Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T cells infiltrating (T-TIL) B cell non-Hodgkin's lymphomas (NHL) are thought to represent a local host response to the tumor. However, tumor progression in the presence of this T cell infiltrate suggests that the T-TIL may be functionally impaired. To address this issue we determined whether response to stimulation of T-TIL from 25 patients with NHL through the T cell receptor (TCR/CD3) and the interleukin-2 (IL-2) receptor (IL-2R) was intact, since activation of these receptors is important for proliferation and cytokine production. Our results demonstrate defects in response to stimulation via TCR/CD3 and the IL-2R in T-TIL cells from patients with NHL that were not observed with T cells from the peripheral blood. T-TIL showed minimal proliferation to anti-CD3 and only modest proliferation to IL-2 alone or when combined with anti-CD3. Moreover, cytokine production in T-TIL was impaired since stimulation through the TCR/CD3 complex did not induce mRNA for interferon gamma (IFN gamma), IL-2, IL-4 or IL-10. The functional unresponsiveness of these cells may be linked to altered signalling through the TCR/CD3 since an abnormal tyrosine phosphorylation pattern was detected in T-TIL after stimulation with anti-CD3.
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PMID:Responses to T cell receptor/CD3 and interleukin-2 receptor stimulation are altered in T cells from B cell non-Hodgkin's lymphomas. 755 87

In the present study, we demonstrate that TGF-beta is capable of enhancing macrophage ability to produce IL-10 in normal and EL4 tumor-bearing mice. We found the increase in IL-10 in ascitic fluid and IL-10 mRNA expression in macrophages in parallel with the TGF-beta level and tumor progression. The macrophage production of IL-10 in the tumor-bearing mice was significantly enhanced without LPS stimulation in vitro, compared with normal controls. To clarify the mechanism wherein increased IL-10 production was induced, anti-TGF-beta or anti-IL-10 Abs were administered to EL4-bearing mice. Administration of anti-TGF-beta Ab led to a reduction in the IL-10 contents in ascitic fluid of tumor-bearing mice; however, anti-IL-10 Ab administration did not prevent the increase in TGF-beta contents. Enhanced IL-10 production and mRNA expression of macrophages from the tumor-bearing mice were also reduced by anti-TGF-beta Ab administration. Both anti-TGF-beta and anti-IL-10 Ab administration restored the TNF-alpha production by macrophages in EL4-bearing mice. In normal macrophages, in vitro pretreatment with TGF-beta 1 potentiated IL-10 production, and when natural TGF-beta 1 was administered to normal mice, the recovered peritoneal macrophages showed enhanced IL-10 production. Based on the above findings it can be concluded that TGF-beta enhances macrophage ability to produce IL-10, which sheds a new light on the role of TGF-beta in the immune system.
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PMID:TGF-beta enhances macrophage ability to produce IL-10 in normal and tumor-bearing mice. 759 97

Most tumors grow progressively and overwhelm the host. The rare but documented cases of spontaneous regression of primary tumors are indicative of the potential of tumor-bearing hosts to develop a significant antitumor response. Because most tumors grow progressively in the host, it is not surprising that the majority of studies have focused on T lymphocytes that infiltrate these tumors. Although these studies have generated significant and useful information during the period of tumor growth, they can only speculate on the mechanisms that are involved in tumor rejection. We have used a well developed sponge model of concomitant tumor immunity that allows us to compare the immunologic events that occur during tumor progression vs rejection. In this model, an animal harboring a primary EMT6 mammary tumor is challenged with a secondary tumor implant through a pre-implanted gelatin sponge. During the manifestation of concomitant tumor immunity, the secondary tumor is rejected and the effector cells mediating the response are retained within the sponge matrix. Using this model we analyzed the TCR usage, cytotoxic activity of lymphocytes, and cytokine production at both tumor sites. The data revealed that tumor-rejecting lymphocytes isolated from the site of secondary tumor implant were cytotoxic toward EMT6 cells, whereas tumor-infiltrating lymphocytes isolated from the progressing primary tumor were not. Interestingly, the TCR-V beta repertoire of the tumor-infiltrating lymphocytes and tumor-rejecting lymphocytes were identical with V beta 1 and V beta 8 being predominant at both sites. Furthermore, the rejection site showed higher gene expression of IFN-gamma, TNF-alpha, and IL-10 whereas TGF-beta expression was slightly higher in the progressing tumors. These findings suggest that the disparate effector functions observed during tumor progression vs rejection are not caused by different T cell phenotypes but may be due instead to influences exerted by cytokines produced at the tumor sites.
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PMID:T lymphocytes infiltrating sites of tumor rejection and progression display identical V beta usage but different cytotoxic activities. 770 35

Peptide regulatory factors, i.e. cytokines, are released spontaneously or upon induction by melanoma cells in culture. Among these cytokines there are factors such as Il-1, IL-6, IL-8, IL-10 as well as TGF-beta 1 which are basically acting as immunoregulatory molecules. However, their contribution to an augmentation and/or suppression of local or systemic immune response against melanoma cells in situ has not yet been elucidated. On the other hand, some of these molecules, e.g. IL-6 and TGF-beta 1, are growth inhibitors, especially in the early phases of melanoma development. During tumor progression, resistance to the inhibitory effect of these cytokines seems to take place. Whether this resistance is due to an excessive production of these cytokines or a downregulation or blockade of receptors is still controversial. The aberrant expression of bFGF in melanoma cells explains how melanoma cells in vitro and probably also in vivo acquire growth autonomy and the capacity of metastasis formation. The expression of bFGF by human melanoma cells and its activity as autocrine growth regulator imply that agents which interfere with heparin-binding growth factors such as Suramin or pentosan sulfate may be of clinical usefulness. Additionally, these latter agents have been shown to be potent anti-angiogenic factors. Their clinical efficacy, however, has to be established in phase I and II studies.
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PMID:Production of polypeptide regulatory factors by human melanoma cells. 772 36

In tumor cells, abnormal proteins expression results from DNA mutations or fusion associated with carcinogenesis or tumor progression. Those abnormal, often clearly defined proteins should be recognized by the immune system and induce an immune response leading to tumor rejection. Actually, most tumors escape the immune response through a specific tolerance, able to suppress or to modify the immune response against tumor associated antigens. Factors which contribute to tumor immunological escape are not elucidated, but could involve a defect in tumor-antigen presentation to the host immune system. An effective immune response against tumor requires tumor-associated antigens to be processed into immunogenic peptides which are presented to T lymphocytes in association with MHC molecules. T-cell fonctional activation requires also a costimulatory signal delivered to the CD28 receptor on T cells by the B7 family of molecules expressed by the antigen-presenting cells. Most tumor cells express MHC class I molecules, a minority also express MHC class II molecules and only a few lymphoma have been reported to express B7. So, tumor cells are not able to present efficiently their specific antigens to competent T cells. Most tumors are yet infiltrated by inflammatory cells, some of them possessing the capacity to process tumor antigens and to present them to competent T cells, either inside the tumor itself, or after migration into the draining lymph nodes. Among antigen-presenting cells, dendritic cells, unlike B lymphocytes and macrophages, are the only cells able to stimulate naive T lymphocytes. They present effectively antigens in situ and stimulate naive and memory T lymphocytes into secondary lymphoid organs. Actually, dendritic cells are supposed to take place in the antitumor immune response, and dendritic cells infiltration inside numerous neoplasms is often associated to an immune response against tumor. However, many questions still underline the failure to recognize stimuli involved in the mobilization (and the retention?) of dendritic cells inside tumor, or which incite them to migrate out of it to ensure their antigen presenting cell function effectively. The secretion of immunosuppressive factors like IL-10, either by tumor cells and by tumor-infiltrating leukocytes represents one of the mechanisms involved in the modulation of the antigen-presenting cell function and in tumor immunological escape. Recent works were undertaken to increase tumor cells immunogenicity. B7.1 molecule transfection allows tumor cells to present directly their antigens and leads to their eradication in vivo. Those results suggest that tumor-antigens presentation is limited in tumor-bearing hosts.
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PMID:[Dendritic cells and immune function in cancer]. 878 96

Cytokines are believed to play an important role in the pathogenesis of cutaneous T cell lymphoma. Data regarding the local cytokine pattern in mycosis fungoides (MF) are partly conflicting. Recent studies have suggested a shift from type 1 to type 2 cytokine pattern because IL-4 and IL-5 mRNA have been more frequently detected in lesions of advanced stages. Another study has described a type 1 cytokine pattern in MF lesions. None of the previous studies of cytokine mRNA expression in MF, however, used quantitative methods, and therefore only the presence of a cytokine, but not the level of expression, could be determined. To gain better insight into the development of cytokine pattern during tumor progression we used semiquantitative reverse transcriptase-polymerase chain reaction to analyze cytokine mRNA expression in MF skin lesions at different stages. Biopsies from patients with patch (n = 11), plaque (n = 6), and tumor (n = 3) stage MF were compared with biopsies from patients with pleomorphic T cell lymphoma (n = 5), psoriasis (n = 7), atopic dermatitis (n = 5), and nonlesional skin (n = 8). MF progression was associated with significantly higher IL-10 and lower interferon-gamma mRNA expression. Moreover, the stage-dependent increase in IL-10 mRNA expression was also found in paired samples from individual patients. Unlike in pleomorphic T cell lymphoma, however, typical T helper 2 cells did not seem to be the source of increasing IL-10 in advanced MF, because stage-independent IL-4 mRNA was rarely detected, suggesting contribution of nonlymphoid cells to local IL-10 production. The overexpression of IL-10 in MF may be of importance for tumor progression, because this immunosuppressive cytokine might be involved in downregulation of immunologic tumor surveillance.
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PMID:Progression of mycosis fungoides is associated with increasing cutaneous expression of interleukin-10 mRNA. 894 70

We analyzed the production and the roles of IL-6, IL-10, and IL-13 in B-lymphoid malignancies and in specific diseases with B-lymphocyte hyperactivity. Both IL-13 and IL-10 genes are expressed in B-cell lymphomas. However, their contribution to tumor progression is unclear. In certain lymphoproliferative disorders that develop in transplanted patients, IL-6 is produced by malignant cells and is a major factor of their proliferation. In other lymphomas, the IL-6 gene is expressed only in malignancies where differentiated malignant cells are present. In these lymphomas, IL-6 is produced by stromal cells, and the malignant cells express the IL-6 receptor. In patients with HIV infection, the level of production of IL-6, IL-10, and IL-13 is not higher than those of other conditions with immune activation. However, IL-6 contributes to increased production of IgG and IgA in vivo. In Castleman's disease, IL-6 is produced in the lymph node germinal centers, partly originating from follicular dendritic cells, which may explain some of the pathogenesis of this disease. In systemic lupus erythematosus, the critical cytokine is IL-10, which is produced in large amounts by B lymphocytes and monocytes and is responsible for autoantibody production. Taken together, these data emphasize the roles of IL-6 and IL-10, usually produced by nonlymphoid cells, on B lymphocytes, either malignant or hyperactivated.
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PMID:Production and roles of IL-6, IL-10, and IL-13 in B-lymphocyte malignancies and in B-lymphocyte hyperactivity of HIV infection and autoimmunity. 899 99

The purpose of this work was to study changes in serum levels of interleukins, growth factors and angiogenin during different stages of endometrial cancer progression. Serum levels were assayed by enzyme-linked immunosorbant assay in 59 women with stages I-IV of endometrial cancer (study subjects: stage I, n = 20; stage II, n = 8; stage III, n = 5; stage IV, n = 6) and compared to the serum levels in 20 women without cancer as control subjects. Patients with endometrial cancer had varied serum levels of interleukins and growth factors. There was a significant increase in serum levels of angiogenin in all stages of tumor progression. Levels of interleukin-8 (IL-8), IL-10 and transforming growth factor beta (TGF beta) were significantly elevated in patients with stages I and II carcinoma. The serum levels of tumor necrosis factor alpha (TNF alpha), granulocyte/macrophage-colony-stimulating factor, basic fibroblast growth factor (BFGF), IL-7 and IL-2 were significantly elevated in patients with stages II and III carcinoma and the serum level of tumor necrosis factor beta (TNF beta) was slightly elevated in patients with stage II carcinoma only. The serum levels of IL-1 alpha, IL-1 beta and IL-6 were not elevated in endometrial cancer patients in any of the clinical stages. The results showed that progression of endometrial cancer is associated with increased serum levels of cytokines, growth factors and angiogenin, which possibly amplify angiogenesis during different clinical stages.
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PMID:Serum levels of interleukins, growth factors and angiogenin in patients with endometrial cancer. 911 82

The response rate to IL-2 immunotherapy, currently used in the treatment of metastatic renal cell cancer, is limited. Based on our earlier demonstration that a combined regimen of monoclonal antibodies directed at the T cell surface protein CD3 (anti-CD3 mAbs) and IL-2 is synergistic in constraining tumor progression in a murine fibrosarcoma hepatic metastasis model, we have explored the efficacy of an anti-CD3 mAbs plus IL-2 regimen in a murine renal cell cancer model. Our studies demonstrate that a regimen of anti-CD3 mAbs plus IL-2 is superior to treatment with anti-CD3 mAbs alone or IL-2 alone in reducing the number of pulmonary metastases and in prolonging survival. Moreover, the efficacious regimen is associated with heightened intrapulmonary expression of mRNA encoding cytotoxic attack molecules (perforin, granzyme B) and immunoregulatory cytokines (IL-4, IL-10 and IFN- gamma).
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PMID:Immunostimulatory therapy with anti-CD3 monoclonal antibodies and recombinant interleukin-2: heightened in vivo expression of mRNA encoding cytotoxic attack molecules and immunoregulatory cytokines and regression of murine renal cell carcinoma. 914 77

We previously reported [Chakrabarti et al. (1992) Cell Immunol 142:54; 144:455] that, in a murine B lymphoma model 2C3, idiotype (Id)-specific CD8+ cytotoxic T lymphocytes (CTL) are generated in mice following hyperimmunization with irradiated tumor cells, and that they are effective in tumor rejection. The present study reveals that 2C3-specific CTL are also induced in spleens during tumor progression, but are not sustained. At the early stage of tumor growth, the splenic T cells following a 5-day incubation in vitro with killed 2C3 tumor targets, produce high levels of cytokines, namely interleukin-4 (IL-4), IL-10 and interferon gamma (IFN gamma). Their cytotoxic T lymphocyte (CTL) activity and cytokine levels, except IL-2, sharply decline at the late stage when the mice are increasingly moribund. Although the decline in cytokine level is also evident with CD4+ T cells, a precipitous and concurrent decrease occurs primarily in the IL-4 level with both CD4+ and CD8+ T cells of late-tumor-bearing animals (TBA). Study with the unseparated splenocytes also reveals that sevenfold less IL-4 is produced at the late stage. Furthermore, the cytotoxicity of CTL from late TBA can be effectively restored by addition of supernatants from the splenocyte culture of early TBA, or by IL-4, but not by IFN gamma and IL-10. In addition, only IL-4-activated CD8+ T cells from the late TBA are found, by Winn assay, to be protective in vivo. Thus it appears that IL-4, required to sustain antitumor CTL activity, is consumed by T and possibly other cells at the late stage of tumor growth, thereby compromising host immunity against the tumor. We contend that induction or maintenance of protective immunity depends not only on the tumor antigen but also on the specific cytokine milieu in a tumor-bearing host.
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PMID:Interleukin-4 is effective in restoring cytotoxic T cell activity that declines during in vivo progression of a murine B lymphoma. 924 64


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