Gene/Protein Disease Symptom Drug Enzyme Compound
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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)

The purpose of this study was to determine the mRNA expression level of multiple cytokine and growth factor genes in human malignant melanoma. Melanoma cells were isolated from several surgical specimens, adapted to growth in culture, characterized for their ability to produce experimental metastases in nude mice, and assessed for cytokine and growth factor steady-state gene expression. Highly metastatic in vivo- and in vitro-derived variants isolated from a single melanoma, A375, were also analyzed. Northern blot analyses revealed that all melanomas analyzed constitutively expressed steady-state mRNA transcripts for the growth and angiogenic factors, basic fibroblast growth factor (bFGF), and transforming growth factor alpha (TGF-alpha), which correlated with metastatic propensity. Only one highly metastatic melanoma, TXM-1, originally isolated from a lymph node metastasis, expressed mRNA transcripts specific for monocyte chemotactic and activating factor (MCAF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Similarly, of the nine melanomas examined, only TXM-1 expressed interleukin (IL)-1 alpha, IL-1 beta, and IL-6, important immunomodulatory cytokines. These data demonstrate the differential and heterogeneous expression of cytokine and growth factor genes in human malignant melanoma.
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PMID:Heterogeneity of cytokine and growth factor gene expression in human melanoma cells with different metastatic potentials. 764 37

Interleukin-2 (IL-2)-dependent large granular lymphocytes (LGL) with a distinctive surface phenotype were generated from histologically normal duodenal biopsy tissues. Immunoperoxidase staining of the mucosa with an anti-CD56 monoclonal antibody revealed LGL localized in the lamina propria rather than in the epithelium. Light and electron microscopy demonstrated azurophilic and electron-dense cytoplasmic granules. Flow cytometry analysis revealed that these cells express CD45, CD56, CD2, CD7, CD11a, CD18, CD69 and the intermediate affinity (p70) IL-2 receptor (IL-2R) but not CD57, CD16, CD3, CD4, CD5, CD8, CD45RA, CD25, or the high affinity p55 IL-2R. The LGL proliferated when cultured in the presence of human rIL-2 but not in the presence of human rIL-4. Functional studies demonstrated that the LGL had strong cytotoxicity against natural killer (NK) target cells, K562, but not NK-resistant targets such as Colo 205, Melanoma and Epstein-Barr virus (EBV)-transformed B-cell lines. The LGL expressed genes for IL-5, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor-alpha (TNF-alpha) and the corresponding cytokines were detected in culture supernatant. These results provide evidence for an important role of gut mucosal LGL in the induction and regulation of inflammation and immunity in the gut.
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PMID:Morphological, phenotypic and functional characteristics of a pure population of CD56+ CD16- CD3- large granular lymphocytes generated from human duodenal mucosa. 769 28

In recent years, several studies have documented that melanoma cell lines produce various cytokine/growth factors and their receptors. Since cell lines can acquire altered properties, such as changes in growth requirements, we studied constitutive cytokine gene expression in melanoma cells from 20 fresh surgical specimens: seven primary melanomas and 13 metastases (12 lymph-node metastases and one subcutaneous metastasis). After tumour cell isolation by discontinuous gradient, we tested for mRNA expression by means of reverse-transcriptase polymerase chain reaction. Most melanoma cells tested expressed growth factors: basic fibroblast growth factor (bFGF), interleukin (IL)1 alpha, IL-1 beta, IL-6 and IL-8 and, in five cases out of 20, expressed granulocyte-macrophage colony-stimulating factor (GM-CSF) (two out of five were also positive for GM-CSF receptor). Our results do not point to a direct correlation between cytokine expression and clinical stage at the time when the bioptic specimen was obtained. However, they allow us to suggest a possible metastatic tumour cell phenotype, in which autogenous GM-CSF expression could modulate immune response against the tumour cell itself or could potentiate metastatic colonization properties.
Melanoma Res 1995 Feb
PMID:Cytokine expression in human primary and metastatic melanoma cells: analysis in fresh bioptic specimens. 773 55

While the primary targets for granulocyte-macrophage colony-stimulating factor (GM-CSF) are hematopoietic precursors and mature myeloid cells, GM-CSF receptors (GMR) are also found on normal tissues including placenta, endothelium, and oligodendrocytes as well as certain malignant cells. The function of GMR in these nonhematopoietic cells is unknown. We studied the function of GMR in human melanoma cell lines. Six of seven cell lines tested (clones 1-5 and 3.44 of SK-MEL-131, SK-MEL-188, SK-MEL-23, SK-MEL-22, and SK-MEL-22A) expressed mRNA encoding the membrane-bound and soluble isoforms of the alpha subunit of the GMR. Melanoma cell lines in early stages of differentiation expressed the largest quantities of alpha-subunit mRNA. Although five of these lines expressed trace levels of mRNA encoding the beta subunit of the GMR, Scatchard analysis of equilibrium binding data derived from three of the cell lines showed that they expressed only low-affinity GMR. Clones 3.44 and 1-5 of SK-MEL-131, and SK-MEL-188 cells expressed receptors with a dissociation constant (kd) for GM-CSF in the following ranges: 0.7 to 0.8, 1.2 to 1.8, and 0.4 to 0.8 nmol/L, respectively. GM-CSF stimulated glucose uptake in four of the melanoma cell lines expressing the alpha subunit, presumably through facilitative glucose transporters, as uptake was blocked by cytochalasin B but not cytochalasin E. Stimulation of glucose uptake was transient, with maximum stimulation occurring at approximately 30 minutes in the presence of 1 nmol/L GM-CSF. GM-CSF stimulated glucose uptake 1.4- to 2.0-fold but did not stimulate cell proliferation. These results suggest a metabolic role for the low-affinity GMR in melanoma cell lines and indicate that the alpha subunit of the GMR can signal for increased glucose uptake in nonhematopoietic tumor cells.
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PMID:Granulocyte-macrophage colony-stimulating factor signals for increased glucose uptake in human melanoma cells. 784 18

A human melanoma cell line, MEL-P, expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and its specific receptor was newly established from a primary nodular lesion of a patient with a particularly unfavourable prognosis. Cytogenetic, immunophenotypic, cytokine and intercellular adhesion molecule (ICAM)-1 production analyses confirmed that this cell line was similar to the fresh melanoma cells from which it had been established. MEL-P constitutes a valuable model for the study of multistep tumour progression and the role of biologically active GM-CSF production in human malignant melanoma. Our results show a decreasing expression of HLA class I molecules during in vitro culture, when GM-CSF secretion attains the highest levels, and a constantly high production of ICAM-1. The inhibitory effect of GM-CSF antisense treatment on cellular growth might suggest the presence of an autocrine mechanism. On the whole, these data are consistent with the possible involvement of high GM-CSF production in the metastatic competence of melanoma cells through the autocrine mechanism of growth and/or the activation of other migration-related molecules by its local production in metastatic invasion.
Melanoma Res 1996 Jun
PMID:MEL-P, a GM-CSF-producing human melanoma cell line. 881 23

Melanoma cells in culture express a variety of growth factors and cytokines and some of their autocrine and paracrine roles have been investigated. However, less information is available on the potential dynamic changes in expression of these molecules on cells during melanoma development and progression in situ. Using immunohistochemistry, we tested 40 nevi and primary and metastatic melanoma lesions for the expression of 10 growth factors and cytokines and the respective receptors representing 10 cell surface molecules. Nevi and thin (< 1 mm) primary melanomas showed little expression of ligands except weak reactivity of tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), interleukin-8 (IL-8) and reactivity of TGF-betaR and c-kit. Marked up-regulation of growth factors, cytokines and receptor expression was observed in thick (> 1 mm) primary melanomas, which were stained with polyclonal or monoclonal antibodies (MAbs) for IL-1alpha, IL-1beta, IL-6, IL-8, TNF-alpha, TGF-beta, granulocyte-macrophage colony-stimulating factor (GMCSF) and stem cell factor (SCF), but not IL-2. Metastases showed similar expression patterns except that SCF was absent. Co-expression of ligand and receptor was observed for TGF-beta, GM-CSF and IL-6, suggesting an autocrine role for these ligands. TNF-alpha appears to be a marker of benign lesions; IL-6 and IL-8 expression is associated with biologically early malignancy; TGF-beta, GM-CSF and IL-1alpha are highly expressed in biologically late lesions; and TNF-beta is an apparent marker of metastatic dissemination. Our results indicate that melanoma cells utilize cascades of growth factors and cytokines for their progression.
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PMID:Immunohistochemical evidence of cytokine networks during progression of human melanocytic lesions. 1009 49

In 2001, the American Joint Committee on Cancer Melanoma Staging Committee proposed and created a new staging system for melanoma. This new system will become official in 2002, with the publication of the sixth edition of the AJCC Cancer Staging Manual. The new system identifies significant prognostic variables in patients with melanoma and validates them in an analysis of 17,600 patients, making it possible to precisely determine the patient's chance for survival In light of physicians' ability to determine with more precision which patients are at high risk for melanoma recurrence, they face the dilemma of which, if any, surgical adjuvant therapy to choose. Alpha-interferon is the only agent approved for adjuvant therapy of melanoma in the United States, but its questionable benefits and substantial side effects make it hard to justify recommending it to patients. Discussion of trials of high- and low-dose interferon is presented here. The author's group has conducted trials of granulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine]) as surgical adjuvant treatment of patients at high-risk for melanoma recurrence. One of the most important activities of GM-CSF is its ability to activate macrophages and cause them to become cytotoxic for human melanoma cells, at doses low enough to avoid the toxicity associated with other cytokines. The author presents promising trial results, discusses GM-CSF in other malignancies, and includes discussion of tumor vaccines, biochemotherapy, and other agents being studied as adjuvant therapy of melanoma. It is hoped that these newer approaches will result in therapies that are more effective and less toxic than interferon.
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PMID:Adjuvant therapy of melanoma. 1182 82

We conducted a pilot study to assess the feasibility and efficacy of immunotherapy for stage IV malignant melanoma patients resistant to conventional therapies involving vaccination with mature dendritic cells (mDCs) combined with administration of low dose interleukin-2. Autologous monocytes were harvested from a single apheresis and cultured for 7 days with granulocyte-macrophage colony-stimulating factor and interleukin-4, yielding immature dendritic cells (iDCs), which were then cryopreserved until use. For 4 days prior to vaccination, iDCs were exposed to autologous tumour lysate combined with tumour necrosis factor-alpha to induce terminal differentiation into mDCs. Patients were then vaccinated weekly with 107 mDCs for 10 weeks and given 350-700 kIU of interleukin-2 three times per week. Of the 10 patients in the study, one showed stable disease, seven showed progressive disease, and two showed mixed responses, including partial tumour regression, and were therefore given 20 additional injections. Only minimal adverse events were noted, including localized skin reactions and mild fever (NIH-CTC grade 0-1). Median survival from the first vaccination was 240 days (range 31-735 days). In vitro, melanoma patient-derived dendritic cells (DCs) showed reduced cell surface expression of CD1a antigen on iDCs and reduced CD86 and HLA-DR expression on mDCs. In addition, antigen uptake, chemotaxis and antigen presentation were all attenuated in DCs from the patients. In summary, although improvement of clinical efficacy will require further research, autologous tumour lysate-pulsed monocyte-derived mDCs could be safely harvested, cryopreserved and administrated to patients without obvious complications.
Melanoma Res 2003 Oct
PMID:Results of a phase I clinical study using autologous tumour lysate-pulsed monocyte-derived mature dendritic cell vaccinations for stage IV malignant melanoma patients combined with low dose interleukin-2. 1451 94

The purpose of this article is to review some of the recent advances and disappointments in the systemic treatment of melanoma and to highlight some of the ongoing trials in this area. Two major advances in the staging of melanoma are the new American Joint Committee on Cancer staging system and the use of the sentinel node biopsy. Interferon remains the standard adjuvant therapy for high-risk patients. Ongoing trials are evaluating 1 month of high-dose interferon versus observation in intermediate-risk patients and comparing standard interferon with biochemotherapy. Allogeneic and peptide vaccines and granulocyte-macrophage colony-stimulating factor are also being evaluated. Dacarbazine and high-dose IL-2 are the only US Food and Drug Administration approved systemic treatments for stage IV disease. Several new agents are being evaluated. Melanoma remains a prototype disease in which patients should be encouraged to participate in clinical trials.
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PMID:Update on the systemic treatment of malignant melanoma. 1512 32

The sentinel lymph node (SLN) is the first draining node from the area in which a tumour is located. The presence or absence of SLN micrometastasis is an important prognostic factor for melanoma. As the first dissemination route for melanoma is lymphatic and we know that the immune system plays an important role in melanoma response, we hypothesize that melanoma and its corresponding SLN should constitute an immunological unit. Small portions of 54 SLNs from 37 patients undergoing selective lymphadenectomy were subjected to quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) to quantify messenger RNA (mRNA) transcripts of the following genes: tyrosinase, telomerase, cyclooxygenase-1 (COX-1), COX-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), interferon-gamma (IFN-gamma), IL-4, IL-10 and IL-12. In addition, 11 non-sentinel lymph nodes (NSLNs) were excised from 11 of the 37 patients and the same study was performed. Immunohistochemistry with different antibodies against dendritic cells (DCs) was performed in 10 pairs of SLNs and NSLNs. Significantly higher mRNA expression of COX-2, GM-CSF, IFN-gamma and IL-10 was found in SLNs compared with NSLNs in the overall group. DCs, as labelled by S-100 and CD1a, were significantly decreased in NSLNs compared with SLNs. These data suggest that the initial increase in GM-CSF observed in SLNs could lead to the attraction of a high number of DCs to SLNs. However, the presence of certain immunosuppressive molecules, such as IL-10 and COX-2, could block their maturation and their ability to become efficient antigen presenters.
Melanoma Res 2005 Apr
PMID:Cytokine expression and dendritic cell density in melanoma sentinel nodes. 1584 42


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