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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lung cancer is the leading cause of malignancy-related mortality in the U.S. and is predicted to increase over the remainder of this decade. Despite attempts to advance early diagnosis and use combination therapies, the clinical response of this cancer yields an overall 5-year survival rate of less than 15%. Clearly, new strategies for therapy are indicated. Although carcinogenesis is complex, tumor growth beyond 1-2 mm3 is dependent on angiogenesis. One of the potential mechanisms that allows for tumorigenesis is dysregulation of the balance of angiogenic and angiostatic factors that favors net neovascularization within the primary tumor. Numerous studies have investigated the role of a variety of molecules in the regulation of angiogenesis. Recently, interleukin-8 (IL-8), a member of the C-X-C chemokine family, has been found to be an angiogenic factor. In contrast, platelet factor 4 (PF4), another C-X-C chemokine, has been shown to have angiostatic properties. It is interesting that the major structural difference between IL-8 and PF4 is the presence of the NH2-terminal ELR (Glu-Leu-Arg) motif that precedes the first cysteine amino acid residue of IL-8 and is important in ligand/receptor interactions. We hypothesize that angiogenesis associated with tumorigenesis is dependent on members of the C-X-C chemokine family acting as either angiogenic or angiostatic factors. This paradigm predicts that the biological balance in the expression of these C-X-C chemokines dictates whether the neoplasm grows and develops metastatic potential or regresses. In this review we discuss our recent laboratory findings that support this contention and suggest that further elucidation of the biology of C-X-C chemokines in the context of neovascularization of nonsmall cell lung cancer will permit novel targeted therapy aimed specifically at attenuating tumor growth and metastasis.
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PMID:Role of C-X-C chemokines as regulators of angiogenesis in lung cancer. 753 29

To study the effect of localised secretion of chemokines on tumour growth, the genes for human (hu) interleukin 8 (IL-8), hu-MCP-1 (MCAF), hu-MIP-1 alpha (LD78), murine (mu)-MCP-1 (JE), mu-MIP-1 alpha or mu-MIP-2 were introduced, via mammalian expression vectors, into Chinese hamster ovary (CHO) cells, and the ability of transfected cells to form tumours in vivo was evaluated. The production of hu-IL-8, hu-MIP-1 alpha or mu-MIP-1 alpha by transfected clones did not influence the growth rate in vitro, but drastically suppressed tumour growth when injected subcutaneously (s.c.) into nude mice. However, clones transfected with hu-MCP-1, mu-MCP-1 or mu-MIP-2 did not show any significant difference in growth rate in vivo compared with clones transfected with vector alone. Histological examination of the site of injection of CHO clones transfected with hu-IL-8, hu-MIP-1 alpha or mu-MIP-1 alpha showed predominantly neutrophilic infiltration. These results indicate that chemokines have potent anti-tumour activity when released, even at low doses, at the tumour site, which may be mediated by recruitment and targeting of neutrophilic granulocytes to chemokine-releasing cells. Our studies highlight the potential usefulness of localised chemokine secretion in inducing potent host anti-tumour defensive responses.
Br J Cancer 1995 Sep
PMID:Chemokine gene transfection into tumour cells reduced tumorigenicity in nude mice in association with neutrophilic infiltration. 766 85

Chemokines may control the macrophage infiltrate found in many solid tumors. In human ovarian cancer, in situ hybridization detected mRNA for the macrophage chemokine monocyte chemoattractant protein-1 (MCP-1) in 16/17 serous carcinomas, 4/4 mucinous carcinomas, 2/2 endometrioid carcinomas, and 1/3 borderline tumors. In serous tumors, mRNA expression mainly localized to the epithelial areas, as did immunoreactive MCP-1 protein. In the other tumors, both stromal and epithelial expression were seen. All tumors contained variable numbers of cells positive for the macrophage marker CD68. MCP-1 mRNA was also detected in the stroma of 5/5 normal ovaries. RT-PCR demonstrated mRNA for MCP-1 in 7/7 serous carcinomas and 6/6 ovarian cancer cell lines. MCP-1 protein was detected by ELISA in ascites from patients with ovarian cancer (mean 4.28 ng/ml) and was produced primarily by the cancer cells. Human MCP-1 protein was also detected in culture supernatants from cell lines and in ascites from human ovarian tumor xenografts which induce a peritoneal monocytosis in nude mice. We conclude that the macrophage chemoattractant MCP-1 is produced by epithelial ovarian cancer and that the tumor cells themselves are probably a major source. MCP-1 may contribute to the accumulation of tumor-associated macrophages, which may subsequently influence tumor behavior.
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PMID:The detection and localization of monocyte chemoattractant protein-1 (MCP-1) in human ovarian cancer. 773 2

Tumor infiltrating lymphocyte (TIL) is commonly observed in renal cell carcinoma (RCC) tissues. First step of lymphocyte accumulation in cancerous tissues is the lymphocyte migration toward cancer cells. However, no conclusion has been drawn which cytokine is involved in TIL of RCC. The purpose of this study is the identification of a lymphocyte chemotactic factor (chemokine) produced by a newly established RCC cell line. A new human renal cancer cell line (TC-2) was established from a primary site of a 52-year-old man. A marked lymphocyte infiltration was noticed at the cancer tissue. A tissue culture has been continued for 24 months. Flow cytometric analysis of this cell line revealed DNA aneuploidy. A human karyotype, with a modal number of 72, and consistent abnormalities, such as 4q+ and 5q-, were demonstrated by Giemsa banding analysis. Approximately 2.9 fold of lymphocyte chemotactic activity was detected in the culture supernatant of TC-2 cells (TC-2CM) as measured by in vitro migration assay. Sixty percent of this activity was abrogated by adding the neutralizing antibody against interleukin-8 (IL-8) into TC-2CM. Analysis of surface markers of migrating lymphocytes disclosed that lymphocytes expressing CD3, CD8 and CD16 phenotype predominantly showed migration. These results suggested that chemotactic activity for lymphocytes derived from TC-2 cells was partly IL-8.
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PMID:[Production of a lymphocyte chemotactic factor by human renal cancer cells]. 780 73

We examined the genetic expression of 2 CXC chemokines (IL-8, IP-10), 5 CC chemokines (MCP-1, MIP-lalpha, MIP-1beta, RANTES, 1309) and 1 C chemokine (SCM-1/lymphotactin/ATAC) in various human T-cell lines. By Northern blot analysis, HTLV-1-positive T-cell lines were found to express a number of chemokine genes at variable levels and in different combinations. However, none of the chemokine genes was expressed in HTLV-1-negative T-cell lines. We further confirmed secretion of 3 chemokines (IL-8, MIP-1alpha and RANTES) by some HTLV-1-positive T-cell lines. To examine the role of the HTLV-1-encoded transactivator Tax in the induction of these chemokine genes, we used JPX-9 and JPX-M, which were stably transformed with tax and non-functional tax, respectively, under the control of a metallothionein promoter. Induction of tax in JPX-9 with Cd2+ was accompanied by rapid induction of IL-8, IP-10, MIP-1alpha, MIP-1beta, 1309 and SCM-1 as determined by reverse transcription PCR. No such induction was seen in JPX-M. We thus suggest that Tax is, at least in part, responsible for constitutive expression of certain chemokine genes in HTLV-1-infected T cells. Aberrant production of various chemokines by HTLV-1- infected T cells may impact on the pathophysiology of HTLV-1-associated diseases.
Int J Cancer 1996 Mar 28
PMID:Constitutive expression of various chemokine genes in human T-cell lines infected with human T-cell leukemia virus type 1: role of the viral transactivator Tax. 860 55

IL-2 mediates the regression of certain malignancies, but clinical use is limited because of associated toxicities, including parenchymal lymphocytic infiltration with multiple organ failure. Secondarily induced cytokines are important mediators of IL-2 toxicity and IL-2-induced lymphocyte-endothelial adherence and trafficking. The recently discovered C-C chemokines, RANTES (regulated on activation, normal T expressed and secreted) and macrophage inflammatory protein-1alpha, have also been implicated in lymphocytic migration. We hypothesized that IL-2 alters cytokine, C-C chemokine, and adhesion molecule expression in association with parenchymal lymphocytic infiltration. C57BL/6 mice were injected with 3x10(5) IU of IL-2 or 0.1 ml of 5% dextrose intraperitoneally every 8 h for 6 d, then killed. IL-2 induced massive lymphocytic infiltration in the liver and lung and moderate infiltration in the kidney in association with organ edema and dysfunction. Immunostaining showed increased intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression in association with this organ-specific lymphocytic infiltration. Flow cytometry showed increased expression of the corresponding ligands (lymphocyte function-associated antigen-1 and very late antigen-4) on splenocytes. IL-2 increased TNF-alpha mRNA and protein expression in the liver. Organs infiltrated by lymphocytes had increased TNF-alpha mRNA, whereas RANTES mRNA was increased in all organs, regardless of lymphocytic infiltration. IL-2 toxicity involves organ-specific TNF-alpha and RANTES production with increased ICAM-1 and VCAM-1 expression as potential mechanisms facilitating lymphocytic infiltration and organ dysfunction.
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PMID:The role of cytokines, adhesion molecules, and chemokines in interleukin-2-induced lymphocytic infiltration in C57BL/6 mice. 862 80

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.
Cancer Res 1996 Mar 15
PMID:Taxol-dependent transcriptional activation of IL-8 expression in a subset of human ovarian cancer. 864 Aug 18

A fusion protein was generated by genetic engineering which combined a Fab fragment of a monoclonal antibody directed to the human epidermal growth factor receptor with the biologically active N-terminally truncated 2-72 amino acid form of the human chemokine IL-8. The Fab IL-8 fusion protein was expressed in E. coli and antibody binding and IL-8 activity were determined. Our data indicate that the N-terminus of IL-8 remains functional for receptor interaction. The fusion protein showed specific binding to IL-8 receptors, induced IL-8 mediated chemotactic activity, and the release of MPO activity. However, N-terminal fusion of IL-8 to the carboxyl terminus of the Fab fragment resulted in reduced binding to IL-8 receptors and consequently to reduced biologic activity of IL-8. The affinity of the antibody arm for EGF-R was improved when compared to a monovalent Fab. Fusion proteins as described herein may represent improved therapeutics for cancer therapy based on their potential to selectively increase and prolong cytokine concentration in the tumour. Since chemokines such as IL-8 recruit effector cells and stimulate effector cell function in situ, a lymphocyte-independent anti-tumour activity followed by tumour-specific immunity could be proposed.
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PMID:A fusion protein of IL-8 and a Fab antibody fragments binds to IL-8 receptors and induces neutrophil activation. 883 36

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

Chemokines, together with adhesion molecules, cytokines, and proteases, are essential for the directional migration of leukocytes during normal and inflammatory processes. Interleukin-8 and monocyte chemotactic protein-1 are the best-characterized members of the C-X-C and C-C chemokine subfamilies, respectively. However, more than 20 human chemokines have been identified but are only partially characterized at the biological level. Chemokines are involved in chemotaxis of monocytes, lymphocytes, neutrophils, eosinophils, basophils, natural killer cells, dendritic cells, and endothelial cells. This review describes the chemokine subfamilies, the chemokine producer and target cells, their receptors, signal transduction mechanisms, and the role of chemokines during physiological and pathological conditions. More and more evidence points to a role for chemokines in chemotaxis-related phenomena, such as the expression of adhesion molecules, the secretion of proteinases, inhibition of apoptosis, hematopoiesis, and angiogenesis. Chemokines are also involved in diseases such as cancer (tumor regression and tumor metastasis), autoimmune diseases, and bacterial or viral infection.
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PMID:The role of chemokines in inflammation. 900 10


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