Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IP-10 is a member of the -C-X-C-chemokine superfamily of proinflammatory cytokines whose secretion is induced by interferon gamma (IFN-gamma) and lipopolysaccharide (LPS). To date no function has been described for IP-10. We have genetically engineered tumor cells to secrete high levels of murine IP-10 and demonstrate that while IP-10 has no effect on the growth of these tumor cells in culture, it elicits a powerful host-mediated antitumor effect in vivo. The IP-10 antitumor response is T lymphocyte dependent, non-cell autonomous, and appears to be mediated by the recruitment of an inflammatory infiltrate composed of lymphocytes, neutrophils, and monocytes. These results document an important biologic property of IP-10 and raise the possibility that some of the T cell-directed effects of IFN-gamma and LPS may be mediated by this chemokine.
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PMID:IP-10, a -C-X-C- chemokine, elicits a potent thymus-dependent antitumor response in vivo. 835 46

Tumor cells are capable of simultaneously producing a number of related inflammatory peptides, now classified as chemokines. We have isolated a new human granulocyte chemotactic protein (GCP-2), coproduced with interleukin-8 (GCP-1/IL-8) by osteosarcoma cells. Furthermore, the bovine homologue of human GCP-2 was purified from kidney tumor cells using the same isolation procedure. Both chemokines occur in at least four NH2-terminally truncated forms. These 5-6 kDa proteins do not differ in potency and efficacy as granulocyte chemotactic factors using a standard in vitro migration assay. The complete primary structures of human and bovine GCP-2 were disclosed by sequencing peptide fragments derived from the natural proteins. On the basis of the conservation of four cysteine residues, the two molecules are to be classified within the C-X-C chemokine family, including IL-8. Human and bovine GCP-2 are 67% similar at the amino acid level. Their sequences show only weak similarity with that of IL-8, and human GCP-2 does not cross-react in a radioimmunoassay for IL-8. Human and bovine GCP-2 are specific granulocyte chemotactic factors in that they do not attract human monocytes. Bovine GCP-2 is not species specific since it is at least as active as human GCP-2 on human granulocytes. Both chemokines can also activate postreceptor mechanisms leading to release of gelatinase B by granulocytes. This is indicative for a possible role in inflammation and tumor cell invasion.
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PMID:Human and bovine granulocyte chemotactic protein-2: complete amino acid sequence and functional characterization as chemokines. 839 43

We report here the ability of the beta chemokines MIP-1 alpha, MIP-1 beta, RANTES, and MCP-1 to enhance some lymphocyte effector functions. Initial studies focused on the effects of chemokines on human and mouse cytotoxic T lymphocyte (CTL)- and natural killer (NK) cell-specific cytolytic responses. The results demonstrate that beta chemokines are capable of augmenting mouse and human CTL and human NK- but not lymphokine-activated killer cell- or antibody-dependent cell cytotoxicity-specific cytolytic responses. Neutralization analysis utilizing integrin-specific antibodies revealed that CTL/NK tumor cell conjugate formation is required for chemokine-induced killing. In addition, both CTLs and NK cells incubated with various beta chemokines were induced to degranulate and release granule-derived serine esterases, suggesting that chemokines may be important costimulators of CTL and NK cell degranulation and may thus augment local target cell destruction. Chemokines also modulate antigen-driven T cell proliferative responses as well as effects on lymphokine production. Many of the beta chemokines were found to potentiate human and mouse antigen-specific Th1 and Th2 clone activation promoting cellular proliferation and the release of various lymphokines. This chemokine-mediated T cell proliferation was chemokine and antigen dose dependent as well as clone dependent. Chemokine pretreatment analyses with T cells and antigen-presenting cells (APCs) revealed that chemokines up-regulate both T cells and antigen- presenting cells (APCs) revealed that chemokines up-regulate both T cell and APC functions. Costimulation assays using immobilized antiCD3 monoclonal antibody-coated plates and purified human and mouse T cells and T cell clones in the presence of various chemokines also exhibited enhanced proliferation and lymphokine secretion. This costimulation was interleukin-2 dependent and required the presence of free extracellular calcium. Examination of chemokine-treated APCs revealed that the T cell costimulatory molecule B7-1 was induced by various beta chemokines. Neutralization of endogenously produced chemokines, with specific antibodies during an antigen-specific T cell response blocked cellular proliferation, suggesting that the chemokines have an autocrine role in antigen-induced T cell proliferative responses. Together, these results suggest that chemokines play a significant role in the activation of polyclonal as well as antigen-specific helper and cytotoxic T cells during the genesis of an immune response.
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PMID:Beta chemokines costimulate lymphocyte cytolysis, proliferation, and lymphokine production. 855 72

Interleukin-8 (IL-8) is an 8 kD chemokine and angiogenic factor produced by alveolar macrophages, endothelial cells, monocytes, fibroblasts, T lymphocytes, and epithelial cells in response to a variety of stimuli, including LPS, TNF-alpha, IL-1, IL-7, and hypoxia. Pulmonary tumors produce a variety of growth factors and cytokines that may act in both autocrine and paracrine fashion. A549, a well-characterized human lung adenocarcinoma line, was cloned for different levels of IL-8 production by limiting dilution. Clone 3B4 produced 361 +/- 73 pg/ml, and clone 2B2 produced 7818 +/- 614 pg/ml of IL-8 (p = 0.003). Clone 3B4 proliferated at 1.7 times the rate of 2B2. Anti-IL-8 reversed the decrement in proliferation of clone 2B2 by 50%, but recombinant IL-8 decreased the proliferation of 3B4 by 40-55% compared with control. In addition to A549, three other non-small cell lung cancer (NSCLC) lines showed significantly decreased proliferation in response to exogenous recombinant IL-8 (5-30 ng/ml; p < 0.05). These findings suggest that in addition to its chemotactic and angiogenic activities, IL-8 may inhibit lung tumor proliferation by both autocrine and paracrine pathways.
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PMID:Interleukin-8 inhibits non-small cell lung cancer proliferation: a possible role for regulation of tumor growth by autocrine and paracrine pathways. 864 Apr 52

Taxol is important in the treatment of both primary and drug-resistant ovarian cancer. Although Taxol is known to stabilize microtubules and block cell mitosis, the effectiveness of this drug exceeds that of other antimitotic agents, suggesting it may have an additional mode of action. Stimulated by murine macrophage studies indicating cytokine induction by Taxol, we have investigated proinflammatory cytokine expression in a series of cell lines and recent explants of human ovarian cancer. Taxol induced secretion of interleukin (IL) 8 but not IL-6, IL-1alpha, or IL-1beta in 4 of 10 samples. Induction was dependent on transcriptional activation, and, in contrast to murine macrophage studies, was apparently independent of an active lipopolysaccharide signaling pathway. Confluent cultures secreted as much IL-8 as proliferating cells. Taxol did not induce IL-8 in breast carcinoma, endometrial stromal, or T-lymphocyte or monocyte cultures. We propose that the local expression of this chemokine in vivo may elicit a host response similar in effectiveness to that of cytokine gene therapy. These data are the first to suggest that a chemotherapeutic agent may have a direct effect on transcription of cytokine and/or growth factor genes in ovarian cancer, and that this effect may not be restricted to proliferating tumor cells.
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PMID:Taxol-dependent transcriptional activation of IL-8 expression in a subset of human ovarian cancer. 864 Aug 18

Human monocyte chemoattractant protein-1 (MCP-1) has been shown to act as a chemokine in the recruitment of monocyte/macrophages during inflammation states. Furthermore, there is increasing evidence that MCP-1 is involved in the recruitment of tumor-associated macrophages. In vivo, one of the major cellular sources of MCP-1 are the smooth muscle cells. As MCP-1 gene expression and/or protein production in these cells is not necessarily correlated with the accumulation of inflammatory cells, there might possibly be additional functions of this cytokine. In the present study, we investigated by use of 35S-labeled antisense RNA probes whether the MCP-1 gene is expressed in tissue specimens of benign prostatic hyperplasia (n = 13) and specimens of prostate carcinoma (n = 8), both of which are characterized by a prominent fibromuscular stroma and inconspicuous inflammatory infiltrates. MCP-1 transcripts were located in stromal smooth muscle cells and, additionally, in basal cells of benign prostatic glands. In prostate carcinoma, the number of MCP-1 mRNA-expressing cells was significantly less than in benign prostatic hyperplasia. MCP-1 transcripts were located in preserved fibromuscular stroma and in basal cells of entrapped non-neoplastic glands but not in carcinomatous cells. Immunohistochemical staining with polyclonal antibodies raised against MCP-1 revealed strong reactivity in the fibromuscular stroma surrounding both benign and malignant glands. MCP-1 gene expression or immunoreactivity for anti-MCP-1 antibodies was not related to the rare, lymphocytic interstitial infiltrates. The results show that 1) in the absence of significant leukocyte accumulation, it is unlikely that MCP-1 exerts chemotactic functions in the prostate and 2) that MCP-1, in contrast to previous findings in a wide variety of other human neoplasms, is not expressed in carcinomatous cells of the prostate.
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PMID:Monocyte chemoattractant protein-1 gene expression in prostatic hyperplasia and prostate adenocarcinoma. 870 89

Leukocyte migration towards injury sites is directed by the interaction of chemokines with their receptors. The stages of migration are closely regulated events that involve chemokine-induced leukocyte adhesion, diapedesis and homing. Current research suggests a pathophysiological role for chemokines in diverse inflammatory states arising from viral, bacterial and parasitic infection, allergic and asthmatic reactions, atherosclerosis and arthritis. A role for chemokines in tumor immunity and angiogenesis has recently been demonstrated. A basis for the rational design of chemokine antagonists is emerging from a knowledge of tertiary structures and mutational analysis of chemokine ligands and receptors. Here, we discuss advances in knowledge about chemokine structure and function, with emphasis on potential therapeutic agents.
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PMID:Chemokines: progress toward identifying molecular targets for therapeutic agents. 874 16

The probability of producing a specific antitumor response should be increased by multiplying the number of T lymphocytes that encounter the malignant cells. We tested this prediction in a murine model, using a recently discovered T-cell chemokine, lymphotactin (Lptn). This chemokine increased tumor cell infiltration with CD4+ lymphocytes but generated little antitumor activity. Coexpression of the T-cell growth factor interleukin-2, however, greatly expanded the T lymphocytes attracted by Lptn, affording protection from the growth of established tumor in a CD4+ and CD8+ T cell-dependent manner. Lesser synergy was seen with GM-CSF. Hence coexpression of a T-cell chemokine and T-cell growth factor potentiates antitumor responses in vivo, suggesting a general strategy to improve cancer immunotherapy.
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PMID:Combined chemokine and cytokine gene transfer enhances antitumor immunity. 901 23

Leukocyte migration from circulation into tissue depends on leukocyte integrin-mediated adhesion to endothelium, but integrins cannot function until activated. However, it remains to be understood how tumor cells adhere to endothelium and infiltrate into underlying tissue. We studied mechanisms of extravasation of leukemic cells using adult T cell leukemia (ATL) cells and report the following novel features of cell surface heparan sulfate proteoglycan on ATL cells in ATL cell adhesion to endothelium: ATL cells adhere to endothelial cells through already activated integrins without exogenous stimulation; different from any other hematopoietic cells, ATL cells express a characteristic heparan sulfate capable of immobilizing heparin-binding chemokine macrophage inflammatory protein (MIP)-1 beta, a potent T cell integrin trigger, produced by the cells themselves; competitive interruption of endogenous heparan sulfate proteoglycan synthesis reduces cell surface MIP-1 beta and prevents ATL cells from integrin-mediated adhesion to endothelial cells or intercellular adhesion molecule-1 triggered through G-protein. We propose that leukemic cells adhere to endothelial cells through the adhesion cascade, similar to normal leukocyte, and that the cell surface heparan sulfate, particularly on ATL cells, is pivotally involved in chemokine-dependent autocrine stimulation of integrin triggering by immobilizing the chemokine on them.
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PMID:Heparan sulfate proteoglycan on leukemic cells is primarily involved in integrin triggering and its mediated adhesion to endothelial cells. 892 Aug 85

Human Burkitt lymphoma cell lines give rise to progressively growing subcutaneous tumors in athymic mice. These tumors are induced to regress by inoculation of Epstein-Barr virus-immortalized normal human lymphocytes. In the present study, analysis of profiles of murine cytokine/chemokine gene expression in Burkitt tumor tissues excised from the nude mice showed that expression of the murine alpha-chemokine interferon-inducible protein-10 (IP-10) was higher in the regressing than in the progressive Burkitt tumors. We tested the effects of IP-10 on Burkitt tumor growth in nude mice. Inoculation of established Burkitt tumors either with crude preparations of murine IP-10 or with purified human IP-10 caused visible tumor necrosis in a proportion of the animals, although no complete tumor regressions were observed. Constitutive expression of murine IP-10 in Burkitt cells reduced their ability to grow as subcutaneous tumors, and caused visible tumor necrosis in a proportion of the animals. Histologically, IP-10-treated and IP-10-expressing Burkitt tumors had widespread evidence of tumor tissue necrosis and of capillary damage, including intimal thickening and vascular thrombosis. Thus, IP-10 is an antitumor agent that promotes damage in established tumor vasculature and causes tissue necrosis in human Burkitt lymphomas established subcutaneously in athymic mice.
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PMID:Interferon-inducible protein-10 identified as a mediator of tumor necrosis in vivo. 894 14


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