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1.
Pathobiology ; 69(4): 230-6, 2001.
Article in English | MEDLINE | ID: mdl-12007283

ABSTRACT

Previous results have shown that the metastatic colonization with B16F10 melanoma in vivo increased after in vitro treatment of the cells with IL-2 or IL-6. To further investigate the mechanisms underlying this effect, we have studied adhesion, invasion, and proliferation properties of B16 melanoma, using two sublines with different metastatic ability. Adhesion of tumor cells to Matrigel coats increased using IL-6, which also induced upregulation of VLA-4 expression in both sublines. Unexpectedly, invasion through Matrigel filters was almost completely inhibited by IL-6 and decreased in the presence of IL-2. Cell growth was not affected by these interleukins; however, IL-6 could partially overcome the proliferation blockade induced by stress conditions. Taken together, these results suggest that upregulation of adhesion properties and/or the protective effect induced by IL-6 could account for the enhancement of metastasis exerted by this interleukin.


Subject(s)
Interleukin-2/pharmacology , Interleukin-6/pharmacology , Melanoma, Experimental/secondary , Neoplasm Metastasis/pathology , Tumor Cells, Cultured/drug effects , Animals , Cell Adhesion/drug effects , Cell Adhesion/physiology , Cell Count , Cell Division/drug effects , Collagen/metabolism , Drug Combinations , Extracellular Matrix/metabolism , Flow Cytometry , Fluorescent Antibody Technique, Indirect , Integrin alpha4beta1 , Integrins/metabolism , Intercellular Adhesion Molecule-1/metabolism , Laminin/metabolism , Melanoma, Experimental/drug therapy , Melanoma, Experimental/metabolism , Neoplasm Invasiveness/pathology , Neoplasm Invasiveness/physiopathology , Neoplasm Metastasis/drug therapy , Neoplasm Metastasis/physiopathology , Proteoglycans/metabolism , Receptors, Interleukin-2/metabolism , Receptors, Lymphocyte Homing/metabolism , Stem Cells/drug effects , Tumor Cells, Cultured/metabolism , Tumor Cells, Cultured/pathology
2.
Eur Cytokine Netw ; 11(4): 654-61, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11125310

ABSTRACT

Previously, we demonstrated that in vitro treatment of B16F10 murine melanoma cells with interleukin-2 (IL-2) enhances proliferation and metastasis. To further investigate the role played by IL-2 in human melanomas, we studied the expression of IL-2/IL-2 receptor and the effect of IL-2 on the proliferation of melanoma cell lines derived from primary (A375 and RMS cell lines) and metastatic (Hs294T cell line) tumours. We found a constitutive expression of cytoplasmic IL-2 and alpha, beta and gamma-subunits of the IL-2R on the surface of the three melanoma cell lines. The presence of IL-2 in the culture increased the proliferation rate in A375 and RMS cell lines, but no effect was observed in Hs294T metastatic cells. Biologically active IL-2 could be found in the supernatant of the three melanoma cell lines, particularly in A375 and RMS cells, in which an inhibition of the proliferation rate was observed when IL-2 was blocked. Moreover, the combination of anti-IL-2R beta and anti-IL-2R gamma blocking antibodies induced a significant down-regulation of cell proliferation in the three melanoma cell lines, and the combination of anti-IL-2R alpha, anti-IL-2R beta and anti-IL-2R gamma blocking antibodies inhibited IL-2-mediated growth stimulation in A375 and Hs294T cell lines. In RMS cells, a more significant effect was observed when only IL-2R gamma was blocked. Finally, exogenous IL-2 modulated the IL-2 endogenously produced by melanoma cells. These data show that IL-2 may modulate the growth of melanoma cells through autocrine or/and paracrine mechanisms.


Subject(s)
Interleukin-2/physiology , Melanoma/immunology , Melanoma/pathology , Antibodies, Monoclonal/immunology , Autocrine Communication , Cell Division/drug effects , Culture Media, Conditioned/pharmacology , Humans , Interleukin-2/biosynthesis , Interleukin-2/pharmacology , Neoplasm Metastasis , Receptors, Interleukin-2/immunology , Recombinant Proteins/pharmacology , Tumor Cells, Cultured
3.
Br J Cancer ; 83(7): 847-52, 2000 Oct.
Article in English | MEDLINE | ID: mdl-10970683

ABSTRACT

Serum soluble interleukin-2 receptor (sIL-2R), intercellular adhesion molecule-1 (sICAM-1) and interleukin-10 (IL-10) have each been reported as useful markers for melanoma progression. To evaluate the clinical relevance of these three markers, we simultaneously analysed their serum levels in patients with melanoma. A longitudinal study with a 3-year follow-up was performed and different stages of the disease were considered. Mean values of sIL-2R were significantly higher than in normal controls in all stages and correlated with the disease progression. The prognosis of patients with levels > 529 U/ml of sIL-2R was significantly poorer than in patients with sIL-2R levels < 529 U/ml. Levels of sICAM-1 were also elevated in melanoma patients, specially at the time of the metastatic disease. Serum IL-10 levels were more frequently detectable in the patients that developed metastasis during follow-up, and the prognosis of patients with detectable IL-10 levels was significantly poorer than in those patients with IL-10 undetected levels. Statistical analysis based on Logistic and Cox regression models showed that only sex, stage and sIL-2R value are factors significantly associated with metastatic progression. Moreover, high levels of sIL-2R could be a risk factor for malignant progression in melanoma.


Subject(s)
Biomarkers, Tumor/blood , Intercellular Adhesion Molecule-1/blood , Interleukin-10/blood , Melanoma/blood , Receptors, Interleukin-2/blood , Adult , Aged , Female , Follow-Up Studies , Humans , Logistic Models , Longitudinal Studies , Male , Melanoma/pathology , Melanoma/secondary , Middle Aged , Neoplasm Staging , Prognosis , Proportional Hazards Models , Solubility , Survival Analysis
4.
Oncology ; 54(5): 400-6, 1997.
Article in English | MEDLINE | ID: mdl-9260602

ABSTRACT

Elevated soluble IL-2 receptor (sIL-2R) and IL-6 serum concentrations have been reported as adverse prognostic factors in several types of cancer. In order to determine whether these factors are predictive of metastatic progression in melanoma, sIL-2R and IL-6 levels were measured in sera from 172 patients with melanoma and 60 in healthy controls. Mean sIL-2R values were significantly higher in the patients than in normal controls and the highest values were observed in those that developed metastasis during follow-up. However, no correlation was found with the stage of the disease. Serum IL-6 levels were found to be correlated with age and sex, but not correlated with sIL-2R levels. Statistical analysis was based on logistic and Cox regression models. The factors considered were age, sex, stage, disease-free interval and serum sIL-2R and IL-6 levels. The analysis showed that only the sIL-2R value is significantly linked to metastatic progression. This finding suggests that high serum levels of sIL-2R could be a predictive factor of metastatic progression in malignant melanoma.


Subject(s)
Interleukin-6/blood , Melanoma/blood , Receptors, Interleukin-2/blood , Skin Neoplasms/blood , Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , Humans , Male , Middle Aged , Prognosis
5.
Anticancer Res ; 17(2A): 1135-41, 1997.
Article in English | MEDLINE | ID: mdl-9137461

ABSTRACT

We had previously shown that murine B16F10 melanoma cells express the receptor for IL-2, transcribe the gene for IL-2 and respond to its factor by increasing their proliferation. In the present work we have investigated the effect of in vitro IL-2 treatment on the metastatic ability of B16F10 cells. In vivo experiments showed that the metastatic colonization of the liver was notably higher after intrasplenic inoculation of IL-2-treated cells. However, no change was observed when cells were intravenously inoculated. In vitro, cells became more resistant to NK lysis although the cytometric analysis of class 1 MHC molecules revealed a decrease in H-2Kb expression. In contrast IL-2 induced a two fold increment in the expression of la antigen. On the other hand slot-blot analysis showed that IL-2 gene expression could be upregulated, however no free IL-2 was released into the culture medium of B16F10 cells. We conclude that IL-2 increases the ability of B16F10 cells to metastase to the liver. The increase in the resistance to NK activity and in la antigen expression could be involved in the mechanisms underlying this effect.


Subject(s)
Interleukin-2/pharmacology , Liver Neoplasms, Experimental/secondary , Melanoma, Experimental/pathology , Animals , Histocompatibility Antigens/analysis , Interleukin-2/genetics , Interleukin-2/metabolism , Killer Cells, Natural/immunology , Melanoma, Experimental/immunology , Mice , Mice, Inbred C57BL , RNA, Messenger/analysis
8.
Tumour Biol ; 17(3): 155-67, 1996.
Article in English | MEDLINE | ID: mdl-8638089

ABSTRACT

In this study, we analyzed interleukin-2 (IL-2) and IL-2 receptor (IL-2R) expression in murine B16F10 melanoma and studied the effect of recombinant IL-2 (rIL-2) on the proliferation of these cells. Flow cytometry analysis revealed the presence of the IL-2R alpha subunit in B16F10 melanoma, with a mean positivity rate of 30%. Using confocal microscopy, the expression of this chain could be visualized on the surface of B16F10 cells and in intracellular compartments when the cells were permeabilized with ethanol. In addition to the alpha subunit, the IL-2R beta subunit was also expressed in B16F10 cells as shown by reverse transcription and polymerase chain reaction analysis. The functionality of the IL-2R on B16F10 cells was shown by the fact that cell proliferation increased dose-dependently with the addition of rIL-2 to the culture medium. We also detected expression of the IL-2 gene in B16F10 cells. In Northern blot assays, a typical band of 0.9 kb corresponding to IL-2 mRNA was observed, although supernatants from B16F10 cultures had no detectable IL-2 activity. Furthermore, the addition of neutralizing antibody (anti-IL-2) to cell cultures had no effect on cell proliferation. From these results, we concluded that an IL-2 signalling system is present in murine B16F10 melanoma cells and that IL-2 favors B16F10 cell proliferation, suggesting a role for this cytokine in the tumoral activity of these cells.


Subject(s)
Interleukin-2/metabolism , Melanoma, Experimental/pathology , Receptors, Interleukin-2/metabolism , Animals , Base Sequence , Cell Division , DNA Primers/chemistry , Fluorescent Antibody Technique, Indirect , Melanoma, Experimental/metabolism , Mice , Mice, Inbred C57BL , Molecular Sequence Data , RNA, Neoplasm/genetics , Tumor Cells, Cultured
9.
Pathobiology ; 62(4): 186-93, 1994.
Article in English | MEDLINE | ID: mdl-7734062

ABSTRACT

Maintaining B16F10 tumor cells in stirring culture for 48 h leads to an increase in lung and liver colonizing capacity in comparison with cells in adherent culture. Parallel to the increased metastatic capacity, we have observed a decrease in the proliferative rate of tumor cells (as the percentage of proliferating cell nuclear antigen-positive cells) and an increase in the population of tumor cells expressing Ia antigen. These results are not exclusive to B16F10 cells, since the same results were obtained when we analyzed 3LL cells maintained in identical culture conditions. In all the tumor lines tested, we found an association between the nonproliferating and the Ia-positive cell populations. We induced Ia expression by treating B16F10 cells in adherent culture with the lectin concanavalin A and again, coincident with an increase in metastatic capacity, we found the same association between the two parameters analyzed--nonproliferating state and Ia antigen expression. In addition, it was found that B16F10 cells induce lymphocytic proliferation, and a direct relationship was established between the number of Ia+ cells and lymphocytic proliferation.


Subject(s)
Histocompatibility Antigens Class II/analysis , Liver Neoplasms/secondary , Lung Neoplasms/secondary , Melanoma, Experimental/immunology , Animals , Concanavalin A/pharmacology , Culture Media , Lymphocyte Activation , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Mitomycins/pharmacology , Proliferating Cell Nuclear Antigen/analysis , T-Lymphocytes/immunology , Tumor Cells, Cultured
10.
Scand J Immunol ; 34(5): 673-7, 1991 Nov.
Article in English | MEDLINE | ID: mdl-1719615

ABSTRACT

Natural killer (NK) activity against Toxoplasma gondii tachyzoites and tumour cells during acute toxoplasmosis was investigated using a single-cell NK assay. During the course of infection the percentage of lymphocytes binding tachyzoites and tumour cells did not vary significantly and NK activity was enhanced due to an increase in the specific cytolytic capacity per cell. To determine whether regulatory mechanisms mediated by cytokines might explain the increased NK activity, the kinetics of interleukin-2 (IL-2) and interferon (IFN) production and the correlation between their concentrations and the level of NK activity were analysed at the same time. As the infection progressed NK activity increased in spite of the fact that IL-2 production decreased (except for a small increase during the first day of infection). However, IFN production increased gradually in close temporal and quantitative association with the overall increase in NK activity. These results suggest that T. gondii, via its ability to produce interferon, enhances NK activity against itself and other cells.


Subject(s)
Interferons/physiology , Interleukin-2/physiology , Killer Cells, Natural/immunology , Toxoplasmosis, Animal/immunology , Acute Disease , Animals , Female , Interferons/biosynthesis , Interleukin-2/biosynthesis , Kinetics , Mice
11.
In Vivo ; 4(3): 185-90, 1990.
Article in English | MEDLINE | ID: mdl-2133261

ABSTRACT

Hybridization of a poorly immunogenic tumor cell with an allogeneic cell was performed in order to improve tumor immune response; several variants derived from one hybrid tumor cell were studied. We compared the immunogenicity of these variants and their allogeneic and syngeneic class I antigen expression before and after IFN gamma treatment. Allogeneic class I antigens were weakly expressed in all variants; IFN treatment enhanced their expression similarly in both immunogenic and nonimmunogenic variants. Syngeneic class I antigen expression differed among variants: IFN treatment induced changes in their expression which corresponded to a posttranscriptional event and which could, at least partly, explain the modifications observed in their immunogenicity.


Subject(s)
Antigens, Neoplasm/biosynthesis , Fibrosarcoma/pathology , Gene Expression Regulation, Neoplastic/genetics , H-2 Antigens/biosynthesis , Hybrid Cells/drug effects , Interferon-gamma/pharmacology , L Cells/drug effects , Animals , Antigens, Neoplasm/genetics , Female , Fibrosarcoma/immunology , H-2 Antigens/genetics , Histocompatibility Antigen H-2D , Hybrid Cells/immunology , L Cells/immunology , Male , Mice , Recombinant Proteins , Stimulation, Chemical , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/immunology
12.
Pathol Biol (Paris) ; 38(1): 13-8, 1990 Jan.
Article in French | MEDLINE | ID: mdl-2407991

ABSTRACT

The effect of treatment with clindamycin, erythromycin, rifamycin and gentamicin on the ingestion capacity of the mouse peritoneal macrophage was studied. Female six-eight week old OF1 mice were treated with minimum and maximum doses clinically used for the different antibiotics (15 and 40 mg/kg/day of clindamycin, 15 and 57.5 mg/kg/day of erythromycin, 10 and 30 mg/kg/day of rifamycin, 3 and 6 mg/kg/day of gentamicin). Two treatment periods of 72 hours and one week were assayed for each antibiotic-dose combination. Antibiotic was administered twice daily, every twelve hours. Twelve hours after the last dose was given, macrophages were obtained through peritoneal lavage and a kinetic study of Candida albicans blastospore ingestion was made. One week treatment with 15 mg/kg/day and 72 hours treatment with 57.5 mg/kg/day of erythromycin produced a significant ingestion enhancement whereas one week treatment with 57.5 mg/kg/day of erythromycin and all treatments with gentamicin gave rise to an ingestion depression. 72 hours treatment with 15 and 40 mg/kg/day and one week treatment with 15 mg/kg/day of clindamycin, 15 mg/kg/day of erythromycin and 10 and 30 mg/kg/day of rifamycin did not modify macrophage ingestion capacity. One week treatment with 40 mg/kg/day of clindamycin and 10 and 30 mg/kg/day of rifamycin gave rise to an acceleration of the ingestion process.


Subject(s)
Clindamycin/pharmacology , Erythromycin/pharmacology , Gentamicins/pharmacology , Macrophage Activation/drug effects , Rifamycins/pharmacology , Animals , Candida albicans , Clindamycin/administration & dosage , Drug Administration Schedule , Erythromycin/administration & dosage , Female , Gentamicins/administration & dosage , Mice , Mice, Inbred Strains , Peritoneal Cavity/cytology , Peritoneal Cavity/microbiology , Phagocytosis/drug effects , Rifamycins/administration & dosage
13.
Biol Cell ; 66(3): 255-61, 1989.
Article in English | MEDLINE | ID: mdl-2532553

ABSTRACT

Prostaglandins are secreted by a variety of tumor cell lines. The prostaglandin synthesis inhibitor indomethacin (IND) inhibits 3LL tumor growth after both intramuscular or intrasplenic transplantation (45 and 72%, respectively). Moreover, when tumor cells were cultured with IND, the sensitivity of 3LL cells to natural cytotoxic (NC) effector cells was increased (30%) and a higher cytotoxicity was reached when both target and effector cells were treated. This effect was reversed partially or totally when the assay was performed in the presence of laminin or an octapeptide from the laminin B1 chain. In addition, we correlate the increased cytotoxicity mediated by IND with an enhanced ability of 3LL tumor cells to bind labeled laminin (55%). In summary, our results show that the blockage or modulation of cell surface laminin binding components could be directly correlated with the sensitivity of tumor target cells to be eliminated by way of natural cytotoxicity.


Subject(s)
Cytotoxicity, Immunologic/drug effects , Indomethacin/pharmacology , Laminin/metabolism , Neoplasms, Experimental/immunology , Receptors, Immunologic/physiology , Amino Acid Sequence , Animals , Cytotoxicity, Immunologic/physiology , Immunoglobulin G/metabolism , Killer Cells, Natural/physiology , Laminin/immunology , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Neoplasm Transplantation , Oligopeptides/pharmacology , Receptors, Immunologic/drug effects , Receptors, Laminin , Tumor Cells, Cultured
14.
Clin Exp Metastasis ; 6(2): 153-69, 1988.
Article in English | MEDLINE | ID: mdl-3257911

ABSTRACT

To investigate the significance of host immunity in metastasis we have simultaneously evaluated metastatic development and the tumoricidal action of host defenses in an experimental system for liver metastasis which involves the intrasplenic injection of B16F10 melanoma cells in syngeneic mice. In addition, three experimental groups were treated with immunosuppressive doses of cyclosporin A (CsA) during the following periods of the malignant process: 1st-5th days, 1st-12th days and 7th-12th days. Analysis of cytolytic effects of macrophages, NK cells and T-lymphocytes on tumor cells reveals a decay in antitumor immunity from the 7th day to the 12th day and a marked resistance of B16F10 melanoma cells derived from hepatic metastases to T-lymphocytes and NK cells. The 1st-5th day CsA treatment of tumor-bearing mice produced a reduction in both T-lymphocyte and macrophage reactions against tumor cells and a significant increase in the 7th day micrometastasis incidence in the liver. Once micrometastases have been established the CsA-treatment suppression on the 5th day allows the tumor growth rate in these mice to become the same as in controls. However, the 7th-12th day CsA treatment produces a clear inhibitory effect on focal metastatic development which may correspond to the in vitro antiproliferative effect of CsA, detected on cultured B16F10 melanoma cells.


Subject(s)
Immunity , Liver Neoplasms, Experimental/secondary , Melanoma/secondary , Animals , Cell Division/drug effects , Cyclosporins/pharmacology , Female , Killer Cells, Natural/physiology , Kinetics , Liver Neoplasms, Experimental/pathology , Macrophages/pathology , Macrophages/physiology , Melanoma/pathology , Mice , Mice, Inbred C57BL , Neoplasm Transplantation , Peritoneal Cavity/pathology , Splenic Neoplasms/pathology , T-Lymphocytes/physiology , Tumor Cells, Cultured
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