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 ovarian surface epithelium (OSE) takes part in the lysis and repair of the ovulatory site. It also forms invaginations and cysts that give rise to the majority of ovarian epithelial carcinomas. In the present study, we investigated the capacity of cultured human OSE to secrete cytokines that may contribute to the regulation of ovarian functions and may influence ovarian carcinogenesis. Bioassays, combined with antibody neutralization experiments, showed that OSE cells in short-term culture secrete bioactive interleukin-1 (IL-1), interleukin-6 (IL-6), macrophage colony-stimulating factor (CSF-1), granulocyte colony-stimulating factor (G-CSF), and limited granulocyte-macrophage colony-stimulating factor (GM-CSF). There was a tendency for these factors to be absent or secreted in reduced amounts in SV40-immortalized OSE lines and in two ovarian carcinoma lines. No IL-2, IL-3, or IL-4 was detected. The results show that normal OSE cells secrete factors that are known to have regulatory effects on follicular growth and differentiation, ovulation, and the distribution of intraovarian cells of the immune system. In addition, the results suggest that the secretion of cytokines by ovarian carcinomas represents the retention of normal precursor cell properties, rather than new characteristics acquired as a result of neoplastic progression.
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PMID:Secretion of bioactive interleukin-1, interleukin-6, and colony-stimulating factors by human ovarian surface epithelium. 769 Nov 94

Following local treatment and doxorubicin-containing standard chemotherapy, 42 patients with surgical Stage II or IIIA breast cancer containing ten or more involved axillary nodes and 13 patients with Stage IIIB disease were treated with high-dose chemotherapy (TMJ) consisting of thiotepa (750 mg/m2), mitoxantrone (40 mg/m2), and carboplatin (1000 mg/m2), with autologous bone marrow (ABM) and peripheral stem cell (PSC) transplant, followed by irradiation and/or hormone therapy. Sargramostim (GM-CSF) support was given to most patients. The median time to transfusion independence was two weeks. Severe non-hematologic toxicity was uncommon, with no intensive care admission or treatment-related death. At a median follow-up of 17 months, eight patients have relapsed and five have died of tumor progression. No statement can yet be made regarding adjuvant efficacy, but this high-dose regimen is very well tolerated.
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PMID:TMJ: a well-tolerated high-dose regimen for the adjuvant chemotherapy of high risk breast cancer. 799 67

A cell-to-cell interaction between tumors and host inflammatory cells is important for the subsequent cancer progression or regression. We examined the expression of interleukin-8 (IL-8) mRNAs by 9 human lung cancer cell lines and the influences of cytokines on IL-8 production and its gene expression. Substantial expressions of IL-8 gene were detected in 3 lung cancer cell lines (RERF-LC-OK, Lu-134-A-H, YO-88 cells). Moreover, 4 lung cancer cell lines (RERF-LC-MS, RERF-LC-OK, A549 and YO-88) were used to examine the effects of exogenous cytokines--interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor--on IL-8 production by the cells at protein and gene levels. TNF-alpha and IL-1 beta significantly augmented the levels of mRNA expression for IL-8 and its production. These observations indicate that tumor-derived IL-8 may be important in recruiting inflammatory neutrophils and promoting interaction between lung cancer and inflammatory cells.
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PMID:Spontaneous production of interleukin-8 by human lung cancer cells and its augmentation by tumor necrosis factor alpha and interleukin-1 at protein and mRNA levels. 805 91

The identification of ras oncogenes in both human and animal tumors as well as in preleukemic and precancerous lesions suggests that activated ras genes participate in neoplastic development, yet the precise role of ras oncogenes in leukemogenesis is not clear. To assess the functional role of ras genes in tumorigenesis, we introduced with a retroviral vector either a wild-type (Gly-12) or a mutant (Val-12) Kirsten ras cDNA into the cells of a factor-dependent myeloid cell line, FDC-P1. FDC-P1 cells are nontumorigenic and their proliferation is dependent on either interleukin-3 (IL-3) or granulocyte-macrophage colony-stimulating factor (GM-CSF). The Ki-Val 12-infected FDC-P1 cell population is still strictly IL-3-dependent but has acquired the ability to survive up to 72 hours in the absence of growth factor and to form tumors in nude mice. These tumors are easily established into cell lines that are clonal and show a multiplicity of phenotypes with respect to their growth factor dependence. These results suggest that, in contrast with the overexpression of a normal Ki-ras, Ki-ras oncogene can efficiently promote the tumorigenic conversion of FDC-P1 cells. However, the clonality of the tumors as well as the distinct phenotypes indicates that other genetic events are required for tumorigenicity. Therefore, in FDC-P1 cells, an activated ras gene acts as a dominant oncogene through the induction of tumor progression. Finally, in this simple experimental system we observed a multiplicity of tumorigenic phenotypes which are reminiscent of those observed in patients with acute myeloid leukemia.
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PMID:Infection with a Kirsten-retrovirus can induce a multiplicity of tumorigenic phenotypes in the interleukin-3-dependent FDC-P1 cells. 829 38

The host-tumor interaction may play an important role in determining tumor progress. Recent studies have shown that this interaction can be influenced by the release of soluble factors by tumor cells and tumor-infiltrating lymphocytes (TIL). The aim of our study is to characterize the nature of cytokines and growth factors and their relationship to the cellular infiltrates in 16 patients with ovarian cancer using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. Total RNA from 20 malignant and 10 benign specimens were used to assay for expression of 12 cytokines. Additionally, monoclonal antibodies (MAbs) were used to detect T cells, CD4+ helper and CD8+ cytotoxic/suppressor T-cell subtypes, B cells, and macrophages. Our results showed the expression of transforming growth factor-beta1 (TGF-beta1), interleukin-10 (IL-10), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in 19, 17, and 10 malignant specimens, P < .001, .001, and .05, respectively. Other cytokines such as interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), TNF-beta/LT, IL-2, and IL-6 were expressed in a few cases, and IL-1alpha and IL-4 expression were not detected. The benign samples did not express IL-10, but GM-CSF, TGF-beta1, and IL-8 were expressed in one, one, and four specimens, respectively. Interestingly, in four cases in which samples from the primary and relapse tumors were available for analysis, the tumors in relapse showed a significant increase for TGF-beta1 (P < .05) and a decreased trend in IL-10 mRNA levels. The source of these factors was tumor cells as detected immunohistochemically. This combined alteration of TGF-beta1 and IL-10 was associated with a significant reduction in number of TIL in general, and CD8+ and macrophages in particular (P = .036 and .049, respectively). Our findings suggest the important role of certain soluble factors in the complex process of tumor progression. Furthermore, understanding the tumor-host relationship and the factors influencing the interaction may be helpful in developing effective and innovative treatment methods.
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PMID:Tumor-host interaction: analysis of cytokines, growth factors, and tumor-infiltrating lymphocytes in ovarian carcinomas. 904 97

We reported previously that tumor cells isolated from metastases of the in vitro transformed squamous cell carcinoma line Pam 212 exhibit an elevation in constitutive production of proinflmmatory cytokines interleukin (IL)-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor, and KC (the murine homologue of chemokine Gro-alpha). The basis for constitutive expression of these cytokines after tumor progression in vivo is unknown. Regulation of the expression of these proinflammatory cytokines involves transcription factor nuclear factor kappaB (NF-kappaB), which can be activated by cytokines such as tumor necrosis factor (TNF)-alpha. In this study, we compared the constitutive and TNF-alpha-induced expression of proinflammatory cytokines in parental Pam 212 and metastatic LY-2 and LY-8 cell lines and determined the relationship of cytokine expression to activation of NF-kappaB. We found that the metastatic cell lines exhibited an increase in constitutive and TNF-alpha-inducible expression of proinflammatory cytokines when compared with parental Pam 212 cells. The increased cytokine expression was associated with an increase in constitutive and TNF-alpha-inducible activation of NF-kappaB as demonstrated by electrophoretic mobility shift assay and luciferase-reporter gene assay. Constitutive nuclear localization of NF-kappaB p65 was observed in LY-2 and LY-8 cells in culture and in tumor specimens but rarely in Pam 212 cells, consistent with the constitutive activation of NF-kappaB in tumor cels after selection in vivo. Induction of NF-kappaB by TNF-alpha was inhibited by the addition of protease inhibitors calpain inhibitor I and N-tosyl-phechloromethyl ketone and antioxidant 1-pyrrolidinecarbodithioic acid, whereas constitutive activation of NF-kappaB and cytokine KC mRNA expression was inhibited by N-tosyl-phechloromethyl ketone alone. Overexpression of a human Ikappa(B)alpha dominant suppresser in Pam 212 cells inhibited TNF-alpha-induced NF-kappaB binding activity and KC expression. These data indicate that activation of NF-kappaB contributes to increased expression of proinflammatory cytokines during metastatic tumor progression of squamous cell carcinoma, and that distinct mechanisms may be involved in the regulation of constitutive and TNF-alpha-induced activation of NF-kappaB in squamous cell carcinoma.
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PMID:The host environment promotes the constitutive activation of nuclear factor-kappaB and proinflammatory cytokine expression during metastatic tumor progression of murine squamous cell carcinoma. 1041 16

Tumor growth is associated with neutrophilia, thrombocytosis, and extramedullar hematopoiesis. The mechanism(s) accounting for these phenomena is unclear, although granulocyte-macrophage colony-stimulating factor (GM-CSF) and/or granulocyte colony-stimulating factor (G-CSF) released by tumor cells have been involved. We studied whether CSF released by Ehrlich tumor (ET) may play a role. A comparative study was performed with two cell variants (ET and ET/0) growing in euthymic, nude, and SCID mice. Extramedullar hematopoiesis was assessed in the spleen by scoring organ enlargement, wheat germ agglutinin ve+ cells, and interleukin 3-dependent granulocyte-macrophage colony-forming unit (GM-CFU). Both cell lines showed the same cytokine profile by reverse transcriptase polymerase chain reaction, including GM-CSF, G-CSF, and macrophage colony-stimulating factor (M-CSF); yet, only ET cells produced detectable colony-stimulating activity in vitro, mainly due to GM-CSF. No differences in tumorigenicity were noted between ET and ET/0 cells inoculated to normal or immunodeficient mice. An increase in extramedullar hematopoiesis, accompanied by neutrophilia and thrombocytosis, was associated with tumor progression irrespective of the cell line. A strong correlation was obtained between the increase in splenic GM-CFU and tumor mass (r = 0.96, p < 0.0001) that was independent on the tumor cell line, strain of mice, or stage of tumor development. The results point against CSF released by tumor cells and/or reactive host T cells as the only factors involved in the extramedullar hematopoiesis in this tumor model. The remarkable correlation between splenic GM-CFU and the tumor mass still suggests that a factor(s) of tumor origin may play a critical role.
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PMID:Ehrlich tumor stimulates extramedullar hematopoiesis in mice without secreting identifiable colony-stimulating factors and without engagement of host T cells. 1064 93

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

This phase II study was performed to determine the induction of a specific T-cell response, the clinical response rate, and toxicity of vaccination with different HLA class I-binding peptide epitopes derived from the melanocyte differentiation antigen tyrosinase in patients with stage IV melanoma. The study population consisted of 16 patients with metastatic disease and two patients who were macroscopically free of disease at study entry after resection of recurrent skin lesions. Patients received intradermal injections of 200 microgram [corrected] peptide corresponding to their HLA type on day 3, and 75 or 150 microg granulocyte-macrophage colony-stimulating factor on days 1 to 4. Vaccinations were repeated at weeks 2, 4, 6, 10, and 14. Monitoring of peptide-specific T-cell frequencies in the peripheral blood was performed using an interferon gamma ELISPOT assay. Eleven of the 16 patients with metastatic disease went off the protocol within the first 10 weeks because of tumor progression. Of the five patients with metastatic disease who received all six vaccinations, one patient showed a mixed response with regression of some lung metastases; two patients with progressive disease before vaccination had stable disease for 6 and 18+ months; and two patients had progression of their disease. The two patients who had all their metastases resected before vaccination did not have relapses for 6 and 12+ months after vaccination. Induction of tyrosinase-reactive T cells was found in these two patients and in two others with metastatic disease, including the one who achieved a mixed response and one with stable disease. This study shows limited clinical and immunologic activity of HLA class 1-peptide vaccination in combination with granulocyte-macrophage colony-stimulating factor in stage IV melanoma patients.
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PMID:Phase 2 trial of vaccination with tyrosinase peptides and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma. 1074 54

An active immunotherapy strategy with cytokine-assisted tumor vaccine, although often effective for small tumor burdens, is much less so for large tumor burdens. This study examines how large tumors might suppress the T cell functions and escape from the immune responses elicited by a granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccine. According to our results, the T cells isolated from the tumor-bearing mice treated late with the vaccine failed to confer protective activity on naive mice against a wild-type tumor challenge, unlike those isolated from the early-treated group. Nevertheless, the antitumor activity of the inactive T cells could be restored on in vitro stimulation. Expression of transforming growth factor beta (TGF-beta) and interleukin 10 (IL-10), the potent immunosuppressive factors, was detected in the parental tumor cell line RLmale 1 (a murine T leukemia cell line), as well as in the tumor region, the levels of which correlated with tumor progression. An in vitro assay of T cell functions revealed that the TGF-beta in the conditioned medium of RLmale 1 cells mainly affected the activation, whereas the IL-1male affected the activation to a lesser extent, but significantly affected the cytolytic activity, of tumor-specific T cells. The immunosuppressive activity of IL-10 was also signified by the findings that administration of the conditioned medium of RLmale 1 cultured in a serum-free medium, in which the TGF-beta activity was then lost while the IL-10 activity still remained, or of recombinant IL-10 to the early-treated group of mice abrogated the known efficacy of tumor vaccine on the small tumors. These data suggested that the efficacy of cytokine-secreting tumor vaccine was blocked by the immunosuppressive factors secreted from the large tumors. The results have important implications for the clinical design of immunotherapeutic strategies for advanced cancer patients.
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PMID:Tumor-induced immunosuppression: a barrier to immunotherapy of large tumors by cytokine-secreting tumor vaccine. 1075 45


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