Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The glycosylphosphatidylinositol (GPI)-anchored membrane protein urokinase plasminogen activator-receptor (uPA-R; CD87) is one of the key molecules involved in migration of leukocytes and tumor cells. uPA bound to uPA-R provides the cell proteolytic potential used for degradation of extracellular matrix. uPA-R is also involved in induction of cell adhesion and chemotaxis. Here, we provide a molecular explanation for these uPA-R-related cellular events. By size fractionation of monocyte lysate and affinity isolation on its natural ligand uPA, we demonstrate uPA-R as a component of a receptor complex of relatively large size. Reprecipitation and immunoblotting techniques allowed us to detect the protein tyrosine kinases (PTKs) p60fyn, p53/56lyn, p58/64hck, and p59fgr as components of this "uPA-R complex". Activation of monocytes even with enzymatically inactivated uPA resulted in induction of tyrosine phosphorylation, suggesting modulation of uPA-R-associated PTKs upon ligand binding. In spite of their presence in large complexes, we did not find the GPI-linked proteins CD14, CD58, and CD59 in the uPA-R complex, which indicates the presence of different receptor domains containing GPI-linked proteins in monocytes. However, we identified the leukocyte integrins LFA-1 and CR3 as components of the uPA-R complex as indicated by coisolation of these molecules, as well as by cocapping and comodulation of uPA-R and leukocyte integrins on the monocyte surface. The assemblage of uPA-R, PTKs and membrane spanning beta 2-integrins in one receptor complex indicates functional cooperation. In regard to the involvement of these molecules in pericellular proteolysis, signal transduction, as well as adhesion and chemotactic movement, we suggest uPA-R complex as a potential cellular device for cell migration.
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PMID:Urokinase plasminogen activator receptor, beta 2-integrins, and Src-kinases within a single receptor complex of human monocytes. 753 37

Recent advance in cell-molecular biological studies have revealed various prognostic factors in lung cancer. The aim of this paper is to critically review the current status of molecular biological prognostic markers in non-small cell lung cancer. DNA ploidy, AgNORs and PCNA as marker of tumor cellular proliferative activity are reported to be a prognostic marker but still remain controversial. The proteases such as uPA, MMPs and CB catalyze degradation of the extracellular matrix and basement membranes. Although the prognostic implications of the uPA and MMPs still remain unclear, cathepsin B appears to be one of the most useful prognostic markers so far reported for non-small cell lung cancer. In a number of studies, genetic abnormalitis has been reported to be a prognostic marker in cancer patients. In non-small cell lung cancer, the prognostic implication of the altered p53 expression or ras p21 expression still remain unclear, especially p53 is conflicting. The most useful clinical prognostic marker may be obtained by the combined analysis of some prognostic information.
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PMID:[Molecular biological prognostic markers in lung cancer]. 904 11

The clinical oncology realizes that the classical approach with systemic adjuvant chemo- and hormonal therapies is not sufficient and will be challenged by cellular and molecular structures which reflect the targets for new therapeutic approaches. These targets are key proteins involved in the signal transduction cascade. In human tumors these proteins have either lost their biological functionality by oncogenic mutations or are constitutively activated. The molecular classification of primary breast cancer was performed by assessing the following factors: estrogen- and progesterone receptors, ERbB-2 mutated p53, uPA, PAI-I, VEGF, DNA-Index and S-Phase. These factors are of prognostic and predictive value.
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PMID:[Molecular factors determine primary and secondary therapy of breast carcinoma]. 938 15

Tumor biological factors uPA, PAI-1, cathepsin D, S-phase fraction (SPF), MIB1 (Ki-67), p53, and HER-2/neu were assessed in 100 node-negative breast cancer patients. Their prognostic impact on disease-free (DFS) as well as overall survival (OS) was compared to that of traditional factors tumor size, grading, and steroid hormone receptor status. Antigen levels of uPA, its inhibitor PAI-1, and cathepsin D were determined in tumor tissue extracts by immunoenzymatic methods. SPF was determined by flow cytofluorometry, MIB1, p53, and HER-2/neu by immunohistochemistry in adjacent routinely formalin-fixed paraffin sections. Median follow-up in all patients still alive at time of analysis was 76 months. Univariate analysis determined PAI-1 (p = 0.0001), uPA (p = 0.0437), MIB1 (p = 0.0214), and SPF (p = 0.0248) as statistically significant prognostic factors for DFS. In contrast, tumor size, steroid hormone receptor status, grading, p53, HER-2/neu, and cathepsin. D failed to be of prognostic value. In multivariate analysis, including the statistically significant prognostic factors PAI-1, uPA, MIB1, and SPF, only PAI-1 (p = 0.0003, relative risk: 4.7) proved to be of independent statistical significance for DFS. Regarding OS, PAI-1 was the only statistically significant prognostic factor in univariate (p = 0.0001) as well as multivariate analysis (p = 0.0000, relative risk: 7.1). Thus, factors describing the invasive and metastatic capacity of tumor cells (uPA, PAI-1) and factors related to their proliferative activity (SPF, MIB1) provide valuable prognostic information in node-negative breast cancer patients.
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PMID:Prognostic impact of tumor biological factors on survival in node-negative breast cancer. 970 82

This study was aimed at testing the hypothesis that the expression of proteases essentially produced by reactive stromal cells (stromelysin-3 [ST3], gelatinase A [GELA], and urokinase [uPA]) is predictive of prognosis in patients with breast cancer. This was a study of patients with node-positive and node-negative breast cancer diagnosed from 1980 to 1986 and with an average of 10 years follow-up. ST3 (665 cases), GELA, and uPA (575 cases each) expression was obtained by in situ hybridization on formalin-fixed, paraffin-embedded material using mRNA antisense probes. ST3 was expressed by 86.6% of the cases; GELA, 77.7%; and uPA, 64.7%. A significant correlation (P < .05) was found between high (more than 10%) ST3 expression and a younger age, lymph node involvement, poor nuclear grade, ductal histology, aneuploidy, and HSP-27 expression. High GELA expression was significantly associated with c-erbB2, ductal histology, and HSP-27 expression. High uPA expression correlated with poor nuclear grade, ductal histology, lack of estrogen and progesterone receptors, and p53 protein accumulation. High level of expression of all three proteases correlated significantly with each other and with cathepsin D expression by reactive stromal cells. By univariate analysis, both ST3 and uPA expression significantly predicted a shorter recurrence-free survival (ST3, P = .0199; uPA, P = .0269). By multivariate analyses, the prognostic significance was lost, most particularly at longer term. This study adds support to the concept that protease expression by reactive stromal cells is related to cancer cell characteristics but that their contribution to cancer progression is marginal.
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PMID:Prognostic significance of stromelysin 3, gelatinase A, and urokinase expression in breast cancer. 974 15

Axillary dissection is presently a routine staging procedure in the management of breast cancer. The use of adjuvant systemic treatment is largely based on the diagnosis of axillary metastases. Routine axillary dissection leads to acute and chronic side-effects in a large proportion of patients. The sentinel node technique is presently explored with the aim of decreasing the need for standard axillary dissection. A complementary way forward is to analyse the primary breast cancer for molecular markers with prognostic significance with reference to the risk for metastatic capacity and thereby obtain a 'biological staging' and identify those patients in need of systemic adjuvant therapy. A large number of molecular biological factors have been shown to have prognostic significance in breast cancer e.g. c-erbB-2, p53, uPA, PAI-I and VEGF. This article reviews the expression of these and other factors in the primary breast cancers in relation to the risk for axillary and systemic metastatic disease, with the long-term aim of excluding routine axillary dissection.
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PMID:Can axillary dissection be avoided by improved molecular biological diagnosis? 1098 28

The aim of this study was to evaluate c-erbB-2 overexpression by means of a quantitative biochemical technique in 488 primary breast cancer patients with long-term follow-up (median, 10 years) and its relation to other biochemical prognostic factors (uPA, p53, and epidermal growth factor receptor) and adjuvant therapy. High levels of c-erbB-2 (>500 IU/mg protein) were associated with estrogen receptor (ER) and progesterone receptor negativity, high histoprognostic SBR grade and high levels of uPA and p53. Univariate analyses showed shorter metastasis-free survival (MFS) and overall survival (OS) in patients whose tumors overexpressed c-erbB-2 in the overall population, in subgroups defined by ER and uPA status, and in patients with positive pathological nodal status, SBR grade II, progesterone receptor, and p53-negative tumors. Patients with ER-positive, c-erbB-2-positive tumors had a shorter MFS and OS than those patients with c-erbB-2-negative tumors. No difference was observed between adjuvant-treated and untreated patients (chemotherapy and/or hormone therapy) in the c-erbB-2-negative subgroup. There was a trend toward a longer short-term MFS in c-erbB-2-positive patients treated with chemotherapy, whereas an opposite effect was observed with hormone therapy. Cox multivariate analyses showed that high levels of c-erbB-2 negatively influenced MFS in the overall population as well as in node-positive patients and in tamoxifen-treated patients, along with pN and uPA. Results for OS were comparable with those obtained for MFS. These results suggest that c-erbB-2 overexpression in breast cancer may be a better predictor of the response to tamoxifen than is ER status alone.
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PMID:Relationship between c-erbB-2 and other tumor characteristics in breast cancer prognosis. 1115 29

The prognosis of hepatocellular carcinoma (HCC) still remains dismal, although many advances in its clinical study have been made. It is important for tumor control to identify the factors that predispose patients to death. With new discoveries in cancer biology, the pathological and biological prognostic factors of HCC have been studied quite extensively. Analyzing molecular markers (biomarkers) with prognostic significance is a complementary method. A large number of molecular factors have been shown to associate with the invasiveness of HCC, and have potential prognostic significance. One important aspect is the analysis of molecular markers for the cellular malignancy phenotype. These include alterations in DNA ploidy, cellular proliferation markers (PCNA, Ki-67, Mcm2, MIB1, MIA, and CSE1L/CAS protein), nuclear morphology, the p53 gene and its related molecule MD M2, other cell cycle regulators (cyclin A, cyclin D, cyclin E, cdc2, p27, p73), oncogenes and their receptors (such as ras, c-myc, c-fms, HGF, c-met, and erb-B receptor family members), apoptosis related factors (Fas and FasL), as well as telomerase activity. Another important aspect is the analysis of molecular markers involved in the process of cancer invasion and metastasis. Adhesion molecules (E-cadherin, catenins, serum intercellular adhesion molecule-1, CD44 variants), proteinases involved in the degradation of extracellular matrix (MMP-2, MMP-9, uPA, uPAR, PAI), as well as other molecules have been regarded as biomarkers for the malignant phenotype of HCC, and are related to prognosis and therapeutic outcomes. Tumor angiogenesis is critical to both the growth and metastasis of cancers including HCC, and has drawn much attention in recent years. Many angiogenesis-related markers, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF), thrombospondin (TSP), angiogenin, pleiotrophin, and endostatin (ES) levels, as well as intratumor microvessel density (MVD) have been evaluated and found to be of prognostic significance. Body fluid (particularly blood and urinary) testing for biomarkers is easily accessible and useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum, and its genetic alterations in HCC are other important trends. More attention should be paid to these two areas in future. As the progress of the human genome project advances, so does a clearer understanding of tumor biology, and more and more new prognostic markers with high sensitivity and specificity will be found and used in clinical assays. However, the combination of some items, i.e., the pathological features and some biomarkers mentioned above, seems to be more practical for now.
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PMID:The prognostic molecular markers in hepatocellular carcinoma. 1204 56

To explore the hypothesis that aging not only increases breast cancer incidence but also alters breast cancer biology, we correlated patient age and diagnosis with tumor histology, stage and biomarkers independently determined from two different tumor archives: an American collection of approximately 800 paraffin-embedded and immunohistochemically analyzed primary breast cancers, and an European collection of approximately 3000 cryobanked primary breast cancers analyzed by ligand-binding and enzyme immunoassay (EIA). The prognostic biomarkers chosen for comparison represented surrogate measures of tumor: (i). proliferation, growth and genetic instability (mitotic and apoptotic indices, Ki-67/MIB-1-positivity, nuclear grade, p53-positivity), (ii). endocrine-dependence (estrogen receptor (ER), progesterone receptors (PR), pS2, Bcl2), (iii). growth factor receptor-dependence (ErbB2, EGFR/ErbB1), and (iv). angiogenic, invasive and proteolytic potential (uPA, PAI-1, Cathepsin D, VEGF). No biomarker reflecting tumor angiogenic, invasive or proteolytic potential showed a significant correlation with patient age at diagnosis. In contrast, significant inverse correlations (|r|>0.1; P< or =0.05) were observed for all measures of tumor growth and genetic instability as well as growth factor receptor overexpression (ErbB2 or EGFR positivity). Only one marker of endocrine-dependence, ER expression, showed a significant positive correlation with patient age at diagnosis. In summary, these findings support the hypothesis that breast cancer biology is significantly affected by patient age. In particular, breast tumors arising in older patients have slower growth rates, are more likely to be ER-positive, and are less likely to be p53-positive, EGFR-positive or ErbB2-positive.
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PMID:Age-associated biomarker profiles of human breast cancer. 1220 28

Cystosarcoma phyllodes (CP) of the breast is a rare biphasic tumor composed of benign epithelium and a spindle cell stroma. Biologic behavior of CP cannot be predicted with certainty on the basis of morphologic criteria only. We studied immunohistochemical expression of basic fibroblastic growth factor (bFGF), urokinase, Ki67, p53 protein, and microvessel density in stromal and epithelial components of 14 low-grade CP (LCP) and 9 high-grade CP (HCP). bFGF was more often positive in LCP than in HCP. The stroma was positive for bFGF in 86% of LCP and 67% of HCP, and the epithelium was positive in 64% of LCP and 14% of HCP. Urokinase was positive in stromal cells of 86% of LCP and 93% of HCP. The epithelial positivity for urokinase in both groups resembled closely that of the stroma. p53 protein was more often positive in stromal cells of HCP (67%) than in LCP (50%). Ki67 was positive in the stroma of 43% of LCP and 89% of HCP and in the epithelium of 14% of LCP and 33% of HCP. There was no significant difference in microvessel density (MVD) in low- and high-grade lesions. Our study demonstrates that stromal Ki67 and p53 immunohistochemical positivity are more often associated with high-grade tumors. The positive immunostaining for bFGF, urokinase, Ki67, and p53 in stroma and epithelium of the majority of CP supports the existence of epithelial-stromal interactions and recognizes epithelium as an integral part of this tumor.
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PMID:Immunohistochemical profile of cystosarcoma phyllodes of the breast: a study of 23 cases. 1239 Mar 61


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