Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In response to a given stimulus, usually a number of cytokines are secreted simultaneously by the immune system. Whether these cytokines are meant to function as a single agent or in combination with others is not understood. Tumor necrosis factor (TNF) has been shown to exhibit antiproliferative effects against a wide variety of tumor cell lines in vitro. In the present report, we investigated the effects of a T-cell-derived cytokine, interleukin 4 (IL-4), on the antiproliferative effects of TNF against different tumor cell lines. The growth characteristics of human breast cancer cells (MDA-MB-330) were minimally affected when the cells were exposed to either TNF or IL-4 alone. However, together these 2 cytokines inhibited cell growth in a dose-dependent manner. The enhancement of the cytotoxic effects of TNF by IL-4 were not just limited to breast tumor cells, but were also observed with human epidermoid carcinoma cells (A-431) and human histiocytic lymphoma cells (U-937). The enhancement of the cytotoxic effect of TNF by IL-4 against various tumor cell lines was found comparable with that by gamma-interferon (IFN-gamma). Interestingly, for certain tumor cell types, IL-4 alone was found to enhance cell proliferation. IL-4 had no effect on the growth-stimulatory activity of TNF on normal human foreskin fibroblasts. Pre-exposure of U-937 cells to IFN-gamma led to a greater than 2-fold induction in TNF receptors, but no modulation of TNF receptors by IL-4 was observed. Moreover, the presence of IFN-gamma was found to further potentiate the antiproliferative effects of TNF and IL-4. These results clearly suggest that IL-4 potentiates the antiproliferative responses of TNF by a mechanism different from that of IFN-gamma. Although it is well known that IL-4 can modulate the production of TNF from macrophages, this is the first report to suggest that IL-4 can also modulate TNF-dependent antiproliferative responses.
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PMID:Interleukin 4 potentiates the antiproliferative effects of tumor necrosis factor on various tumor cell lines. 165 Nov 57

Numerous interactions between malignant and stromal/inflammatory cells take place within solid human tumours, which are mediated, in part, by the release of signalling proteins called cytokines. In the present study, we have compared the secretion of two important immunomodulatory cytokines, IFN-gamma and IL-4 by individual, immunophenotyped NK cells freshly isolated from either malignant tumour biopsies, or peripheral blood samples from patients with ductal invasive breast cancer. Due to the marked heterogeneity amongst cells isolated from these clinical samples, we have employed a technique called the reverse haemolytic plaque assay to identify and enumerate cytokine-secreting cells at the single cell level. Our data indicate that NK cells isolated directly from the tumour site secrete more IFN-gamma and IL-4 than NK cells from the blood of the same patients. However, a greater proportion of CD16+ cells from both sources in breast cancer patients secreted IFN-gamma than of those from the blood of healthy donors. We also show that factors secreted by the human breast cell lines, MCF-7 and MDA-231 PN9, were able to mimic the stimulatory influence of the tumour microenvironment on secretory activity of NK cells.
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PMID:Human tumour-associated NK cells secrete increased amounts of interferon-gamma and interleukin-4. 191 Nov 84

Tumour tissues are frequently seen with monocyte/macrophage infiltration. This study was to establish the role of monocytes on the motile and invasive behaviour of human cancer cells. By using a co-culture technique, we have shown that both human peripheral blood monocytes and a monocytic cell line, U937, stimulated colon and breast cancer cell colony scattering, motility, and invasion into a basement membrane (Matrigel). This effect was enhanced when monocytic cells were stimulated by a particulate stimulus. IL-4 and IL-10 reduced these effects of monocytes. We conclude that monocytic cells enhance the motility and invasion of tumour cells. These effects can be regulated by inhibitory cytokines of monocytes.
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PMID:Regulation of motility and invasion of cancer cells by human monocytic cells. 765 13

Human tumor-infiltrating lymphocytes (TIL) include a minor population of tumor-specific T cells, but the nature of the majority of TIL remains unknown. Recently, it has been suggested that T cells that recognize stressed cells may play an important role in immune surveillance. We have examined the proliferative response of anti-CD3-activated TIL cultures from human tumors against heat-stressed (hs) (42.8 degrees C, 25 min) B cell lines (TK6 (HLA-DR7+, -DRw13+, -DRw52+, and -DRw53+) and JY (HLA-DR4+ and -DRw52+)) and the mutant cell line (T2 (no HLA-DR)) by measuring [3H]thymidine incorporation. TIL lines from three of four ovarian cancers, two of four lung cancers, one of two renal cell cancers, one of two melanomas, and one of one breast cancer showed a positive proliferative response against hs-TK6 and/or hs-JY, but not against hs-T2. These TIL did not respond to autologous tumor cells. The response to hs-B cells was mediated by CD4+ TIL and inhibited by anti-HLA-DR Ab, but not by anti-HLA class I. Protein analysis revealed a significant increase of heat shock protein 70 (hsp70) expression in hs-TK6 and hs-JY. In addition, the CD4+ TIL responded to TK6 that had been pulsed with hsp70. This response could be blocked by anti-HLA-DR Ab. The CD4+ TIL produced IFN-gamma, but not IL-4, in response to hs-TK6. From these results, we conclude that hsp70-reactive CD4+ T cells exist in tumor tissues. Furthermore, these TIL recognize stressed cells and seem to play a Th1-like role that may support antitumor T cell responses at local tumor sites.
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PMID:Human tumor-infiltrating CD4+ T cells react to B cell lines expressing heat shock protein 70. 793 Jun 18

Women who have breast cysts with intracystic Na/K < 3 may have a higher risk of breast cancer than those with intracystic Na/K > 3. Low/undetectable concentrations of TNF alpha and IL-4, both of which have been shown to inhibit growth of human breast cancer cell lines, were found in the majority of breast cyst fluid samples. Intracystic oestradiol concentrations were significantly higher in the low electrolyte ratio group than in the high electrolyte ratio group. Imbalance between growth stimulatory and growth inhibitory substances in cystic breast disease may be an explanation for the higher risk of breast cancer particularly in the low electrolyte ratio group.
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PMID:Growth inhibitory substances in human breast cyst fluid. 847 17

We tested the influence of recombinant human interleukin (rhIL)-l3 and rhIL-4 on clonal growth of human breast cancer cell lines. rhIL-13 and rhIL-4 inhibited clonal growth of three of nine lines to approximately 50% of controls (ED50, 0.5 ng/ml). rhIl-13 reduced [3H]thymidine incorporation in all three cell lines: two showing a minor (84% and 83% of controls) and one showing a major response (25% of control). Both cytokines markedly reduced serum-induced G(0/1) exit (approximately 25% versus 60%). 125I-labeled interleukin (IL) 13 binding assays revealed high-affinity binding sites for IL-13 on two of the three responding cell lines (KD approximately 60 pM). (Y124D)IL-4 effectively antagonized all effects of rhIl-13 and rhIL-4, arguing for shared receptor components between them. However, neither rhIl-4 nor (Y124D) IL-4 could displace 125I-labeled IL-13 from binding, although unlabeled rhIL-13 effectively did so. Using reverse transcription-PCR, we studied the expression of the common gamma chain (gammac) in responding cell lines, putatively being shared between IL-4 receptor and IL-13 receptor; none of the three cell lines express gammac. In conclusion, we demonstrate antiproliferative effects of IL-4 and IL-13 on carcinoma cells which express IL-13 binding sites without participation of gammac.
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PMID:Inhibition of proliferation and clonal growth of human breast cancer cells by interleukin 13. 875 30

In this study, we used immunohistochemical and biochemical analysis to show that gp200-MR6, a 200 kDa molecule that is functionally associated with the human interleukin 4 (IL-4) receptor complex, is expressed at high levels on normal breast epithelial tissues, at lower levels on in situ carcinomas, and that the expression is lost in the invasive carcinoma of the breast. Furthermore, a preliminary study showed that benign epithelial hyperplasia of the breast expresses the gp200-MR6 heterogeneously. Two populations of cells have been observed: MR6 positive and MR6 negative. Interestingly, MR6-positive cells were observed to have different morphology from those that were MR6 negative; the nuclei of the former were larger and rounded in shape, whereas the nuclei of the latter were relatively small and oval in shape. In sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting, monoclonal antibody MR6 detects the same molecular weight molecule in both normal and transformed tissue, indicating that the molecule is not a product of a truncated gene. The intensity of the gp200-MR6 bands correlates with the immunohistochemical data, indicating that the molecule is expressed at high levels in normal tissue and at lower levels in malignant tissue. These results suggest that analysis of gp200-MR6 expression may be useful in tumour grading and prognostic evaluation in breast cancer. Moreover, the molecule may be involved early in the process of tumorigenesis of the breast, in which a loss or a down-regulation of gp200-MR6 could contribute towards tumour development and progression via an effect on cell growth and differentiation.
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PMID:Differential expression of gp200-MR6 molecule in benign hyperplasia and down-regulation in invasive carcinoma of the breast. 885 66

Several in vitro studies stress a potentially important role of interleukin 4 (IL-4) and the related gp200-MR6 molecule in the immunological response to cancer and in tumour proliferation. In the present study, we assessed the expression of gp200-MR6 in primary breast cacrinomas using the MR6 monoclonal antibody. Results were correlated with tumour parameters (T-,N-stage, histology, grade, oestrogen and epidermal growth factor (EGF) receptors), and the impact on survival was assessed. Twenty-four out of 110 cases (22%) were positive for gp200-MR6, 62 out of 110 (56%) expressed weak staining and 24 out of 114 (22%) did not stain. The normal breast epithelia were invariably stained for gp200-MR6 showing that down-regulation or loss of this molecule occurred during the evolution of breast cancer. Gp200-MR6 loss was independent from differentiation, nodal positivity and oestrogen receptor levels as well as patients' age. Loss of the gp200-MR6 molecule was more frequent in lobular cases (P=0.03). The overall survival was better, although not reaching statistical significance, in patients with positive gp200-MR6 expression (92% alive at 5 years compared with 70% for those with weak or no expression, P=0.1). The local relapse-free survival was independent of gp200-MR6 status. It is concluded that loss of gp200-MR6 may be one of the mechanisms through which breast cancer cells escape immune surveillance, resulting in an increased metastatic potential and poorer outcome. Evidence of down-regulation of the gp200-MR6 molecule has implications for IL-4-linked toxin therapy and, as IL-4 is an inhibitor of breast epithelial growth, may represent loss of a tumour-suppression mechanism.
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PMID:Loss of interleukin 4 receptor-associated molecule gp200-MR6 in human breast cancer: prognostic significance. 893 45

Cytotoxic T-cell (CTL) cultures were generated from five ovarian cancer patients (OvCTL) and from three breast cancer patients (BrCTL). All CTL lines were T-cell receptor (TcR) alphabeta+ and predominantly CD8+ (73 +/- 13%). These CTL lines preferentially recognized autologous tumor cells in an HLA class I-restricted, and in part HLA-A2-restricted, manner. In addition, the CTL lines recognized allogeneic HLA-A2+ ovarian and breast tumor cells. Specific recognition was determined by T-cell-mediated cytotoxicity as well as cytokine release. Coculture of irradiated autologous tumor cells with OvCTL induced secretion of IFN-gamma, GM-CSF and TNF-alpha, but not IL-4, indicating a T helper-1-type response. Similar results were obtained when OvCTL and BrCTL were stimulated with histologically matched HLA-A2+ tumor cells. Also, BrCTL stimulated with HLA-A2+ but not HLA-A2- ovarian tumor cells produced significant levels of GM-CSF and TNF-alpha. Finally, the Her2/neu peptide p654-662, earlier identified as a tumor antigen in both ovarian and breast cancer, induced cytotoxicity as well as the specific release of IFN-gamma and TNF-alpha but not IL-4 by OvCTL and BrCTL. Thus, tumor-specific recognition by CTL was verified by cytotoxicity and cytokine release. The secretion of Th1-like cytokines as opposed to Th2-like cytokines suggest that therapeutically OvCTL and BrCTL could potentially enhance the endogenous immune response to tumor.
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PMID:Simultaneous production of T helper-1-like cytokines and cytolytic activity by tumor-specific T cells in ovarian and breast cancer. 902 20

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


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