The aim of this study was to compare the serum levels of the anti-angiogenic factor endostatin (S-endostatin) as a potential marker of vasculogenesis after autologous cell therapy (ACT) versus percutaneous transluminal angioplasty (PTA) in diabetic patients with critical limb ischemia (CLI). A total of 25 diabetic patients with CLI treated in our foot clinic during the period 2008-2014 with ACT generating potential vasculogenesis were consecutively included in the study; 14 diabetic patients with CLI who underwent PTA during the same period were included in a control group in which no vasculogenesis had occurred. S-endostatin was measured before revascularization and at 1, 3, and 6 months after the procedure. The effect of ACT and PTA on tissue ischemia was confirmed by transcutaneous oxygen pressure (TcPO2) measurement at the same intervals. While S-endostatin levels increased significantly at 1 and 3 months after ACT (both P < 0.001), no significant change of S-endostatin after PTA was observed. Elevation of S-endostatin levels significantly correlated with an increase in TcPO2 at 1 month after ACT ( r = 0.557; P < 0.001). Our study showed that endostatin might be a potential marker of vasculogenesis because of its significant increase after ACT in diabetic patients with CLI in contrast to those undergoing PTA. This increase may be a sign of a protective feedback mechanism of this anti-angiogenic factor.
- MeSH
- angioplastika * MeSH
- antigeny CD34 analýza MeSH
- autologní transplantace MeSH
- buněčná a tkáňová terapie MeSH
- diabetes mellitus 2. typu krev komplikace MeSH
- diabetická noha krev terapie MeSH
- endostatiny krev MeSH
- fyziologická neovaskularizace MeSH
- ischemie krev terapie MeSH
- kmenové buňky cytologie MeSH
- končetiny krevní zásobení MeSH
- lidé středního věku MeSH
- lidé MeSH
- onemocnění periferních cév terapie MeSH
- senioři MeSH
- transplantace kmenových buněk * MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
INTRODUCTION: Multiple myeloma (MM) is still incurable due to resistance against various therapies. Thus, the identification of biomarkers predicting progression is urgently needed. Here, we evaluated four biomarkers in bone marrow and peripheral blood of MM patients for their prognostic significance. MATERIALS & METHODS: Bone marrow- and peripheral blood plasma levels of FLT3-L, soluble TIE2, endostatin, and osteoactivin were determined in patients with monoclonal gammopathy of undetermined significance (MGUS, n = 14/n = 4), patients with newly diagnosed MM (NDMM, n = 42/n = 31) and patients with relapsed/refractory MM (RRMM, n = 27/n = 16) by sandwich ELISA. RESULTS: Median FLT3-L expression increased from MGUS (58.77 pg/ml in bone marrow; 80.40 pg/ml in peripheral blood) to NDMM (63.15 pg/ml in bone marrow; 85.05 pg/ml in peripheral blood) and was maximal in RRMM (122 pg/ml in bone marrow; 160.47 pg/ml in peripheral blood; NDMM vs. RRMM p<0.001). A cut-off value of FLT3-L >92 pg/ml in bone marrow and >121 pg/ml in peripheral blood was associated with relapse or refractoriness in MM patients. FLT3-L was found to be a high predictive marker for discrimination between NDMM and RRMM as well in bone marrow as in peripheral blood (AUC 0.75 in bone marrow; vs 0.84 in peripheral blood). CONCLUSION: High levels of FLT3-L in bone marrow and peripheral blood of MM patients identify patients with progressive disease and are associated with relapse or refractoriness in MM patients. FLT3-L could be useful as a marker to identify RRMM patients and should be evaluated as target for future therapies.
- MeSH
- diferenciální diagnóza MeSH
- dospělí MeSH
- ELISA MeSH
- endostatiny metabolismus MeSH
- kostní dřeň metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- membránové glykoproteiny metabolismus MeSH
- membránové proteiny metabolismus MeSH
- mnohočetný myelom metabolismus MeSH
- nádorové biomarkery metabolismus MeSH
- prognóza MeSH
- receptor TIE-2 metabolismus MeSH
- recidiva MeSH
- ROC křivka MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- buněčná a tkáňová terapie metody MeSH
- diabetická noha * etiologie krev terapie MeSH
- endostatiny krev MeSH
- fyziologická neovaskularizace imunologie účinky léků MeSH
- lidé MeSH
- onemocnění periferních arterií komplikace MeSH
- transplantace kmenových buněk metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
The release of proangiogenic cytokines into the circulation after stem cell (SC) therapy and compensatory increase of angiogenesis inhibitors may reflect local vasculogenesis but also can increase the risk of side effects. The aim of our study was to evaluate serum levels of angiogenic cytokines with regard to the assessment of local and systemic vasculogenesis in diabetic patients with no-option critical limb ischemia (NO-CLI). Twenty-five diabetic patients with NO-CLI treated with SCs isolated from bone marrow or stimulated peripheral blood were included in the study. Serum levels of proangiogenic cytokines (VEGF, bFGF, Ang-1, PDGF-AA, and PDGF-BB) and an antiangiogenic cytokine (endostatin) were assessed 6 months after cell treatment, compared to baseline values, and correlated with the number of injected CD34(+) cells. The clinical effect of SC therapy (assessed by changes in TcPO2) and potential systemic vasculogenesis (assessed by eye fundus examination) were evaluated after 6 months. Serum levels of angiogenic inhibitor endostatin increased significantly after 1 and 3 months (p = 0.0003), but no significant increase in serum levels of proangiogenic cytokines was observed. A significant correlation between number of injected CD34(+) cells and serum levels of endostatin was observed (r = 0.41, p < 0.05); however, proangiogenic cytokines did not correlate with CD34(+) cells. No correlation between increase in TcPO2 after treatment and serum levels of any of the angiogenic cytokines were seen, and no signs of systemic vasculogenesis in the retina were observed after 6 months. Despite the significant increase in the levels of the angiogenic inhibitor endostatin following SC treatment, there was no risk of systemic vasculogenesis after SC therapy as documented by serum levels of proangiogenic cytokines or changes in the retina.
- MeSH
- antigeny CD34 metabolismus MeSH
- autologní transplantace MeSH
- cytokiny krev MeSH
- diabetes mellitus krev terapie MeSH
- endostatiny krev MeSH
- fyziologická neovaskularizace * MeSH
- ischemie krev komplikace terapie MeSH
- kyslík metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- parciální tlak MeSH
- senioři MeSH
- transplantace kmenových buněk * MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We investigated whether a genetic modification of BCR-ABL-transformed mouse cells that resulted in endostatin (ES) production altered their oncogenic potential. Mouse B210 cells, which express p210bcr-abl fusion protein and induce leukemia-like disease and extremely rarely solid tumors after intravenous (i.v.) administration, were used. The cells were transfected with a plasmid carrying genes for mouse ES and resistance to blasticidine. Transduced cells were isolated in media supplemented with blasticidine. Production of ES was determined by Western blotting. For further tests, two clones were selected, and their pathogenicity after i.v. inoculation was tested. Compared with the parental B210 cells, the capability of both gene-modified cell clones to induce lethal leukemia was reduced. However, mice that did not succumb to leukemia subsequently developed solid tumors. They were composed of poorly differentiated cells with irregular nuclei and roughly granular chromatin and were well vascularized. FISH revealed the presence of the BCR-ABL fusion gene both in tumors and spleens. Immunohistological investigation of the tumors demonstrated the production of ES in vivo and the cell lines derived from the tumors produced detectable amounts of ES, this demonstrating that the formation of solid tumors was not associated with the loss or silencing of the ES gene.
- MeSH
- bcr-abl fúzové proteiny genetika metabolismus MeSH
- endostatiny metabolismus farmakologie sekrece MeSH
- endoteliální buňky pupečníkové žíly (lidské) účinky léků fyziologie MeSH
- histokompatibilita - antigeny třídy I metabolismus MeSH
- Kaplanův-Meierův odhad MeSH
- kultivační média speciální farmakologie MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- nádorová transformace buněk MeSH
- proliferace buněk MeSH
- transformované buněčné linie metabolismus patologie transplantace MeSH
- transplantace nádorů MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The aim of our study was to evaluate the concentration changes in the proangiogenic hepatocyte growth factor (HGF) and antiangiogenic endostatin during the sampling of large bone marrow volumes in patients with multiple myeloma. HGF and endostatin concentrations were measured in the 1st ml, the 5th ml, the 19th ml, the 30th ml, and the 45th ml of the sample. Concentrations of HGF, which is produced by bone marrow and myeloma cells, decreased significantly in the course of BM sampling due to the admixture of peripheral blood. Endostatin concentrations did not change significantly during the procedure of sampling, as endostatin is mainly secreted by the parenchymatous organs such as liver, lungs, and others. In conclusion, the admixture of the peripheral blood could be partly responsible for conflicting results of studies of HGF in multiple myeloma. Standardisation of HGF sampling is required for valid comparisons between different studies.
Two mouse HPV16-transformed cell lines, viz. MK16 cells, which induce metastasizing tumors, and TC-1 cells, which induce non-metastasizing tumors were transduced with the gene for mouse endostatin. Two clones constitutively expressing endostatin were isolated from each of them. They were denoted ME3 and ME9, and TE2 and TE5, respectively. When inoculated into mice, ME3 cells were non-oncogenic. Nearly all mice inoculated with ME9 cells developed tumors, but considerably later than did the parental MK16 cells and metastasis formation was strongly reduced in these animals. On the other hand, TE2 and TE5 cells displayed oncogenic potential similar to that of the parental cells. To provide more information on these different effects of endostatin production, cell lysates of all six lines studied were tested for the content of 25 factors known to be involved in angiogenesis. The parental MK16 cells differed from the parental TC-1 cells and also from all endostatin producing sublines by a markedly higher production of interleukin 1alpha (IL-1alpha) and, to a lesser extent, by a higher production of several other factors tested. Additional experiments indicated that the suppression of the production of IL-1alpha by the parental MK16 caused by endostatin was due to an autocrine mechanism.
- MeSH
- autokrinní signalizace MeSH
- časové faktory MeSH
- endostatiny genetika metabolismus MeSH
- endoteliální buňky metabolismus MeSH
- geny ras MeSH
- interleukin-1alfa metabolismus MeSH
- interleukin-2 genetika metabolismus MeSH
- kultivační média speciální metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorová transformace buněk MeSH
- nádory plic genetika imunologie metabolismus prevence a kontrola sekundární virologie MeSH
- onkogenní proteiny virové genetika MeSH
- Papillomavirus E7 - proteiny MeSH
- proliferace buněk MeSH
- represorové proteiny genetika MeSH
- transdukce genetická MeSH
- transformované buněčné linie MeSH
- virová transformace buněk MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Cíle: Endostatin a midkin jsou proteiny, které přímo ovlivňují angiogenezu a podílejí se pravděpodobně na diferenciaci tumoru. E-FABP je epiteliální protein, který se pravděpodobně uvolňuje při vzniku maligních lézí. Cílem práce bylo hodnocení možností stanovení koncentrací endostatinu, midkinu a E-FABP v séru i v moči jako nádorového markeru u jedinců s karcinomem močového měchýře. Soubor a metody: Do studie bylo zařazeno 96 osob, z toho 64 jedinců s endoskopicky a histologicky potvrzeným karcinomem močového měchýře a 32 osob s benigním onemocněním urotraktu. U všech byla provedena cystoskopie (histologie) a vyšetření venózní krve a moče na endostatin, midkin a E-FABP. Výsledky: Pacienti s prokázaným uroteliálním karcinomem močového měchýře měli hodnoty endostatinu, midkinu a E-FABP v moči významně vyšší (p<0,01) než kontrolní skupina. Hodnoty endostatinu, midkinu a E-FABP v séru byly taktéž u osob s karcinomem měchýře vyšší, avšak pouze stanovení endostatinu dosahovalo uspokojivé diagnostické efektivity (senzitivita 47%, specifičnost 83%, AUC = 0,75, cut-off hodnota 201 ?g/l). Závěr: Pacienti s karcinomy močového měchýře mají vyšší hodnoty endostatinu, midkinu, E-FABP a endostatinu v séru i v moči, avšak pouze stanovení endostatinu v séru má dostatečnou diagnostickou efektivitu pro odhad přítomnosti této diagnózy.
Purpose: Endostatin and midkine are proteins which directly affect angiogenesis and are likely to be involved in tumour differentiation. E-FABP is an epithelial protein likely to be released when malignant lesions arise. The aim was to assess the options for determining both serum and urine concentrations of endostatin, midkine, and E-FABP as tumour markers in individuals with bladder cancer. Material and methods: The study enrolled 96 people, including 64 people with endoscopically and histologically confirmed bladder cancer and 32 people with benign urinary tract disease. All underwent cystoscopy (histology) and venous blood and urine test for endostatin, midkine, and E-FABP. Results: The patients with confirmed urothelial carcinoma of the bladder had significantly higher urinary levels of endostatin, midkine, and E-FABP than the control group (p<0.01). Endostatin, midkine, and E-FABP serum levels were also higher in subjects with bladder cancer, endostatin detection, however, was the only to reach satisfactory diagnostic effectiveness (sensitivity 47%, specificity 83%, AUC = 0.75; cut-off value 201 ?g/I). Conclusion: Patients with bladder cancer have higher serum and urine concentrations of endostatin, midkine, and E-FABP, detection of serum endostatin, however, is the only to have a diagnostic effectiveness sufficient enough to estimate the presence of this diagnosis.
BACKGROUND: Adipose tissue produces both vascular growth factors and inhibitors. Since obesity is associated with expansion of the capillary bed in regional adipose depots the balance between these factors may favor angiogenesis. OBJECTIVE: To investigate the relationship between body mass index and serum concentrations of vascular growth factors in human subjects. METHODS: Vascular endothelial growth factor (VEGF), VEGF-C, VEGF-D, soluble VEGF receptor-2 (sVEGFr2), hepatocyte growth factor (HGF), angiopoietin-2, angiogenin and endostatin concentrations were measured in serum collected from 58 lean (24 males, 34 female, mean BMI, 22.2+/-0.3) and 42 overweight and obese (16 males and 26 females, mean BMI, 33.5+/-1.2) subjects after an overnight fast. RESULTS: Sexual dimorphism was apparent in the serum concentrations of VEGF-C, VEFG-D and angiopoietin-2 with significantly higher levels in female compared to male subject. VEGF, VEGF-C, VEGF-D, soluble VEGF receptor-2, angiopoietin-2, angiogenin and endostatin but not HGF were significantly elevated in overweight and obese subjects. Positive correlations between BMI and the serum concentrations of VEGF-C, VEGF-D, sVEGF-R2, angiopoietin-2, angiogenin and endostatin were observed even after adjustment for gender and age. CONCLUSIONS: Increased levels of vascular growth factors as well as the angiogenesis inhibitor endostatin are present in overweight and obese subjects and may contribute to previously documented increased risk of metastatic disease in obese subjects with cancer.
- MeSH
- adiponektin krev MeSH
- analýza rozptylu MeSH
- angiogenní proteiny * krev MeSH
- angiopoetin-2 krev MeSH
- dospělí MeSH
- endostatiny * krev MeSH
- hepatocytární růstový faktor krev MeSH
- inzulinová rezistence MeSH
- leptin krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- lineární modely MeSH
- nadváha MeSH
- obezita * krev MeSH
- pankreatická ribonukleasa krev MeSH
- pohlavní dimorfismus MeSH
- receptor 2 pro vaskulární endoteliální růstový faktor krev MeSH
- vaskulární endoteliální růstový faktor A krev MeSH
- vaskulární endoteliální růstový faktor C krev MeSH
- vaskulární endoteliální růstový faktor D krev MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
