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)

Human prostate cancer displays a high degree of variability in its rate of spread, which could be due largely to differences in the invasive potential of the tumor cells. The degradation of the basal lamina and stromal extracellular matrix is mediated in part by the secretion of matrix metalloproteinases (MMPs). Matrilysin (PUMP-1, MMP-7) and gelatinase A (M(r) 72,000 type IV collagenase, MMP-2) have been shown to be overexpressed in prostate carcinoma. We have expressed the single MMP matrilysin in the tumorigenic but nonmetastatic human prostate tumor cell line DU-145 to determine if matrilysin has a functional role in prostate tumor cell invasion. DU-145 cells expressing matrilysin were significantly more invasive than vector-only transfected cell lines as assayed by a severe combined immunodeficient mouse model of tumor cell invasion. Vector-only transfected DU-145 cells injected i.p. into severe combined immunodeficient mice invaded the diaphragm in only 1 of 9 mice (11%), whereas matrilysin-transfected DU-145 cells invaded the diaphragm in 12 of 18 mice (66%). The difference between the controls and matrilysin-transfected cells was statistically significant (P < 0.006). These results suggest a functional role for matrilysin in the initial invasion of prostate cancer through the epithelial basal lamina and into the surrounding stroma.
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PMID:Expression of the metalloproteinase matrilysin in DU-145 cells increases their invasive potential in severe combined immunodeficient mice. 841 33

Tumor progression to the stage of metastasis may result in part from the selection of certain primary tumor cell clones which are phenotypically competent for survival, invasion, and growth at secondary sites. Selection for traits such as loss of growth inhibitory responses, acquisition of increased adhesiveness, increased local immunosuppression, and enhanced motility and collagenase activities likely contribute to cancer progression and may be regulated through the action of growth factors. The transforming growth factors (TGF-beta) family of growth factors has often been associated with these traits and tumor progression; therefore, elimination or subversion of TGF-beta-responsive pathways should be considered as a mechanistic framework for metastatic events. In this report, we have compared growth and extracellular matrix responses to TGF-beta in six metastatic and six primary tumor-derived cell lines in a mouse model of prostate cancer. We have found that tumor cell lines derived from focal pulmonary metastasis secreted relatively greater quantities of total TGF-betas, lost most or all TGF-beta1 growth inhibition, but responded to TGF-beta1 through induction of the type IV collagenase matrix metalloproteinase-9, whereas cell lines derived from tumors which proliferated at the primary site retained the growth inhibition but lacked collagenase activity. Synthesis of another extracellular matrix protein, plasminogen activator inhibitor 1, was stimulated by TGF-beta1 in both primary as well as metastatic tumors. These results suggest that acquisition of differential responses to the TGF-beta family could result in phenotypic traits which facilitate tumor metastasis from certain primary site clones.
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PMID:Transforming growth factor beta1 stimulates contrasting responses in metastatic versus primary mouse prostate cancer-derived cell lines in vitro. 876 34

Matrilysin (PUMP-1) is a member of the matrix metalloproteinase (MMP) family of extracellular matrix degrading enzymes that has been found to be overexpressed in human prostate cancer. The rat ventral prostate (RVP) following castration has been used as a model for both tissue involution and apoptosis. Northern analysis and in situ hybridization were used to determine the time course and localization of matrilysin during 8 days of RVP involution. Northern analysis revealed that the 1.2 kb matrilysin mRNA was undetectable in normal RVP. An increase in the steady-state levels of matrilysin mRNA was observed 5 days after castration, and the levels began to decline by 8 days after castration. The mRNAs for tissue inhibitor of metalloproteinase-1 and urokinase-type plasminogen activator also showed a time-dependent induction during the course of involution. Localization of matrilysin by in situ hybridization indicated that the mRNA was produced by epithelial cells of the involuting RVP. The matrilysin message was observed in a small number of glands within the whole RVP. Matrilysin protein was present in the RVP and peaked 3 days after castration. The combination of proteinase genes expressed in the RVP following castration indicate that the MMP and serine protease families of enzymes may interact during tissue remodeling of the RVP following castration.
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PMID:Matrilysin expression in the involuting rat ventral prostate. 882 84

Previous immunolabeling studies have indicated that increased expression of the matrix metalloproteinase-2 (MMP-2) zymogen is associated with an increased Gleason score for human prostate cancer. In the accompanying paper, we have found by immunoblotting and ELISA that the MMP-2 enzyme (termed MMP-2a) is expressed in prostate cancer and that increased expression is associated with progression. Monoclonal antibodies specific for MMP-2a were used to investigate the expression of MMP-2a in human prostate tissue sections of benign and malignant cancers. Immunohistochemistry indicated that MMP-2a expression was undetectable in fetal (n = 4), benign (n = 11), and low Gleason score 4 (n = 8) tissue. MMP-2a was faintly expressed (+) in cancer assigned Gleason scores 5 (n = 20) and 6 (n = 13). In comparison, MMP-2a was expressed at an intermediate level (++) in tissues of Gleason score 7 (n = 24), and at a intense level ( to +) in tissues of score 8 (n = 48), 9 (n = 9) and 10 (n = 35) and in lymph node metastases (n = 10). These observations were confirmed by quantitative Computer Assisted Imaging Analysis. In general, MMP-2a was primarily expressed by the glandular epithelial cells, and in high Gleason score 10 specimens (n = 25/35) there was clear evidence of MMP-2a localization at the cell surface. These data suggest that increased MMP-2a expression may be associated with malignant progression and metastases.
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PMID:Immunohistochemical studies of activated matrix metalloproteinase-2 (MMP-2a)expression in human prostate cancer. 885 76

The identification of active chemotherapeutic agents for use in the treatment of advanced hormone-refractory prostate cancer remains a priority of clinical research. An estimated 317,100 new cases will be diagnosed in 1996. This increased diagnosis of disease can be directly attributed to the widespread use of screening serum prostate-specific antigen. However, this has not been associated with a reduction in mortality; more than 41,000 men in the United States are expected to die of the disease this year. The natural history of hormone-resistant disease has remained unaltered, with patients having a median survival of only approximately 12 months. Use of surrogate endpoints, such as a reduction in prostate-specific antigen or improvement in pain, may be appropriate for the evaluation of novel agents or combinations. A number of promising new approaches have been recently tested and brought to trial, including combined antimicrotubular therapy, camptothecins, and matrix metalloproteinase inhibitors. It is only through the development of these and other novel compounds that we can hope to affect the natural course of prostate cancer.
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PMID:New therapeutic agents for hormone-refractory prostate cancer. 899 86

Although a number of effective therapies are available for localized prostate cancer, metastatic prostate cancer is difficult to treat and impossible to cure. Identification of the gene products that enable a prostatic carcinoma cell to metastasize should facilitate an understanding of the processes leading to metastasis. To characterize the contribution of matrix metalloproteinase-9 (MMP-9, gelatinase B or the 92-kd type IV gelatinase/collagenase) to the development of metastasis in prostate cancer, we reduced MMP-9 expression in metastatic murine prostatic carcinoma cells using a ribozyme. The ribozyme transfected cells had lower basal levels of MMP-9 as well as decreased levels after stimulation by transforming growth factor-beta or phorbol 12-myristate 13-acetate when compared with the parental cells or with control transfectants. The cells with down-regulated MMP-9 were unable to form lung colonies in the experimental metastasis assay, whereas the controls and parental cells readily formed metastases. All cell types readily formed tumors after injection and down-regulation of MMP-9 did not adversely affect the rate of tumor growth. Thus, MMP-9 expression is required for hematogenous metastasis in a murine prostate model system raising the possibility that it may play an equivalent role in human prostate cancer.
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PMID:Requirement for matrix metalloproteinase-9 (gelatinase B) expression in metastasis by murine prostate carcinoma. 946 86

We examined whether the serum matrix metalloproteinase-2 (MMP-2) level and MMP-2 density could be predictors of the development and extension of prostate cancer. Serum samples were collected before any clinical treatment from 98 patients with prostate cancer and from 76 patients with benign prostatic hyperplasia (BPH). Control sera were obtained from 70 healthy men. The serum level of MMP-2 was determined by 1-step enzyme immunoassay. A newly defined MMP-2 density parameter was determined by dividing the serum level of MMP-2 by the prostate volume, which was measured by ultrasonography. The mean serum level of MMP-2 in prostate cancer patients was significantly higher than in the control and BPH groups. Furthermore, the serum MMP-2 levels in prostate cancer patients with metastasis were highly elevated compared with those without metastases. The MMP-2 density in pathologically organ-confined prostate cancer was significantly higher than that in BPH. There was a statistically significant difference in the MMP-2 density between pT2N0M0 and pT1N0M0 prostate cancers. Moreover, the serum MMP-2 level correlated well with the clinical course of prostate cancer with bone metastasis. Our results suggest that MMP-2 plays an important role in the development and extension of prostate cancer and that the serum level of MMP-2 and the MMP-2 density indicate prostate cancer extension and are, therefore, useful for the followup of prostate cancer patients.
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PMID:Serum matrix metalloproteinase-2 and its density in men with prostate cancer as a new predictor of disease extension. 976 79

In in vitro angiogenesis assays, aggregates of human papilloma virus (HPV)-18-immortalized primary human prostate cancer cells (HPCA-5aHPV-18 or HPCA-10aHPV-18 cells) induced human bone marrow endothelial cells (HBMCE-1 cells) to form microvessels in three-dimensional collagen I gels after 1-2 days incubation at 37 degrees C. The microvessels aligned perpendicular to the tumor aggregates and abutted on the edges of the aggregates. The number and length of the microvessels increased significantly from day 1 to 2 (i.e., by approximately 30%). ELISAs showed that the HPCA-5aHPV-18 cells normally secreted low levels of tissue inhibitor of metalloproteinase (TIMP)-2, matrix metalloproteinase (MMP)-2, and MMP-9 but relatively high levels of TIMP-1. In contrast, HPCA-10aHPV-18 cells secreted high levels of MMP-2 and MMP-9 (>40 pg/microg protein) but low levels of TIMP-1 and TIMP-2 (<5 pg/microg protein). Interleukin 10 (IL-10) (15 ng/ml) induced TIMP-1 production (>15 pg/microg protein) but reduced MMP-2 and MMP-9 secretion (<5 pg/microg protein) by the HPCA-5aHPV-18 and HPCA-10aHPV-18 cells. IL-10 (15 ng/ml) and MMP-9/MMP-2 antibodies all blocked induction of microvessel formation in the coculture experiments. In contrast, IL-10 receptor antibodies and TIMP-1 antibodies countered IL-10's effects and promoted angiogenesis. The data demonstrated that IL-10 stimulation of TIMP-1 and inhibition of MMP-2 and MMP-9 secretion by prostate tumor cells can control induction of angiogenesis in vitro.
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PMID:Interleukin 10 (IL-10) inhibition of primary human prostate cell-induced angiogenesis: IL-10 stimulation of tissue inhibitor of metalloproteinase-1 and inhibition of matrix metalloproteinase (MMP)-2/MMP-9 secretion. 991 18

The type IV collagenases/gelatinases matrix metalloproteinase-2 (MMP-2) and MMP-9 play a variety of important roles in both physiological and pathological processes and are regulated by various growth factors, including transforming growth factor-beta1 (TGF-beta1), in several cell types. Previous studies have suggested that cellular control of one or both collagenases can occur through direct transcriptional mechanisms and/or after secretion through proenzyme processing and interactions with metalloproteinase inhibitors. Using human prostate cancer cell lines, we have found that TGF-beta1 induces the MMP-9 proenzyme; however, this induction does not result from direct effects on gene transcription but, instead, through a protein synthesis-requiring process leading to increased MMP-9 mRNA stability. In addition, we have examined levels of TGF-beta1 regulation of MMP-2 in one prostate cancer cell line and found that TGF-beta1 induces higher secreted levels of this collagenase through increased stability of the secreted 72-kDa proenzyme. These results identify two novel nontranscriptional pathways for the cellular regulation of MMP-9 and MMP-2 collagenase gene expression and activities.
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PMID:Novel regulation of type IV collagenase (matrix metalloproteinase-9 and -2) activities by transforming growth factor-beta1 in human prostate cancer cell lines. 995 Jun 85

Metastatic prostate cancer is a leading cause of cancer-related death in men. Although most patients will respond to androgen ablation as initial systemic therapy, nearly all patients will develop androgen-independent prostate cancer (AI CaP) and will succumb to the disease. Advances in molecular biology have demonstrated mutations in and persistent expression of the human androgen receptor in metastatic disease. Furthermore, recent evidence indicates that an apoptotic block through p53 mutations or bcl-2 overexpression may have a potential role in the poor responses seen with standard chemotherapy. Presently, the six general treatment options available for AI CaP are best supportive care, radiation therapy, radioisotopes, secondline hormonal therapy, chemotherapy (single agent or combination), and investigational therapies such as monoclonal antibodies, cyclin-dependent kinase inhibitors, matrix metalloproteinase inhibitors, and antiangiogenesis agents, among others. None of these modalities have produced durable remissions, although some have demonstrated palliative benefit. The next generation of clinical trials should not consist of futile hormonal manipulations or repetitive chemotherapy. Therapeutic strategies aimed at circumventing molecular blocks to cell death or targeting unique cancer molecules and genes will be more likely to improve quality of life and longevity. Furthermore, the aggressive use of palliative care will ensure effective caring for patients and the healing of families in the absence of cure.
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PMID:Treatment options in androgen-independent prostate cancer. 1007 98


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