UMLS:C0699790 - FACTA Search

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Query: UMLS:C0699790 (colon cancer)
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Ezrin is a membrane-cytoskeleton linker protein and belongs to the TERM family. It has been implicated in the membrane ruffling, motility, and metastatic process of tumour cells. This study examined the effects of a range of cytokines on the expression of ezrin in the human colon cancer cell line, HT29. Levels of ezrin were determined by Northern and Western blotting and indirect immunofluorescence. We report that IL-2, IL-8, IL-10 and IGF-I had an inhibitory effect on the expression, whereas EGF and IL-11 enhanced cellular ezrin levels. Immunofluorescence confirmed that these changes were seen both in cytosol and generalised membrane. It is concluded that ezrin expression in tumour cells can be regulated by cytokines and this bears importance in the understanding of its role in tumour biology.
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PMID:Cytokine regulation of ezrin expression in the human colon cancer cell line HT29. 868 42

The story of tumor immunology includes periods of hope followed by ones of disenchantment as far as clinical applications are concerned. In antiquity, cancer was considered "contrary to Nature", a concept which was confirmed by Ehrlich at the beginning of our century when the layed down the foundations of immunology. The latter was defined as the defence against all "non-self" intruders, including cancer, as opposed to the protection of "self". This concept was further accentuated by the theory immune surveillance proposed by Burnet in 1969 which implicated a destruction of nascent neoplastic cells by T lymphocytes. To increase host defence was the basis of tumor immunotherapy with BCG, levamisol and other adjuvants. The appearance of the nude mouse, athymic, and yet free of spontaneous tumors, led to a new paradigm, the network theory proposed by Jerne. This was based on immunological homeostasis implicating that both "self" and "non-self" can be rejected and tolerated. Cancer gradually ceased to be considered as "contrary to Nature". As for the proposed viral etiology of cancer which was the basis of the National Cancer Act signed by Nixon in 1971, this led to various breakthroughs and Nobel Prizes (Table 1), to discoveries such as reverse transcriptase, cellular oncogenes, tumor suppressor genes, which gave a new explanation for neoplastic transformation. The latter can now be considered as the consequence of a cascade of molecular events which include oncogene expression, anti-oncogene deletion, etc... converting, step by step, for instance, a polyp into a colon cancer and its metastases. The availability of monoclonal antibodies capable of attacking tumor cells did not lead to the expected success because of the complexity of the immune system. Attempts at a better understanding of the latter have led to a subdivision of the T lymphocyte CD4 population into Th1 and Th2. Th1 favor rejection (tumoral, fetal or of transplants) through the elaboration of IL-2, IFN and TNF while Th2 led to tolerance or acceptation through the production of IL-4, IL-5 and IL-10: both functions neutralize each other establishing a "normal" equilibrium Th1 vs Th2. This could explain the state of "tumor dormancy" or tumors in situ which are apparently quite frequent. That any immunological stimulation would cause these dormant tumors to proliferate is the basis of the immunostimulation theory proposed by Prehn and supported by the clinical observations of Stewart. This new concept has led some authors to propose that instead of destroying the tumor cells an attempt be made to maintain them in a state of dormancy in congenial company with normal cells.
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PMID:[A retrospective view of tumor immunology]. 922 70

Cytokines released from tumour cells may have function as signals to neighbouring immune and inflammatory cells. Several studies have shown that the immunoregulatory cytokines IL-10 and transforming growth factor-beta1 (TGF-beta1) as well as prostaglandin-E2 (PGE2) play an important role in tumour-induced immunosuppression. The aim of the study was to investigate the effect of colon carcinoma cell lines on IL-10 production in peripheral monocytes (PBMC) and lamina propria mononuclear cells (LPMC). We examined four colon carcinoma cell lines (HT-29, Caco-2, Colo-320 and HCT-116) and determined their production of TGF-beta1, IL-10 and PGE2. Peripheral monocytes were isolated by density gradient centrifugation and LPMC were isolated from surgical specimens using a collagenase digestion method. Monocytes and LPMC were cultured with colon carcinoma cell conditioned medium or in co-culture with colon carcinoma cells. Supernatants were then determined for the production of IL-10 by ELISA assays. All colon carcinoma cell lines stimulated peripheral monocytes as well as LPMC to produce markedly increased levels of IL-10. Colon cancer cells secreted negligible levels of IL-10, but high amounts of TGF-beta1 and PGE2. Neutralization of TGF-beta1 by administration of anti-TGF-beta as well as neutralization of PGE2 with anti-PGE2 antisera reduced the IL-10 production of monocytes markedly, indicating that tumour cell-derived TGF-beta1 and PGE2 are major factors for IL-10 stimulation. In vitro stimulation of monocytes with TGF-beta1 and PGE2 could confirm that TGF-beta1 as well as PGE2 at picogram concentrations were able to prime monocytes for enhanced IL-10 production. Our results demonstrate that colon carcinoma cell lines enhance the ability of monocytes and intestinal macrophages to produce IL-10. The stimulation of monocyte IL-10 by colon cancer cell-derived TGF-beta1 and PGE2 may act as a tumour-protecting mechanism by impairing the activation of anti-tumour cytokines.
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PMID:Colon carcinoma cell lines stimulate monocytes and lamina propria mononuclear cells to produce IL-10. 936 16

Current research has still not clarified the biological role of soluble interleukin(IL)-2 receptor (sIL-2R) and the significance of its increase in the serum of colon cancer patients compared to healthy subjects. To address these questions at the immunological level in a group of patients and healthy subjects, we determined the sIL-2R level in the serum and its release from peripheral blood mononuclear cells (PBMC) as a function of tumour necrosis factor (TNF) alpha, IL-1 alpha, IL-1 beta, IL-2, interferon (IFN) gamma, IL-4, IL-6 and IL-10 levels in the serum and PBMC production; and PBMC proliferative responses to IL-2, IL-4 and anti-CD3 monoclonal antibody (CD3), variously combined. The level of sIL-2R in patients' serum was higher than in healthy subjects and correlated with the stage of advancement. Moreover, while in healthy subjects the serum level of sIL-2R was not significantly correlated with other parameters, in patients it was positively related to IL-4, IL-6 and IL-10 serum levels, PBMC IL-4 production and to the PBMC proliferative response to CD3 and CD3 + IL-2; it was negatively correlated to IL-2 serum level and IL-1 beta PBMC release. A negative connection between IFN gamma serum level and the PBMC production of sIL-2R was also found. This suggests that the increase of sIL-2R in the serum of patients, compared to healthy subjects, is involved in the inappropriate expansion of the T helper (TH2) suppressive immune response, which we previously reported. The multivariate statistical method supported the above suggestions and we also found that, in healthy subjects, the up- and down-regulation of sIL-2R in the serum within the physiological ranges seems to have a regulating role in the relationships between TNF alpha, IFN gamma and IL-4, IL-6, contributing to the operation of the cytokine network between TH1 and TH2 cells. However, in patients compared to healthy subjects the increased sIL-2R serum level seems to direct the immune response towards a suppressive type, which may be due to an alteration in the above-mentioned physiological regulating role.
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PMID:The significance of an increase in soluble interleukin-2 receptor level in colorectal cancer and its biological regulating role in the physiological switching of the immune response cytokine network from TH1 to TH2 and back. 943 47

IL-10 modulation of human intestinal T lymphocyte functions was studied for the first time. Lymphocyte proliferation was determined by 3H-thymidine incorporation; cytokine production, by ELISA; expression of surface markers, by immunofluorescence and flow cytometric analysis; and cytotoxicity, by lysis of 51Cr-labelled target cells. IL-10 blocked phytohaemagglutinin (PHA)-induced activation and proliferation of CD8+ T cells from the epithelium and lamina propria. It was a greater inhibitor of IL-2, interferon-gamma, and tumour necrosis factor-alpha production than were IL-4 or transforming growth factor-beta. In contrast, IL-10 enhanced IL-2-stimulated proliferation of both CD4+ and CD8+ T cells by increasing cell division after activation. It also augmented IL-2- but not IL-15-induced cytotoxicity of intestinal lymphocytes against colon cancer by a mechanism independent of natural killer cells. In conclusion, IL-10 blocking of proinflammatory cytokine secretion probably reduces intestinal inflammation. IL-10 augmentation of IL-2-induced cytotoxicity may help to maintain host defence.
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PMID:IL-10 enhances IL-2-induced proliferation and cytotoxicity by human intestinal lymphocytes. 1069 13

The DCC (deleted in colon cancer) gene has a brain restricted high expression pattern. It encodes a transmembrane protein of the immunoglobulin superfamily identified as the netrin-1 receptor. It might be a member of the so called "brain-lymphoid" molecules, which control key cell surface events. To test this hypothesis we have assessed the DCC mRNA level in human normal and malignant myeloid and lymphoid cells. A high mRNA content has been observed only in mature B cells at the secreting or presecreting stage. Expression of DCC was also assessed in the anti-CD40 model of immunopoiesis. Activation of purified tonsillar B cells by anti-CD 40 antibody strongly increased the DCC mRNA level and this effect was dramatically enhanced by the association of IL-2 + IL-10, which is a potent and selective in vitro inducer of the B cell memory phenotype. In contrast no effect has been detected after activation of T cells by anti-CD3. These data suggest that the DCC encoded netrin receptor is involved in B cell immunopoiesis.
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PMID:Upregulation of the netrin receptor (DCC) gene during activation of b lymphocytes and modulation by interleukins. 1135 76

We previously reported that a novel promoter enhancer element "human tissue inhibitors of metalloproteinases 1 (TIMP-1) enhancer" (HTE) and a novel transacting protein "cysteine rich transcription factor" (CRTF) induced TIMP-1 synthesis in prostate cancer cells 2xN.I.PC-3. In the present study, to clarify the significance of CRTF in gastrointestinal cancers we measured the binding activity of CRTF to HTE using an electrophoretic mobility shift assay (EMSA), and the TIMP-1 concentration by ELISA after various stimulation of six cancer cell lines (KE-3, TE-9, MKN-28, MKN-45, KM12SM, SW620). In three cell lines (KE-3, MKN-45, SW620), both the binding activity of CRTF and TIMP-1 concentration significantly increased after IL-10 stimulation. Fetal bovine serum (FBS) did not affect the binding activity of CRTF, whereas FBS induced TIMP-1 synthesis in all cell lines. In KE-3 esophageal cancer cells and SW620 colon cancer cells, both the binding activity of CRTF and TIMP-1 concentration increased in the presence of a conditioned medium (CM) of fibroblasts which was isolated from human colon cancer tissues, but did not increase in MKN-45 cells. Moreover, in the fibroblasts, both the binding activity of CRTF and the TIMP-1 concentration increased in the presence of CM from KM12SM, SW620, and TE-9 cancer cell lines. These results suggested that IL-I0, and unknown factors in addition to IL-10, induced TIMP-1 synthesis via an increase in the binding activity of CRTF in gastrointestinal cancers, and that interaction between cancer cells and fibroblasts may play an important role in TIMP-1 synthesis through a signal transduction pathway consisting of CRTF phosphorylation and HTE activation.
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PMID:Significance of cysteine rich transcription factor (CRTF) in the synthesis of tissue inhibitor of metalloproteinases 1 (TIMP-1) in gastrointestinal cancers. 1137 Aug 21

The prognostic significance of IL-10 and IL-6 serum levels in colon cancer patients undergoing surgery was investigated. To this end, 50 candidate patients with colon cancer for surgery were admitted to the study. Of these, 30 could be subjected to a potentially curative surgery. Cytokine serum levels at several time points before and after surgery were measured by ELISA. Circulating levels of IL-10 and IL-6 were found to be elevated in cancer patients with respect to controls. Both IL-10 and IL-6 serum levels were demonstrated to predict the likelihood of curative surgery (predictive accuracy, 83.3%). IL-10 serum levels returned to normal in all but 6 patients who underwent curative surgery. These latter had tumor recurrence (predictive accuracy, 100%). In contrast, IL-6 serum levels significantly decreased in all patients, regardless of whether cure was surgically achieved, but did not normalize. On multivariate analysis, basal IL-10 serum levels were found to be among the variables significantly predicting the disease-free survival rate. Stepwise regression selected tumor stage, basal IL-10 serum level, and basal CEA serum level as the best combination of variables for prediction of the likelihood of tumor recurrence. In conclusion, preoperative serum levels of IL-10 were shown to be useful markers for predicting both likelihood to perform curative surgery and, in combination with the 16th postoperative day IL-10 serum levels, tumor recurrence (predictive accuracy, 73.6 and 96%, respectively). IL-6 serum levels were found to have a more limited prognostic role.
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PMID:Prognostic significance of circulating IL-10 and IL-6 serum levels in colon cancer patients undergoing surgery. 1184 59

We report the immunological characterization of three colon carcinoma cell lines, COLO 205, SW620 and SW403, which we selected to combine with cytokine-secreting fibroblasts for the development of an allogeneic tumour cell vaccine. The cell lines expressed HLA-A2 as well as shared tumour-associated antigens (TAAs) representative of colon carcinomas: CEA, Ep-CAM, MUC1, HER2/neu and MAGE antigens. They did not secrete high levels of the immunosuppressive factors TGF-beta, IL-10 or prostaglandins. The lines presented TAAs in a manner recognized by immune effector cells, which was demonstrated by the lysis of SW620 by HLA-A2-restricted anti-p53 cytotoxic T lymphocytes (CTL). COLO 205 and SW620 were genetically modified to express the co-stimulatory molecule CD80 (B7.1), which increased the ability of the cells to stimulate CTL in vitro. CTL clones derived from HLA-A2+ peripheral blood mononuclear cells stimulated with the CD80-expressing lines lysed the stimulator cell and an HLA-A2+ colon cancer cell line, but did not lyse an isogeneic fibroblast line or an HLA-A2- colon cancer cell line. CTL clones derived from colon carcinoma patients immunized with an allogeneic vaccine containing these lines demonstrated killing of autologous tumour cells, the vaccine cell lines and other HLA-A2+ colon cancer cell lines, but not fibroblasts isogeneic to certain of the target cell lines. Our studies demonstrate that these colon carcinoma cell lines express shared TAAs that can induce CTLs which recognize and lyse other colon carcinoma cells, and support the continued clinical evaluation of the CD80 gene modified allogeneic colon cell/cytokine-secreting fibroblast carcinoma vaccine.
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PMID:Antigenic and immunologic characterization of an allogeneic colon carcinoma vaccine. 1210 28

The beneficial effect of yoghurt consumption on health and on the improvement of the mucosal immune system is well established, as is the diet-associated risk of colon cancer. In an experimental model in BALB/c mice we demonstrated that yoghurt added to the diet for 10 consecutive days, with the procedure repeated each 10 days for 6 months, inhibited the development of a colorectal carcinoma induced by 1,2 dimethylhydrazine (DMH). The immunoregulatory mechanisms involved in the inhibition of tumour growth by yoghurt were also examined in these studies. We determined B lymphocytes IgA(+) and IgG(+), as well as CD4(+) and CD8(+) T cells in the large intestine. We measured cellular apoptosis and the cytokines TNF-alpha, IFN-gamma and IL-10. An increase in the number of IgA(+) (P<0.01) was observed, but not in IgG(+) (P<0.01), or in the CD4(+) population (P<0.01) in the mice treated with DMH and yoghurt. While in the group with the carcinogen there was an enhancement in the IgG(+) B cells (P<0.01) and CD8(+) T cells (P<0.01). Yoghurt increased the number of apoptotic cells and induced IFN-gamma and TNF-alpha cytokine release, their production being regulated by an increase in IL-10 (P<0.001). We demonstrated that yoghurt may exert antitumour activity by a decrease in the inflammatory immune response mediated by IgA(+) increase, apoptosis induction and IL-10 release.
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PMID:Role of yoghurt in the prevention of colon cancer. 1214 67

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