25 results on '"Lilja H"'
Search Results
2. Species- and organ-specificity of secretory proteins derived from human prostate and seminal vesicles.
- Author
-
Aumüller, G., Seitz, J., Lilja, H., Abrahamsson, P.-A., Von Kammer, H. Der, and Scheit, K.-H.
- Published
- 1990
- Full Text
- View/download PDF
3. Partial characterization of a thyroid-stimulating hormone-like peptide in neuroendocrine cells of the human prostate gland.
- Author
-
Abrahamsson, P.-A. and Lilja, H.
- Published
- 1989
- Full Text
- View/download PDF
4. Three predominant proteins secreted by the human prostate gland.
- Author
-
Lilja, H. and Abrahamsson, P.-A.
- Published
- 1988
- Full Text
- View/download PDF
5. Immunohistochemical distribution of the three predominant secretory proteins in the parenchyma of hyperplastic and neoplastic prostate glands.
- Author
-
Abrahamsson, P.-A., Lilja, H., Falkmer, S., and Wadströ, L. B.
- Published
- 1988
- Full Text
- View/download PDF
6. Genome-wide association study identifies novel single nucleotide polymorphisms having age-specific effect on prostate-specific antigen levels.
- Author
-
Li W, Bicak M, Sjoberg DD, Vertosick E, Dahlin A, Melander O, Ulmert D, Lilja H, and Klein RJ
- Subjects
- Adult, Age Factors, Aged, Aged, 80 and over, Biomarkers, Tumor blood, Genome-Wide Association Study, Humans, Male, Middle Aged, Prostatic Neoplasms blood, Quantitative Trait Loci, Genetic Predisposition to Disease, Kv1.3 Potassium Channel genetics, Membrane Transport Proteins genetics, Phosphoinositide Phospholipase C genetics, Polymorphism, Single Nucleotide, Prostate-Specific Antigen blood, Prostatic Neoplasms genetics
- Abstract
Background: Testing for prostate-specific antigen (PSA) levels in blood are widely used and associated with prostate cancer risk and outcome. After puberty, PSA levels increase by age and multiple single nucleotide polymorphisms (SNPs) have been found to be associated with PSA levels. However, the relationship between the effects of SNPs and age on PSA remains unknown., Methods: To test for SNP × age interaction, we conducted a genome-wide association study using 2394 men without prostate cancer diagnosis from Malmö, Sweden as a discovery set and 2137 men from the eMERGE study (USA) for validation. Linear regression was used to identify significant interactions between SNP and age (p < 1 × 10
-4 for discovery, p < .05 for validation)., Results: The 15 SNPs from three different loci (8p11.22, 8p12, 3q25.31) are found to have age-specific effect on PSA levels. Expression quantitative trait loci (eQTLs) analysis shows that 12 SNPs from 3q25.31 locus affect the expression level of three genes: KCNAB1, SLC33A1, PLCH1., Conclusions: Our results suggest that SNPs may have age-specific effect on PSA levels, which provides new direction to study genetic markers for PSA., (© 2020 Wiley Periodicals LLC.)- Published
- 2020
- Full Text
- View/download PDF
7. Kallikrein markers performance in pretreatment blood to predict early prostate cancer recurrence and metastasis after radical prostatectomy among very high-risk men.
- Author
-
Assel MJ, Ulmert HD, Karnes RJ, Boorjian SA, Hillman DW, Vickers AJ, Klee GG, and Lilja H
- Subjects
- Aged, Biomarkers, Tumor blood, Humans, Male, Middle Aged, Neoplasm Grading, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Recurrence, Local pathology, Prostate-Specific Antigen blood, Prostatectomy, Prostatic Neoplasms pathology, Prostatic Neoplasms surgery, Risk Factors, Seminal Vesicles pathology, Kallikreins blood, Neoplasm Recurrence, Local blood, Prostatic Neoplasms blood
- Abstract
Background: To assess whether a prespecified statistical model based on the four kallikrein markers measured in blood-total, free, and intact prostate-specific antigen (PSA), together with human kallikrein-related peptidase 2 (hK2)-or any individual marker measured in pretreatment serum were associated with biochemical recurrence-free (BCR) or metastasis-free survival after radical prostatectomy (RP) in a subgroup of men with very high-risk disease., Methods: We identified 106 men treated at Mayo Clinic from 2004 to 2008 with pathological Gleason grade group 4 to 5 or seminal vesicle invasion at RP. Univariable and multivariable Cox models were used to test the association between standard predictors (Kattan nomogram and GPSM [Gleason, PSA, seminal vesicle and margin status] score), kallikrein panel, and individual kallikrein markers with the outcomes., Results: BCR and metastasis occurred in 67 and 30 patients, respectively. The median follow-up for patients who did not develop a BCR was 10.3 years (interquartile range = 8.2-11.8). In this high-risk group, neither Kattan risk, GPSM score, or the kallikrein panel model was associated with either outcome. However, after adjusting for Kattan risk and GPSM score, separately, preoperative intact PSA was associated with both outcomes while hK2 was associated with metastasis-free survival., Conclusions: Conventional risk prediction tools were poor discriminators for risk of adverse outcomes after RP (Kattan risk and GPSM risk) in patients with very high-risk disease. Further studies are needed to define the role of individual kallikrein marker forms in the blood to predict adverse prostate cancer outcomes after RP in this high-risk setting., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2020
- Full Text
- View/download PDF
8. Increased EZH2 expression in prostate cancer is associated with metastatic recurrence following external beam radiotherapy.
- Author
-
Wu X, Scott H, Carlsson SV, Sjoberg DD, Cerundolo L, Lilja H, Prevo R, Rieunier G, Macaulay V, Higgins GS, Verrill CL, Lamb AD, Cunliffe VT, Bountra C, Hamdy FC, and Bryant RJ
- Subjects
- Bone Neoplasms metabolism, Bone Neoplasms secondary, Cell Line, Tumor, Disease Progression, Humans, Male, Neoplasm Grading, Prostate pathology, Prostatic Neoplasms radiotherapy, Soft Tissue Neoplasms metabolism, Soft Tissue Neoplasms secondary, Enhancer of Zeste Homolog 2 Protein metabolism, Prostate metabolism, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology
- Abstract
Background: Enhancer of zeste 2 (EZH2) promotes prostate cancer progression. We hypothesized that increased EZH2 expression is associated with postradiotherapy metastatic disease recurrence, and may promote radioresistance., Methods: EZH2 expression was investigated using immunohistochemistry in diagnostic prostate biopsies of 113 prostate cancer patients treated with radiotherapy with curative intent. Associations between EZH2 expression in malignant and benign tissue in prostate biopsy cores and outcomes were investigated using univariate and multivariate Cox regression analyses. LNCaP and PC3 cell radiosensitivity was investigated using colony formation and γH2AX assays following UNC1999 chemical probe-mediated EZH2 inhibition., Results: While there was no significant association between EZH2 expression and biochemical recurrence following radiotherapy, univariate analysis revealed that prostate cancer cytoplasmic and total EZH2 expression were significantly associated with metastasis development postradiotherapy (P = 0.034 and P = 0.003, respectively). On multivariate analysis, the prostate cancer total EZH2 expression score remained statistically significant (P = 0.003), while cytoplasmic EZH2 expression did not reach statistical significance (P = 0.053). No association was observed between normal adjacent prostate EZH2 expression and biochemical recurrence or metastasis. LNCaP and PC3 cell treatment with UNC1999 reduced histone H3 lysine 27 tri-methylation levels. Irradiation of LNCaP or PC3 cells with a single 2 Gy fraction with UNC1999-mediated EZH2 inhibition resulted in a statistically significant, though modest, reduction in cell colony number for both cell lines. Increased γH2AX foci were observed 24 hours after ionizing irradiation in LNCaP cells, but not in PC3, following UNC1999-mediated EZH2 inhibition vs controls., Conclusions: Taken together, these results reveal that high pretreatment EZH2 expression in prostate cancer in diagnostic biopsies is associated with an increased risk of postradiotherapy metastatic disease recurrence, but EZH2 function may only at most play a modest role in promoting prostate cancer cell radioresistance., (© 2019 The Authors. The Prostate Published by Wiley Periodicals, Inc.)
- Published
- 2019
- Full Text
- View/download PDF
9. Association of reported prostate cancer risk alleles with PSA levels among men without a diagnosis of prostate cancer.
- Author
-
Wiklund F, Zheng SL, Sun J, Adami HO, Lilja H, Hsu FC, Stattin P, Adolfsson J, Cramer SD, Duggan D, Carpten JD, Chang BL, Isaacs WB, Grönberg H, and Xu J
- Subjects
- Case-Control Studies, Genetic Predisposition to Disease genetics, Humans, Male, Multivariate Analysis, Prostate-Specific Antigen blood, Prostatic Neoplasms blood, Prostatic Neoplasms diagnosis, Registries, Risk Factors, Sweden, Gene Frequency genetics, Polymorphism, Single Nucleotide genetics, Prostate-Specific Antigen genetics, Prostatic Neoplasms genetics
- Abstract
Background: Prostate specific antigen (PSA) is widely used for prostate cancer screening but its levels are influenced by many non cancer-related factors. The goal of the study is to estimate the effect of genetic variants on PSA levels., Methods: We evaluated the association of SNPs that were reported to be associated with prostate cancer risk in recent genome-wide association studies with plasma PSA levels in a Swedish study population, including 1,722 control subjects without a diagnosis of prostate cancer., Results: Of the 16 SNPs analyzed in control subjects, significant associations with PSA levels (P < or = 0.05) were found for six SNPs. These six SNPs had a cumulative effect on PSA levels; the mean PSA levels in men were almost twofold increased across increasing quintile of number of PSA associated alleles, P-trend = 3.4 x 10(-14). In this Swedish study population risk allele frequencies were similar among T1c case patients (cancer detected by elevated PSA levels alone) as compared to T2 and above prostate cancer case patients., Conclusions: Results from this study may have two important clinical implications. The cumulative effect of six SNPs on PSA levels suggests genetic-specific PSA cutoff values may be used to improve the discriminatory performance of this test for prostate cancer; and the dual associations of these SNPs with PSA levels and prostate cancer risk raise a concern that some of reported prostate cancer risk-associated SNPs may be confounded by the prevalent use of PSA screening., (2008 Wiley-Liss, Inc.)
- Published
- 2009
- Full Text
- View/download PDF
10. Immunohistochemical detection of cysteine-rich secretory protein 3 in tissue and in serum from men with cancer or benign enlargement of the prostate gland.
- Author
-
Bjartell A, Johansson R, Björk T, Gadaleanu V, Lundwall A, Lilja H, Kjeldsen L, and Udby L
- Subjects
- Enzyme-Linked Immunosorbent Assay, Humans, Immunoassay, Immunohistochemistry, Male, Neoplasm Invasiveness, Oligonucleotide Array Sequence Analysis, Prostate-Specific Antigen analysis, Prostate-Specific Antigen genetics, Prostatectomy, Salivary Proteins and Peptides blood, Salivary Proteins and Peptides genetics, Seminal Plasma Proteins blood, Seminal Plasma Proteins genetics, Prostatic Hyperplasia pathology, Prostatic Neoplasms pathology, Salivary Proteins and Peptides analysis, Seminal Plasma Proteins analysis
- Abstract
Background: Recently, the gene for cysteine-rich secretory protein 3 (CRISP-3) was reported to be highly upregulated in prostate cancer (PCa) compared to benign prostatic tissue. The current aims were to investigate diagnostic use of tissue expression and immunodetection in serum of CRISP-3 for detection or monitoring of PCa., Methods: Radical prostatectomy specimens and tissue microarrays from transurethral resections and metastases were analyzed for CRISP-3 and PSA by immunohistochemistry. CRISP-3 in tissue homogenates and in serum was measured by an in-house ELISA and PSA by a commercially available immunoassay., Results: Immunostaining for CRISP-3 in benign prostatic epithelium was generally weak or not detectable. Specific and strong immunostaining was found in a major proportion of cells in high-grade prostatic-intraepithelial-neoplasia (HG-PIN,12/17 patients), in most primary tumors (111/115), and in lymph node (11/15) and bone (12/15) metastases. CRISP-3 immunostaining intensity was regularly strong in areas of Gleason grades 4/5, where PSA-immunoreaction was less intense. Serum levels of CRISP-3 were not different in patients with PCa (n=152) compared to men with BPH (n=81). There was a very weak co-variation between levels of CRISP-3 versus PSA in serum from PCa patients (P<0.05). After orchiectomy, levels of CRISP-3 in serum decreased in median with 11% compared to a 97% median decrease of PSA in serum from 15/20 patients with advanced PCa., Conclusions: Strong immunostaining for CRISP-3 is common in HG-PIN and preserved in most PCa specimens, which warrant further immunohistochemical studies of CRISP-3 in PCa. Serum levels of CRISP-3 do not primarily reflect PCa., (Prostate 66:591-603, 2006. (c) 2005 Wiley-Liss, Inc.)
- Published
- 2006
- Full Text
- View/download PDF
11. Pharmacokinetics, biodistribution, and antitumor efficacy of a human glandular kallikrein 2 (hK2)-activated thapsigargin prodrug.
- Author
-
Janssen S, Rosen DM, Ricklis RM, Dionne CA, Lilja H, Christensen SB, Isaacs JT, and Denmeade SR
- Subjects
- Animals, Area Under Curve, Humans, Infusions, Intravenous, Male, Maximum Tolerated Dose, Mice, Mice, Inbred BALB C, Thapsigargin analogs & derivatives, Tumor Cells, Cultured, Prodrugs pharmacokinetics, Prodrugs pharmacology, Prostatic Neoplasms pathology, Thapsigargin pharmacokinetics, Thapsigargin pharmacology, Tissue Kallikreins pharmacokinetics, Tissue Kallikreins pharmacology
- Abstract
Background: Prostate cancer cells secrete unique proteases such as prostate-specific antigen (PSA) and human glandular kallikrein 2 (hK2) that represent targets for the activation of prodrugs as systemic treatment of metastatic prostate cancer. Previously, a combinatorial peptide library was screened to identify a highly active peptide substrate for hK2. The peptide was coupled to an analog of the potent cytotoxin thapsigargin, L12ADT, to generate an hK2-activated prodrug that was efficiently hydrolyzed by purified hK2, stable to hydrolysis in human and mouse plasma in vitro and selectively toxic to hK2 producing prostate cancer cells in vitro., Methods: In the current study, toxicology, pharmacokinetics, prodrug biodistribution, and antitumor efficacy studies were performed to evaluate the hK2-activated prodrug in vivo., Results: The single intravenous maximally tolerated dose of prodrug was 6 mg/kg (i.e., 3.67 micromole/kg) which produced peak serum concentration of approximately 36 microM and had a half-life of approximately 40 min. In addition, over a 24 hr period <0.5% of free L12ADT analog was observed in plasma. The prodrug demonstrated significant antitumor effect in vivo while it was being administered, but prolonged intravenous administration was not possible due to local toxicity to tail veins. Subcutaneous administration of equimolar doses produced lower plasma AUC compared to intravenous dosing but equivalent intratumoral levels of prodrug following multiple doses., Conclusions: The hK2-activated prodrug was stable in vivo. The prodrug, however, was rapidly cleared and difficult to administer over prolonged dosing interval. Additional studies are underway to assess antitumor efficacy with prolonged administration of higher subcutaneous doses of prodrug. Second-generation hK2-activated thapsigargin prodrugs with increased half-lives and improved formulations are also under development., ((c) 2005 Wiley-Liss, Inc)
- Published
- 2006
- Full Text
- View/download PDF
12. Assessment of intra-individual variation in prostate-specific antigen levels in a biennial randomized prostate cancer screening program in Sweden.
- Author
-
Bruun L, Becker C, Hugosson J, Lilja H, and Christensson A
- Subjects
- Aged, Cohort Studies, Fluorometry, Humans, Individuality, Male, Mass Screening, Middle Aged, Predictive Value of Tests, Prostatic Neoplasms epidemiology, Sweden epidemiology, Prostate-Specific Antigen blood, Prostatic Neoplasms blood
- Abstract
Background: The degree of variability in prostate-specific antigen (PSA) measurements is important for interpreting test results in screening programs, and particularly for interpreting the significance of changes between repeated tests. This study aimed to determine the long-term intra-individual variation for PSA in healthy men., Methods: A randomly selected cohort of men in a biennial prostate cancer screening program (ERSPC) conducted in Sweden from 1995-1996 to 2001-2002. We studied men who had total PSA (tPSA) levels < 2.0 ng/ml in 2001-2002. This included 791 men with tPSA < or = 0.61 ng/ml (group A), 1,542 men with tPSA < or = 0.99 ng/ml (group B), and 1,029 men with tPSA 1.00-1.99 ng/ml (group C). The intra-individual variability of free PSA (fPSA) and tPSA was assessed by calculating coefficients of variation (CV) for each individual's PSA measurements from the first and second round of screening (1995-1996 and 1997-1998)., Results: Intra-individual CV (geometric means) for tPSA were 13.7%, 12.7%, and 11.5% in groups A, B, and C, respectively. Corresponding CVs for fPSA were significantly lower, ranging from 12.1% to 10.4%. The estimated biological variation of tPSA and fPSA in groups A to C were 12.5%, 11.4%, 10.0% and 9.7%, 7.8%, 7.5%, respectively., Conclusions: In healthy men with PSA levels less than 2 ng/ml, the natural long-term variability for tPSA was less than 14%, and with 95% probability, a change in tPSA greater than 30% indicates a change beyond normal random variation., (Copyright 2005 Wiley-Liss, Inc)
- Published
- 2005
- Full Text
- View/download PDF
13. Blood levels of free-PSA but not complex-PSA significantly correlates to prostate release of PSA in semen in young men, while blood levels of complex-PSA, but not free-PSA increase with age.
- Author
-
Sävblom C, Malm J, Giwercman A, Nilsson JA, Berglund G, and Lilja H
- Subjects
- Adolescent, Adult, Age Factors, Humans, Male, Middle Aged, Prostate-Specific Antigen metabolism, alpha 1-Antitrypsin analysis, Prostate-Specific Antigen blood, Semen metabolism
- Abstract
Background: The proportion of free- and complex-prostate specific antigen (PSA) in serum is used for differentiating between benign and malignant prostate disease. To further understand the physiological relationship between PSA in seminal plasma and blood, we have analyzed free-PSA (fPSA) and complex-PSA (cPSA) in blood and PSA in seminal plasma in young healthy men. We also compared age-related changes of PSA-forms in blood from young versus older men., Methods: Total-PSA (tPSA), fPSA, and cPSA were measured in (i) blood and semen from 289 male conscripts (mean age 18.1 years) and in (ii) blood from a representative population of 1,389 men (mean age 46.5 years) without diagnosis of prostate cancer (PCa) during long-term follow-up., Results: fPSA in serum (r = 0.40, P < 0.0001) but not cPSA (r = 0.09, P = 0.11), correlates to PSA in seminal fluid. fPSA levels in blood in young (geometric mean: 0.20 ng/ml) versus middle-aged men (geometric mean: 0.18 ng/ml) was not different (P = 0.06), whereas cPSA in middle-aged men (geometric mean: 0.38 ng/ml) was higher (P < 0.0001) than in young men (geometric mean: 0.28 ng/ml)., Conclusions: fPSA in blood, but not cPSA, is associated to PSA in semen ( approximately 17% co-variation). In blood cPSA, but not fPSA, increase with age in healthy men, which may reflect an increasing incidence of prostate disease.
- Published
- 2005
- Full Text
- View/download PDF
14. Association of free-prostate specific antigen subfractions and human glandular kallikrein 2 with volume of benign and malignant prostatic tissue.
- Author
-
Steuber T, Niemela P, Haese A, Pettersson K, Erbersdobler A, Felix Chun KH, Graefen M, Kattan MW, Huland H, and Lilja H
- Subjects
- Aged, Biomarkers, Biopsy, Diagnosis, Differential, Humans, Male, Middle Aged, Predictive Value of Tests, Prostatic Hyperplasia blood, Prostatic Neoplasms blood, Prostate-Specific Antigen blood, Prostatic Hyperplasia pathology, Prostatic Neoplasms pathology, Tissue Kallikreins blood
- Abstract
Background: We investigated the association of different subfractions of prostate specific antigen (PSA) and human glandular kallikrein 2 (hK2), such as total PSA (tPSA), complexed PSA (cPSA), free PSA (fPSA), "single-chain Intact fPSA" (fPSA-I), "multi-chain nicked fPSA" (fPSA-N), and total hK2 with volumes of total prostate gland, transition zone (tz), and prostate cancer (PCa) tissue in patients with benign and malignant prostatic disease., Methods: Serum samples were collected from men with negative biopsy (n=164) and PCa (n=252). Total and fPSA were measured using a commercially immunoassay. We measured hK2 and fPSA-I by previously reported in-house research assays specific for hK2 and single-chain, non-cleaved fPSA, respectively. Levels of fPSA-N (=fPSA-fPSA-I) and cPSA (=tPSA-fPSA) were calculated. Total prostate and tz volume were measured using transrectal ultrasound (TRUS); PCa volume was calculated using a computer assisted volumetric program. Association with tz and cancer volumes (CaVols) was performed by linear regression analysis., Results: All PSA subfractions and hK2 were associated with tz volume in multivariable linear regression analysis. Only hK2, fPSA, and fPSA-N were significantly associated with CaVol in multivariable analysis, fPSA-I seemed to be cancer related., Conclusions: The multi-chain fPSA-N subfractions of fPSA may be a valuable predictor of both benign prostate hyperplasia (BPH) and CaVol that is likely to be more useful in predicting tz volumes than CaVols. fPSA-I may provide information on cancer without being influenced by the presence of BPH., (Copyright (c) 2004 Wiley-Liss, Inc.)
- Published
- 2005
- Full Text
- View/download PDF
15. Androgen receptor CAG repeat length correlates with semen PSA levels in adolescence.
- Author
-
Giwercman YL, Richthoff J, Lilja H, Anderberg C, Abrahamsson PA, and Giwercman A
- Subjects
- Adult, Genotype, Humans, Luteinizing Hormone blood, Male, Risk Factors, Semen chemistry, Sequence Analysis, DNA, Testosterone blood, Adolescent physiology, Prostate-Specific Antigen analysis, Prostatic Neoplasms genetics, Prostatic Neoplasms physiopathology, Receptors, Androgen genetics, Trinucleotide Repeat Expansion genetics
- Abstract
Background: Androgens exert their action through the androgen receptor (AR). The length of the AR CAG repeat is inversely correlated to receptor function and short CAG length might be a risk factor for development of prostate cancer. Our aim was to investigate whether CAG repeat number might have an impact on prostate function in adolescence., Methods: AR genotyping was performed by direct sequencing of leukocyte DNA from 274 military conscripts. All men underwent endocrine evaluation and semen analysis., Results: PSA in seminal plasma, total sperm count and motility all are inversely correlated with CAG numbers (rho = -0.128, P = 0.038; rho = -0.156, P = 0.010; rho = -0.158, P = 0.011), whereas serum levels of free testosterone (rho = 0.132; P = 0.029) and luteinizing hormone (rho = 0.126; P = 0.037) are positively correlated to CAG length. No correlation between seminal PSA and serum testosterone, neither free nor total, was found., Conclusions: In adolescence, AR genotype, but not serum testosterone, is associated with the level of seminal PSA., (Copyright 2004 Wileey-Liss, Inc.)
- Published
- 2004
- Full Text
- View/download PDF
16. Expression of protein C inhibitor (PCI) in benign and malignant prostatic tissues.
- Author
-
Cao Y, Becker C, Lundwall A, Christensson A, Gadaleanu V, Lilja H, and Bjartell A
- Subjects
- Androgens physiology, Blotting, Western, Carcinoma genetics, Cell Line, Tumor, Humans, Immunohistochemistry, In Situ Hybridization, Male, Neoplasms, Hormone-Dependent genetics, Prostate-Specific Antigen genetics, Prostate-Specific Antigen metabolism, Prostatic Hyperplasia genetics, Prostatic Neoplasms genetics, Protein C Inhibitor genetics, RNA, Neoplasm chemistry, RNA, Neoplasm genetics, Carcinoma metabolism, Neoplasms, Hormone-Dependent metabolism, Prostatic Hyperplasia metabolism, Prostatic Neoplasms metabolism, Protein C Inhibitor biosynthesis
- Abstract
Background: Protein C inhibitor (PCI) occurs at high concentration in seminal plasma, and inhibits human glandular kallikrein-2 and, less readily, prostate-specific antigen. Previous studies have localized PCI in the male genital tract. Here we have performed a detailed investigation of PCI expression in the prostatic tissues, metastases, and cell lines., Methods: Immunohistochemistry, in situ hybridization, and Western blotting were used to study prostatic tissues, metastases, and PC-3, DU-145, and LNCaP cells., Results: PCI was immunolocalized in tissue microarray spots with BPH epithelium (detection rate 100%), PIN lesions (100%), tumors (96%), metastases (88%), and in all cell lines. ISH and WB supported the findings., Conclusions: PCI is widely expressed in benign prostatic epithelium, and may act as a local regulator of enzymatic activity in seminal fluid, of importance for normal sperm function. Lack of PCI expression in a subpopulation of high-grade tumor cells in combination with maintained protease expression may facilitate invasive growth patterns., (Copyright 2003 Wiley-Liss, Inc.)
- Published
- 2003
- Full Text
- View/download PDF
17. Quantitative PSA RT-PCR for preoperative staging of prostate cancer.
- Author
-
Kurek R, Ylikoski A, Renneberg H, Konrad L, Aumüller G, Roddiger SJ, Zamboglou N, Tunn UW, and Lilja H
- Subjects
- Humans, Leukocytes, Mononuclear, Male, RNA, Messenger analysis, Sensitivity and Specificity, Gene Dosage, Neoplasm Staging methods, Prostate-Specific Antigen analysis, Prostate-Specific Antigen genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Reverse Transcriptase Polymerase Chain Reaction
- Abstract
Background: The clinical value of detecting prostate specific antigen (PSA) mRNA in the peripheral blood mononuclear cell fraction of patients (pts) by standard RT-PCR assays with localized prostate cancer remains controversial. We used a quantitative RT-PCR assay to measure the PSA mRNA copy number in addition to the qualitative PSA RT-PCR and correlated the results with clinical parameters., Methods: Total RNA was extracted from the peripheral blood mononuclear cell fraction of 115 prostate cancer pts prior to radical retropubic prostatectomy (RP) who received 3 months of neoadjuvant androgen deprivation. For quantitative RT-PCR, a PSA-like internal standard (IS) was added to each sample prior to reverse transcription and the PCR products for PSA and IS were selectively detected with fluorescent europium chelates after hybridization. Corresponding qualitative PSA-RT-PCR was performed for all samples., Results: The median PSA copy number was 126 (range: 0-37988). There were no significant correlations established between qualitative or quantitative RT-PCR results and given clinical parameters. Corresponding quantitative and qualitative RT-PCR results were significantly associated (P = 0.01)., Conclusions: We were unable to show any additional value of quantitative as well as qualitative PSA RT-PCR for preoperative staging of prostate cancer so far. Nevertheless, the long-term follow up of the patients has to be awaited., (Copyright 2003 Wiley-Liss, Inc.)
- Published
- 2003
- Full Text
- View/download PDF
18. Prostate-specific antigen (PSA) protein does not affect growth of prostate cancer cells in vitro or prostate cancer xenografts in vivo.
- Author
-
Denmeade SR, Litvinov I, Sokoll LJ, Lilja H, and Isaacs JT
- Subjects
- Animals, Cell Division drug effects, Enzyme Activation genetics, Humans, In Vitro Techniques, Male, Prostate-Specific Antigen genetics, Rats, Transfection, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Prostate-Specific Antigen metabolism, Prostate-Specific Antigen pharmacology, Prostatic Neoplasms drug therapy, Prostatic Neoplasms enzymology
- Abstract
Background: Prostate-specific antigen (PSA) is produced in high amounts by normal and malignant prostate cancer cells. PSA is a serine protease with substrates that include semenogelin I and II, insulin-like growth factor binding protein 3, fibronectin, and laminin. PSA, via its enzymatic activity, may play a role in growth, invasion, and metastasis of prostate cancer cells. Recent data also suggest that the PSA protein itself, independent of enzymatic activity, may also function as an endothelial cell-specific inhibitor of angiogenesis., Methods: Human (PC3, DU145) and rat (AT2, AT6) prostate cancer cell lines were transfected with the full PSA gene encoding preproPSA protein. PSA-producing clones of each cell line were selected and the amount of enzymatically active PSA produced by each cell line determined using a PSA-specific fluorescent peptide substrate. In vitro and in vivo growth characteristics of PSA-producing transfectants were compared to neomycin controls and wild type cells., Results: All selected clones produced and secreted PSA (5-120 ng/ml/10(5) cells). None of the PSA-transfected cell lines produced detectable amounts of enzymatically active PSA. Production of enzymatically inactive PSA by prostate cancer cell lines did not alter growth kinetics in vitro. PSA-producing xenograft doubling times in vivo were similar to neomycin controls and wild type., Conclusion: Although recent reports suggest the PSA protein itself may be antiangiogenic, our results demonstrate that production of PSA protein by prostate cancer cells does not significantly alter growth in vitro or in vivo., (Copyright 2003 Wiley-Liss, Inc.)
- Published
- 2003
- Full Text
- View/download PDF
19. The role of human glandular kallikrein 2 for prediction of pathologically organ confined prostate cancer.
- Author
-
Haese A, Graefen M, Becker C, Noldus J, Katz J, Cagiannos I, Kattan M, Scardino PT, Huland E, Huland H, and Lilja H
- Subjects
- Area Under Curve, Biomarkers, Biomarkers, Tumor, Humans, Male, Multivariate Analysis, Neoplasm Staging, Predictive Value of Tests, Prostate-Specific Antigen blood, Sensitivity and Specificity, Prostatic Neoplasms blood, Prostatic Neoplasms diagnosis, Tissue Kallikreins blood
- Abstract
Background: In recent studies serum levels of human glandular kallikrein 2 (hK2) demonstrated significant differences in pathologically organ-confined versus non-organ-confined prostate cancer (PCa). In this study we investigated whether hK2 adds independent information when considered together with traditionally used parameters to predict organ confined (pT2a/b) PCa., Methods: Serum levels of hK2, total and free prostate-specific antigens (PSA) were obtained one day before radical prostatectomy in 245 consecutive men. These were included with clinical stage and biopsy Gleason grade into univariate analysis and multivariate logistic regression models., Results: pT2a/b PCa was found in n = 148 patients. In univariate analysis all preoperative parameters demonstrated significant association with the presence of pT2a/b PCa. Using multivariate logistic regression model hK2 (P = 0.022), clinical stage (P < 0.0001), and Gleason grade (P < 0.0001) were independent predictors of pT2a/b PCa whereas PSA (P = 0.3) was not. In bootstrap corrected logistic regression based nomograms the addition of hK2 density marginally enhanced predictive accuracy when PSA, PSA density, clinical stage, and Gleason grade were considered (AUC = 0.879 without hK2 density and 0.883 with hK2 density)., Conclusions: hK2 and hK2 density could independently predict pT2a/b PCa. However, improvement in predictive accuracy was marginal when nomograms based on traditional variables were complemented with this serum marker., (Copyright 2002 Wiley-Liss, Inc.)
- Published
- 2003
- Full Text
- View/download PDF
20. Human glandular kallikrein 2 levels in serum for discrimination of pathologically organ-confined from locally-advanced prostate cancer in total PSA-levels below 10 ng/ml.
- Author
-
Haese A, Graefen M, Steuber T, Becker C, Pettersson K, Piironen T, Noldus J, Huland H, and Lilja H
- Subjects
- Area Under Curve, Cohort Studies, Humans, Immunohistochemistry, Male, Neoplasm Staging, Prostate-Specific Antigen blood, ROC Curve, Statistics, Nonparametric, Prostatic Neoplasms blood, Prostatic Neoplasms pathology, Tissue Kallikreins blood
- Abstract
Background: We measured serum levels of human glandular kallikrein 2 (hK2) in patients treated with radical retropubic prostatectomy (rrP) for clinically localized prostate cancer (PCa) with a total PSA (tPSA)-level below 10 ng/ml to investigate whether hK2 can be applied to preoperatively distinguish organ-confined (pT2a/b) from nonorgan-confined (> or = pT3a)-PCa more accurately than total PSA. Further, we evaluated hK2, free- and tPSA-concentrations in all pathologic stages of PCa., Methods: 161 serum samples from men scheduled for rrP were collected 1 day before surgery prior to any prostatic manipulation. Pathologic work-up revealed > or = pT3a-PCa in 48 and pT2a/b-PCa in 113 patients. HK2-levels in serum were measured using an immunofluorometric assay with an analytical sensitivity of 0.5 pg/ml, a functional sensitivity of 5 pg/ml and insignificant cross-reactivity with PSA (< 0.005%). Total (tPSA) and free PSA (fPSA) levels were measured using a commercially available assay from which we calculated %fPSA and an algorithm that combined hK2 and PSA-levels [hK2] x [tPSA/fPSA]. Means, medians, and ranges were calculated for pT2a/b vs. >/= pT3a-PCa and for all pathologic stages. Statistical significance of differences was calculated using Mann-Whitney-U and Kruskal-Wallis tests. Calculation of receiver-operator-characteristic (ROC) curves were performed for hK2, [hK2] x [tPSA/fPSA] and tPSA to compare diagnostic performance., Results: A mean tPSA level in serum of 6.12 ng/ml in > or = pT3a-PCa was not significantly different (P = 0.366) from 5.78 ng/ml in pT2a/b-PCa. Also, there were no statistically significantly different levels of fPSA (P = 0.947) or %fPSA (0.292) for these two groups. By contrast, mean hK2-level in pT2a/b-PCa of 80 pg/ml was significantly different (P = 0.004) from a mean hK2 level of 120 pg/ml in > or = pT3a-PCa as shown by Mann-Whitney-analysis Moreover, the algorithm of [hK2] x [tPSA/fPSA] was significantly lower (P = 0.0004) in pT2a/b-PCa vs. > or = pT3a-PCa. Calculation of areas under curve (AUC) by receiver-operator-characteristics (ROC) demonstrated that the AUC for hK2 (0.64) was larger and the AUC for [hK2] x [tPSA/fPSA] (=0.68) significantly larger (P = 0.007) compared to the AUC of tPSA (0.55). Furthermore, Kruskal-Wallis Test revealed a highly significant correlation to pathologic stage using hK2 (P = 0.008) and [hK2] x [tPSA/fPSA] (P = 0.0015) compared to no significant differences in serum concentration of tPSA (P = 0.296). Also at tPSA-levels from 10-20 ng/ml, the hK2-levels in pT2a/b-PCa were close to significantly different (P = 0.051) from those in men with >/= pT3a-PCa, while the algorithm of [hK2] x [tPSA/fPSA] in that tPSA-range was significantly lower (P = 0.002) in pT2a/b-PCa compared to > or = pT3a0-PCa., Conclusions: Highly significant differences in serum concentration enable hK2 to be a powerful predictor of organ-confined disease and pathologic stage of clinically localized prostate cancer, especially in the PSA-range below 10 ng/ml. As such, there are important clinical consequences for the application of hK2 for the adequate treatment of prostate cancer patients, i.e., the option of nerve-sparing surgery. (c) 2001 Wiley-Liss, Inc.
- Published
- 2001
- Full Text
- View/download PDF
21. Activation of latent protease function of pro-hK2, but not pro-PSA, involves autoprocessing.
- Author
-
Denmeade SR, Lövgren J, Khan SR, Lilja H, and Isaacs JT
- Subjects
- Enzyme Induction, Humans, Hydrolysis, Kinetics, Male, Prostate-Specific Antigen metabolism, Signal Transduction, Tissue Kallikreins metabolism, Prostate enzymology, Prostate-Specific Antigen biosynthesis, Tissue Kallikreins biosynthesis
- Abstract
Background: Human glandular kallikrein 2 (hK2) and prostate-specific antigen (PSA) are members of an extensive kallikrein family of proteases. Both proteases are secreted as zymogens or proenzymes containing a seven amino acid propeptide that must be proteolytically removed for enzymatic activation. The physiological proteases that activate pro-hK2 and pro-PSA are not known., Methods: The pro-hK2 peptide sequence is Val-Pro-Leu-Ile-Gln-Ser-Arg (VPLIQSR). For PSA, the amino acid sequence of the propeptide is Ala-Pro-Leu-Ile-Leu-Ser-Arg (APLILSR). Fluorescent substrates were made by coupling these peptide sequences to 7-amino-4-methylcoumarin (AMC). The hydrolysis of the VPLIQSR-AMC and APLILSR-AMC substrates by hK2, PSA, and a panel of purified proteases was determined., Results: HK2 readily cleaved the pro-hK2 peptide substrate VPLIQSR-AMC with a rate of hydrolysis that was approximately 8-fold higher than an equimolar amount of purified trypsin. HK2 also had the highest hydrolysis rate from among a group of other trypsin-like proteases. In contrast, neither hK2 nor PSA was able to appreciably cleave the pro-PSA substrate APLILSR-AMC. The pro-PSA substrate was most readily hydrolyzed by urokinase and trypsin., Conclusions: HK2 can hydrolyze the pro-hK2 substrate suggesting that maturation of pro-hK2 to enzymatically active hK2 involves autoprocessing. As expected, PSA, a chymotrypsin-like protease, was unable to hydrolyze either of the propeptide substrates. Therefore, it is unlikely that PSA can auto-process its own enzymatic function. HK2 has trypsin-like specificity but was unable to hydrolyze the pro-PSA substrate. These results raise the possibility that an additional processing protease may be required to fully process PSA to an enzymatically active form.
- Published
- 2001
- Full Text
- View/download PDF
22. Similar rates of exponential decrease in serum concentrations of free prostate-specific antigen (PSA), PSA complexed to alpha-1-antichymotrypsin, and human glandular kallikrein 2 (hK2) in prostate cancer patients treated with GnRH-analogues.
- Author
-
Björk T, Schalken J, Wittjes W, Ljungberg B, and Lilja H
- Subjects
- Aged, Aged, 80 and over, Gonadotropin-Releasing Hormone analogs & derivatives, Humans, Male, Middle Aged, Predictive Value of Tests, Prostatectomy, Prostatic Neoplasms surgery, Gonadotropin-Releasing Hormone administration & dosage, Prostate-Specific Antigen blood, Prostatic Neoplasms blood, Prostatic Neoplasms drug therapy, Tissue Kallikreins blood, alpha 1-Antichymotrypsin blood
- Abstract
Background: Our recently reported finding of rapid bi-exponential elimination of free prostate-specific antigen (PSA) after radical retropubic prostatectomy in patients with moderately elevated PSA levels, which contrasted a very slow, linear elimination of PSA complexed to alpha-1-antichymotrypsin (ACT), prompted us to study whether these elimination rates were applicable for patients selected for castration treatment with very high pretreatment concentrations of PSA in serum. In addition, serum concentrations of hK2, the activator of proPSA, were measured., Methods: Pretreatment serum was obtained from 21 previously untreated prostate cancer patients due for hormonal treatment with a GnRH-analog. Samples were also collected during treatment up to a minimum of 24 weeks at 2-week intervals and analyzed with immunofluorometric assays for free PSA (PSA-F), PSA complexed to alpha-1-antichymotrypsin (PSA-ACT), total PSA (PSA-T), and human kallikrein 2 (hK2). For pharmaco-kinetic analysis the serum concentrations of hK2 and PSA forms for each patient were plotted against time both before and after logarithmic transformation and the half-lives were calculated as ln2/k., Results: Median pretreatment serum concentrations were 322 ng/ml (range, 1.9-2210) for PSA-T, 27.8 ng/ml (range, 1.14-259) for PSA-F, and 207 ng/ml (range, 0.8-2080) for PSA-ACT. All patients had castrate levels of serum testosterone (< 2.5 nmol/l) in less than 21 days after initiation of GnRH-analog treatment. It was possible to evaluate data from 19/21 patients which showed an exponential decrease of all PSA concentrations in serum, with mean half-lives of 12.9 days (range, 7.3-30) for PSA-T, 15.5 days (range, 7.7-37.5) for PSA-F, and 12.3 days (range, 6.6-30) for PSA-ACT. Median pretreatment percent free PSA (PSA-F/PSA-T) was 12% compared to 18% at nadir. The median pretreatment level of hK2 was 3.5 ng/ml (range, 0.29-30.3). There was an exponential decrease in hK2 concentrations in serum after initiation of hormonal treatment with a mean half-life of 18.7 days (range, 7.5-37.5)., Conclusions: For the majority of patients with hormonally treated prostate cancer the serum concentrations of PSA-T, PSA-F, PSA-ACT, and hK2 decreased slowly in parallel and mono-exponentially after initiation of treatment. Mean half-lives were between 12 and 19 days.
- Published
- 2001
- Full Text
- View/download PDF
23. Enzymatic action of prostate-specific antigen (PSA or hK3): substrate specificity and regulation by Zn(2+), a tight-binding inhibitor.
- Author
-
Malm J, Hellman J, Hogg P, and Lilja H
- Subjects
- Amino Acid Sequence, Cations, Divalent, Enzymes, Humans, Hydrolysis, Molecular Sequence Data, Prostate-Specific Antigen antagonists & inhibitors, Semen, Sequence Homology, Amino Acid, Substrate Specificity, alpha 1-Antichymotrypsin metabolism, Enzyme Inhibitors metabolism, Gonadal Steroid Hormones metabolism, Prostate-Specific Antigen metabolism, Seminal Plasma Proteins, Seminal Vesicle Secretory Proteins, Zinc metabolism
- Abstract
Background: In semen, prostate-specific antigen (PSA or hK3) digests the gel proteins semenogelin I and II, resulting in liquefaction and the release of motile spermatozoa. We characterized the substrate specificity and zinc-mediated inhibition of PSA., Methods: The proteolysis of human semenogelin I (SgI) and II (SgII) by PSA was characterized by purification of generated SgI and SgII fragments, N-terminal sequencing, and mass spectrometry. Zn(2+)-inhibition of PSA was studied using a chromogenic substrate., Results: Eighteen cleavage sites in SgI and 16 in SgII were identified. Cleavages were identified mainly as the C-terminal of certain tyrosine and glutamine residues, but also the C-terminal of histidine, aspartic acid, leucine, serine, and asparagine residues. No cleavages were identified at any arginine, lysine, phenylalanine, tryptophan, or methionine residues, indicating that the substrate specificity of PSA is distinct from that of trypsin, chymotrypsin, tissue kallkrein (hK1), and kallikrein 2 (hK2). Zn(2+) ions have a dramatic effect on PSA activity; the data indicate that Zn(2+) is a tight-binding inhibitor of PSA activity., Conclusions: The data will enable the optimized design of PSA activity assays, which may prove instrumental to uncovering the role of PSA in cancer and reproduction. The inhibition data indicate that Zn(2+) could regulate PSA activity, which may prove important in the development of efficient inhibitors of PSA activity., (Copyright 2000 Wiley-Liss, Inc.)
- Published
- 2000
- Full Text
- View/download PDF
24. Cloning and characterization of the alpha 1-antichymotrypsin produced by human prostate tissue.
- Author
-
Wu G, Lilja H, Cockett AT, and Gershagen S
- Subjects
- Base Sequence, Blotting, Northern, Cloning, Molecular, DNA, Complementary, Humans, Male, Molecular Sequence Data, Polymerase Chain Reaction, Prostatic Hyperplasia metabolism, Prostatic Hyperplasia pathology, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Serine Proteinase Inhibitors biosynthesis, Tumor Cells, Cultured, alpha 1-Antichymotrypsin biosynthesis, Prostate metabolism, Serine Proteinase Inhibitors genetics, alpha 1-Antichymotrypsin genetics
- Abstract
Background: alpha 1-antichymotrypsin (ACT) forms stable complexes with prostate-specific antigen (PSA), a serine protease, and this complex is the major form of PSA in the blood circulation. alpha 1-antichymotrypsin occurs in the blood in approximately 10(5) molar excess to PSA, mainly due to hepatic production, but local prostatic production of ACT has been demonstrated by immunohistochemistry and in situ hybridization. The present study was performed to further characterize this prostate-produced ACT., Methods: The nucleotide structure of the prostatic transcript was determined from ACT coding clones isolated from prostatic cDNA. The occurrence of a prostatic ACT transcript was analyzed by Northern blot. RT-PCR was used to detect ACT transcripts in cultured prostatic cancer cells., Results: Screening of two prostatic cDNA libraries showed the frequency of ACT transcripts to be about 1 clone in 40,000. The cDNA sequence of prostatic ACT is identical to that of the previously published hepatic ACT. Northern blot analysis of mRNA extracted from prostatic tissue showed a single transcript of approximately 1.5 kb. RT-PCR analysis demonstrated an ACT transcript in cultured prostatic cancer cells., Conclusions: In this study we provide further evidence for a local, prostatic production of ACT. The cDNA sequence data suggest that the peptide backbone of prostatic ACT is identical to the protein derived from the liver, and thus may be functional as a protease inhibitor.
- Published
- 1998
- Full Text
- View/download PDF
25. Immunoreactivity of recombinant human glandular kallikrein using monoclonal antibodies raised against prostate-specific antigen.
- Author
-
Eerola R, Piironen T, Pettersson K, Lövgren J, Vehniäinen M, Lilja H, Dowell B, Lövgren T, and Karp M
- Subjects
- Epitopes, Escherichia coli genetics, Humans, Recombinant Proteins immunology, Tissue Kallikreins, Antibodies, Monoclonal immunology, Kallikreins immunology, Prostate-Specific Antigen immunology
- Abstract
The gene encoding human glandular kallikrein (KLK2) was expressed in Escherichia coli, and the corresponding protein (hK2) was produced by fermentation. The hK2 was characterized by Western blotting and epitope map using monoclonal antibodies (MAbs) specific for another protease, prostate-specific antigen (PSA) with high structural identity (80%). MAbs that recognized three different epitopes were bound to hK2, representing 7 out of 23 MAbs tested. One epitope was localized to the sequence region around amino acid position 78, which is believed to be glycosylated in hK2. The affinities of MAbs recognizing hK2 were similar to those for PSA, suggesting that common epitopes seem to contain very conserved structures. The results may help in designing specific diagnostic assays for the assessment of prostate cancer.
- Published
- 1997
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.