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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Research and clinical observations during the past six decades have shown that: 1. Iron promotes cancer cell growth; 2. Hosts attempt to withhold or withdraw iron from cancer cells; and 3. Iron is a factor in prevention and in therapy of neoplastic disease. Although normal and neoplastic cells have similar qualitative requirements for iron, the neoplastic cells have more flexibility in acquisition of the metal. Excessive iron levels in animals and humans are associated with enhanced neoplastic cell growth. In invaded hosts, cytokine-activated macrophages increase intracellular ferritin retention of the metal, scavenge iron in areas of tumor growth, and secrete reactive nitrogen intermediates to effect efflux of nonheme iron from tumor cells. Procedures associated with lowering host intake of excess iron can assist in prevention and in management of neoplastic disease. Chemical methods for prevention of iron assimilation by neoplastic cells are being developed in experimental and clinical protocols. The antineoplastic activity of a considerable variety of chemicals, as well as of radiation, is modulated by iron. The present article focuses on recent findings and suggests directions for further cancer-iron research.
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PMID:Roles of iron in neoplasia. Promotion, prevention, and therapy. 138 34

Hairy cell leukemia (HCL) is a B-cell tumor affecting the preplasma stage of B-cell differentiation. One important feature of the disease is its exquisite sensitivity to interferon-alpha (IFN-alpha) therapy. Because we showed earlier that the CD20 molecule is consistently hyperphosphorylated in hairy cells and because previous studies showed that CD20 is involved in regulating intracytoplasmic free calcium concentrations ([Ca2+]i) in normal B lymphocytes, we measured [Ca2+]i in tumor cell samples from patients with HCL and studied the effect of IFN-alpha on this parameter. Using the Ca(2+)-sensitive fluorophore fura-2, we observed that hairy cells display a slightly but consistently higher [Ca2+]i than normal 48-hour-activated B cells or other leukemic cells. Furthermore, both in vitro preincubation of cell samples with IFN-alpha and in vivo administration of this cytokine reduced the [Ca2+]i in hairy cells. This effect was observed together with a decrease in transmembrane Ca2+ influx. However, preincubation with IFN-gamma had no effect. The in vivo correlation between the diminution of CD20 phosphorylation and [Ca2+]i in tumor cell samples from patients at the beginning of IFN-alpha therapy suggests that these two parameters are connected.
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PMID:Interferon-alpha downregulates the abnormal intracytoplasmic free calcium concentration of tumor cells in hairy cell leukemia. 138 18

Peripheral blood lymphocytes cultured in interleukin-2 IL-2 acquire the ability to recognize and kill a wide range of tumor cells. Such promiscuous killer cells are termed lymphokine-activated killer (LAK) cells. We recently reported that the interaction of LAK cells with tumor cells stimulated the LAK cells to release interferon (IFN) gamma. Here, we report that the release of IFN gamma by LAK cells can be further enhanced by addition of the monoclonal antibodies (mAbs), anti-CD3, anti-(T cell receptor alpha beta) (TCR alpha beta) and a mitogenic combination of anti-CD2 (T112 + T113). Other antibodies, including a non-mitogenic anti-CD2 mAb (Leu5b), that recognize T cell-associated antigens were not stimulatory. The same stimulatory mAbs also synergized with tumor cells to stimulate tumor-infiltrating lymphocytes (TIL) to secrete IFN gamma. Additional experiments indicated that it was the T cell subset of LAK cells (LAK-T cells) that was stimulated by tumor cells and mAbs to release IFN gamma. Inhibition studies with specific mAbs suggest that the stimulation of IFN gamma release by LAK-T cells was dependent both on the aggregation of TCR-CD3 complexes on the LAK-T cell, and on the interaction of accessory molecules with their ligands. The accessory molecules we have identified as critical are LFA 1 and CD2/LFA-2 on LAK-T cells interacting with their respective ligands ICAM-1 and LFA3. Thus our data suggest that cytokine production in LAK-T cells can be regulated by multiple molecular interactions, involving the TCR-CD3 complex and adhesion molecules.
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PMID:Monoclonal antibodies anti-CD3, anti-TCR alpha beta and anti-CD2 act synergistically with tumor cells to stimulate lymphokine-activated killer cells and tumor-infiltrating lymphocytes to secrete interferon gamma. 138 56

Thymocyte-derived lymphokine-activated killer (LAK) cells were used as a model for the study of the cytokine driven development of cytotoxicity. These cells are devoid of initial cytotoxic activity but upon culture in IL-2 they develop into cytotoxic effectors. The parameters of the response of thymocytes to IL-6 are similar to that of PBL in that IL-6, at concentrations as low as 1 mu/ml, increases cytotoxicity of thymocyte-LAK cells when generated in low doses (25-50 mu/ml) of IL-2. IL-6-enhanced thymocyte-LAK cytotoxicity is observed when tested against both NK-resistant and NK-sensitive tumor cell lines. IL-6 alone does not induce any cytotoxicity from thymocytes nor does IL-6 change the time course of thymocyte-LAK cell generation in IL-2 culture. IL-6 does not affect DNA synthesis, total cell number, proportion of CD56+ cells, or the expression of IL-2R (both P55 and P75 glycoproteins) in IL-2-cultured thymocytes. Instead, IL-6 used to treat mature thymocyte-LAK effector cells for as little as 1 hr prior to 51Cr-release assay increases LAK cytotoxicity. This enhancement is abrogated by pretreatment of effector cells with cycloheximide, suggesting that protein synthesis is required for IL-6 to enhance LAK cell activity. The precursor phenotypes of IL-6-responsive thymocyte-LAK cells are CD3-/CD5-. The effector phenotypes of IL-6-enhanced thymocyte-LAK cells are CD5-/CD56+. Thus, IL-6 depends on synthesis of rapid-turnover proteins to act on mature CD56+/CD5- LAK cells to increase their cytotoxic function.
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PMID:IL-6 enhances the cytotoxic activity of thymocyte-derived CD56+ cells. 138 61

Hepatocyte growth factor (HGF) functions as a hepatotrophic and renotrophic factor for regeneration of the liver and kidney. When 1 ng/ml of interleukin-1 alpha (IL-1 alpha) or interleukin-1 beta (IL-1 beta) was added to cultures of human skin fibroblasts, the production of HGF was 5-6 fold higher than levels in the controls. HGF mRNA level in the cells was increased to 4-fold higher levels at 6 h after exposure to IL-1 alpha. Tumor necrosis factor-alpha and interferon-gamma but no other cytokine tested had slightly stimulatory effects on HGF production. The tumor promoter, tetradecanoylphorbol 13-acetate (TPA) markedly enhanced the stimulatory effect of IL-1 alpha and IL-1 beta on the production of HGF. The stimulatory effect of both IL-1 alpha and IL-1 beta and the synergistical stimulation with TPA were completely abrogated by 10 ng/ml TGF-beta 1 or 1 microM dexamethasone. These results suggest that IL-1 alpha and IL-1 beta are positive regulators for expression of the HGF gene and are likely have a role in regeneration of tissues following the occurrence of inflammatory diseases.
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PMID:Up-regulation of hepatocyte growth factor gene expression by interleukin-1 in human skin fibroblasts. 138 79

Autologous mixed lymphocyte-tumor cell cultures (MLTC) were initiated with cytokine (IFN gamma and TNF alpha)-treated ex-vivo tumor cells of lung, ovarian, breast and stomach carcinomas. The cytokine-treated tumors expressed class-I but not class-II molecules. Although the proportion of CD8+ lymphocytes increased in the bulk culture of MLTCs, in 5/7 experiments the majority of the established T-cell clones were CD4+. Among the CD8+ clones a high proportion (77%) was cytotoxic, while the proliferative response was more frequent among the CD4+ clones (70%). In 4/26 cytotoxic T-lymphocyte (CTL) clones (3/17 CD4+ and 1/9 CD8+), derived from a patient with class I+ class II- stomach carcinoma, lysis was restricted to the autologous tumor cells. These auto-tumor-specific clones did not lyse the autologous ConA blasts, the 5 allogeneic ex-vivo tumors, the NK-sensitive K562 or the relatively sensitive Daudi cells. The cytotoxicity of these clones was inhibited by pre-incubation of the tumor cells with W6/32 (alpha-class I) MAb, or by preincubation of the lymphocytes with OKT3 (alpha-CD3) MAb. The alpha-CD4 (OKT4) MAb had only a marginal effect on the CD4+ clones, while the lytic function of the CD8+ clone was inhibited by the alpha-CD8 (OKT8) MAb. The 3 CD4+ CTL clones also responded with proliferation to the autologous tumor cells. This proliferative response was inhibited by the presence of W6/32 MAb. Our results indicate that the auto-tumor lysis exerted by CD4+ CTL clones was restricted by the class-I antigens, and that the CD4 molecules of the clones were not essential for the lytic interaction.
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PMID:MHC class-I-restricted auto-tumor-specific CD4+CD8- T-cell clones established from autologous mixed lymphocyte-tumor-cell culture (MLTC). 138 48

Transforming growth factor-beta (TGF-beta) is known phenomenologically as a negative regulator of several functions of mouse bone marrow macrophages. The studies reported here extend this list by showing that TGF-beta can suppress cytolytic activity of mouse bone marrow culture-derived macrophages that already have become activated by IFN-gamma and LPS for tumor cell killing, as well as confirm that this cytokine can interfere with the induction of activation. Suppression was caused by a shift in the dose response curve for IFN-gamma rather than absolute inhibition; the 50% effective dose for IFN-gamma was increased approximately fourfold by treatment with TGF-beta. TGF-beta also decreased the absolute number of IFN-gamma R on the surfaces of pretreated macrophages by approximately 30 to 35%, without altering the affinity with which IFN-gamma bound. The increased concentration of IFN-gamma needed to produce the higher level of receptor occupancy explained the observed shift in the IFN-gamma dose response curve. These results suggest that TGF-beta mediates its negative regulatory effects on macrophage activation by interfering with coupling of the IFN-gamma R to the pathways that induce and maintain macrophage activation for tumor cell killing. Such effects are consistent with the view that TGF-beta is a negative regulator of macrophage activation for tumor cell killing. Because of this fact, neoplastic cells that secrete this cytokine may have a distinct survival advantage.
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PMID:Regulation by transforming growth factor-beta 1 of expression and function of the receptor for IFN-gamma on mouse macrophages. 138 70

Interleukin-6 (IL-6) is a pleiotropic cytokine and has been shown to support the growth of T and B lymphocytes in the presence of mitogens in vitro. IL-6 can induce human natural killer (NK) and interleukin-2 (IL-2)-induced lymphokine-activated killer cell (LAK) activity in vitro. It can also mediate antitumor effects in various murine models. In order to understand the mechanism of in vivo action, we have investigated the proliferation of lymphoid cells in vivo and the effects on NK, and LAK cell activities in response to IL-6 administration in mice. In vivo proliferation was measured by labeling the DNA of dividing cells with [125I]iodo-2'-deoxyuridine. C57BL/6 mice were injected ip with either IL-6 or HBSS control two times a day for 3 days and in vivo proliferation was measured. For comparative purpose IL-2 was administered and in vivo effects were analyzed. IL-6 caused significant proliferation of cells mainly in the spleen, while, IL-2 caused proliferation in the lungs, liver, spleen, and kidneys. Pretreatment irradiation (500 rad) of mice abrogated the IL-6-induced proliferation indicating radiosensitive cells are involved. Furthermore, in vivo proliferation was not observed in young nude mice treated with IL-6. To investigate whether the proliferating cells were cytotoxic, we tested for LAK (vs. fresh MCA-102 tumor targets) and NK (vs. Yac-1 tumor targets) activities in the organs of mice treated with IL-6 or IL-2 by 4 h 51Cr-release assay. IL-2 administration induced the generation of LAK activity and increased NK cytotoxicity in various organs, but IL-6 had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Systemic administration of recombinant interleukin-6 in mice induces proliferation of lymphoid cells in vivo. 139 Dec 32

We examined the expression of interleukin-6 (IL-6) by 12 established human melanoma cell lines. Two constitutively produced low levels of IL-6 protein, as measured by enzyme-linked immunosorbent assay. Cells from these two lines, as well as those from two non-IL-6-producing cell lines, contained IL-6-specific mRNA as demonstrated by Northern hybridization. Treatment of the two IL-6-producing melanoma cell lines with interleukin-1 beta, tumor necrosis factor-alpha, or phorbol myristate acetate caused a marked increase in IL-6 production. These induction signals failed to stimulate IL-6 production in the nonproducing cells, even those that expressed IL-6 mRNA. IL-6 did not appear to act as an autocrine growth factor since the addition of exogenous human recombinant IL-6 or polyclonal anti-IL-6 antibody did not alter cellular proliferation. The production of this multifunctional cytokine by tumors may play a role in tumor-host interactions and this should be recognized in the design of biologic therapy trials.
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PMID:Interleukin-6 production by human melanoma cell lines. 139 Dec 35

Interleukin 6 (IL-6) is a multifunctional cytokine important in the inflammatory response. Its potential role as an antitumor agent has been suggested by its demonstrated activity in a variety of tumor models. The mechanism of antitumor activity has been proposed to be its enhancement of cytotoxic T-cell function. In the current work we demonstrate clear antitumor activity for this cytokine in a nonimmunogenic tumor system. B16 melanoma cells transfected with the human IL-6 complementary DNA demonstrated slower tumor growth in vivo. Tumors that developed from these cells had a prominent stromal matrix, an easily recognized infiltration of inflammatory cells, fewer mitotic figures, and fewer blood vessels. These in vivo findings corresponded with a greater adhesion of the IL-6-transfected B16 cells to stromal matrix proteins (laminin, fibronectin, and vitronectin) and a less prominent vascular response in an intradermal angiogenesis assay. Therefore, we propose that with weakly antigenic tumors, such as B16 melanoma, IL-6 may mediate important antitumor responses by nonspecific proinflammatory mechanisms.
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PMID:In vivo and in vitro characteristics of interleukin 6-transfected B16 melanoma cells. 139 47


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