Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have engineered highly aggressive murine mammary tumor cell line 410.4 to express interleukin-10 (IL-10) and compared the behavior in vivo of these cells to parental 410.4 and 410.4 transfected with the control plasmid (410.4-neo). Transplantation of parental 410.4 and 410.4-neo tumor cells to syngeneic mice resulted in progressive growth and death from pulmonary metastases. In contrast, both subcutaneous growth and metastatic disease were completely inhibited by IL-10 expression. We had shown previously that the antimetastatic activity of IL-10 is expressed in T-cell-deficient mice but is lost when NK activity is suppressed. This study confirms that IL-10 is dependent on NK activity, since no therapeutic effect is seen in C.B-17/IcrCrl-SCID/Beige mice which lack T, B, and NK cell function. We compared the sensitivity to NK lysis of four IL-10-expressing clones with 410.4 and 410.4-neo and found that IL-10 expression resulted in enhanced NK lysis of all four clones. Furthermore, IL-10 expression was correlated with decreased surface expression of MHC class I Kd, Ld, and Dd. Pretreatment of IL-10-expressing cell lines with IFN-gamma reversed the class I downregulation and reduced the sensitivity of these cells to NK lysis. Taken together, these studies in vitro and in vivo are consistent with a mechanism by which IL-10 expression downregulates class I expression, leading to enhanced NK lysis of tumor cells, resulting in control of metastatic disease.
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PMID:Interleukin-10 inhibits tumor metastasis, downregulates MHC class I, and enhances NK lysis. 931 39

The adoptive transfer of tumor-sensitized T cells can eradicate disseminated malignancy in murine animal models. T cells must be sensitized to tumor antigens in vivo to acquire antitumor reactivity. T-cell sensitization has been demonstrated to be dependent on host antigen-presenting cells. Tumor-associated macrophages are a heterogeneous population of cells that may have both inhibitory and stimulatory influences on the sensitization of naive T cells. Here we demonstrate that a weakly immunogenic tumor, the MCA 205 sarcoma, produces substantial amounts of murine monocyte chemoattractant protein 1 (MCP-1). Neutralization of MCP-1 during in vivo T-cell sensitization resulted in T cells that possessed enhanced therapeutic activity against established pulmonary metastases. These T cells sensitized during MCP-1 depletion also exhibited enhanced production of IFN-gamma upon recognition of tumor targets. These results demonstrate that MCP-1 can have a potent inhibitory influence on the development of tumor-reactive T cells.
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PMID:Monocyte chemoattractant protein inhibits the generation of tumor-reactive T cells. 935 48

The presence of mRNA transcripts for cytokines in normal and neoplastic human breast tissue has been investigated. Using reverse transcriptase-linked polymerase chain reaction (RT-PCR), we have specifically screened for the following cytokines: interleukin (IL)-1alpha, IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, tumour necrosis factor (TNF)-alpha, TNF-beta and interferon (IFN)-gamma. No significant differences in expression of IL-1alpha, IL-1beta, IL-4, IL-6, TNF-alpha or TNF-beta were observed between the 2 groups of tissues. However, there was a significant difference in expression of IL-8 transcripts (p = 0.0017) which was higher in the neoplastic population. Transcripts for IL-2, IL-3, IL-5, IL-7 and IFN-gamma were not detected in either group. There was no evidence of associations between cytokine expression and tumour histological grade, patient age or lymph node metastases. Correlating tumour types with specific cytokine transcripts revealed high expression of IL-8, and to a lesser extent, IL-8 and TNF-beta irrespective of tumour origin. Analysis of primary epithelial and stromal cultures derived from both types of tissue showed that increased levels of IL-8, but not IL-6, were secreted by cells obtained from tumours. Thus, breast tissue of both normal and neoplastic origin expresses a wide range of cytokines. Increased or aberrant expression of cytokines, in particular IL-8, may be involved in the development/progression of breast cancer.
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PMID:Expression of cytokine messenger RNA in normal and neoplastic human breast tissue: identification of interleukin-8 as a potential regulatory factor in breast tumours. 937 54

Experiments were performed to compare the ability of ocular and skin melanoma cells to stimulate T cells. Primary melanoma cell lines were obtained from a series of patients with either eye or skin melanoma. The ability of tumor cells to stimulate T cells in the absence of exogenous growth factors was assessed in mixed-lymphocyte tumor cell cultures in which allogeneic lymphocytes were stimulated with irradiated ocular or skin melanoma cells. Expression of HLA class I and class II on tumor cells, in the presence or absence of IFN-gamma, was determined by flow cytometry. The ability of tumor cells to inhibit T-cell proliferation was determined by adding various concentrations of irradiated tumor cells to standard mixed-lymphocyte cultures. Our results indicate that primary skin melanoma cells induce vigorous proliferation of allo-antigen-specific T cells. By contrast, ocular melanoma cells failed to induce significant T-cell proliferation. The failure of ocular melanoma cells to stimulate lymphocyte proliferation was not due to low levels of either class I or class II on tumor cells since tumor cells treated with IFN-gamma expressed high levels of class I and class II but still failed to induce lymphocyte proliferation. Ocular melanoma cells inhibited lymphocyte proliferation, as shown by experiments in which a small number of tumor cells prevented proliferation of T cells in mixed-lymphocyte cultures. Inhibition of lymphocyte proliferation required cell-to-cell contact, and supernatants from tumor cell cultures did not prevent lymphocyte proliferation. Moreover, the ability of ocular melanoma cells to inhibit T-cell proliferation was lost when tumor cells migrated from the eye and formed hepatic metastases. We conclude that there is a fundamental difference in the immunogenicity of ocular and skin melanoma cells. Ocular melanomas, but not primary skin melanomas, are poorly immunogenic tumors that inhibit T-cell proliferation. Our results imply that the immunogenicity of melanoma cells is altered when they develop within the unique ocular micro-environment.
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PMID:Melanomas that develop within the eye inhibit lymphocyte proliferation. 938 58

A new HLA-class-I altered phenotype is described in melanoma. This phenotype is the result of a combination of HLA-B-locus down-regulation and HLA-haplotype loss. The alteration was found in 2 melanoma cell lines generated from 2 patients; one was derived from an in vivo lesion (FM37) and the other was obtained after in vitro immunoselection (R22.2). The R22.2 cell line was isolated from FM55P, a cell line derived from a primary melanoma, after in vitro treatment with a heterologous HLA-A2-restricted cytotoxic-T-lymphocyte (CTL) clone. Two additional cell lines from patient 55 were obtained from 2 s.c. metastases (FM55M1 and FM55M2). Iso-electric focusing and flow-cytometric studies showed a significant reduction in the expression of both HLA-B alleles in all cell lines studied. The expression of HLA-B-locus products recovered completely after IFN-gamma treatment of FM55P, M1 and M2. In contrast, FM37 and R22.2 tumour cells showed an additional HLA defect: the absence of one HLA haplotype. Simple tandem-repeat polymorphism markers spanning chromosome 6 showed that DNA from the 2 samples (FM37 and R22.2) showed loss of heterozygosity (LOH). In both cases, homozygosity was observed on 6p, which maps the HLA region, the final consequence being a tumour cell that expressed a single HLA-class-I allele (HLA-A3 and HLA-A1 respectively). FM37 cells may thus reflect the in vivo counterpart of resistance to lysis by HLA-A2-restricted tumour-infiltrating lymphocytes.
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PMID:In vivo and in vitro generation of a new altered HLA phenotype in melanoma-tumour-cell variants expressing a single HLA-class-I allele. 946 25

This study examines whether a correlation may be found between Th1- or Th2-type cytokine responses and resistance or susceptibility to tumour growth. Cytokine profiles were investigated in a well-defined mouse tumour model in which the injection site and the genetic background determine the phenotype of either tumour resistance or tumour susceptibility. DBA/2-derived ESb lymphoma variant cells with high metastatic capacity were inoculated into syngeneic mice either s.c., where they grow and metastasize, or into the ear pinna (i.e.), where they do not grow because of induction of protective immunity. Alternatively, the tumour cells were injected s.c. or i.e. into allogeneic B10.D2 mice, which are resistant to the tumour although they are identical at the MHC locus. Between 1 and 10 days after tumour cell injection the spleen-derived mRNA was tested for cytokine gene expression or the spleen cells were analysed by FACScan for T cell activation. The strongest cytokine response was observed in i.e. inoculated B10.D2 mice. This was characterized by an early (days 2-3) peak of interferon gamma (INF-gamma), interleukin-2 (IL-2), IL-2 receptor alpha (IL-2Ralpha) and IL-4. The cytokine mRNA response of i.e. inoculated DBA/2 mice was quite similar except that no IFN-gamma could be detected. In s.c. inoculated B10.D2 mice, the IL-2, IL-2Ralpha and IFN-gamma responses were weaker than after i.e. injection while the IL-4 response was comparable. The most striking difference between these cytokine profiles from tumour-resistant mice and those of s.c. inoculated tumour-susceptible DBA/ 2 mice was a delay in the latter in the IL-2, IL-2Ralpha and IFN-gamma responses and the observation that the IL-4 response was not down-regulated. The persisting IL-4 response could down-regulate a Th1-type response and thereby explain tumour susceptibility as a consequence of host conditioning.
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PMID:Superiority of the ear pinna over a subcutaneous tumour inoculation site for induction of a Th1-type cytokine response. 949 Feb 3

A spontaneously metastatic murine mammary adenocarcinoma, TSA, has been transduced with the gene for interferon alpha1 (IFN-alpha). Transfectants were used for the immunotherapy of mice bearing lung colonies induced by the intravenous inoculation of non-transduced parental cells. A significant reduction in the number of tumor colonies was obtained when repeated subcutaneous administrations of mitomycin C-blocked transfectant cells were given, commencing 3 days after an intravenous challenge with TSA cells. Intraperitoneal vaccination induced a stronger anti-tumor response than subcutaneous vaccination, and the proportion of tumor-free mice reached 50%. The potency of IFN-alpha transfectants was similar to that of IFN-gamma transfectants previously obtained from TSA. Admixture of IFN-alpha and IFN-gamma transfectant cells in the same vaccine did not increase the curative effect over that of single vaccines. In nude mice vaccination with IFN-alpha or IFN-gamma transfectants did not lead to a reduction in the number of lung colonies, indicating that an intact T cell response was required for the therapeutic effect observed in immunocompetent mice.
Clin Exp Metastasis 1998 Feb
PMID:Inhibition of lung colonisation of a mouse mammary carcinoma by therapeutic vaccination with interferon-alpha gene-transduced tumor cells. 951 93

The aim of this study was to evaluate the safety profile of s.c. administered recombinant human interleukin 12 (rHuIL-12). Pharmacokinetics and pharmacodynamics of rHuIL-12 and any evidence of antitumor effect were also considered. Ten pretreated patients with progressive metastatic melanoma were enrolled in this pilot study. Patients received a fixed dose of rHuIL-12 (0.5 microgram/kg) for two identical 28-day cycles, with injections given on days 1, 8, and 15 of each cycle. In case of any evidence of response or disease stabilization, the treatment was continued for two further 28-day cycles. Toxicity mainly consisted of a flu-like syndrome. Transient increases in transaminasemia (6 of 10 patients) and triglyceridemia (8 of 10 patients) were observed. Peak serum IL-12 levels were reached 8-12 h after the first injection in all patients; no serum IL-12 was detectable in 6 of 9 evaluable patients after the last injection of the second cycle. No antibody response to rHuIL-12 could be detected in any of the patients. A marked, transient reduction in circulating CD8+ and CD16+ lymphocytes and neutrophils was observed after the first administration and high levels of serum IFN-gamma and IL-10 were detected in all patients within 24-48 h. Tumor shrinkage, not reaching partial or complete remission, involved the regression of s.c. nodules (2 of 3 patients), superficial adenopathies (1 of 3 patients), and hepatic metastases (1 of 3 patients); regressions were detected after the first cycle of treatment and were maintained in spite of progression at different sites. s.c. rHuIL-12 treatment was well tolerated and had marked effects on immune parameters and potential antitumor activity.
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PMID:Pilot study of subcutaneous recombinant human interleukin 12 in metastatic melanoma. 951 55

Administration of tumor necrosis factor (TNF) and gamma interferon (IFN-gamma) to melanoma patients causes selective disruption of the tumor vasculature but the mechanism of this disruption is unknown. Here we report that exposure of human endothelial cells to TNF and IFN-gamma results in a reduced activation of integrin alphaVbeta3, an adhesion receptor that plays a key role in tumor angiogenesis, leading to a decreased alphaVbeta3-dependent endothelial cell adhesion and survival. Detachment and apoptosis of angiogenic endothelial cells was demonstrated in vivo in melanoma metastases of patients treated with TNF and IFN-gamma. These results implicate integrin alphaVbeta3 in the anti-vascular activity of TNF and IFN-gamma and demonstrate a new mechanism by which cytokines control cell adhesion.
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PMID:Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. 954 82

Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and systemic low dose rIL-2 effectively eradicates pulmonary metastases of the murine MCA-105 sarcoma. We described earlier that host CD8+ T cells are critical for tumor eradication and that successful treatment is associated with production of high levels of IFN-gamma and granulocyte/macrophage (GM)-CSF by donor TIL in vitro. Here, we propose the mechanism through which adoptively transferred Thy-1.1+ TIL induce a host antitumor response in congenic Thy-1.2+ tumor-bearing mice. Donor Thy-1.1+ TIL were detected at the tumor site 12 h after transfer. These Thy-1.1+ cells produced IFN-gamma and GM-CSF in situ. The percentage of Thy-1.1+ TIL at the tumor site increased up to 16.4 +/- 4.9% 24 h after transfer but decreased to undetectable levels thereafter. In contrast, the percentages of host cells producing IFN-gamma and GM-CSF continued to increase at the tumor site. These increases were significantly higher in TIL + rIL-2-treated mice compared with untreated mice and rIL-2-treated mice 48 h after TIL transfer. The appearance of IFN-gamma+ and GM-CSF+ cells was followed by a large influx of host CD4+, CD8+, and Thy-1.2+ TIL and eventually by tumor eradication. This response was tumor specific since TIL obtained from MCA-205 did not induce high levels of IFN-gamma and GM-CSF and did not induce tumor eradication of MCA-105 tumor. Coinjection of Thy-1.1+ TIL and anti-IFN-gamma or anti-GM-CSF mAb significantly inhibited antitumor efficacy of the TIL + rIL-2 treatment. We conclude that successful adoptive immunotherapy in this model is mediated through cytokine production by adoptively transferred TIL that induce a host T cell-dependent antitumor response.
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PMID:Successful adoptive cellular immunotherapy is dependent on induction of a host immune response triggered by cytokine (IFN-gamma and granulocyte/macrophage colony-stimulating factor) producing donor tumor-infiltrating lymphocytes. 955 89


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