL DESIGN: A wide spectrum of prostate cancer tissue and serum specimens representing different stages of prostate cancer was examined for the accumulation of the 80 kDa fragment of E-cadherin. Additionally, an expression array analysis was used to identify putative proteases that may have been involved in the cleavage of E-cadherin. RESULTS: A reproducible E-cadherin fragment was detected as a strong 80 kDa band in tissue samples. This fragment was detectable almost exclusively in metastatic sites. It was not visible in normal prostate tissue and was weak in 1 of 16 localized prostate cancers. The fragment is shed into the extracellular space and was detectable in patient serum in which the expression of the fragment showed a strong association with advanced prostate cancer. On the basis of cDNA expression analysis, several members of the metalloproteinase family could be identified as potentially responsible for the cleavage of the fragment from full-length E-cadherin. CONCLUSIONS: In this study, we present the first report of serum levels of the 80 kDa fragment of E-cadherin in prostate cancer patients. This fragment is exclusively seen in neoplastic prostate tissue and may represent a useful biomarker of prostate cancer disease progression. This study also demonstrates an association of increased levels of several metalloproteinases with metastatic prostate cancer and could provide a useful correlation between metalloproteinase expression/activity and E-cadherin cleavage and the metastatic progression of prostate cancer.

Blotting, Western↗