The urokinase receptor: involvement in cell surface proteolysis and cancer invasion.
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Animals↗
Biomedical subjects
J Eriksen
Publications and source records attributed to J Eriksen.
A soluble form of the glycolipid-anchored receptor for urokinase-type plasminogen activator is secreted from peripheral blood leukocytes from patients with paroxysmal nocturnal hemoglobinuria.
The cellular urokinase-type plasminogen-activator (uPA) receptor (uPAR) is a glycolipid-anchored membrane protein thought to be involved in pericellular proteolysis during cell migration and tumor invasion. In the present study, we have identified and characterized two soluble forms of uPAR which have retained their ligand-binding capability. One variant was generated in vitro by treatment of intact normal cells with either a phosphatidylinositol-specific phospholipase C (PLC) or endoproteinase Asp-N. The other soluble uPAR variant was secreted in vivo from peripheral blood leukocytes affected by the stem-cell disorder paroxysmal nocturnal hemoglobinuria (PNH), and was found in the plasma from these PNH patients as well as in the conditioned medium from cultured PNH leukocytes. Under normal conditions, we find no evidence for any shedding or secretion of a soluble uPA-binding counterpart to human uPAR in plasma. Unlike normal leukocytes, the PNH-affected cells do not express uPAR on the cell surface, although they do contain apparently normal levels of uPAR-specific mRNA. The secreted uPAR derived from PNH cells has a mobility in SDS/PAGE that is slightly higher than that of uPAR solubilized by PtdIns-specific PLC or detergent, but resembles that of a truncated, recombinant uPAR variant, which has its C-terminus close to the proposed glycolipid-attachment site, suggesting that the secreted protein has been proteolytically processed for glycolipid attachment. The presence in plasma from PNH patients of such a secreted, hydrophilic form of uPAR lends support to the hypothesis that the lesion underlying the PNH disorder resides either in glycolipid biosynthesis or in the function of an as-yet-unidentified transamidating enzyme assumed to cleave and assemble the truncated uPAR with the preformed glycolipid moiety.
Amino Acid Sequence↗
Identification and characterization of the murine cell surface receptor for the urokinase-type plasminogen activator.
Cell-binding experiments have indicated that murine cells on their surface have specific binding sites for mouse urokinase-type plasminogen activator (u-PA). In contrast to the human system, chemical cross-linking studies with an iodinated ligand did not yield any covalent adducts in the murine system, but in ligand-blotting analysis, two mouse u-PA-binding proteins could be visualized. To confirm that these proteins are the murine counterpart of the human u-PA receptor (u-PAR), a peptide was derived from the murine cDNA clone assigned to represent the murine u-PAR due to cross-hybridization and pronounced sequence similarity with human u-PAR cDNA [Kristensen, P., Eriksen, J., Blasi, F. & Danø, K. (1991) J. Cell Biol. 115, 1763-1771]. A rabbit antiserum raised against this peptide specifically recognized two polypeptide bands with electrophoretic mobilities identical to those identified by ligand-blotting analysis. Binding of mouse u-PA to its receptor showed species specificity in ligand-blotting analysis, since mouse u-PA did not bind to human u-PAR and human u-PA did not bind to mouse u-PAR. The apparent M(r) of mouse u-PAR varied between different mouse cell lines and ranged over M(r) 45,000-60,000. In four of the cell lines, mouse u-PA bound to two mouse u-PAR variant proteins, whereas in the other two cell lines studied, there was only one mouse u-PA-binding protein. In the monocyte macrophage cell line P388D.1, trypsin-treatment of intact cells could remove only the large mouse u-PAR variant (M(r) 60,000) indicating that only this type was a cell-surface-exposed molecule. The smaller mouse u-PAR variant (M(r) 45,000), was deglycosylated by the enzyme endo-beta-N-acetylglucosaminidase H and is probably an intracellular precursor form carrying only high-mannose carbohydrate. Deglycosylation of this variant yielded a polypeptide with an apparent M(r) of about 30,000, which corresponds to the Mr calculated from the cDNA derived protein sequence of mouse u-PAR. Receptor-bound mouse u-PA could be released by phosphatidylinositol-specific phospholipase C treatment, indicating that mouse u-PAR is attached to the cell surface by glycosylphosphatidylinositol. Purification of the two mouse u-PAR variant proteins by diisopropylfluorophosphate-inactivated mouse u-PA-Sepharose affinity chromatography yielded two silver-stained bands when analysed by SDS/PAGE, corresponding in electrophoretic mobility to those seen by ligand-blotting analysis.(ABSTRACT TRUNCATED AT 400 WORDS)
Amino Acid Sequence↗
[Severe prolonged hypotension after the first dose of enalapril in a patient with essential hypertension].
A case of severe and prolonged hypotension following intake of 10 mg enalapril in a patient with slight hyponatraemia is described. Despite administration of isotonic NaCl and treatment with dopamine infusion, it did not prove possible to maintain a stable blood pressure. Adrenaline and ephedrine were required intravenously on repeated occasions on account of symptom-producing hypotension with a systolic pressure as low as 60 mmHg. On account of the increasing use of ACE-inhibitors, it is recommended that the specific antidote, angiotension II, should be registered in Denmark and should be available in all hospitals.
Enalapril↗
The plasminogen activation system in human colon cancer: messenger RNA for the inhibitor PAI-1 is located in endothelial cells in the tumor stroma.
Fourteen human colon adenocarcinomas were examined by in situ hybridization for the presence of mRNA for plasminogen activator inhibitor type 1 (PAI-1). All specimens contained PAI-1 mRNA in endothelial cells of some vessels in the stroma immediately surrounding the invasive tumor glands, in granulation tissue, and in some capillaries located under the free luminal surface of carcinomatous epithelium. In addition, a limited number of stromal cells in the cancerous areas located at the periphery of newly formed capillary networks, and presumably representing sprouting endothelial cells, contained PAI-1 mRNA. Cancer cells were devoid of detectable PAI-1 mRNA in all cases. PAI-1 mRNA was not seen in three biopsies of normal colon. Together with previous findings of urokinase-type plasminogen activator and its mRNA being located in fibroblast-like cells in the tumor stroma and mRNA for the urokinase receptor in the cancer cells at invasive foci, these results indicate a complex cooperativity among several cell types in regulation of plasminogen activation in colon cancer. A possible role of PAI-1 in protecting the extracellular matrix in the tumor tissue against degradation and a role in tumor-induced angiogenesis are discussed.
Adenocarcinoma↗
[Factitious disorder--an iatrogenic disease?].
The case of a woman aged 31 years with numerous contacts with the health care system is reported. The patient presented an extremely varied pattern of complaints with pain as one of the most frequently recurring reasons for admission. During the past 12 to 13 years, the patient was admitted to inpatient units on numerous occasions and was submitted to numerous examinations, most of which revealed normal findings. This article lists a number of possible background causes which might permit a career like this to develop. Measures for prevention of similar "case-stories" in future are discussed.
Adult↗
Omeprazole 20 mg three days a week and 10 mg daily in prevention of duodenal ulcer relapse. Double-blind comparative trial.
In a double-blind, parallel-group clinical trial of 195 patients with duodenal ulcers who after a short-term study had relief of pain and healed ulcers proved endoscopically, 65 were randomized to receive 20 mg omeprazole 3 days a week (once in the morning from Friday to Sunday), 64 to receive 10 mg omeprazole once daily in the morning, and 66 to receive placebo for up to 6 months. The patients underwent repeat endoscopy with biopsy of the gastric fundic mucosa (qualitative assessment of argyrophilic cell population), assessment of symptoms, and laboratory screening with measurement of basal serum gastrin concentrations at 3 and 6 months or more often if indicated by recurrence of symptoms. At 3 months, endoscopically proved ulcer relapse occurred in 16% receiving 20 mg omeprazole 3 days a week; 21% receiving 10 mg omeprazole daily; and 50% receiving placebo. At 6 months, corresponding rates were 23%, 27%, and 67% with 95% confidence intervals of difference between the placebo group and omeprazole groups of 28%-60% and 24%-56% (P less than 0.00001), respectively, and between omeprazole groups of -19%-11% (NS). No major clinical or laboratory side effects were noted. Thus both omeprazole regimens are effective and safe in preventing duodenal ulcer relapse.
Adolescent↗
Two alternatively spliced mouse urokinase receptor mRNAs with different histological localization in the gastrointestinal tract.
Two mouse urokinase-type plasminogen activator receptor (muPAR) cDNAs were isolated: muPAR1 is homologous to the human urokinase-type plasminogen activator receptor while muPAR2 codes for a 199 residue protein sharing the first 133 residues with muPAR1. Mouse genomic DNA sequencing indicates that the two different mRNAs arise by alternative splicing. In situ hybridization showed differential expression of the two mRNAs in mouse gastric mucosa. muPAR1 mRNA is located in luminal epithelial cells situated close to urokinase-type plasminogen activator-producing connective tissue cells of the lamina propria, pointing to plasmin generation controlled by the cooperation of different cells that may play a role in the release of gastric epithelial cells. muPAR2 mRNA is expressed in the basal epithelial cells, and the deduced protein sequence includes the receptor ligand binding domain, but omits the region involved in glycolipid-mediated membrane anchoring, suggesting that muPAR2 may code for a secreted uPA binding protein.
Amino Acid Sequence↗
Differential expression of urokinase-type plasminogen activator and its type-1 inhibitor during healing of mouse skin wounds.
The expression of urokinase-type plasminogen activator (u-PA) and its type-1 inhibitor (PAI-1) was examined in vivo in mouse wounds by in situ hybridization and immunohistochemistry. u-PA mRNA was present in both basal and suprabasal keratinocytes in the regenerative epithelial outgrowths at the edge of the wounds. In the same area, PAI-1 mRNA was only present in the basal keratinocytes. u-PA protein was detected in keratinocytes in several layers of the epithelial outgrowth, whereas PAI-1 protein was confined to the basal keratinocytes and to the area of the basal membrane. The two proteins and their mRNA were not detected in normal epidermis or in normal-looking epidermis adjacent to the wounds. Fibroblast-like cells and fairly large stellate cells (possibly macrophages) in the granulation tissue underneath the wound contained both the two proteins and their mRNA. The large stellate cells, showing a strong hybridization signal for PAI-1 mRNA, were especially abundant at the border between the necrotic wound and the newly formed granulation tissue. The specificity of these results was supported by the use of two different non-overlapping antisense probes, sense mRNA probes, antibody preparations preabsorbed with purified proteins, and Northern analysis of tissue extracts. The localized and regulated expression of u-PA and PAI-1 seen in this study may reflect that plasminogen activation plays a role in the migration of keratinocytes and connective tissue cells during reepithelialization and tissue remodeling in wound healing.
Animals↗
Localization of urokinase-type plasminogen activator messenger RNA in the normal mouse by in situ hybridization.
The histological distribution of urokinase-type plasminogen activator (u-PA) mRNA was analyzed in normal mouse tissue by in situ hybridization with anti-sense RNA transcribed from three different subclones of a mouse u-PA cDNA. Hybridization signal was found over a distinct fibroblast-like cell in the lamina propria of the gastrointestinal tract, over proximal, distal, and collecting tubules of the kidney, and over the epithelium of the bladder, ductus deferens, and epididymis. No hybridization signal was found over cells of the lung, pancreas, liver, adrenal, pituitary, cerebrum, hypothalamus, cerebellum, sciatic nerve, and striated muscle, nor over endothelial cells in any tissue investigated. The lack of u-PA mRNA in lung tissue was confirmed by Northern analysis and is in contrast to the high amounts of u-PA protein found in this tissue.
Animals↗
Urokinase-type plasminogen activator is expressed in stromal cells and its receptor in cancer cells at invasive foci in human colon adenocarcinomas.
In this study in situ hybridization methods were used to examine biopsy samples from 13 adenocarcinomas of the colon for the presence of mRNA for the urokinase-type plasminogen activator (u-PA) and its specific cell-surface receptor (u-PAR). In all cases, u-PA mRNA was present in fibroblastlike cells in the stroma adjacent to the invasive tumor nodules. Urokinase-type plasminogen activator mRNA was not detected in the malignant cells. All specimens also contained u-PAR mRNA in cells located at the tumoral-stromal interface of invasive foci, but in contrast at least some of these cells were in all but one case identified as being of malignant origin. Stromal cells, probably tumor-infiltrating macrophages and neutrophils, also were positive in these areas. These results support the view that components of the plasminogen activation system may act to influence proteolytic events occurring at the interface between stroma and malignant cells in adenocarcinomas of the colon in humans.
Adenocarcinoma↗
[Why are chronic pain patients given opioids via injections?].
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Chronic Disease↗
[Transcutaneous nerve stimulation as palliative treatment of pain].
The value of transcutaneous nerve stimulation (TNS) for palliative relief of pain is reviewed. The presumed mechanisms of effect are briefly described and a review of recent literature concerning TNS for acute and chronic pain, respectively, is presented. In addition, advice is given for the choice of apparatus and the technique employed is described. It is concluded that TNS may be tried with advantage in the treatment of a number of acute and chronic painful conditions of neurogenic/nocioceptive nature and that TNS has the advantage over e.g. acupuncture that the patient can administer the treatment himself.
Evaluation Studies as Topic↗
Morphine, morphine-6-glucuronide and morphine-3-glucuronide concentrations in plasma and cerebrospinal fluid during long-term high-dose intrathecal morphine administration.
The kinetics of morphine, morphine-6-glucuronide (M6G), and morphine-3-glucuronide (M3G) were studied in a 56-year-old female with lung cancer. Long-term treatment with morphine intrathecally 28 mg every 6 h was used for pain control. Cerebrospinal fluid (CSF) concentrations of morphine were high with an elimination half-life of 2.1 h. The plasma/CSF ratios for M6G and M3G were 1:0.8 and 4:1, respectively, suggesting that M6G penetrates the blood-brain barrier more easily than M3G. The low CSF concentrations indicate that M6G played hardly any major analgetic role in the patient studied.
Female↗
Glycosylated haemoglobin (HbA1c) in iron- and vitamin B12 deficiency.
Glycosylated haemoglobin (HbA1c) was measured in 10 patients with iron deficiency anaemia, 10 patients with vitamin B12 deficiency anaemia and 10 healthy controls. Initially there were no significant differences between the groups (P greater than 0.4), but after treatment with iron and vitamin B12 for 3 and 6 weeks, the glycosylated haemoglobin concentration decreased significantly (P less than 0.01). It was concluded that glycosylated haemoglobin is a sensitive marker of the changes in the erythrocyte population that are observed when predominantly immature erythrocytes are being produced.
Adult↗
Acyclovir in the prevention of duodenal ulcer recurrence.
This study tests the hypothesis that reactivation of a latent herpes simplex virus infection may be a cause of recurrent duodenal ulceration. Patients with recently healed duodenal ulcer were entered into a double blind, randomised study of maintenance treatment with the antiviral drug acyclovir (400 mg bid) versus placebo, to determine if suppression of herpes virus infection would influence the natural history of the ulcer disease. One hundred and fifteen patients entered the trial and 76 patients completed it according to the protocol. Endoscopy was performed when ulcer symptoms recurred and at the end of the 25 week trial period. In the acyclovir group the cumulated relapse rate was 63% compared with 56% in the placebo group (NS). This result suggests that reactivation of herpes simplex virus is not a cause of recurrent duodenal ulcer.
Acyclovir↗
[Long-term treatment with intrathecal morphine in severe painful cancer].
Intrathecal treatment with morphine was instituted in seven cancer patients with severe pain. All of the patients had already received treatment with epidural morphine and the reason for the change in treatment was insufficient effect, side effects and/or pain connected with the injections in the epidural form of therapy. The duration of treatment was 5-136 days (median 40 days). The daily intrathecal dosage of morphine which was administered by 1-4 daily injections was initially 2.4-16.0 mg (median 3.6 mg) and had to be increased to 3.2-112 mg (median 16 mg) at the conclusion of treatment. Five patients became free from pain and one had acceptable relief of pain on this treatment. One patient received accidentally too great a dose of morphine intrathecally as compared with the usual dose and required treatment for respiratory insufficiency. Apart from postural headache on account of leakage of cerebro-spinal fluid, which could be treated by epidural blood "patch", the method was without complications which could be attributed to the intrathecally placed catheter. Treatment of pain with opioids injected intrathecally may thus be recommended in the cases in which epidural treatment cannot be carried out on account of the reasons mentioned above.
Adult↗
[An mobile intensive care unit manned with medical personnel. Experience from a 16-year period].
An attempt is made to assess the value of a medically-staffed mobile intensive care unit which has functioned for 16 years at Holstebro Central Hospital. The medically-staffed ambulance responded to emergency calls concerning 2,048 patients. The average age was 56 years, 1,225 patients were men, 461 were women and in 362 cases the sex was not recorded. Of these 753 were non-cardiac cases, 883 were cardiac cases and in 412 cases, the diagnosis was not recorded. Resuscitation was commenced in 649 cases and this proved successful primarily in 175 cases (27%). Sixty-seven of these patients (38%) were discharged from hospital. In nine cases only defibrillation was performed while supplementary drugs were administered in 434 cases. Treatment consisted mainly of cardiovascular drugs, divretics, analgesics, intravenous fluid and in 518 cases intubation. The drug treatment required the presence of a doctor. The cost was modest, particularly as this arrangement has, hitherto, not required extra staffing. Improvements in the existing prehospital emergency treatment are proposed. In particular, the alarm system should be changed. A medically-staffed mobile intensive care arrangement will render commencement of thrombolytic treatment possible in cases of acute myocardial infarction as early as possible.
Adolescent↗