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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the relationships between serum endogenous cytokine levels and their clinical implications in cancer patients, we measured the serum levels of endogenous granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and interleukin 6 (IL-6) in patients with untreated primary lung cancer. The serum G-CSF level was measured using a chemiluminescent ELISA, and the other cytokine levels were measured using ELISA. Fifty healthy adults and 183 patients with primary lung cancer were studied. The mean M-CSF level in the lung cancer patients (1106.4 units/ml) was significantly higher than that in the healthy adults (836 units/ml, P = 0.0001). In patients with large cell carcinoma, endogenous G-CSF, M-CSF, and IL-6 levels were significantly higher than those in patients with carcinomas of other cell types (P < 0.05). Univariate analysis showed that survival of 159 non-small cell lung cancer patients with high (more than cutoff level) G-CSF, M-CSF, and IL-6 levels was significantly poorer than that of patients with low levels (Wilcoxon's test, P = 0.018, P < 0. 0001, and P < 0.0001, respectively). Survival of patients with high levels of two or more cytokines was poorer than that of those with high levels of one cytokine or normal cytokine levels (P < 0.0001). Multivariate analysis using Cox's proportional hazards model showed that high M-CSF and C-reactive protein levels correlated significantly with poor survival (P = 0.037 and 0.037, respectively). Our preliminary data suggest that high M-CSF levels in non-small cell lung cancer may be of poor prognostic value.
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PMID:Serum levels of cytokines in patients with untreated primary lung cancer. 981 3

An in vitro carcinogenesis model of human skin keratinocytes has been developed based on the spontaneously immortalized keratinocyte cell line HaCaT. Immortalization, the initial stage in human carcinogenesis in vitro, was induced by ultraviolet-type mutations in the p53 gene followed by further genetic alterations leading to the loss of senescence genes, in particular on chromosome 3p. Despite multiple genetic changes, the HaCaT cell line sustained its genomic balance up to high passage levels and maintained a non-tumorigenic phenotype. Tumorigenic transformation was induced by ras oncogene transfection but also by culture stress and elevated temperature, resulting in benign and malignant tumorigenic clones. Malignant conversion was associated with the loss of a copy of chromosome 15, leading to a decrease in thrombospondin-1 (TSP-1) expression. Heat-induced malignant conversion was associated with a gain of material on chromosome 11, including the cyclin D1 gene. The microenvironment plays a major role in tumorigenic transformation and the control of malignant cells. Overexpression of platelet-derived growth factor in HaCaT cells caused mesenchyme activation and formation of benign tumors. Halting tumor angiogenesis completely prevented invasion of malignant cells and induced a benign tumor phenotype. Transfer of a normal chromosome 15 or TSP-1 transfection into a skin carcinoma line resulted in tumor suppression due to TSP-1-blocked tumor vascularization. Because of the reduced TSP-1 expression, blood vessels infiltrated the tumor, and it expanded. Progression to more aggressive tumor phenotypes required the in vivo environment and was caused by selection of a subpopulation and further genetic modifications. The improved autonomous growth of these cells was associated with new expression of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, which acted in an autocrine manner to stimulate proliferation and migration. With this in vitro skin carcinogenesis model we were able to demonstrate multiple stages in the transformation process that were associated with different genetic and phenotypic characteristics. In addition, we documented that modulation of the tumor stroma plays an important and decisive role in tumor development and progression. From this we hypothesize that the growth restraints of the microenvironment are increasingly lost with advancing stages of carcinogenesis but can be restored by modulation of the tumor stroma.
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PMID:Multiple stages and genetic alterations in immortalization, malignant transformation, and tumor progression of human skin keratinocytes. 983 75

The physiologically active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has influence over osteoclastogenesis and myelopoiesis, but the regulational mechanism is not well-defined. In this report, formation of osteoclast-like (OCL) cells from primitive myeloid colony-forming cells (PM-CFC) as mediated by 1,25(OH)2D3 was examined. Our results present in this report clearly show that 1,25(OH)2D3 dose-dependently stimulated OCL cell formation when added to suspension cultures of individually replated PM-CFC colonies. Marrow cells were plated with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or the human bladder carcinoma cell line 5637 conditioned medium (5637 CM) as the source of colony-stimulating activity. The 1,25(OH)2D3 effect of osteoclast differentiation was associated with a concomitant decrease in clonogenic growth of myelopoietic progenitors in response to colony-stimulating activity. Secondly, the effect of adding the known stimulator of hematopoiesis, interleukin-1beta (IL-1beta) and/or 1,25(OH)2D3 on human myeloid colony growth was assessed. IL-1beta enhanced the formation of primitive myeloid colonies in response to GM-CSF by 160%. On the other hand, 1,25(OH)2D3 dose-dependently inhibited both GM-CSF- and 5637 CM-driven myeloid colony formation by as much as 90% at 100 nM. Addition of IL-1beta to GM-CSF-stimulated cultures dampened the inhibitory effect of 1,25(OH)2D3. The inhibition of myeloid clonogenic growth by 1,25(OH)2D3 was almost abolished (89%) by simultaneously adding anti-tumor necrosis factor-alpha monoclonal antibody (anti-TNF-alpha MoAb) to the culture medium. These results collectively suggest divergent roles for 1,25(OH)2D3 in osteoclastogenesis and myelopoiesis, promoting the differentiation of OCL cells from primitive myeloid cells but inhibiting the proliferation of later myeloid progenitor cells. This inhibition of myeloid progenitors may be mediated by TNF-alpha.
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PMID:Divergent regulation of 1,25-dihydroxyvitamin D3 on human bone marrow osteoclastogenesis and myelopoiesis. 1002 20

In this study, we have assessed the development of neutralizing and nonneutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in two groups of patients with metastatic colorectal carcinoma receiving two different GM-CSF products. Three clinical trials were carried out, and a combination of GM-CSF and a colon carcinoma-reactive antibody was used in the absence of any concomitant chemotherapy. Two different GM-CSF products, both rDNA-derived and produced in Escherichia coli, were used. Patients in Trial 1 received product X, and those in Trials 2 and 3 received product Y. Patients in Trial 2 also received interleukin 2 in an attempt to potentiate immune responses. After the first cycle of treatment, no GM-CSF antibodies were detected, but on subsequent therapy, 28 of the 38 patients tested receiving product Y (Trials 2 and 3) developed antibodies that bound to the GM-CSF product used for therapy. However, none of the patients developed antibodies that neutralized the biological activity of GM-CSF, as assessed using an in vitro bioassay. Furthermore, there was no in vivo impairment in GM-CSF-induced expansion of leukocytes, neutrophils, and eosinophils in the patients. In contrast, 19 of the 20 patients given product X (Trial 1) developed GM-CSF binding antibodies, and 9 of these patients were shown to develop antibodies that neutralized the biological activity of GM-CSF. The presence of the latter was associated with a significant reduction in GM-CSF-induced expansion of leukocytes, neutrophils, and eosinophils in patients. Therefore, product X appears to be more immunogenic than product Y. Immunochemical characterization confirmed that the specificity of the antibody responses varied depending on the product used for therapy. Whereas sera from Trial 1 patients treated with product X showed the presence of antibodies with strong recognition of GM-CSF proteins, sera from patients treated with product Y showed varied recognition of GM-CSF ranging from fairly strong to very weak but bound predominantly to two E. coli-derived, non-GM-CSF-related proteins of Mr approximately 20,000 and Mr approximately 30,000. Therefore, in sera from patients receiving product Y, the antibody specificity appeared to be directed not only against GM-CSF but also against non-product-related host cell contaminants. This study shows that GM-CSF products used for therapy are potentially immunogenic and generate antibodies to GM-CSF and/or other non-product-related contaminants. However, only antibodies that neutralize the biological activity of GM-CSF compromise therapeutic efficacy of the cytokine.
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PMID:Immunogenicity of granulocyte-macrophage colony-stimulating factor (GM-CSF) products in patients undergoing combination therapy with GM-CSF. 1038 19

There is increasing evidence that spontaneous anticytokine autoantibodies are associated with chronic infections and autoimmune diseases. We report the sporadic occurrence in autoimmune diseases of such autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine involved in inflammation and the regulation of proliferation, differentiation and function of granulocytic and monocytic cell lineages. In 41 of 425 patients tested, we found low to moderate levels of autoantibodies binding to GM-CSF in serum or plasma. These were most prevalent in patients with myasthenia gravis (MG). However, neutralizing autoantibodies against GM-CSF were very rare, being found in only three patients. Two had autoimmune MG, one with thymoma (Patient A) and the other (Patient B) with 'seronegative' MG, i.e. without the antiacetylcholine receptor autoantibodies characteristic of most MG patients, and a third (Patient D) had multiple sclerosis. Only very limited amounts of Patient A and Patient D serum/plasma were available for analysis and therefore further studies were carried out on the more plentiful samples from Patient B. The anti-GM-CSF autoantibodies of Patient B were predominantly polyclonal immunoglobulin G and strongly neutralized recombinant human (rh) GM-CSF derived from different expression systems. They had similar immunological and immunochemical characteristics to anti-GM-CSF antibodies that developed in immunocompetent colorectal carcinoma patients following (rh)GM-CSF therapy. In serial samples from Patient B, the anti-GM-CSF autoantibodies were undetectable from diagnosis at age 8 years until at least age 13, but then developed spontaneously during (temporary) withdrawal of immunosuppressive treatment. Their neutralizing activity has persisted since their first detection at age 15 years 1 month, and was at its highest level recently at age 17 years 7 months. There was no obvious association with other autoimmune phenomena, nor were any haematological deficiencies overtly manifested, suggesting that any loss of GM-CSF function may have been compensated for by other cytokines.
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PMID:Spontaneously occurring neutralizing antibodies against granulocyte-macrophage colony-stimulating factor in patients with autoimmune disease. 1044 77

Thrombocytosis is occasionally seen in patients with carcinomas and has been assumed to be attributable to interleukin-6 or granulocyte-macrophage colony-stimulating factor produced by carcinoma cells. In this study, we clarified whether thrombopoietin (TPO) is involved in carcinoma-associated thrombocytosis. Expression of TPO mRNA was observed in the majority of 27 carcinoma cell lines as determined by reverse transcriptase-polymerase chain reaction (RT-PCR). There were 6 PCR products differing in size; sequence analysis showed the full-length TPO mRNA (TPO-1), 12- and 116-bp deleted variants (TPO-2 and TPO-3, respectively), and 3 novel isoforms (197- and 128-bp deleted forms and a 60-bp insert form of TPO-3; named TPO-4, TPO-5, and TPO-6, respectively). Of 27 lines, 24 expressed TPO-1 mRNA with various other isoforms. Culture supernatants of COS-1 cells transfected with TPO-5 or TPO-6 cDNA did not promote the proliferation of TPO-responsive cells, whereas Western blot analysis on the cell lysates demonstrated TPO-5 but not TPO-6 protein, suggesting poor extracellular secretion (TPO-5) or poor protein synthesis (TPO-6). TPO protein was detected in 10-fold concentrated culture supernatants of cells of these carcinoma lines, with a median concentration of 0.38 fmol/mL as evaluated by enzyme-linked immunosorbent assay. High blood TPO levels were observed with a median value of 3.46 fmol/mL (range, 0.34 to 8.67 fmol/mL) in patients with advanced carcinomas associated with thrombocytosis. These results indicate that thrombocytosis in patients with carcinomas might be caused, at least in part, by TPO produced by carcinoma cells.
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PMID:Production of thrombopoietin by human carcinomas and its novel isoforms. 1047 24

Natural killer-like T lymphocytes termed cytokine-induced killer (CIK) cells have been shown to eradicate established tumours in a severe combined immune deficient (SCID) mouse/human lymphoma model. Recently, we demonstrated that CIK cells transfected with cytokine genes possess an improved proliferation rate and a significantly higher cytotoxic activity as compared to non-transfected cells. Here, in a phase I clinical protocol, autologous CIK cells were generated from peripheral blood obtained by leukapheresis in patients with metastatic renal cell carcinoma, colorectal carcinoma and lymphoma. CIK cells were transfected with a plasmid containing the interleukin-2 (IL-2) gene via electroporation. Transfected cells generated IL-2 in the range of 330-1800 pg 10(-6) cells 24 h(-1) with a mean of 836 pg 10(-6) cells 24 h(-1). Ten patients received 1-5 intravenous infusions of IL-2-transfected CIK cells; five infusions with transfected CIK cells were given. In addition, the same patients received five infusions with untransfected CIK cells for control reasons. In three patients, WHO grade 2 fever was observed. Based on polymerase chain reaction of peripheral blood transfected cells could be detected for up to 2 weeks after infusion. There was a significant increase in serum levels of interferon gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor beta (TGF-beta) during treatment. Interestingly, there was also an increase in CD3+ lymphocytes in the blood of patients during therapy. In accordance, a partial increase in cytotoxic activity in peripheral blood lymphocytes (PBLs) was documented when patient samples before and after therapy were compared. Concerning clinical outcome, six patients remained in progressive disease, three patients showed no change by treatment, and one patient with lymphoma developed a complete response. In conclusion, we were able to demonstrate that CIK cells transfected with the IL-2 gene can be administered without major side-effects and are promising for future therapeutic trials.
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PMID:Phase I clinical study applying autologous immunological effector cells transfected with the interleukin-2 gene in patients with metastatic renal cancer, colorectal cancer and lymphoma. 1057 58

The clearance of apoptotic cells is crucial to avoid chronic inflammation and autoimmunity. Little is known about the factors that regulate it in vivo. We show that granulocyte-macrophage colony-stimulating factor (GM-CSF) administration to carcinoma patients confers to their leukocytes a significantly higher ability to phagocytose apoptotic cells than before (P < 0.005). GM-CSF increased the concentration of monocytes and polymorphonuclear leukocytes in the peripheral blood and activated circulating polymorphonuclear leukocytes. Both effects abated early after treatment, whereas phagocytosis of apoptotic cells was still significantly higher after 18 days compared with basal values (P < 0.005 and P < 0.025 for monocytes and polymorphonuclear leukocytes, respectively). On in vitro phagocytosis of apoptotic cells monocytes, but not polymorphonuclear leukocytes, up-regulated MHC class II membrane expression. These findings are consistent with the possibility that GM-CSF endows both scavenger and antigen-presenting leukocytes with the ability to internalize apoptotic tumor cells.
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PMID:In vivo administration of GM-CSF promotes the clearance of apoptotic cells: effects on monocytes and polymorphonuclear leukocytes. 1067 May 77

We have examined the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in tumor-bearing BALB/c mice using the syngeneic F3II mammary carcinoma. In the present model, progression of subcutaneous tumors induced massive myelopoiesis in bone marrow and spleen due to GM-CSF secretion by tumor cells. In vitro, the addition of recombinant mouse GM-CSF (5- 25 ng/ml) caused a significant increase in F3II cell growth, either in the presence or absence of serum. Zymographic analysis of conditioned media from F3II monolayers showed that GM-CSF exerted a dose-dependent enhancement in the metalloproteinases MMP-9 (105 kD) and MMP-2 (70 kD), key enzymes in mammary tumor cell invasion. Our data suggest that ectopic GM-CSF production stimulates myelopoiesis and may also play an important role in tumor progression and metastasis formation.
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PMID:Role of tumor-derived granulocyte-macrophage colony-stimulating factor in mice bearing a highly invasive and metastatic mammary carcinoma. 1073 79

Interleukin (IL)-1beta stimulates the release of granulocyte macrophage colony-stimulating factor (GM-CSF) from lung epithelial cells. To investigate the molecular mechanisms underlying GM-CSF regulation, we studied GM-CSF production, messenger RNA (mRNA) expression levels, and GM-CSF promoter activity in A549 human alveolar carcinoma cells stimulated with IL-1beta. Coincubation with IL-4 or IL-13 dose-dependently inhibited IL-1beta-induced GM-CSF release. Time-course studies of intracellular and extracellular protein release and mRNA expression indicated tight coupling of protein and mRNA synthesis within 6 h after stimulation. IL-4 and IL-13 both inhibited expression of GM-CSF mRNA and protein by 2 h after stimulation. Stable transfection of A549 cells, with GM-CSF promoter/ enhancer constructs containing up to 3.3 kb upstream of the transcription start site, revealed maximal activation by IL-1beta and phorbol 12-myristate 13-acetate (PMA) with a reporter containing the proximal promoter (-627 to +35). This excludes sequences further upstream from a major regulatory role in GM-CSF promoter activation by IL-1beta or PMA in these cells. IL-4 and IL-13 downregulated promoter activation but had no effect on GM-CSF mRNA half-life. However, IL-1beta activation of all constructs was far less pronounced than in Jurkat T cells, suggesting a requirement for additional mechanisms, possibly post-transcriptional, to potentiate the observed transcriptional induction.
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PMID:Molecular regulation of granulocyte macrophage colony-stimulating factor in human lung epithelial cells by interleukin (IL)-1beta, IL-4, and IL-13 involves both transcriptional and post-transcriptional mechanisms. 1078 30


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