Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

New technology allows highly sensitive flow cytometric detection and quantitative analysis of intracellular antigens in normal and malignant hemopoietic cells. With this technology, the earliest stages of myeloid and lymphoid differentiation can easily and reliably be identified using antibodies directed against (pro-)myeloperoxidase/MPO, CD22 and CD3 antigens, respectively. Particularly for the analysis of undifferentiated acute myeloblastic leukemia (AML) cells, the immunological demonstration of intracellular MPO or its enzymatically inactive proforms is highly relevant, since other myeloid marker molecules such as CD33, CD13, or CDw65 are either not restricted to the granulomonocytic lineage or appear later in differentiation. By combining MPO staining with staining for lactoferrin (LF), undifferentiated cells can be distinguished from the granulomonocytic maturation compartment in bone marrow, since LF is selectively expressed from the myelocyte stage of differentiation onward. The list of informative intracellular antigens to be used in leukemia cell analysis will certainly expand in the near future. One candidate, intracellular CD68, has already been tested by us, and results are presented. Also dealt within this article are surface marker molecules not (as yet) widely used in leukemia cell analysis but with the potential to provide important additional information. Among them are the surface structures CD15, CD15s, CDw65, CD79a (MB-1), CD79b (B29), CD87 (uPA-R), and CD117 (c-kit).
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PMID:Flow cytometric analysis of cell-surface and intracellular antigens in leukemia diagnosis. 753 75

We previously reported that urokinase (uPA) is produced by the human prostate cancer cell line, PC-3, and could function as a growth factor for cells of the osteoblast phenotype. To examine the role of uPA in metastasis to the skeleton and to extraskeletal sites, we have developed a homologous model of uPA overexpression in a rat prostate cancer cell line. Full length cDNA encoding rat (r) uPA was isolated and subcloned as a 1.4-kilobase XbaI-BspHI fragment in the sense and antisense orientation into the Moloney murine leukemia retroviral vector pYN. The control (pYN) and experimental (pYN-ruPA, pYN-ruPA-AS) plasmids were transfected into Dunning R 3227, Mat LyLu rat prostate carcinoma cells. Experimental clones expressing at least 5-fold higher (pYN-ruPA) or 3-fold lower (pYN-ruPA-AS) than controls were selected, and control and experimental cells were inoculated into the left ventricles of inbred male Copenhagen rats. Animals were sacrificed at timed intervals to examine the evolution of metastatic lesions. Control animals developed metastases to the lumbar vertebrae resulting in spinal cord compression and hind limb paralysis at 20-21 days postinoculation. Animals inoculated with cells overexpressing uPA developed hind limb paralysis significantly earlier (by day 14-15 postinoculation). Additionally, more widespread skeletal (ribs, scapula, and femora) metastases were seen. Serum from experimental animals showed a progressive elevation in alkaline phosphatase levels, and histological examination of lumbar metastases revealed markedly increased osteoblastic activity over that observed in control animals. In contrast to this, animals inoculated with cells underexpressing uPA developed hind limb paralysis significantly later (days 25-29 postinoculation) and displayed decreased tumor metastasis. These studies support a role for the catalytic domain of uPA in enhancing both skeletal and nonskeletal prostate cancer invasiveness and are consistent with a role for the growth factor domain of uPA in mediating an osteoblastic skeletal response.
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PMID:Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo. 816 83

We have examined the mononuclear cell fraction from 35 individuals, 18 with hematologic malignancies and 17 healthy controls for the presence of cell surface-associated plasminogen activator (PA) activity. PA activity was found on the cell surface of 10 out of 12 samples from patients with acute leukemia. In addition to active urokinase (uPA) found on the cell surface in four out of five acute myeloid leukemia patients, tissue-type PA activity was detected in the same samples (3 of 5). Two out of four samples from acute lymphoid leukemia displayed only uPA activity and three out of three samples from biphenotypic leukemia were also clearly uPA-positive. Plasmin activity was not detected in any of the samples. PA activity was not found on the surface of mononuclear cells from either patients with chronic lymphoid leukemia or healthy controls and, in this respect, the cell surface-bound uPA activity behaved as a marker for acute leukemia. The finding of PA activity on the cell surface in acute leukemia suggests that there may be continuous generation of plasmin with consequent consumption of plasma plasmin inhibitors.
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PMID:Abundant urokinase activity on the surface of mononuclear cells from blood and bone marrow of acute leukemia patients. 833 54

Urinary trypsin inhibitor (UTI) is a Kunitz-type protease inhibitor. We have reported that UTI inhibited TNF-induced urokinase (uPA) production via a protein kinase C (PKC)-dependent mechanism. It is likely that UTI suppresses tumor cell invasion and metastasis by a mechanism, possibly by inhibiting uPA production. In the present study, we attempted to determine how UTI is associated with PKC, and how UTI is involved in uPA-dependent tumor cell invasion and metastasis. The increments of membrane-associated PKC activity by TNF were subsequently accompanied by a rapid loss of cytosol-associated PKC activity in U937 leukemia cells. Semi-quantitative immunoblotting of membrane and cytosol fractions showed that the translocation of PKC-alpha, -beta, and -epsilon were blocked by the addition of UTI in cells stimulated with TNF but not in cells stimulated with PMA, demonstrating that PKC itself is not sensitive to UTI. This effect was dependent on the carboxyl-terminus of UTI. In addition, UTI neither inhibited TNF binding to cellular receptors nor inactivate PKC and uPA activities directly. Taken together, the experiments suggest that the carboxyl-terminus of UTI may inhibit the PKC-signalling pathways upstream of diacylglycerol by a mechanism, possibly by interrupting the coupling of receptor and effector systems. UTI was shown to have an interesting new function besides being a protease inhibitor. This is the first report that UTI has a selective inhibition of TNF-activated PKC. We conclude that UTI suppresses tumor cell invasion and metastasis by a mechanism that UTI inhibits TNF-stimulated uPA production via a PKC-dependent mechanism.
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PMID:Urinary trypsin inhibitor, a Kunitz-type protease inhibitor, modulates tumor necrosis factor-stimulated activation and translocation of protein kinase C in U937 cells. 945 92

All-trans retinoic acid (RA) has been successfully used in the treatment of patients with acute promyelocytic leukemia (APL). It induces differentiation of APL cells and reduces the bleeding tendency in APL patients. It has been proposed that plasminogen activation could affect the fibrinolytic balance in patients with leukemia. In our earlier study we found that treatment of APL cells with RA results in changes in urokinase (uPA) production. As interferons (IFNs) and dexamethasone can be used together with RA in the treatment of patients with APL, we have now studied the effects of RA together with IFNs and dexamethasone on the plasminogen activation cascade of these cells, including measurement of plasmin generation and uPA receptor (uPAR), using enzyme immunoassays, fluorescence-activated cell sorter analysis and RNA extraction with Northern blotting. Our main results were: (1) plasmin was formed on the surface of APL cells; (2) RA stimulated transiently plasmin generation and increased uPAR mRNA level; (3) IFNs alpha and gamma potentiated RA in its effects on uPA and plasmin activities and on uPAR level; (4) dexamethasone suppressed totally the effect of RA on uPA induction and plasminogen activation; and (5) IFNs and dexamethasone alone did not have potent effects on plasminogen activation. These results may assist in the design of therapy for APL patients.
Leukemia 1998 Feb
PMID:Interferons and retinoids enhance and dexamethasone suppresses urokinase-mediated plasminogen activation in promyelocytic leukemia cells. 951 78

The receptor for urokinase plasminogen activator (uPAR; CD87) is a 50- to 65-kDa glycosylphosphatidylinositol (GPI)-anchored glycoprotein expressed by leukocytes and tumor cells where it facilitates uPA-dependent, plasmin-mediated pericellular proteolysis during cellular invasion. Because uPAR is inducibly shed into culture supernatants and human body fluids, we tested the hypothesis that soluble uPAR (suPAR) can bind to the plasma membrane of hematopoietic cells where it might modulate their invasive phenotype. As measured by flow cytometry, recombinant biotinylated-suPAR (B-suPAR) bound in a specific fashion to THP-1 leukemia cells and blood PMNs and monocytes (but not to lymphocytes). B-suPAR also demonstrated specific binding to a variety of leukemic lines, including cells that are positive or negative for membrane uPAR expression. Binding of B-suPAR to THP-1 cells was enhanced four- to sevenfold by 24-h exposure of cells to PMA or by co-incubation with uPA ligand (but not its isolated catalytic and binding fragments). Conversely, binding of B-suPAR to PMNs was unaffected by brief exposure to fMLP, and was inhibited by co-incubation with uPA. B-suPAR biding to PMA-differentiated THP-1 cells in the presence of uPA was further enhanced by acid washing (removing endogenous uPA) but was partially inhibited by treatment of cells with trypsin. Pretreatment of PMA-differentiated THP-1 cells and unstimulated PMNs with soluble sugars, calcium chelators, and antibodies specific for integrins or extracellular matrix proteins failed to consistently block the binding of B-suPAR. Whereas the binding of suPAR did not measurably affect cell-associated plasmin activation, suPAR did competitively inhibit the binding of exogenous uPA to membrane-associated uPAR. These observations support the hypothesis that suPAR can bind specifically to trypsin-sensitive receptors expressed by certain normal and neoplastic hematopoietic cells where its binding is variably influenced by uPA ligand.
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PMID:A soluble form of the urokinase plasminogen activator receptor (suPAR) can bind to hematopoietic cells. 971 60

Human ovarian adenocarcinoma cells N.1 secrete an autocrine activity that stimulates active cell death under serum-reduced conditions. To substitute the autocrine activity by a single physiological component, 28 cytokines, growth factors and biomodulators were tested [interleukin 1alpha (IL-1alpha), IL-1beta, IL-2, IL-3, IL-4, IL-6, IL-10, IL-11, stem cell factor (SCF), platelet-derived growth factor (PDGF), acid fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF-1), IGF-2, insulin, macrophage colony-stimulating factor (M-CSF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), oncostatin, RANTES (regulated on activation normal T cell expressed and secreted), angiogenin, leukaemia inhibitory factor (LIF), erythropoietin (EPO), interferon alpha (INF-alpha), INF-gamma, transferrin, tumour necrosis factor alpha (TNF-alpha, TNF-beta and bovine serum albumin for control reasons]. In these experiments, only TNF-alpha and TNF-beta rapidly induced apoptosis. TNF-alpha and TNF-receptor 1 were expressed by N.1 cells, and the secretion of TNF-alpha was verified by enzyme-linked immunosorbent assay (ELISA). Autocrine factor-triggered apoptosis was inhibited when conditioned supernatant was preincubated with anti-TNF-alpha antibody. These findings suggested that the apoptosis-inducing component of the N.1 autocrine activity was TNF-alpha. In the presence of antisense c-myc oligonucleotides, induction of cell death by autocrine factor was partly inhibited. Autocrine factor and TNF-alpha stimulated transcription of the invasiveness-related protease plasminogen activator/urokinase mRNA (upa) with similar kinetics. When N.1 cells were exposed to purified plasminogen activator/urokinase protein (uPA), cell matrix contact was disrupted. Thus, uPA might serve a physiological role during TNF-induced apoptosis by affecting the interactions between cells and the basal membrane, thereby facilitating anoikis. This mechanistic study, which was restricted to a single human ovarian carcinoma model cell line (N.1), provides evidence that N.1 maintains the capacity to undergo c-myc-dependent apoptosis by the TNF-TNF-receptor pathway, and no additional pharmacological stimuli for induction of apoptosis are required.
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PMID:Autocrine self-elimination of cultured ovarian cancer cells by tumour necrosis factor alpha (TNF-alpha). 976 76

Plasminogen activation in leukemia has been less well characterized than in other malignancies. However, the increased tendency to bleeding and tissue infiltration by leukemic cells are processes in which plasminogen activation may be involved. We have examined plasma and the peripheral blood mononuclear cell fraction from 80 patients including 53 patients with newly diagnosed acute leukemia and 27 patients with other hematological disorders as well as 21 healthy controls. In 28 of 29 examined patients with acute myeloid leukemia (AML) and in two of three patients with hybrid leukemia we found urokinase receptor (uPAR) on the cell surface, while most (7/9) samples from patients with acute lymphoblastic leukemia (ALL) were negative for uPAR. The plasma mean value for soluble uPAR (suPAR) was significantly elevated in patients with AML and ALL. In AML the highest values were found in patients who had residual disease after several cycles of chemotherapy. Compared to controls the uPA antigen levels in patient plasmas were elevated and decreased along with uPAR during treatment. Our results suggest that cell surface uPAR may be a useful marker for leukemia classification and in our material a high level of plasma suPAR correlated with resistance to chemotherapy in AML.
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PMID:Blast cell-surface and plasma soluble urokinase receptor in acute leukemia patients: relationship to classification and response to therapy. 1036 41

Plasminogen activation is implicated in solid tumour growth, invasion and metatastic spread. However, little is known about its role in leukaemia. We investigated the production by leukaemic cells of plasminogen activators [urokinase (uPA) and tissue-type PA (tPA)], cell surface receptor for uPA (uPAR) and PA inhibitors (PAI-1 and PAI-2). Leukaemic cells from 37 patients [26 with acute myeloid leukaemia (AML) and 11 with acute lymphoid leukaemia (ALL)] were analysed for mRNA content and enzymatic activities. High levels of uPA mRNA were found in M1, M2, M3 and M4-M5 AMLs, whereas tPA mRNA was not detected in any of the analysed cases. uPAR mRNA was confined to subtypes M4-M5. PAI-1 mRNA was detected in M3 and M4-M5. PAI-2 mRNA was found predominantly in M2 and M4-M5. SDS-PAGE/zymography analyses of cell extracts and supernatants after 24 and 48 h of culture confirmed the production of active uPA by AML cells (mainly M4-M5). but not by ALL. The finding of uPA, uPAR, PAI-1 and PAI-2 synthesized by leukaemic cells suggests that plasminogen activation may contribute to the invasive behaviour of these cells, the fibrinolytic imbalance observed in leukaemic patients and the differentiation and proliferation of M4-M5 by interaction of uPA with uPAR.
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PMID:Plasminogen activation in human acute leukaemias. 1055 1

Current research suggests that the appearance of endometrial integrins and pinopode appearance signal the opening of the receptive phase of the endometrium. These integrins may be activated by the interleukin-1 system (IL-1). IL-1beta, expressed by the blastocyst, induces vascular endothelial growth factor (VEGF) which, in turn, promotes angiogenesis and integrin expression in endometrial cells. The IL-1 system also triggers the expression of gamma interferon (IFN-gamma) from T lymphocytes. Decidual natural killer (NK) lymphocytes interact with invading trophoblast to generate leukaemia inhibitory factor (LIF). LIF induces uPA and gelatinase, enzymes which play a crucial role in trophoblastic invasion. Progesterone is a potent inhibitor of LIF, while oestrogen is a potent inducer. Oestrogen in serum reflects follicular IL-1beta level and correlates with the outcome of embryo transfer after in vitro fertilization (IVF). Progesterone induces nitric oxide (NO) synthesis in the decidua, and NO promotes local vasodilatation and uterine quiescenceMeasurement of placental protein 14 (PP14, glycodelin-A) in serum may be of value as a screening test for implantation potential. However, human chorionic gonadotrophin (hCG) remains the most reliable predictor of successful implantation and pregnancy viability. An ovulation + 14 hCG level < 50 IU/l is often predictive of a non-viable outcome, while an ovulation + 21 hCG of < 200 IU/l always indicates a non-viable pregnancy. hCG secretion by invading trophoblast appears to be negatively modulated by endothelin-1 (ET-1) and prostaglandin F(2alpha)(PGF2alpha), while tissue growth factors and collagenases are positive modulators of hCG expression.ProalphaC, an inhibin pro-monomer, may have some value in monitoring corpus luteum function. Inhibin A, activin A and follistatin all rises throughout pregnancy and peak at 36 weeks of gestation. Relaxin is another ovarian hormone that may have a role in predicting implantation. Relaxin induces placental protein 14 (PP14, glycodelin-A) expression in a receptive endometrium, and measurement of serum PP14 may be of value as a screening test for implantation potential.
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PMID:Endocrinology of the peri-implantation period. 1102


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