Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.23.5 (cathepsin D)
4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

After long-term follow-up, the prognostic impact of the following proteolytic factors associated with tumor invasion and metastasis was evaluated in 276 primary breast cancer patients: uPA (urokinase-type plasminogen activator), PAI-1 (uPA inhibitor type 1), and cathepsins B, D and L. The median follow-up of patients still alive at the time of analysis was 109 months. To date 119 patients (43%) have relapsed and 117 (42%) have died. Antigen levels of uPA and PAI-1 were determined by ELISA in detergent extracts; cathepsin B, D, and L content was determined in cytosol fractions of the primary tumor: cathepsin D by ELSA and cathepsin B and L by ELISA. In multivariate analysis (Cox model) for disease-free survival (DFS), lymph node status (p < 0.001; RR = 3.8), cathepsin L (p < 0.001; RR = 2.6) and PAI-1 (p = 0.027; RR = 1.7) were significant factors in all patients. In addition to these factors, grading was significant for overall survival (OS). In another multivariate approach, CART (Classification And Regression Trees) analysis, lymph node status (p < 0.001) turned out to be the strongest discriminator for patients at high risk of relapse. In the node-negative patient subset, PAI-1 was the strongest risk group discriminator (p < 0.001): in this subset, patients with low levels of both PAI-1 and cathepsin D had a very low relapse rate of only 3.2% compared to 39% in the remaining node-negative patients. In node-positive patients cathepsin L gave the best risk group assessment (p = 0.001). In conclusion, tumor-associated PAI-1 and cathepsins D and L provide significant, statistically independent prognostic information for DFS and OS in primary breast cancer, even after a median follow-up period of almost 10 years.
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PMID:Long-term follow-up confirms prognostic impact of PAI-1 and cathepsin D and L in primary breast cancer. 1076 46

Urokinase-type plasminogen activator (uPA), its receptor (uPAR) and inhibitor, plasminogen activator-type 1 (PAI-1) are proposed to be of prognostic significance in some cancers. To determine the prognostic value of the urokinase plasminogen activation system in ovarian cancer, levels of uPA, uPAR, and PAI-1 were measured in extracts of ovarian cancer tissue using ELISA tests. uPA and PAI-1 were determined in 70 tumor extracts and uPAR in 43 extracts. Levels were correlated with age, tumor histology, stage, grade, lymph node and metastatic status, residual disease, risk of recurrence, epidermal growth factor receptor (EGFR) expression, cathepsin D (Cath-D), and c-erbB-2 levels. uPA and uPAR did not exhibit correlation with any of these parameters. However, patients with high grade tumor, recurrence, and lower EGFR and Cath-D had significantly higher PAI-1 levels compared to those of others (P < 0.05). Kaplan-Meier plots of survival were compared. uPA and uPAR were not related to disease-free or overall survival. Although low PAI-1 appeared to predict a longer overall survival, the difference was not statistically significant. Multivariate analysis revealed that PAI-1 was a predictor for overall survival although it was not as strong as stage. These results suggest that elevated PAI-1 seems to be correlated with an unfavorable prognosis in ovarian cancer.
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PMID:Clinical relevance of urokinase-type plasminogen activator, its receptor and inhibitor type 1 in ovarian cancer. 1124 Jul 1

In our previous work we showed that the drug-resistance of cervical carcinoma, laryngeal carcinoma and glioblastoma cells may be accompanied by increased levels of tumor markers for invasion and metastasis (i.e. urokinase-type plasminogen activator, plasminogen activator inhibitor type 1, and/or cathepsin D). In the present study we examined the concentration of cathepsins B, L and H in three drug-resistant clones isolated from human laryngeal carcinoma (HEp2). The basal levels of cathepsins B, L and H were determined by enzyme linked immunoabsorbent assay (ELISA). Our results showed that all three clones had an increased level of cathepsin B (in two clones an almost 4-fold increase was determined). The level of cathepsin L was altered (increased) only in VK2 clone, while the levels of cathepsin H were similar in parental cells and drug-resistant clones. Thus, our results suggest that drug-resistance may be accompanied by an increased level of cathepsin B, i.e. tumor associated protease, involved in invasion and metastasis.
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PMID:Drug-resistant human laryngeal carcinoma cells have increased levels of cathepsin B. 1129 83

The paper presents recent data on the role of oncogenes and suppressive genes, receptors of steroidal hormones, secretory protein pS2, cathepsin D, urokinase and tissue plasminogen activators and their inhibitor PAI-I, polypeptide growth factors and somatostatin and their receptors in the evaluation of proliferative activity and drug therapy responses and in the prediction of disease and on the simultaneous estimation of the limited number of mutually complementing parameters that can characterize the proliferative activity of a tumor, its metastatic potential and sensitivity to different types of overall and regional regulation. The main task for investigators engaged in this area is to choose a qualitatively and quantitatively optimal ratio of molecular markers of breast cancer to evaluate the biological behavior of a tumor.
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PMID:[Modern prospects for molecular-biochemical methods for evaluating biological "behavior" of breast neoplasms]. 1167 60

There is ample information on the clinical role of biologic factors in female breast cancer: urokinase-type plasminogen activator (uPA), its receptor uPAR, its inhibitors PAI-1 and PAI-2, cathepsin D and pS2-protein. However such reports are missing or very rare for male breast cancer. We determined the cytosolic levels of oestrogen receptor (ER), progesterone receptor (PgR), cathepsin D, pS2-protein, uPA, uPAR, PAI-1 and PAI-2 of the primary tumour tissues from 40 male breast cancer patients. The tumour levels were compared with those of 180 matched females and 4114 historic females with breast cancer. In male breast tumours the level of PgR was higher, those of uPA, PAI-1, PAI-2 and cathepsin D lower. The tumour level of ER in men was similar to those in the matched and postmenopausal women, but much higher than those in the historic women. Male breast cancer seems to be biologically different from female breast cancer. Correlation of the eight cell biologic factors with disease outcome showed that PAI-1 (p = 0.03) was the only independent predictive factor for poor prognosis in male breast cancer.
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PMID:Clinical relevance of biologic factors in male breast cancer. 1172 61

The expression levels and the prognostic impact of urokinase-type plasminogen activator (uPA) and cathepsin D (CD) were evaluated in patients with locally advanced laryngeal squamous cell carcinoma (LSCC). uPA and CD protein levels were determined by immunoluminometric or immunoenzymatic assays in the cytosol of paired sets of tumor tissues and corresponding adjacent normal mucosa (NLM) from 57 patients with stage III/IV LSCC and were correlated with a number of clinicobiological parameters of this tumor including anatomical site, tumor grade, nodal status, clinical stage, DNA ploidy, proliferation rate, and patient outcome. Median uPA levels were significantly higher in LSCC than in NLM (1.8 ng/mg of protein vs 0.3 ng/mg; p<0.001) whereas median CD levels were not significantly increased in tumor tissue compared to NLM (24 pmol/mg vs 19 pmol/mg, p=0.063). No significant correlation was observed between uPA and CD concentrations in tumor tissues (r=-0.1; p=0.4). Furthermore, the distribution analysis of uPA and CD in tumors showed no correlation between expression levels of these proteinases and the parameters mentioned above including patient outcome. However, when data were matched according to each parameter examined it was observed that the differences in uPA content between LSCC and NLM, expressed as uPA tumor/normal tissue ratio (T/M), were more marked in clinically advanced and/or aggressive forms of LSCC (i.e., node positive, stage IV, poorly and moderately differentated, aneuploid multiclonal, low S-phase, subglottis tumors). These data suggest that in such tumors altered regulation of uPA may occur to a greater extent than in less aggressive and less advanced forms of LSCC. This phenomenon was not observed for CD. However, in tumors with a high proliferation rate, in stage IV tumors as well as in those located in the supraglottis, CD levels were significantly higher than those found in the corresponding NLM (p=0.008, p=0.02 and p=0.03, respectively). In conclusion, uPA is highly expressed in locally advanced LSCC and appears to be implicated in some key events of progression of this tumor such as local invasion and/or nodal involvement, whereas CD does not seem to have a role in promoting these processes. Nevetheless, neither of these proteinases seem to be prognostically useful in patients with stage III/IV tumors.
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PMID:Differential expression levels of urokinase-type plasminogen activator and cathepsin D in locally advanced laryngeal squamous cell carcinoma: clinical implications. 1182 Jul 19

A multitude of molecules involved in breast cancer biology have been studied as potential prognostic markers. In the present review we discuss the role of established molecular markers, as well as potential applications of emerging new technologies. Those molecules used routinely to make treatment decisions in patients with early-stage breast cancer include markers of proliferation (e.g. Ki-67), hormone receptors, and the human epidermal growth factor receptor 2. Tumor markers shown to have prognostic value but not used routinely include cyclin D1 and cyclin E, urokinase-like plasminogen activator/plasminogen activator inhibitor, and cathepsin D. The level of evidence for other molecular markers is lower, in part because most studies were retrospective and not adequately powered, making their findings unsuitable for choosing treatments for individual patients. Gene microarrays have been successfully used to classify breast cancers into subtypes with specific gene expression profiles and to evaluate prognosis. RT-PCR has also been used to evaluate expression of multiple genes in archival tissue. Proteomics technologies are in development.
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PMID:Prognostic molecular markers in early breast cancer. 1508 31

Cancer invasion and metastasis develop through a sequence of processes involving loss of cell-cell and cell-matrix adhesions, proteolysis and induction of angiogenesis. We reviewed the current literature on the molecules that have been shown to play a significant role in these three steps of metastatisation in bladder cancer (BC) cells and their host microenvironment. Particular emphasis was given to markers that are assessable through immunohistochemistry and for which an additional prognostic value over the TNM variables has been recognized, in order to identify a subset of tumour markers readily available for application in daily clinical practice. We conclude that markers such as E-cadherin, Sialosyl-LeX, laminin, collagen IV, TSP-1 and MVD are useful prognostic markers, alpha, beta, and gamma catenin, MMP-2 and -9, uPAR, PD-ECGF and Bfgf can be considered potentially useful, while research on CD44, MMP-1 and -3, uPA, cathepsin D and VEGF has proved inconclusive. Further research in this field should concentrate on the molecules listed in the first group.
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PMID:Metastasis markers in bladder cancer: a review of the literature and clinical considerations. 1530 99

The available monolayer culture systems for the study of bone metastases constitute a suboptimal simulation of the in vivo pathophysiology of bone metastases, and therefore, do not provide sufficient information to assess the morphologic evidence of bone reaction to cancer cells, the nature of cell-specific mediators of osteolysis and osteoplasia and the response to treatment. Therefore, we have developed a three-dimensional (3-D) type I collagen gel system that allows co-culture of human osteoblasts (MG-63) with cancer cells, such as MCF-7, MDA-MB-231 or ZR-75 breast cancer cells, PC-3 prostate cancer, KLE endometrial cancer cells and Calu-1 lung cancer cells. We used type I collagen purified from rat tail tendons and the 3-D system was prepared by mixing MG-63 cells with type I collagen in 24-well plates. The 3-D system was inoculated with cancer cells and processed with standard cell culture procedures. After 1 week of culture, the matrix gel was fixed with formalin and embedded in paraffin. Serial sections were stained with trichrome Masson stain and modified Masson-Goldner stain, as well as analyzed by in situ hybridization, immunohistochemistry and the TUNEL technique for semi-quantitative detection of apoptotic cell death, assessing the response to adriamycin therapy. The inoculation of PC-3 cells in this collagen matrix produced a blastic reaction, documented by an increased number of MG-63 cells and increased density of type I collagen. The human KLE cells and inoculation of cell-free media produced no reaction, while ZR-75, MCF-7 and Calu-1 cells produced local degradation of the collagen matrix. In situ hybridization revealed the expression of Insulin-like growth factor 1 (IGF-1) and urokinase-type plasminogen activator (uPA) mRNA, while immunohistochemistry detected differential expression of uPA and cathepsin D. Adriamycin induced apoptotic cell death in prostate cancer cells and estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells, while adriamycin did not induce apoptosis but cytostasis in ER+ MCF-7 cells. The adriamycin-induced apoptosis was inhibited by co-culture with osteoblast-like cells (MG-63). We conclude that this 3-D culture system is a useful in vitro model allowing the analysis of local mediators of osteolytic and osteoblastic reactions to bone metastases and treatment response.
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PMID:Three-dimensional type I collagen co-culture systems for the study of cell-cell interactions and treatment response in bone metastases. 1575 11

Cancer development is essentially a tissue remodeling process in which normal tissue is substituted with cancer tissue. A crucial role in this process is attributed to proteolytic degradation of the extracellular matrix (ECM). Degradation of ECM is initiated by proteases, secreted by different cell types, participating in tumor cell invasion and increased expression or activity of every known class of proteases (metallo-, serine-, aspartyl-, and cysteine) has been linked to malignancy and invasion of tumor cells. Proteolytic enzymes can act directly by degrading ECM or indirectly by activating other proteases, which then degrade the ECM. They act in a determined order, resulting from the order of their activation. When proteases exert their action on other proteases, the end result is a cascade leading to proteolysis. Presumable order of events in this complicated cascade is that aspartyl protease (cathepsin D) activates cysteine proteases (e.g. cathepsin B) that can activate pro-uPA. Then active uPA can convert plasminogen into plasmin. Cathepsin B as well as plasmin are capable of degrading several components of tumor stroma and may activate zymogens of matrix metalloproteinases, the main family of ECM degrading proteases. The activities of these proteases are regulated by a complex array of activators, inhibitors and cellular receptors. In physiological conditions the balance exists between proteases and their inhibitors. Proteolytic-antiproteolytic balance may be of major significance in the cancer development. One of the reasons for such a situation is enhanced generation of free radicals observed in many pathological states. Free radicals react with main cellular components like proteins and lipids and in this way modify proteolytic-antiproteolytic balance and enable penetration damaging cellular membrane. All these lead to enhancement of proteolysis and destruction of ECM proteins and in consequence to invasion and metastasis.
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PMID:Proteolytic-antiproteolytic balance and its regulation in carcinogenesis. 1576 61


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