Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A human prostate cancer model was established by inoculating a prostate specific antigen (PSA)-producing LNCaP cell line with either prostate or bone fibroblasts. Alternatively, this human prostate cancer model can also be established by inoculating LNCaP cells with growth factor(s) (GFs) and extracellular matrix (ECM) immobilized on Gelfoam. The resulting LNCaP tumors were used to evaluate PSA production and excretion in athymic hosts. This model was also employed to examine the biochemical nature of mesenchymal cell-derived growth-promoting protein(s) and to assess the efficacy of potential chemotherapeutic agents. Because of the propensity of human prostate cancer to metastasize to the bone, this study defined a 1.0 M NaCl-eluted fraction, MS1, from the conditioned medium of a bone stromal cell line (MS) by heparin-affinity column chromatography. The growth-promoting activity was assayed both in vivo (e.g., tumor formation) and in vitro (e.g., soft agar colony formation). We found that the growth-promoting activity was trypsin- and heat-sensitive, and partially degraded by acid and dithiothreitol. Immunochemical studies indicated that the polyclonal antibody raised against MS1 blocked the growth-promoting effect elicited by the bone-conditioned media. This growth-promoting factor was found to be immunochemically dissimilar to KGF, HGF, and bFGF. However, addition of bFGF, HGF and NGF, but not aFGF, TGF beta, IGF1, IGF2, PDGF, EGF, TGF alpha and KGF, stimulated anchorage-independent growth of prostate cells, a condition closely parallel to tumor formation in vivo. We found that the MS1 fraction also contained fibronectin and tenascin but not laminin or collagen IV.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human prostate cancer model: roles of growth factors and extracellular matrices. 128 80

Human seminal plasma (SP) has been known to contain both growth-inhibitory and -stimulatory factors. We attempted to identify a factor that inhibited DNA synthesis in some metastatic prostate cancer cell lines. The SP factor was sensitive to digestion by trypsin, but its activity increased after boiling or dialysis against 1 M acetic acid, by 3- to 4-fold. The SP factor was partially purified using a cation-exchange resin. Apparent molecular mass determination by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed it to be a M(r) 25,000 protein, and M(r) 13,000 after reduction. This protein strongly inhibited DNA synthesis in two metastatic androgen-independent human prostatic carcinoma cell lines (PC3 and DU145) and the Dunning R3327G rat prostatic adenocarcinoma. It was ineffective on androgen-dependent LNCaP cells. The proliferation-inhibiting activity of this SP protein was specifically and completely abolished by a neutralizing anti-transforming growth factor beta (TGF-beta) antiserum. Furthermore, immunoblot analysis using the anti-TGF-beta antiserum showed the similarity of this protein to TGF-beta. The maximum concentration of this protein in SP was 165 +/- 11.7 ng/ml (mean +/- SD), of which only one-fourth may be present in active form under normal conditions. Identification of a TGF-beta-like protein in SP might also explain the variety of growth and immune modulation properties of human SP.
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PMID:Isolation of a prostate carcinoma cell proliferation-inhibiting factor from human seminal plasma and its similarity to transforming growth factor beta. 139 10

We have investigated the possibility of the secretion of gonadotrophin-releasing-hormone (GnRH)-like peptides by prostatic cancer cells in culture and their presence in cytosolic preparations from human prostatic biopsy specimens. A GnRH-specific radioimmunoassay showed GnRH-like activity in concentrated cytosolic preparations and conditioned media from DU 145, an androgen-insensitive human prostatic cell line and from LNCaP, an androgen-responsive prostatic cancer cell line. GnRH immunoreactivity in culture media correlated directly with cell numbers. HPLC demonstrated that this GnRH-like material co-migrated with synthetic GnRH. This homology between synthetic GnRH and partially purified prostatic GnRH was confirmed following V8 protease and trypsin digestion which resulted in similar alterations in HPLC characteristics. The mean content of GnRH-like activity/g specimen tissue was significantly more in malignant tissue (88.5 +/- 80.5 fmol) than in benign (29.6 +/- 22 fmol), though more specimens of benign tissue were positive (37/54) than malignant tissue (6/22). This observation, taken with an earlier finding of GnRH-specific receptors in a hormone-sensitive cell line and human cancer specimens provides supportive evidence for the autocrine hypothesis of cell regulation.
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PMID:The partial purification and characterization of GnRH-like activity from prostatic biopsy specimens and prostatic cancer cell lines. 228 4

At present, there is no established diagnostic method by which the metastatic ability of an individual prostatic cancer can be accurately predicted. Metastasis is a multistep process, the first critical step of which is invasion. Tumor invasion has been suggested to involve a variety of hydrolytic enzyme activities; therefore, the tumor levels of these activities might be indicative of the overall metastatic ability of the cancer. In order to evaluate if the quantitative levels of hydrolytic enzymes can be used to predict the metastatic ability of individual prostatic cancers, five different Dunning R-3327 rat prostatic adenocarcinoma sublines, with widely varying metastatic abilities, were assayed for the respective levels of a variety of hydrolytic enzyme activities (collagenase, trypsin-like, cathepsin B, neutral protease, N-acetyl-beta-glucosaminidase, chymotrypsin-like, leucine aminopeptidase, elastase, and plasminogen activator). These studies demonstrated that most hydrolytic activities are not elevated when going from normal prostate to prostatic cancer. In addition, only the levels of elastase and chymotrypsin-like activity were found to be consistently higher in highly metastatic prostatic cancers than in either the normal prostate or low-metastatic prostatic cancers. It was found that, by combining the relative activities of elastase and chymotrypsin-like activity and then dividing by the relative activities of N-acetyl-beta-glucosaminidase, a biochemical metastatic index could be constructed which accurately reflected the respective metastatic ability of the Dunning sublines.
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PMID:Biochemical methods for predicting metastatic ability of prostatic cancer utilizing the dunning R-3327 rat prostatic adenocarcinoma system as a model. 653 99

Extracts of human benign prostatic hyperplasia, well-differentiated prostatic adenocarcinoma, and normal post-pubertal prostate stimulate 3H-thymidine incorporation by resting phase cultures of fetal rat osteoblasts and fibroblasts. The stimulation is concentration dependent and reaches a maximum at twenty-four hours of incubation. Prostatic extracts are also mitogenic in cell cultures of newborn human foreskin fibroblasts and the human cell lines, BUD-8 and DoT. The growth-stimulating factor is both heat and trypsin sensitive indicating that the factor is either a protein or contains a protein moiety. The growth-stimulating activity is not related to prostatic polyamine concentration. Experiments also show the activity is not due to human prostatic acid phosphatase. A prostatic growth factor may explain the growth of fibrous nodules in benign prostatic hyperplasia and the osteoblastic response of bone to prostatic cancer.
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PMID:Mitogenic factor in human prostate extracts. 696 86

PSA is a 34-kDa 240-amino-acid glycoprotein produced exclusively by prostatic epithelial cells. PSA is a serine protease, is a member of the kallikrein gene family, and has a high sequence homology with human glandular kallikrein. It has chymotrypsin-, trypsin-, and esterase-like activities. In the serum it is present mainly in a complex form with alpha 1-antichymotrypsin. It is secreted in the seminal plasma and is responsible for liquefaction of the seminal coagulum. The production of PSA proteins appears to be under the control of circulating androgens acting through the androgen receptors. The PSA gene is up-regulated predominantly by androgens at both the protein and mRNA levels. DRE causes minimal changes in the PSA level, while prostate massage, ultrasonography, systoscopic examination, and prostate biopsy can all cause clinically significant elevations. Other conditions, such as prostatitis, prostate intraepithelial neoplasia, acute urinary retention, and renal failure can also elevate the PSA level. The value of PSA as a screening tool is questionable because of the great deal of overlap in PSA levels between BPH and prostate cancer. However, if used in men over 50, in conjunction with DRE and/or ultrasonography, it may become a vital part of the early detection program. PSA's role in determining the clinical and pathological stage is also limited, in spite of the direct correlation between the pathological stage and the PSA level, because of great overlap in the PSA levels in various stages. The most important clinical utility of PSA is in monitoring patients after definitive therapy. PSA is most sensitive and reliable in the detection of a residual tumor, possibly recurrence, or disease progression following treatment, irrespective of the treatment modality. PSA can accurately predict the tumor status and can detect recurrence several months before its detection by any other method. PSA is also a very sensitive and specific immunohistochemical marker for tumors of prostatic origin. Compared to PAP, PSA is a more precise and meaningful marker in all clinical situations. With the development of ultrasensitive assays and the adoption of an international standard PSA calibrator, so that results from multicenter studies can be compared, PSA could become one of the most useful tumor marker in cancer biology.
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PMID:Prostatic specific antigen. 753 74

Prostate-specific antigen (PSA) provides an excellent serum marker for prostate cancer, the most frequent form of cancer in American males. PSA is a 237-residue protease based on sequence homology to kallikrein-like enzymes. To predict the 3-dimensional structure of PSA, homology modeling studies were performed based on sequence and structural alignments with tonin, pancreatic kallikrein, chymotrypsin, and trypsin. The structurally conserved regions of the 4 reference X-ray proteins provided the core structure of PSA, whereas the loop structures were modeled on the loops of tonin and kallikrein. The unique "kallikrein loop" insert, between Ser 95b and Pro 95k of kallikrein, was constructed using molecular mechanics, dynamics, and electrostatics calculations. In the resulting PSA structure, the catalytic triad, involving residues His 57, Asp 102, and Ser 195, and hydrophobic and electrostatic interactions typical of serine proteases were extremely well conserved. Similarly, the 5-disulfide bonds of kallikrein were also conserved in PSA. These results, together with the fact that no major steric clashes arose during the modeling process, provide strong evidence for the validity of the PSA model. Calculation of the electrostatic potential contours of kallikrein and PSA was carried out using the finite difference Poisson-Boltzmann method. The calculations revealed matching areas of negative potential near the catalytic triad, but differences in the positive potential surrounding the active site. The PSA glycosylation site, Asn 61, is fully accessible to the solvent and is enclosed in a positive region of the isopotential map. The bottom of the substrate specificity pocket, residue S1, is a serine (Ser 189) as in chymotrypsin, rather than aspartate (Asp 189) as in tonin, kallikrein, and trypsin. This fact, plus other features of the S1 binding-pocket region, suggest that PSA would prefer substrates with hydrophobic residues at the P1 position. The location of a potential zinc ion binding site involving the side chain of histidines 91, 101, and 233 is also suggested. This PSA model should facilitate the understanding and prediction of structural and functional properties of this important cancer marker.
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PMID:A structural model for the prostate disease marker, human prostate-specific antigen. 753 13

Prostate-specific antigen (PSA) is a tissue-specific serine protease similar in structure to the trypsin-like glandular kallikreins but which is unique inasmuch as the enzyme activity is similar to that of chymotrypsin. The active enzyme is a single chain glycoprotein of 237 amino acids. The major form of PSA in serum is complexed to alpha 1-antichymotrypsin (ACT). A small amount is free, non-complexed despite a large excess of ACT. This suggests that the form in serum lacks enzyme activity. Although serum PSA concentrations are regularly abnormally high (above 4 micrograms/L) in prostate cancer (CAP), the utility of PSA measurements in the early detection of CAP is limited, as many tumors are undetected at a cut-off of 4 micrograms/L. Also, 25% of all men with benign prostate hyperplasia (BPH) have serum PSA levels above 4 micrograms/L. Using assays specially developed to measure free and complexed forms of PSA in serum, we found the proportion of PSA-ACT complexes to be higher in CAP than in BPH, but the ratio of free-to-total PSA in serum to be lower. Using an abnormally low ratio of free-to-total PSA to detect CAP increases diagnostic specificity by 15 to 20%, compared to using a high serum PSA concentration. This suggests that the ratios of free-to-total PSA significantly increase the ability to distinguish BPH from localized CAP. The molecular basis is unclear, but may be related to the high incidence of prostate tumor cells producing both PSA and ACT. This is in contrast to the lack of ACT production in BPH epithelium. Possibly owing to lack of ACT production in BPH areas, conditions are not optimal for complex formation, whereas tumors producing both ACT and PSA may promote the formation of PSA-ACT complexes in CAP.
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PMID:Regulation of the enzymatic activity of prostate-specific antigen and its reactions with extracellular protease inhibitors in prostate cancer. 754 78

The biological behavior of prostatic cancer is influenced by many host and tumor factors. The proliferative activity of the malignancies can be one of those parameters which serve as the basis to estimate prognosis and design treatment. Here, DNA content and S-phase fraction of prostatic cancer samples obtained by radical prostatectomy from 46 patients were related to other known tumor characteristics (PSA, staging, grading). Nuclei from the paraffin embedded materials were isolated with overnight trypsin-ribonuclease mixture digestion. DNA content and cell cycle distribution were determined by flow cytometry. A correlation was found between the PSA concentration, grading and staging on the one hand and S-phase fraction on the other. DNA content correlated with grading. No kinetic parameter correlated with the nodal involvement. Due to the association between abnormal DNA content plus SPF > 5% with advanced stage and less differentiated appearance of the tumor, we can conclude that these parameters are useful to estimate prognosis.
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PMID:DNA content of prostatic cancer measured by flow cytometry in patients undergoing radical prostatectomy. 764 37

Prostate-specific antigen (PSA), a M(r) 34,000 serine protease, is recognized as a useful marker for the detection and prognosis of patients with prostate cancer. Although serum PSA is an excellent prognostic indicator, an increasing number of factors were found to regulate the PSA expression of prostatic cancer cells, which include androgenic steroids, the growth factors (GFs) and the extracellular matrix. The purpose of this study is to define a novel protein factor that may be responsible for regulating PSA expression by androgen-independent (AI) human prostate cancer cells. We have established a LNCaP subline (C4) from a parental LNCaP tumor grown in a castrated host. The C4 subline overexpressed PSA mRNA and protein. Serum-free conditioned medium (CM) isolated from the C4 subline is able to stimulate PSA gene expression in parental LNCaP cells in a concentration-dependent manner. This autocrine PSA-inducing activity was found to be organ specific because CMs from other fibroblast cell lines (such as bone, prostate, kidney, and lung fibroblasts) and the CMs from several prostatic carcinoma cell lines (such as parental LNCaP, PC-3, DU-145) and a bladder transitional carcinoma cell line (WH) fail to exhibit similar activity. The activity of the CM from the C4 subline cannot be substituted by GFs such as TGF-alpha, TGF-beta, bFGF, HGF, KGF, or NGF; neuropeptide (bombesin/GRP); secondary messenger analogue (dibutyryl cAMP); beta 2-adrenergic agonist (isoproterenol); or alpha 1-adrenergic agonist (phenylephrine), indicating that the factor(s) may be a novel prostate-specific autocrine factor (PSAF). Both androgen and PSAF exhibit an additive effect on up-regulating PSA gene expression, suggesting that the signal transduction pathway elicited by PSAF may differ from that mediated by the androgen receptor. Further characterization of PSAF by heat, acid, and trypsin digestion revealed that the PSAF may be a protein factor with a unique amino acid composition. These observations suggest that a novel autocrine pathway mediated by PSAF may be responsible for the overexpression of PSA mRNA and protein in a human prostatic cancer cell line. The potential clinical significance of this factor will be discussed.
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PMID:Autocrine regulation of prostate-specific antigen gene expression in a human prostatic cancer (LNCaP) subline. 768 49


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