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Carsten Stephan

Publications and source records attributed to Carsten Stephan.

54 records · Page 3Linked to original sources
PubMed2003

Quantitative analysis of kallikrein 15 gene expression in prostate tissue.

PURPOSE: The newly discovered human kallikrein 15 gene KLK15 has been shown in preliminary analysis to be associated with more aggressive types of prostate cancer. We quantitatively measured and compared gene expression of KLK15 in malignant and benign prostate tissues. MATERIALS AND METHODS: Matched prostate tissue samples from the cancerous and noncancerous parts of the same prostates were obtained from 90 patients who underwent radical prostatectomy. Quantitative reverse transcriptase-polymerase chain reaction using SYBR Green I and the LightCycler system (Roche Applied Science, Mannheim, Germany) was performed. Associations of KLK15 expression with clinicopathological parameters were analyzed. RESULTS: KLK15 over expression in cancerous versus noncancerous tissue was found in 76 of the 90 patient samples (84.4%, p <0.001). The ratio of cancerous-to-noncancerous KLK15 expression tended to be higher in patients with stage pT3/4 versus pT2 tumors (p = 0.1). KLK15 expression tended to be higher in grade 3 than in grade 2 tumors and in Gleason score 7 or greater than in Gleason score less than 7 tumors (p = 0.18 and 0.23, respectively). A 1.7 cutoff at the 40th percentile provided a significant difference in stages pT2 and pT3/4 tumors (p = 0.029). CONCLUSIONS: On quantitative real-time polymerase chain reaction KLK15 expression was significantly higher in cancerous than in noncancerous tissue. Up-regulation of the KLK15 gene in advanced and more aggressive tumors may indicate a possible role for KLK15 protein as future serum marker for prostate cancer and for distinguishing tumor aggressiveness.

Actins↗
PubMed2003

Quantitative analysis of hippostasin/KLK11 gene expression in cancerous and noncancerous prostatic tissues.

OBJECTIVES: Hippostasin/kallikrein 11 (KLK11) is a member of the human kallikrein gene family, which includes prostate-specific antigen (PSA), human kallikrein 2 (hK2), and another 12 members, all localized on chromosome 19q13.4. Hippostasin has two alternative splicing isoforms, known as the brain type and prostate type. We have previously reported that the prostate-type isoform is not expressed in human prostate cancer cell lines. METHODS: We compared the expression of hippostasin/KLK11 isoforms in 76 matched pairs of human normal and prostate cancer tissues by quantitative reverse transcriptase-polymerase chain reaction. RESULTS: The expression of both isoforms of KLK11 was 25% to 45% higher in cancer tissues compared with their normal counterparts. Regarding prostate-type KLK11, we identified a significant association between lower expression and higher tumor stage, Gleason score, and tumor grade. No such association was seen with the brain-type isoform. CONCLUSIONS: : The expression of the prostate-type isoform of KLK11 is increased in prostate cancer. This parameter should be examined further as a new prognostic indicator of prostate cancer.

Adenocarcinoma↗
PubMed2003

An artificial neural network to predict the outcome of repeat prostate biopsies.

OBJECTIVES: To develop an advanced artificial neural network (ANN) to predict the presence of prostate cancer (PCa) and to predict the outcome of repeat prostate biopsies. The predictive accuracy was compared with the accuracy obtained using standard cutoffs for the free/total (f/t) prostate-specific antigen (PSA) ratio, PSA density (PSAD), PSA density of the transition zone (PSA-TZ), and the total and transition zone volumes. Clinical and biochemical diagnostic tests have been shown to improve PCa detection. When these tests are combined using an ANN, significant increases in specificity at high sensitivity are observed. METHODS: The Vienna-based multicenter European referral database for early PCa detection of 820 men with a PSA level between 4 and 10 ng/mL was used. The presence of PCa was determined using transrectal ultrasound-guided octant needle repeat biopsy. Variables in the database consisted of age, PSA, f/t PSA ratio, digital rectal examination findings, PSA velocity, and the transrectal ultrasound-guided variables of prostate volume, transition zone volume, PSAD, and PSA-TZ. The ANN used in the analysis was an advanced multilayer perceptron selected for accuracy by a genetic algorithm. RESULTS: The repeat biopsy PCa detection rate was 10% (n = 83). At 95% sensitivity, the specificity for ANN was 68% compared with 54%, 33.5%, 21.4%, 14.7%, and 8.3% for multivariate logistic regression analysis, f/t PSA ratio, PSA-TZ, PSAD, and total PSA, respectively. The ANN reduced unnecessary repeat biopsies by 68% in this study. The area under the curve was 83% for the ANN versus 79%, 74.5%, 69.1%, 61.8%, and 60.5% for multivariate analysis, f/t PSA ratio, PSA-TZ, PSAD, and total PSA, respectively. CONCLUSIONS: The current ANN found a strong pattern predictive of PCa in patients with a negative initial biopsy. By combining the individual clinical and biochemical markers into the ANN, 68% specificity at 95% sensitivity was achieved. The ANN allows more accurate and individual counseling of patients with a negative initial biopsy.

Aged↗
PubMed2003

A multicenter clinical trial on the use of complexed prostate specific antigen in low prostate specific antigen concentrations.

PURPOSE: The determination of complexed prostate specific antigen (cPSA) has been suggested to be promising for prostate cancer (PCa) diagnosis. In a multicenter trial we evaluate the diagnostic use of PSA forms in the low total PSA (tPSA) range. MATERIALS AND METHODS: A total of 283 white men with and 417 without PCa and tPSA concentrations between 0 and 6 ng/ml were retrospectively analyzed. All 700 untreated subjects underwent a multisector needle biopsy of the prostate. The Elecsys analyser 1010 (Roche Diagnostics, Mannheim, Germany) was used for determination of tPSA and free PSA. Determination of cPSA and tPSA was performed using immunoassays of the Bayer Immuno 1 system (Bayer Diagnostics, Tarrytown, New York). RESULTS: Receiver operating characteristics analyses for discrimination between cases with and without PCa were performed. The areas under the curves (AUC) for cPSA, tPSA and free-to-total PSA (f/tPSA) showed no significant differences in the tPSA ranges of 0 to 6 (700 cases), 0 to 4 (510) and 0.5 to 2.5 ng/ml (253). Within the tPSA range of 2.5 to 4 ng/ml (230 cases) the AUC for cPSA (0.61) was significantly larger than that for tPSA (Roche 0.51, Bayer 0.54) but did not differ from the AUC of f/tPSA (Roche). On the basis of the cutoffs for 95% specificity or sensitivity, no significant increase in corresponding sensitivity or specificity was found between tPSA with cPSA. CONCLUSIONS: In the tPSA range of less than 4 ng/ml no improvement in diagnostic accuracy was shown between cPSA with tPSA or the ratio of f/tPSA. The search for a useful marker in the low PSA range must continue.

Aged↗
PubMed2003

Serum osteoprotegerin and receptor activator of nuclear factor-kappa B ligand as indicators of disturbed osteoclastogenesis in patients with prostate cancer.

PURPOSE: We evaluated the behavior and diagnostic usefulness of the osteoclastogenesis proteins osteoprotegerin and receptor activator of nuclear factor-kappaB ligand (RANKL) in the serum of patients with prostate cancer (PCa). MATERIALS AND METHODS: Serum osteoprotegerin and RANKL were retrospectively measured in 117 patients with prostate cancer, including 39 with stage pN0M0, 34 with stage pN1M0 and 44 with bone metastases, in 35 presumably healthy men and in 35 patients with benign prostatic hyperplasia (BPH). The association of these components with clinical data (tumor stage and grade) and receiver operating characteristics curves compared with the bone formation marker alkaline phosphatase and bone resorption marker crosslaps (cross-linked C-terminal telopeptides of type I collagen) were calculated. RESULTS: Osteoprotegerin was increased in patients with bone metastases, while those with localized cancer or lymph node metastases had values similar to those in presumably healthy controls and patients with BPH. RANKL did not differ among the control, BPH and PCa subgroups. Thus, the ratio of osteoprotegerin-to-RANKL showed behavior similar to that of osteoprotegerin. Osteoprotegerin and RANKL did not show any significant correlation with tumor stage, histological tumor grade, total prostate specific antigen, alkaline phosphatase activity or crosslaps. ROC analysis data proved that osteoprotegerin had a better diagnostic accuracy than alkaline phosphatase or crosslaps for detecting bone metastases in PCa cases. CONCLUSIONS: Serum osteoprotegerin but not RANKL indicates disturbed osteoclastogenesis in patients with PCa and bone metastatic spread. It could be used as a marker for bone metastases.

Adult↗
PubMed2003

Comparison of eight computer programs for receiver-operating characteristic analysis.

BACKGROUND: ROC analysis is widely accepted to assess and compare diagnostic validity of laboratory tests. Within the last few years, many new ROC programs have become available but have not been systematically evaluated. The aim of this study was to assess different ROC programs regarding their ease of use, mathematical correctness, final output, and their compatibility with other graphics programs. METHODS: Eight available programs running under Windows (AccuROC, Analyse-It, CMDT, GraphROC, MedCalc, mROC, ROCKIT, and SPSS) were evaluated. ROC analyses of prostate-specific antigen and related values were performed from a dataset of 928 men with prostate cancer and benign prostatic hyperplasia and corresponding subsets. Criteria such as data input, data output, and correctness and completeness of results were used to evaluate the practicability of the programs. RESULTS: Although the programs produced equivalent results (areas under the curves and their characteristics), we observed deficiencies concerning input of data, processing of the output data, and completeness of the results. Analyse-It, AccuROC, and MedCalc exhibited good performance, but each program had different shortcomings. Only GraphROC could compare curves at a certain sensitivity or specificity cutoff. CONCLUSIONS: Adequate ROC analysis and ROC plotting cannot be performed with a single program. Analyse-It, AccuROC, and MedCalc can be recommended with certain limitations. Further improvements of the programs are necessary.

Area Under Curve↗
PubMed2003

Determination of non-alpha1-antichymotrypsin-complexed prostate-specific antigen as an indirect measurement of free prostate-specific antigen: analytical performance and diagnostic accuracy.

BACKGROUND: A new assay measures prostate-specific antigen (PSA) not complexed to alpha(1)-antichymotrypsin (nACT-PSA) after removing PSA complexed to ACT by use of anti-ACT antibodies. We evaluated nACT-PSA and its ratio to total PSA (tPSA) as alternatives to free PSA (fPSA) and its ratio to tPSA in differentiating prostate cancer (PCa) and benign prostatic hyperplasia (BPH) in patients with tPSA of 2-20 micro g/L. METHODS: PSA in serum of 183 untreated patients with PCa and 132 patients with BPH was measured retrospectively on the chemiluminescence immunoassay analyzer LIAISON(R) (Byk-Sangtec Diagnostica) with the LIAISON tPSA and LIAISON fPSA assays. The nACT-PSA fraction was determined with a prototype assay measuring the residual PSA after precipitation of ACT-PSA with an ACT-precipitating reagent. RESULTS: nACT-PSA was higher than fPSA in samples with fPSA concentrations <1 microg/L but lower in samples with >1 microg/L fPSA. The median ratios of fPSA/tPSA and of nACT-PSA/tPSA were significantly different between patients with BPH and PCa (19.4% vs 12.2% and 17.4% vs 13.0%, respectively). Within the tPSA ranges tested (2-20, 2-10, and 4-10 microg/L), areas under the ROC curves for the fPSA/tPSA ratios were significantly larger than those for nACT-PSA/tPSA. In the tPSA ranges <10 microg/L, the areas under the ROC curves for fPSA/tPSA were significantly larger than those for tPSA, whereas the areas for nACT-PSA/tPSA were not. At decision limits for 95% sensitivity and specificity, both ratios significantly increased specificity and sensitivity, respectively, compared with tPSA, but the fPSA/tPSA ratio showed higher values. CONCLUSIONS: nACT-PSA and its ratio to tPSA provide lower diagnostic sensitivity and specificity than fPSA/tPSA. The fPSA/tPSA ratio represents the state-of-the-art method for differentiating between PCa and BPH.

Aged↗
PubMed2002

An artificial neural network considerably improves the diagnostic power of percent free prostate-specific antigen in prostate cancer diagnosis: results of a 5-year investigation.

Our study was performed to evaluate the diagnostic usefulness of %fPSA alone and combined with an ANN at different PSA concentration ranges, including the low range 2-4 ng/ml, to improve the risk assessment of prostate cancer. A total of 928 men with prostate cancer and BPH without any pretreatment of the prostate in the PSA range 2-20 ng/ml were enrolled in the study between 1996 and 2001. An ANN with input data of PSA, %fPSA, patient's age, prostate volume and DRE status was developed to calculate the individual's risk before performing a prostate biopsy within the different PSA ranges 2-4, 4.1-10 and 10.1-20 ng/ml. ROC analysis and cut-off calculations were used to estimate the diagnostic improvement of %fPSA and ANN in comparison to PSA. At the 90% sensitivity level, %fPSA and ANN performed better than PSA in all ranges, enhancing the specificity by 15-28% and 32-44%, respectively. For the low PSA range 2-4 ng/mL, we recommend a first-time biopsy at an ANN specificity level of 90%. For PSA 4-10 ng/mL, we recommend a first-time biopsy based on the ANN at the 90% sensitivity level. Use of an ANN enhances the %fPSA performance to further reduce the number of unnecessary biopsies within the PSA range 2-10 ng/ml.

Adult↗
PubMed2002

Identification of single nucleotide polymorphisms in the human kallikrein 10 (KLK10) gene and their association with prostate, breast, testicular, and ovarian cancers.

BACKGROUND: The KLK10 gene (also known as the normal epithelial cell-specific 1 gene) is a member of the expanded human kallikrein gene family. Recently, it has been reported that KLK10 is a tumor suppressor gene and that its expression is downregulated in various forms of cancer and cancer cell lines. KLK10 is also upregulated in ovarian cancer. We thus hypothesized that the KLK10 gene may be a target for mutations in various cancers. METHODS: We sequenced the five coding exons of the KLK10 gene using genomic DNA from various tumors, normal tissues, and blood, by PCR amplification and automated sequencing. RESULTS: In none of the tumor-derived DNAs, we identified somatic mutations that could inactivate this gene. However, we identified a prevalent germline single nucleotide variation at codon 50 (exon 3) of this gene [GCC (alanine) to TCC (serine)]. The GCC genotype was less prevalent in prostatic cancer patients in comparison to control subjects (P = 0.027) but no differences were seen with testicular, ovarian, and breast cancer. We also identified four genetic variations in exon 4, at codons106 [GGC (glycine) to GGA (glycine)], codon 112 [ACG (threonine) to ACC (threonine)], codon 141 [CTA (leucine) to CTG (leucine)], and at codon 149 [CCG (proline) to CTG (leucine)]. None of these variations was significantly different between normal subjects and cancer groups. CONCLUSIONS: We found no evidence for somatic mutations of the KLK10 gene in cancers of the prostate, breast, ovary, and testis. The single nucleotide variation at codon 50 appears to be associated with prostate cancer risk.

Breast Neoplasms↗
PubMed2002

The new synthetic matrix metalloproteinase inhibitor (Roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model.

The therapeutic efficacy of synthetic inhibitors of matrix-metalloproteinases (MMPs) in various cancers has been demonstrated. A novel inhibitor, Ro 28-2653, with high selectivity for MMP2, MMP9 and membrane type 1-MMP was evaluated in an orthotopic prostate cancer rat model. Efficacy was determined by recording tumor growth and survival endpoints. Prostate cancer was induced by inoculating R3327 Dunning tumor cells (MatLyLu) into the ventral lobe of the prostates of 148 Copenhagen rats. Daily oral treatment with Ro 28-2653 (10-300 mg/kg per day) was started on day 1 or on day 6 after tumor cell injection. Animals were sacrificed on day 20 for determination of tumor weights. For survival studies, rats received daily oral Ro 28-2653 (100 mg/kg per day) or vehicle for up to 30 days. Tumor induction was successful in 100% of the animals. Ro 28-2653 reproducibly reduced the tumor weights by up to 90% in a dose-dependent manner. In addition, an inhibitory effect in rats with established tumors (treatment start at day 6) was shown. A significantly prolonged survival of Ro 28-2653-treated rats was also demonstrated. Selective inhibition of MMP activity is a novel therapeutic approach, which bears promise for studies in patients with prostate cancer.

Animals↗
PubMed2002

Differential expression of Kallikrein gene 5 in cancerous and normal testicular tissues.

OBJECTIVES: Kallikrein gene 5 (KLK5; formerly designated as kallikrein-like gene 2, or human stratum corneum tryptic enzyme) is one of the new members of the human kallikrein gene family on chromosome 19q13.4. Although it is expressed at low levels in various tissues, KLK5 expression is highest in the human mammary gland and testis. Previous investigations have established that the expression of KLK5 is estrogen and progestin driven in the BT-474 breast cancer cell line. In this study, we focused on KLK5 expression in normal and cancerous testicular tissue. METHODS: Fourteen matched testicular tumor and adjacent normal tissue samples were minced on dry ice and homogenized. Total RNA was extracted and mRNA was reverse transcribed. The cDNA samples were amplified by real-time quantitative polymerase chain reaction with KLK5-specific primers to compare the relative KLK5 levels in normal and cancerous testicular tissues. RESULTS: In 13 (93%) of the 14 patients, KLK5 expression in the cancerous area was significantly lower than in the adjacent, histologically confirmed, normal testicular tissue samples (P <0.001). The KLK5 level was 9.0 +/- 3.9 (mean +/- standard error, arbitrary units) in the noncancerous tissue and 4.5 +/- 2.9 in the cancerous tissue. We noted significantly lower KLK5 expression in seminomas than in nonseminomas (P = 0.009), as well as in late-stage (II/III) tumors versus early-stage (I) tumors (P = 0.026). KLK5 expression was also associated with the extent of primary tumor, with tumors with vascular/lymphatic invasion (T2/T3) expressing lower KLK5 message than did tumors limited to the testis and epididymis (T1) (P = 0.008). CONCLUSIONS: We found significantly lower expression of KLK5 in testicular tumors than in normal testicular tissue. More studies are necessary to investigate the mechanism behind this finding.

Adolescent↗
PubMed2002

Detection of human kallikrein 4 in healthy and cancerous prostatic tissues by immunofluorometry and immunohistochemistry.

BACKGROUND: Human kallikrein 4 (gene, KLK4; protein, hK4), a recently discovered member of the kallikrein gene family, shares many characteristics with prostate-specific antigen, the best available marker for prostate cancer. Because the protein has not been detected in any human tissue, we attempted to develop immunologic methods for hK4 analysis and use them to detect hK4 in healthy and cancerous tissue extracts and biological fluids. METHODS: We extracted total RNA from 20 pairs of matched (healthy-cancer) prostate tissue samples. KLK4 cDNA was amplified by reverse transcription-PCR (RT-PCR) and cloned in a pPICZalphaA expression vector. We then transformed the construct product into Pichia pastoris yeast strains and induced secreted recombinant protein production by addition of methanol. We purified the recombinant protein by nickel ion-affinity chromatography and used it as an immunogen in rabbits and mice to generate polyclonal anti-hK4 antibodies. These antibodies were used to develop a sandwich-type immunoassay suitable for hK4 quantification in biological fluids and tissue extracts. RESULTS: The immunoassay had a detection limit of 0.1 microg/L. We detected hK4 in 10 of 21 matched (healthy-cancer) prostate tissues, and hK4 was frequently higher in healthy tissues. In one matched-sample pair, the hK4 content was relatively high in both the healthy [4.62 microg/g of total protein (TP)] and the cancerous (1.22 microg/g of TP) prostate tissue. Among tissue extracts, we found the highest concentrations of hK4 in healthy (0.0-4.62 microg/g of TP) and cancerous (0.0-1.72 microg/g of TP) prostatic extracts and in placental extracts (0.0-0.05 microg/g of TP). We also detected traces of hK4 protein immunoreactivity in amniotic fluid (<0.1-0.6 microg/L), human breast milk (<0.1-0.75 microg/L), and seminal plasma (0.2-0.9 microg/L). Immunohistochemical studies showed cytoplasmic staining for hK4 protein in both malignant and benign epithelial cells of the prostate. However, we did not detect hK4 in cerebrospinal fluid, healthy and cancerous ovarian tissue extracts, and many other human tissue extracts. CONCLUSIONS: hK4 protein is present in some prostatic tissue extracts but at relatively low concentrations, although KLK4 mRNA is readily detectable by RT-PCR. We propose that the protein either is not synthesized efficiently or is degraded very quickly.

Animals↗
PubMed2002

Multicenter evaluation of an artificial neural network to increase the prostate cancer detection rate and reduce unnecessary biopsies.

BACKGROUND: The percentage of free prostate-specific antigen (%fPSA) has been shown to improve specificity for the diagnosis of prostate cancer (PCa) over total PSA (tPSA). A multicenter study was performed to evaluate the diagnostic value of a %fPSA-based artificial neural network (ANN) in men with tPSA concentrations between 2 and 20 microg/L for detecting patients with increased risk of a positive prostate biopsy for cancer. METHODS: We enrolled 1188 men from six different hospitals with PCa or benign prostates between 1996 and 2001. We used a newly developed ANN with input data of tPSA, %fPSA, patient age, prostate volume, and digital rectal examination (DRE) status to calculate the risk for the presence of PCa within different tPSA ranges (2-4, 4.1-10, 2-10, 10.1-20, and 2-20 microg/L) at the 90% and 95% specificity or sensitivity cutoffs, depending on the tPSA concentration. ROC analysis and cutoff calculations were used to estimate the diagnostic improvement of the ANN compared with %fPSA alone. RESULTS: In the low tPSA range (2-4 microg/L), the ANN detected 72% and 65% of cancers at specificities of 90% or 95%, respectively. At 4-10 microg/L tPSA, the ANN detected 90% and 95% of cancers with specificities of 62% and 41%, respectively. Use of the ANN with 2-10 microg/L tPSA enhanced the specificity of %fPSA by 20-22%, thus reducing the number of unnecessary biopsies. CONCLUSIONS: Enhanced accuracy of PCa detection over that obtained using %fPSA alone can be achieved with a %fPSA-based ANN that also includes clinical information from DRE and prostate volume measurements.

Adult↗
PubMedDate not supplied

Molecular cloning of a new gene which is differentially expressed in breast and prostate cancers.

OBJECTIVE: The chromosomal region 19q13 is non-randomly rearranged in many solid tumors. METHODS: Using the positional candidate gene approach, we cloned a new gene, tentatively named cancer-associated gene (CAG), which is differentially expressed in breast and prostate cancers. RESULTS: The gene is formed of 3 exons and 2 intervening introns. Its coding region is 1,047 bp in length and is predicted to encode a 348-amino-acid polypeptide. The new gene maps to chromosome 19q13.4 and is located 14 kb telomeric to the kallikrein gene locus (KLK14 gene) and 17 kb centromeric from the Siglec family of genes (Siglec-9). The gene is expressed in a wide variety of tissues including the brain, colon, kidney and pancreas. The CAG protein shows a high degree of conservation among species and phylogenetically is most closely related to its mouse ortholog. In silico analysis indicates that this gene is differentially expressed in a variety of tumors including brain, colon, ovarian and prostate cancers. CONCLUSIONS: Our preliminary experimental data show that CAG is upregulated in prostate cancer tissues compared to normal prostatic tissues. CAG also appears to be downregulated in breast cancer tissues. The physiological function of the CAG protein is currently unknown.

Amino Acid Sequence↗
PubMedDate not supplied

Differential expression of a human kallikrein 5 (KLK5) splice variant in ovarian and prostate cancer.

The presence of more than one mRNA form is common among kallikrein genes. We identified an mRNA transcript of the human kallikrein gene 5 (KLK5), denoted KLK5 splice variant 1 (KLK5-SV1). This variant has a different 5'-splice site, but encodes the same protein as the classical KLK5 transcript. RT-PCR analysis of this variant transcript expression in 29 human tissues indicated highest expression in the cervix, salivary gland, kidney, mammary gland, and skin. Comparative analysis of the expression levels of KLK5-SV1, another splice variant named KLK5 splice variant 2 (KLK5-SV2), and the classical KLK5 form showed that out of all three mRNA transcripts, the classical form is predominantly expressed (found in more tissues and at higher expression levels) followed by KLK5-SV1. KLK5-SV1 is expressed at high levels in ovarian, pancreatic, breast and prostate cancer cell lines. KLK5-SV1 was also found to be expressed in 9/10 ovarian cancer tissues, but it was not found in one normal ovarian tissue tested. Hormonal regulation experiments suggest that KLK5-SV1 is regulated by steroid hormones in the BT-474 breast cancer cell line. Furthermore, this variant had significantly higher expression in normal prostate tissues compared to their matched cancer tissue counterparts. KLK5-SV1 may have clinical utility in various malignancies and should be further explored as a potential new biomarker for prostate and ovarian cancer.

Base Sequence↗
PubMedDate not supplied

The kallikrein gene 5 splice variant 2 is a new biomarker for breast and ovarian cancer.

The presence of more than one mRNA form for the same gene is common among kallikreins, and many of the kallikrein splice variants may hold significant clinical value. The human kallikrein gene 5 (KLK5) is a member of the human kallikrein gene family of serine proteases on chromosome 19q13.4. KLK5 has been shown to be differentially expressed in a variety of endocrine tumors including ovarian, breast and prostate cancer. Utilizing Expressed Sequence Tag database analysis and reverse transcriptase polymerase chain reaction, we identified a new alternatively spliced form of KLK5(KLK5-splice variant 2, KLK5-SV2). This variant mRNA is 1,438 bp in length; formed of 195 bp of 5' untranslated region, 882 bp of protein coding sequence and a 3' untranslated region of 326 nucleotides. KLK5-SV2 has 7 exons, the first 2 of which are untranslated, and 6 intervening introns. KLK5-SV2 is different from the classic form of the KLK5 mRNA in its 5' untranslated region, where the first 5' untranslated exon of the classic form is split into 2 exons with an intervening intron of 135 nucleotides. KLK5-SV2 is expressed in a variety of tissues, with higher expression levels in the mammary gland, cervix, salivary gland and trachea. The steroid hormone receptor-positive breast cancer cell line BT-474 was used to examine the effect of different steroids on the expression levels of KLK5-SV2. Expression levels were significantly higher after stimulation with androgens, but not estrogens, progestins, aldosterone or corticosteroids. While relatively high levels of expression were found in all 10 normal breast tissues examined, no expression was detected in 16 breast cancer tissues, and expression was significantly lower than normal in the remaining 4 cancers. Expression levels comparable to normal were found in only 1 breast cancer cell line. Weak to no expression was detected in 3 other breast cancer cell lines. KLK5-SV2 was not detectable in any of the 10 normal ovarian tissues examined. It was, however, expressed at relatively high levels in 10 out of 20 ovarian cancer tissues, and lower levels were found in 4 other cancers. No expression was detected in the remaining 6 cancers. High expression levels were also detected in the CAOV-3 ovarian cancer cell line. KLK5-SV2 is a potential biomarker for breast and ovarian cancers.

Androgens↗
PubMedDate not supplied

mRNA expression profile of matrix metalloproteinases and their tissue inhibitors in malignant and non-malignant prostatic tissue.

BACKGROUND: Increased expression of matrix metalloproteinases (MMPs) was found in various carcinomas. The aim of this study was to present a comprehensive mRNA expression profile of MMPs in benign and malignant prostatic tissue. MATERIALS AND METHODS: mRNA expression patterns of MMP-1, -2, -7, -9, -11, -14 and their tissue inhibitors (TIMPs) -1, -2 and -3 were studied in cancerous and non-cancerous parts of 17 prostates removed by radical prostatectomy. Competitive reverse transcritpion PCR was used for quantification of MMP and TIMP mRNA. RESULTS: Both decreased (MMP-2, MMP-11, MMP-14) and a tendency to increased (MMP-9) MMP values in cancerous compared to the non-cancerous samples were observed. Significantly reduced TIMP-2 and TIMP-3 values were remarkable. Relatively strong associations were found among the three TIMPs while only a significant correlation between MMPs was observed between MMP-2 and MMP-7. There were no significant correlations between MMPs and tumor grade and stage and serum prostate-specific antigen. Receiver operation characteristic analyses proved that MMP and TIMP mRNA and their ratios have an insufficient capability to differentiate between cancerous and non-cancerous tissue. The ratios of MMP-9 to all three TIMPs and the ratio of MMP-14 to TIMP-3 were significantly increased. CONCLUSION: These increased ratios support the view of an imbalance between MMP-9 activity and its inhibitory counterparts in cancerous tissue as an important step in the development of prostate carcinoma and implicate the rationale of using synthetic inhibitors of MMPs as potential therapeutic tools.

Adenocarcinoma↗