UMLS:C0006142 - FACTA Search

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Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunotherapy of breast cancer at an early stage of the disease increases the likelihood of success. Here, in a mouse model, we report a new strategy that enables vaccines to be prepared from microgram amounts of tumor tissue. The vaccine is prepared by transfer of a cDNA expression library from relatively small numbers of breast cancer cells into a highly immunogenic cell line, where genes specifying TAA are expressed. As the transferred DNA is integrated and replicated as the recipient cells divide, the number of vaccine cells can be conveniently expanded for repeated immunizations. A cDNA expression library prepared from a breast cancer that arose spontaneously in a C3H/He mouse (H-2(k)) was transferred into a mouse fibroblast cell line derived from C3H/He mice. To augment their nonspecific immunogenic properties, the fibroblasts were genetically modified before DNA transfer to secrete IL-2 and to express allogeneic MHC class I H-2K(b)-determinants. C3H/He mice, highly susceptible to growth of the breast cancer cells, were immunized with the cDNA-transfected cells. Robust breast cancer-specific CD8(+) T-cell-mediated immunity was generated in the mice, raising the possibility that an analogous treatment strategy could be used to treat breast cancer patients at an early stage of the disease.
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PMID:Immunity to breast cancer in mice immunized with fibroblasts transfected with a cDNA expression library derived from small numbers of breast cancer cells. 1590 59

For cancer immunotherapy the loading of dendritic cells (DCs) with whole tumor cell lysate preparations represents a simple and promising approach for presentation of tumor-associated antigens (TAAs), avoiding the disadvantages of HLA-matching and definition of TAAs. The aim of this study was to investigate whether lysate-pulsed DCs efficiently cross-prime CD8+ T cells and induce a strong T(H)1 cell response, as compared to DCs pulsed with specific peptides (FLU M1 and Melan-A/Mart-1). As a model system breast carcinoma cell lysate from either MCF-7 or MDA-MB-231 cell lines (both HLA-A*0201+) expressing the TAA MUC1 were selected. Both cell lines expressed MUC1, the epithelial mucin, which is a large molecular weight O-glycosylated protein expressed in the majority of breast, ovarian, and other epithelial malignancies and is under evaluation as a target antigen in cancer immunotherapy. We developed a simple lysate preparation method to solubilize all cell proteins without degradation. For loading of monocyte-derived dendritic cells, 100 microgmL(-1) of breast carcinoma cell lysate was used, accompanied by an adjuvant consisting of tumor necrosis factor-alpha (TNF-alpha) and prostaglandin-E2. T cells were co-cultivated with lysate or peptide pulsed DCs and were restimulated weekly. Before cultivation, and after the 3rd stimulation, tetramer frequencies for the MUC1 epitopes M1.2 and F7 as well as for the FLU M1 and Melan-A/Mart-1 epitopes were determined. After stimulation with lysate, higher frequencies for M1.2-specific T cells were observed compared with the F7 epitope. Furthermore, we found expansion factors for M1.2-specific T cells that had been stimulated with MCF-7 lysate-pulsed DCs of up to 43-fold. The analysis of typical T(H)1/T(H)2 cytokines (IFN-gamma, TNF-alpha, IL-12p70, IL-2, IL-4, IL-5, and IL-10) revealed a strong T(H)1 response. These results provide evidence for a strong T(H)1 polarization and cross-priming of MUC1-specific CD8+ T cells and demonstrate the feasibility of using lysate-pulsed dendritic cells in breast cancer immunotherapy.
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PMID:Breast carcinoma cell lysate-pulsed dendritic cells cross-prime MUC1-specific CD8+ T cells identified by peptide-MHC-class-I tetramers. 1591 76

In contemporary medicine cancer has an exceptionally important role, even though it is not a new disease. Tumors are found in all animals and plants, and today are more frequent than before, when they were found predominantly in advanced ages. The frequency occurrence depends of many factors, and it is more frequent in countries with higher degree of civilization, what is the consequence of irradiation of other diseases as well as more pronounced industrialization, leading to in proper nourishment, many sources of intoxication with carcinogenic factors arising from environmental pollution, and even by the use of some diagnostic and therapeutic procedures. Cancer is the result of disturbance in cell growth and differentiation. In the appearance and spreading of tumors many factors are involved. In the Department of Experimental and Clinical Oncology of the Institute for Oncology and Radiology, we in the first place investigated the role of immunity, hormones and central nervous system, predominantly in experimental conditions, based on the investigations on animals, the in vitro investigations is tissue cultures and some disturbances which are found in blood of patients with tumors. As in the processes of carcinogenesis the immune system has in important role, in the immunological investigations we primarily investigated parameters of the status of the immune system in patients with malignant processes. The number and function of particular cell subsets of the immune system was investigated, namely T and B lymphocytes and their subclasses, NK cells and monocytes-macrophages. In the majority of analyzed patients with breast and lung cancer, lymphoproliferative diseases and other malignancies, it was shown that the majority of them had a decreased number of immune cells that correlated with the clinical advances of disease and applied cytostatic therapy. However, it was shown that the function of these cells, primarily NK, but also of T lymphocytes, was markedly decreased even before changes in the cell number, indicating that a functional impairment is present even before the cell number decrease and proportional to the advancement of the disease. As the results of exploring of investigation of the immunological status indicate the concrete defects in the function of the separate components of the immune system, these findings make it possible to direct immunotherapy for the correction of existing defects. The activity and pathways of mechanisms of NK cells and the possibility of their modulation were also investigated. Also, the possibility of the application of mAbs in the precise diagnostics of some malignancies was explored. The role in carcinogenesis was investigated in tumors whose appearance, growth and spreading is hormone-dependent. One of the hormone-dependent tumors is breast cancer. It was shown that they are significantly dependent on estrogen and growth factor presence, steroid-receptor content, and that these characteristics can change during the disease and do not have to be identical in their metastasis. Numerous investigations that we performed were in the in vitro conditions, i.e. in cell cultures. The obtained data show how some tumor cells react to applied agents, cytostatical and biological. However their effect in vivo is very often different, as in the in vivo conditions many other factors are involved, suggesting a need for further investigations of these factors. The role of the central nervous system neurotransmiters in carcinogenesis in experimental animals exposed to chemical cancerogen (5-methylcholantrene) with simultaneous treatment of the monoamine system was investigated. It was shown that monoamines expressed their influence on carcinogenesis by regulating the brain homeostasis, as well as by direct influence on the intracellular processes during cell development and differentiation. The obtained results will direct our further investigations toward obtaining mAbs for receptors for TNFalpha and IFNgamma, transfection of suppressor gene into tumor cell cultures and genes for IL-2 and TNFalpha. At the same time we will work on isolation of malignant melanoma tumor antigen and construction of a vaccine using some epitopes and adjuvantes. We will try to introduce appropriate immunotherapy in the advancedehZAD.
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PMID:[Accomplishments and perspectives in tumor diagnostics and treatment]. 1607 39

The immune system has an important role in tumor appearance and spreading. One of the most efficient subpopulations of cytotoxic cells in the destruction of tumors are NK cells. NK cells are activated and increase their cytotoxic potential and modulate their cytokine production after treatment with IFNgamma, IL-12, TNFalpha and IL-2. The investigation of the activity of NK cells was performed on peripheral blood lymphocytes (PBL) of 16 healthy controls and of 40 patients with metastatic breast carcinoma. Modulation of NK cells was performed with IL-2, IL-7, IL-12, TNFalpha, monoclonal antibodies (mAb) for TNFalpha and TNFalpha receptors type I and II, as well as with sera of healthy controls and patients with breast cancer in different clinical stages. Modulating effect of the applied factors after in vitro treatment of PBL was evaluated by the cytotoxic assay using 51chromium. Our results indicate that IL-2 significantly increased the activity of NK cells of controls and breast cancer patients. The sera of patients with advanced breast cancer significantly reduced NK cell activity. IL-7, IL-12 and mAb for TNFalpha do not significantly change the activity of NK cells. The presence of anti-TNFalpha mAb did not change the inhibitory effect of the sera of breast cancer patients with advanced disease on the activity of NK cells of controls and patients with breast cancer. Blocking of TNFalpha Rcs with mAbs decrease the reactivity of NK cells for IL-2. The treatment of breast cancer patients with advanced clinical stage of breast cancer with IL-2, as an additional therapy, could be advantageous, as NK cells after this treatment increase their cytotoxic activity against tumor cells and can improve therapeutical results.
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PMID:[The possibilities of modulation of NK cell activity]. 1607 44

Studies in cancer patients have suggested that breast tumors recruit regulatory T cells (Tregs) into the tumor microenvironment. The extent to which local Tregs suppress antitumor immunity in breast cancer is unknown. We questioned whether inhibiting systemic Tregs with an IL-2 immunotoxin in a model of neu-mediated breast cancer, the neu-transgenic mouse, could impact disease progression and survival. As in human breast cancer, cancers that develop in these mice attract Tregs into the tumor microenvironment to levels of approximately 10-25% of the total CD4+ T cells. To examine the role of Tregs in blocking immune-mediated rejection of tumor, we depleted CD4+CD25+ T cells with an IL-2 immunotoxin. The treatment depleted Tregs without concomitant lymphopenia and markedly inhibited tumor growth. Depletion of Tregs resulted in a persistent antitumor response that was maintained over a month after the last treatment. The clinical response was immune-mediated because adoptive transfer of Tregs led to a complete abrogation of the therapeutic effects of immunotoxin treatment. Further, Treg down-modulation was accompanied by increased Ag-specific immunity against the neu protein, a self Ag. These results suggest that Tregs play a major role in preventing an effective endogenous immune response against breast cancer and that depletion of Tregs, without any additional immunotherapy, may mediate a significant antitumor response.
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PMID:IL-2 immunotoxin therapy modulates tumor-associated regulatory T cells and leads to lasting immune-mediated rejection of breast cancers in neu-transgenic mice. 1678 2

In recent decades many advances have occurred in the understanding of the role of cytokines in breast cancer. New signalling pathways of interleukin (IL)-1 family, IL-6, IL-11, IL-18, interferons (IFNs) and interferon regulatory factors 1 (IRF-1) and 2 (IRF-2) have been found within tumour microenvironments and in metastatic sites. Some cytokines (IL-1, IL-6, IL-11, TGFbeta) stimulate while others (IL-12, IL-18, IFNs) inhibit breast cancer proliferation and/or invasion. Similarly, high circulating levels of some cytokines seem to be favourable (soluble IL-2R) while others are unfavourable (IL-1beta, IL-6, IL-8, IL-10, IL-18, gp130) prognostic indicators. So far IL-2, IFNalpha, IFNbeta and occasionally IFNgamma, IL-6, IL-12 have been the cytokines used for anti tumour treatment of advanced breast cancer either to induce or increase hormone sensitivity and/or to stimulate cellular immunity. Disappointing results occurred in most trials; however, two long-term pilot studies suggest that IL-2 and IFNbeta, when used appropriately can have a positive effect on clinical benefit and overall survival of patients with minimal residual disease after chemotherapy or with disseminated disease controlled by conventional endocrine therapy.
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PMID:Cytokines in breast cancer. 1693 Nov 7

Reports showing susceptibility of multidrug resistant (MDR) cancer cells to immune effectors, together with P-glycoprotein (P-gp) expression in immune effector subsets, including immature natural killer (NK) cells, and some activated T cells, suggest P-gp or some changes associated with it, have implications in immune-mediated mechanisms. A series of experiments were done to determine the nature of alterations associated with susceptibility to immune effector cells of MDR tumor cells. A cell line isolated from the malignant pleural effusion of a breast cancer patient was transfected with human and murine MDR1 genes, and four variants with different levels of MDR were obtained. Lymphokine-activated killer (LAK) activity was measured by a 51Chromium release, and conjugate formation assays. MDR1 transfectant P-gp+ breast carcinoma lines had increased LAK susceptibility compared to their parent line. Some part of the increased LAK susceptibility of drug-resistant cell lines was at the binding/recognition level as shown by conjugate formation assays. This suggests that differences may exist between paired cell lines with respect to the expression of cell adhesion molecules (CAMs). Monoclonal antibodies (mAbs) to CAMs and flow cytometry were used to quantitate these antigens. The CAMs studied were those previously found to be upregulated by stimulating NK cells with (interleukin-2) IL-2; ICAM-1 (CD54), LFA-3 (CD58), N-CAM (CD56), and the beta chain of LFA-1 (CD18). Although no differences in these CAMs were found between the breast carcinoma line and its MDR1-transfected variants, the target susceptibility results given above suggest that IL-2 treatment could be effective in combination with current protocols using chemotherapeutics, monoclonal antibodies (mAbs) and stem cell transplantation.
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PMID:Lymphokine-activated killer cell susceptibility and adhesion molecule expression of multidrug resistant breast carcinoma. 1708 16

We have reported important benefits and survival with an immunotherapy schedule in patients with endocrine-dependent breast cancer and distant metastases. Here clinical outcome is updated and its correlation with new immunological data is shown. In 32 evaluated breast cancer patients with endocrine-dependent distant metastases treated with a new immunotherapy schedule (cyclic administration of beta-interferon and interleukin-2), cellular immunity, cytokines and CRP were related to the clinical course. Estimated and true 5-10 year overall survival rates from first line antiestrogen and distant metastases were higher than previously reported in a similar population. Interleukin-2 administration was followed by a significant increase in total lymphocytes, CD4+, CD8+, CD16+56+ (NK) cells, IL-6, IL-12, and CRP (from P<0.04 to P<0.000) but no change in IL-10 and TGFbeta1 during clinical benefit. During progressive disease no change was observed in the former parameters, concomitant with a significant increase in IL-10 (P=0.020) and a significant decrease in TGFbeta1 (P=0.023). These findings confirm that cellular immunity is significantly stimulated by IL-2 only during clinical benefit. Furthermore, these results demonstrate that different changes of proinflammatory cytokines, CRP and inhibiting factors are consistent with associated clinical benefit or with disease progression, respectively.
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PMID:Relationship of cellular immunity, cytokines and CRP with clinical course in breast cancer patients with endocrine-dependent distant metastases treated with immunotherapy. 1721 77

Interleukin-7-receptor-signaling plays a pivotal role in T-cell development and maintenance of T-cell memory. We studied IL-7Ralpha (CD127) expression in PBMCs obtained from patients with breast cancer and examined IL-7 receptor-mediated downstream effects defined by STAT5 phosphorylation (p-STAT5). Reduced numbers of IL-7Ralpha-positive cells were identified in CD4+ T-cells as well as in a CD8+ T-cell subset defined by CD8alpha/alpha homodimer expression in patients with breast cancer. PBMCs obtained from healthy donors (n = 19) and from patients with breast cancer (n = 19) exhibited constitutive p-STAT5 expression in the range of 0-6.4% in CD4+ T-cells and 0-4% in CD8+ T-cells. Stimulation with recombinant human IL-7 for 15 min increased p-STAT5 expression up to 36-97% in CD4+T-cells and to 26-90% in CD8+T-cells obtained from healthy control donors (n = 19). In contrast, PBMCs obtained from 13/19 patients with breast cancer did not respond to IL-7 as defined by STAT5 phosphorylation, despite expression of IL-7Ralpha on T-lymphocytes. T-cells were further characterized for IL- 2 and IFN-gamma production induced by PMA/Ionomycin. PBMCs from 9/19 patients with breast cancer showed decreased IL-2 and IFN-gamma production combined with IL-7-signaling defects; PBMCs from 4 patients with breast cancer exhibited deficient IL-7-signaling, yet intact cytokine production. Reduced numbers of IL-7Ralpha-positive cells and nonresponsiveness to IL-7, defined by lack of STAT5 phosphorylation, characterizes the immunological profile in T-cells from patients with breast cancer.
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PMID:Reduced numbers of IL-7 receptor (CD127) expressing immune cells and IL-7-signaling defects in peripheral blood from patients with breast cancer. 1754 96

An important characteristic of tumors is that they at some point in their development overcome the surveillance of the immune system. Tumors secrete exosomes, multivesicular bodies containing a distinct set of proteins that can fuse with cells of the circulating immune system. Purified exosomes from TS/A breast cancer cells, but not non-exosomal fractions, inhibit (at concentrations of nanograms per ml protein) IL-2-induced natural killer (NK) cell cytotoxicity. The dietary polyphenol, curcumin (diferuloylmethane), partially reverses tumor exosome-mediated inhibition of natural killer cell activation, which is mediated through the impairment of the ubiquitin-proteasome system. Exposure of mouse breast tumor cells to curcumin causes a dose-dependent increase in ubiquitinated exosomal proteins compared to those in untreated TS/A breast tumor cells. Furthermore, exosomes isolated from tumor cells pretreated with curcumin have a much attenuated inhibition of IL-2 stimulated NK cell activation. Jak3-mediated activation of Stat5 is required for tumor cytotoxicity of IL-2 stimulated NK cells. TS/A tumor exosomes strongly inhibit activation of Stat5, whereas the tumor exosomes isolated from curcumin-pretreated tumor cells have a lowered potency for inhibition of IL-2 stimulated NK cell cytotoxicity. These data suggest that partial reversal of tumor exosome-mediated inhibition of NK cell tumor cytotoxicity may account for the anti-cancer properties of curcumin.
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PMID:Curcumin reverses breast tumor exosomes mediated immune suppression of NK cell tumor cytotoxicity. 1755 31

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