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

Blood monocytes (MO) undergo maturation into macrophages (MAC) upon migration from the capillary bed to tissue sites of inflammation where they are exposed to environmental signals. Functional competence and phenotype heterogeneity is the result of both differentiation-inducing and -activating events. In vitro, MO to MAC maturation is induced by serum factors, can be followed by the expression of specific maturation-associated antigens and is accompanied by a characteristic change in the secretory repertoire of MAC in comparison to MO. Here we report that bacterial lipopolysaccharides (LPS) at subnanogram quantities very effectively inhibited the serum-induced maturation of human MO in vitro. At the same time LPS induced the up-regulation of CD14 antigens. The lipid A moiety was shown to be responsible for this novel biological activity of the LPS molecule. Inhibition of maturation was not due to secondary LPS-induced signals like interleukin (IL)-1, IL-6, tumor-necrosis factor (TNF)-alpha or interferon (IFN)-alpha--even though the latter by itself suppressed MAC maturation in vitro. The inhibitory activity of IFN-alpha could be abolished by neutralizing anti-IFN-alpha antibodies whereas these antibodies had no effect on LPS-induced suppression of MAC maturation. Functional analysis of LPS-treated MO long-term cultures showed that the pattern of secretory products released was similar to that of freshly-isolated immature blood MO: compared with mature MAC, LPS-treated MO released high amounts of IL-6 but significantly less TNF-alpha, neopterin, lysozyme and beta-2-microglobulin. At the same time, in LPS-treated MO cultures the MAC maturation-associated molecules alpha-2-macroglobulin and fibronectin could be detected only in trace amounts. The ability to secrete IL-1, however, was lost both in control as well as in LPS-treated MO cultures. The results indicate that endotoxins may influence the biology of the MO/MAC system distinctively: they not only induce a functional activation but also interfere with the ontogeny of this cell family.
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PMID:Inhibition of in vitro differentiation of human monocytes to macrophages by lipopolysaccharides (LPS): phenotypic and functional analysis. 171 Sep 26

We have previously demonstrated that a short heat treatment protects target cells from lysis by tumor necrosis factors (TNFs). Here we show that a similar heat treatment of human umbilical vein endothelial cells and human fetal adrenal cells does not alter noncytotoxic actions of TNF, suggesting that heat shock may specifically inhibit the cytotoxic action of TNF. To find clues to the mechanisms by which heat shock protects cells from TNF killing, its effects on TNF-alpha-TNF-receptor interactions, on the metabolism of the ligand, and on the expression of mRNAs for possible protective proteins were studied. The affinity of binding and the internalization of the ligand were slightly reduced after heat shock. These effects were, however, very vague and seen both in heat-responsive tumor cells and in endothelial and adrenal cells. Thus, it is unlikely that they could explain the heat-induced TNF resistance. Heat shock increased the expression of mRNAs for heat shock proteins (hsps) 27 and 70 in all the cells studied, but did not alter the expression of manganous superoxide dismutase (MnSOD) mRNA, which has previously been shown to play a crucial role in TNF resistance. Based on these results, we suggest that cells have multiple mechanisms to escape TNF-mediated lysis and that heat-induced protection from TNF killing may be mediated by hsps or other heat-inducible protective proteins, which act after receptor binding and protect cells from TNF-induced cellular damage without inhibiting the signal transduction mediating noncytotoxic effects of TNF.
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PMID:Heat shock inhibits the cytotoxic action of TNF-alpha in tumor cells but does not alter its noncytotoxic actions in endothelial and adrenal cells. 171 72

Because of their paternal antigens, the fetus and placenta may be considered an allograft in the maternal host. Understanding the mechanisms which prevent maternal immunological rejection of the fetus remains a fundamental unsolved problem in immunology. We have previously reported that macrophages are inhibited by maternal decidual stromal cells residing at the maternal-fetal interface. In view of the central role of macrophages in cell-mediated immunity, this inhibition may contribute to preventing maternal antifetal responses. We now report that it was the solid phase signals embedded in the extracellular matrix (ECM) made by decidual cells which are responsible for inhibiting macrophage-mediated lysis of TNF-alpha-resistant P815 mastocytoma cells. The latter macrophage function is acquired after stimulation by interferon gamma and endotoxin. All these macrophage functions were also inhibited by ECM isolated from the Engelberth-Holm-Swarme (EHS) tumor. This tumor ECM has a similar biochemical composition to decidual ECM. This ECM inhibited the effector, as opposed to the stimulator, phase of macrophage-mediated tumor lysis. Laminin, type IV collagen, and heparan sulfate proteoglycans, the major known components of decidual and EHS ECMs, did not inhibit the above macrophage functions. Altogether these data indicate that macrophages were inhibited by solid phase signals embedded in decidual and EHS ECMs. Whether the solid phase signals in these two ECMs are biochemically identical remains to be determined. To our knowledge, such signals are a novel pathway of inhibiting macrophage functions which may be important in understanding the maternal-fetal immunologic relationship, and the pathogenesis of perinatal infections. Furthermore, the ability of EHS tumor ECM to inhibit macrophage functions may indicate that some tumors may defend themselves against host macrophage responses using solid phase signals. This may be important in understanding some host-tumor relationships.
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PMID:Macrophage functions are regulated by murine decidual and tumor extracellular matrices. 172 66

In previous studies we showed that tumor-associated macrophages isolated from murine mammary tumors are mutagenic to bacteria and mammalian cells and thus may contribute to tumor progression. We reported previously, and confirm here, that inflammatory macrophages induce DNA strand breaks in cultured mammary tumor cells co-incubated at a 1:1 ratio for 1 h. This activity is prevented by inhibitors of arachidonate metabolism or the removal of H2O2 with catalase. In the present study, we show that two antibodies to recombinant murine tumor necrosis factor alpha (rMuTNFa)--a hamster monoclonal antibody (TN3-19.12) and a rabbit polyclonal antibody (Genzyme)--partially protect tumor cells from DNA strand breaks induced by elicited but not resident peritoneal macrophages. Antibody protection was reversed upon the addition of excess exogenous rMuTNFa. Purified rMuTNFa alone was unable to induce DNA strand breaks in the absence of macrophages, indicating that TNFa is necessary but not sufficient to mediate damage. Tumor target cells were completely resistant to the cytotoxic effects of rMuTNFa in the absence of actinomycin D and relatively resistant (in comparison to WEHI 164 clone 13 cells) in its presence. The incomplete protection seen with either catalase or anti-TNF suggests that macrophage-released TNFa, in the presence of other factors, induces non-cytotoxic DNA effects in tumor cells.
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PMID:The role of macrophage-derived TNFa in the induction of sublethal tumor cell DNA damage. 173 75

Morphological and biochemical studies were performed using tissue culture methods in 14 cases of giant cell tumor of bone. Primary cultures consisted of three types of cells, multinucleated giant cells, mononuclear round cells and spindle-shaped cells. The round cells were considered to be infiltrating macrophages, not neoplastic cells, according to the results obtained by morphological and immunohistochemical studies. The spindle-shaped cells were apparently neoplastic since they extensively proliferated and showed chromosomal abnormalities. Western blotting analysis of the supernatant fluid from the culture of the spindle-shaped cells showed the presence of several cytokines; M-CSF, IFN-gamma, TNF-alpha, which were known to show chemotactic, differentiation-inducing and activating effects on macrophages. When the conditioned mediums of cultured spindle-shaped cells were added to the culture of U-937 macrophage cell line, U-937 cells were induced to differentiate and became multinucleated giant cells. The results indicate that the spindle-shaped cells which could be passaged are neoplastic elements and that the cytokines produced by these cells have a significant role in clinicopathological status of the giant cell tumor of bone.
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PMID:[Identification of cytokines produced by cells cultured from human giant cell tumors of bone]. 177 Feb 61

The anti-tumor cytotoxic activity of four newly synthesized aza alkyl lysophospholipids (AALP), namely BN 52205, BN 52207, BN 52208 and BN 52211, was investigated. Using the 51Cr release assay, the four compounds were endowed with cytotoxic activity, in a concentration-dependent fashion, against various human tumor cell lines of different histological origin. Two different mechanisms appear to be involved in the AALP-mediated cytotoxicity. A rapid membrane damaging effect was observed in less than one hour's incubation of tumor cells with AALP and cytotoxicity was temperature-independent when AALP were used at greater than or equal to 200 micrograms/ml. A slower cytotoxic mechanism was observed after 18 hours incubation at 37 degrees C when AALP were used at concentrations of 30-100 micrograms/ml. The pattern and magnitube of the cytotoxic activity achieved with all the 4 AALP compounds tested were similar and the cytotoxicity mediated by combination of two compounds was additive. In addition to the cytotoxic effect, the AALP compounds also exerted a cytostatic anti-tumor effect, as assessed by inhibition of 3H TdR incorporation. Using a variety of human tumor cell lines as targets, the cytotoxic effect observed with the AALP was noted with tumor cells that were either sensitive or resistant to TNF-alpha and/or chemotherapeutic drugs such as mitomycin C, adriamycin and cis-platinum. The LD50 toxicity in mice was 100-125 mg/kg. The present findings demonstrate that AALP are cytotoxic to a variety of human tumor cell lines and do not appear to discriminate between drug/cytokine sensitive or resistant cells. Thus the present study suggests that some aza alkyl lysophospholipids may be considered as potential anticancer agents.
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PMID:Cytotoxic activity of synthetic aza alkyl lysophospholipids against drug sensitive and drug resistant human tumor cell lines. 177 63

Conditions for generating and expanding cytotoxic tumor-specific, tumor-infiltrating lymphocytes (TIL) were studied to improve the efficacy of adoptive cancer immunotherapy. Thus, we have examined the growth and cytolytic patterns of bulk culture TIL from human renal cell carcinoma (RCC) cultured in low (20 U/ml) or high (1,000 U/ml) dose interleukin (IL)-2, with or without irradiated autologous tumor stimulation. By 55 days in culture, TIL grown in the presence of IL-2 without tumor stimulation lost their lytic activity, whereas those exposed to tumor stimulation maintained high levels of cytotoxicity against autologous and/or nonautologous tumor targets. Only TIL grown with low dose IL-2 and autologous tumor maintained long-term (over 4 months in culture) specific cytotoxicity against the autologous tumor, even upon cryopreservation and regrowth. These TIL were 88-97% and 80% positive for CD3 and CD8, with a persistent subset exhibiting CD4+ CD8+ double positive staining. Their specific cytotoxic activity was major histocompatibility complex Class I-restricted and inhibited by pretreating the TIL with anti-CD3 monoclonal antibody. TIL exposed to the four types of culture conditions, low or high dose IL-2, with or without irradiated autologous tumors, and exhibiting different lytic specificities, all expressed mRNA for interferon-gamma and tumor necrosis factor (TNF)-alpha, but not for IL-1-beta, IL-4, IL-6, and granulocyte-macrophage colony stimulating factor. The degree of TNF-alpha mRNA expression correlated with the degree of autologous tumor-specific cytotoxicity of these TIL. This initial report demonstrates that antigen-specific cytotoxicity against the autologous tumor does, in fact, exist within the RCC tumors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Autologous tumor-specific cytotoxicity of tumor-infiltrating lymphocytes derived from human renal cell carcinoma. 179 Jan 42

Expression of the Cytokine genes in human astroglial cell lineage was studied. Primers for 5 different human cytokine, TNF-alpha, -beta, IFN-gamma, G-CSF and GM-CSF, were used to analyze messenger RNA transcripts in 5 cultured human astrocytoma, one neuroblastoma cell lines and fresh brain specimens by polymerase chain reaction (PCR). Three out of 5 unstimulated astrocytomas, U138, U251, U373 MG and IMR32 neuroblastoma cells expressed TNF-alpha genes. After stimulation with IL-1 beta (1000 U/ml) all these cell lines expressed TNF-alpha genes. TNF-beta genes could not be detected in these cell lines even in the presence of any cytokine stimuli. We were able to detect expression of IFN-gamma genes within 2 astrocytoma cell lines (U87MG and A172), which interestingly did not show TNF-alpha activity. Constitutive expression of mRNA transcripts of GM -CSF could be detected in all astrocytoma and two out of 5 unstimulated astrocytomas, U87MG and U138MG, expressed G-CSF genes. After stimulation with IL-1 beta, all cell lines expressed G-CSF. In addition, we also examined gene expression of these cytokines within 4 human malignant astrocytoma specimens, 2 peritumoral brain and 2 autopsied normal brains. The results show that tumor and surrounding lesions express TNF-alpha (4 of 6), TNF-beta (1/6), IFN-gamma (4/6), G-CSF (3/6) and GM-CSF (5/6) but not normal brains. One tumor specimen also expresses TNF-beta as well as TNF-alpha genes (case 2). From these results, it is suspected that astroglial cell-derived cytokines may participate in local immune reactions accompanying glioma in the brain.
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PMID:[Expression of cytokine genes within astrocytoma cell lines and brain specimens]. 179 21

A double grafted tumor model (colon 26 and Meth-A) was established in BALB/c mice. The primary colon 26 tumor growth was inhibited by the secondary transplantation of Meth-A tumor cells into the same host, and the prolongation of mean survival time was also observed. To investigate the mechanism of the prolongation of survival, the role of tumor necrosis factor (TNF) was examined. The intraperitoneal inoculation of human TNF-alpha (1 x 10(4) units) for 5 days, as well as the secondary Meth-A tumor cell transplantation, resulted in the prolongation of survival. Moreover, the prolongation of survival disappeared by the inoculation of rabbit anti-TNF-alpha antibodies. These results suggest that TNF-alpha play an important role in the mechanism of a prolongation of survival by the secondary transplantation of the tumor cells.
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PMID:[Establishment of double grafted tumor model in mice and role of "tumor necrosis factor" (TNF)]. 180 96

We have compared the mechanisms by which human PBL targeted with bispecific antibodies either lyse tumor cells or block their growth in culture or in mice. We found that resting PBL were unable to mediate lysis, but were able to block tumor growth. Moreover, targeted PBL were unable to lyse bystander cells, whereas targeted PBL did block the growth of bystander tumor cells in culture and in nude mice. Supernatants from cultures of targeted PBL, or from PBL grown on anti-CD3-coated flasks, blocked the growth of tumor cells in the absence of added effector cells, and antibodies against TNF-alpha and IFN-gamma reversed the inhibition of tumor growth, but had no effect upon cytolysis mediated by targeted by PBL. Our results show that targeted human PBL mediate two different antitumor activities: lysis, which occurs rapidly and requires the direct attachment of the target cell to the cytotoxic cell, and tumor growth inhibition, which is mediated by cytokines released into the medium as a result of receptor cross-linking. The inhibition of bystander tumor growth in mice by targeted PBL suggests that factor release is sufficient to block tumor growth in vivo. Targeted factor release therefore provides a mechanism by which targeted PBL could block the growth of tumor cells in vivo that were not bound by the effector cells, but which were located in the vicinity of tumor cells that were bound.
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PMID:Human peripheral blood lymphocytes targeted with bispecific antibodies release cytokines that are essential for inhibiting tumor growth. 182 9


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