Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We reported previously that tumor cells isolated from metastases of the in vitro transformed squamous cell carcinoma line Pam 212 exhibit an elevation in constitutive production of proinflmmatory cytokines interleukin (IL)-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor, and KC (the murine homologue of chemokine Gro-alpha). The basis for constitutive expression of these cytokines after tumor progression in vivo is unknown. Regulation of the expression of these proinflammatory cytokines involves transcription factor nuclear factor kappaB (NF-kappaB), which can be activated by cytokines such as tumor necrosis factor (TNF)-alpha. In this study, we compared the constitutive and TNF-alpha-induced expression of proinflammatory cytokines in parental Pam 212 and metastatic LY-2 and LY-8 cell lines and determined the relationship of cytokine expression to activation of NF-kappaB. We found that the metastatic cell lines exhibited an increase in constitutive and TNF-alpha-inducible expression of proinflammatory cytokines when compared with parental Pam 212 cells. The increased cytokine expression was associated with an increase in constitutive and TNF-alpha-inducible activation of NF-kappaB as demonstrated by electrophoretic mobility shift assay and luciferase-reporter gene assay. Constitutive nuclear localization of NF-kappaB p65 was observed in LY-2 and LY-8 cells in culture and in tumor specimens but rarely in Pam 212 cells, consistent with the constitutive activation of NF-kappaB in tumor cels after selection in vivo. Induction of NF-kappaB by TNF-alpha was inhibited by the addition of protease inhibitors calpain inhibitor I and N-tosyl-phechloromethyl ketone and antioxidant 1-pyrrolidinecarbodithioic acid, whereas constitutive activation of NF-kappaB and cytokine KC mRNA expression was inhibited by N-tosyl-phechloromethyl ketone alone. Overexpression of a human Ikappa(B)alpha dominant suppresser in Pam 212 cells inhibited TNF-alpha-induced NF-kappaB binding activity and KC expression. These data indicate that activation of NF-kappaB contributes to increased expression of proinflammatory cytokines during metastatic tumor progression of squamous cell carcinoma, and that distinct mechanisms may be involved in the regulation of constitutive and TNF-alpha-induced activation of NF-kappaB in squamous cell carcinoma.
Cancer Res 1999 Jul 15
PMID:The host environment promotes the constitutive activation of nuclear factor-kappaB and proinflammatory cytokine expression during metastatic tumor progression of murine squamous cell carcinoma. 1041 16

Breast carcinoma is the most common malignant disease among women and the second most lethal one. In search for a better understanding of the role of cellular mediators in the progression of this disease, we investigated the potential involvement of the CC chemokine Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) in breast carcinoma progression. To this end, RANTES expression was determined in breast tumor cell lines and in sections of breast carcinomas, followed by analysis of the incidence and intensity of its expression in different stages of the disease. Our study reveals that high and physiologically relevant levels of RANTES are constitutively produced by T47D and MCF-7 breast tumor cell lines. Analysis of RANTES expression in sections of breast carcinomas demonstrates a high incidence of RANTES expression in epithelial tumor cells; the chemokine was expressed in 74% of the sections. RANTES expression was rarely detected in normal duct epithelial cells or in epithelial cells that constitute benign breast lumps, which were located in proximity to tumor cells. High incidence and intensity of RANTES expression were detected in sections of most of the patients with stage II and stage III of the disease (expression was detected in 83 and 83.3%, respectively), whereas RANTES was expressed at a lower incidence and intensity in sections of patients with stage I of breast carcinoma (55% of the cases). Most importantly, the expression of RANTES was minimally detected in sections of patients diagnosed with benign breast disorders and of women that underwent reduction mammoplasty (15.4% of the cases). These results indicate that the expression of RANTES is directly correlated with a more advanced stage of disease, suggesting that RANTES may be involved in breast cancer progression. Moreover, it is possible that in patients diagnosed with benign breast disorders, RANTES expression may be indicative of an ongoing, but as yet undetectable, malignant process.
Cancer Res 1999 Sep 15
PMID:Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma. 1049 25

The systemic transfer of ex vivo-activated tumor-sensitized T lymphocytes can mediate immunologically specific regression of established tumors. However, it has not been conclusively established whether the infiltration of systemically transferred T cells into metastases is required for their effector function. In this study, T cells from lymph nodes draining the murine fibrosarcoma MCA 205 cells were activated ex vivo with anti-CD3 monoclonal antibody and interleukin-2. During the final 24 h of culture, the T cells were treated with pertussis toxin (PTX) to inhibit signaling through G protein-coupled chemokine receptors required for diapedesis. Systemically transferred PTX-treated cells did not have any therapeutic efficacy against 3-day established pulmonary metastases. This lack of efficacy correlated with their failure to infiltrate the tumor parenchyma. However, PTX-treated cells responded to tumor antigen stimulation with IFN-gamma secretion in vitro. More importantly, PTX-treated effector T cells prevented tumor growth when they were admixed with tumor cells and inoculated s.c. These results demonstrate that systemically transferred tumor-reactive T lymphocytes need to infiltrate the tumor parenchyma through the endothelium to initiate tumor regression, but PTX-sensitive proteins are not required for either antigen recognition or effector functions.
Cancer Res 1999 Oct 15
PMID:Infiltration of tumors by systemically transferred tumor-reactive T lymphocytes is required for antitumor efficacy. 1053 4

The chemokine monocyte chemoattractant protein (MCP)-1 is an important mediator of monocyte infiltration in various solid tumours of epithelial origin. The aim of the present study was to evaluate the role of MCP-1 in the natural history of ovarian cancer and to determine its value as differentiation marker and prognostic marker regarding disease free and overall survival. This retrospective study comprises 86 patients with ovarian cancer, 48 with primary ovarian cancer and 38 with recurrent ovarian cancer, 67 patients with benign ovarian cysts and 42 healthy women. Median serum levels in patients with primary ovarian cancer, recurrent ovarian cancer, benign ovarian cysts and in healthy women were 535.6 (range 129.6-1200) pg ml(-1), 427.3 (range 193.4-1101) pg ml(-1), 371.2 (range 222-986.8) pg ml(-1) and 318.7 (range 241.3-681.4) pg ml(-1) respectively (Mann-Whitney U-test, P < 0.001). Univariate logistic regression models revealed a significant influence of MCP-1 serum levels on the odds of presenting with primary ovarian cancer versus benign cysts and versus healthy women respectively (univariate logistic regression, P < 0.001 and P < 0.001 respectively). In a multivariate logistic regression model considering MCP-1 and CA 125 serum levels simultaneously, both MCP-1 and CA 125 revealed statistical significance on the odds of presenting with primary ovarian cancer versus benign cysts (multivariate logistic regression, P = 0.05 and P < 0.001 respectively). In ovarian cancer patients, MCP-1 serum levels showed a statistically significant correlation with histological grade (Mann-Whitney U-test, P = 0.02) and age at the time of diagnosis (Mann-Whitney U-test, P = 0.03). Elevated MCP-1 serum levels prior to therapy were not associated with disease-free and overall survival (log-rank test, P = 0.2 and P = 0.7 respectively). In summary these data indicate that MCP-1 might play a functional role in the natural history of ovarian cancer and might serve as differentiation marker between benign ovarian cysts and ovarian cancer, providing additional information to the established tumour marker CA 125.
Br J Cancer 1999 Nov
PMID:Monocyte chemoattractant protein-1 serum levels in ovarian cancer patients. 1055 58

B-cell malignancy-derived Ig may be considered a model tumor antigen for vaccine development. However, as a non-immunogenic self antigen, it must also be first rendered immunogenic by chemical or genetic fusion to carriers which enable the induction of protective antitumor immunity in murine tumor models. Our group has demonstrated that active immunizations of human patients with idiotypic vaccines elicited antigen-specific CD8+ T-cell responses and antitumor effects. Several alternative preclinical strategies to develop vaccines have been previously reported, including fusion of tumor idiotype-derived single chain Fv with cytokines and immunogenic peptides. On the other hand, we have recently explored a different approach in which the model antigen is rendered immunogenic in mice by genetically fusing it to a chemokine moiety. Administration of these vaccines as fusion proteins or naked DNA vaccines may allow efficient targeting of antigen-presenting cells in vivo. Potent antitumor immunity was dependent on the generation of specific anti-idiotypic antibodies and both CD4+ and CD8+ effector T cells. We propose that chemokine fusion may represent a novel, general strategy for formulating existing or newly identified tumor and HIV antigens into vaccines for cancer and AIDS, respectively, which elicit potent CD8+ T-cell immunity.
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PMID:B-cell malignancies as a model for cancer vaccines: from prototype protein to next generation genetic chemokine fusions. 1056 46

DNA vaccines were introduced less than a decade ago but have already been applied to a wide range of infectious and malignant diseases. Here we review the current understanding of the mechanisms underlying the activities of these new vaccines. We focus on recent strategies designed to enhance their function including the use of immunostimulatory (CpG) sequences, dendritic cells (DC), co-stimulatory molecules and cytokine- and chemokine-adjuvants. Although genetic vaccines have been significantly improved, they may not be sufficiently immunogenic for the therapeutic vaccination of patients with infectious diseases or cancer in clinical trials. One promising approach aimed at dramatically increasing the immunogenicity of genetic vaccines involves making them 'self-replicating'. This can be accomplished by using a gene encoding RNA replicase, a polyprotein derived from alphaviruses, such as Sindbis virus. Replicase-containing RNA vectors are significantly more immunogenic than conventional plasmids, immunizing mice at doses as low as 0.1 microg of nucleic acid injected once intramuscularly. Cells transfected with 'self-replicating' vectors briefly produce large amounts of antigen before undergoing apoptotic death. This death is a likely result of requisite double-stranded (ds) RNA intermediates, which also have been shown to super-activate DC. Thus, the enhanced immunogenicity of 'self-replicating' genetic vaccines may be a result of the production of pro-inflammatory dsRNA, which mimics an RNA-virus infection of host cells.
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PMID:DNA and RNA-based vaccines: principles, progress and prospects. 1058 Jan 87

In an attempt to define the molecular changes associated with the paclitaxel-resistant phenotype in human cancer, a paclitaxel-resistant ovarian cancer cell line, SKOV-3TR, was established through stepwise selection in increasing paclitaxel concentrations. SKOV-3TR was cross- resistant to doxorubicin and vincristine and overexpressed multidrug resistance gene 1 but not multidrug resistance associated protein. SKOV-3TR and the paclitaxel-sensitive SKOV-3 parent line were characterized using human cDNA array technology that examined expression of a wide variety of genes involved in cell growth, signal transduction, cell death, and immune function. cDNA probes from reverse transcribed mRNAs of both paclitaxel-resistant and parent cells were compared to identify genes differentially expressed in the paclitaxel-resistant cells. Of 588 different human cDNA transcripts compared, 6 genes were found to be markedly decreased, and 12 genes increased in the resistant subline. Northern analysis and/or reverse transcription-PCR confirmed that 12 of these 18 genes were over- or underexpressed in SKOV-3TR. In addition, at least eight of the genes were found differentially expressed in several other paclitaxel- and/or doxorubicin-resistant cell lines, both those with increased multidrug resistance expression and those without. Included in the set of overexpressed genes were the cytokines/chemokines interleukin 6, interleukin 8, and monocyte chemotactic protein 1. ELISA assays confirm that mRNA overexpression of these cytokine/chemokines was associated with the increased secretion of these molecules in the tissue culture supernatant. Evaluation of supernatants from an expanded collection of paclitaxel- and Adriamycin-resistant cell lines demonstrated that all of the resistant lines had significant overexpression of at least one cytokine/chemokine as compared with their drug-sensitive parent line. The overexpression of these cytokines seemed to be stable and associated with a drug-resistant phenotype with only a modest induction of cytokine expression in the parent line with short-term paclitaxel exposure. These findings suggest that the development of paclitaxel resistance is accompanied by multiple changes in gene expression including stable alterations in selective chemokine and cytokine expression. The role these associated genetic changes have in the drug-resistant phenotype is discussed.
Clin Cancer Res 1999 Nov
PMID:Discovery of differentially expressed genes associated with paclitaxel resistance using cDNA array technology: analysis of interleukin (IL) 6, IL-8, and monocyte chemotactic protein 1 in the paclitaxel-resistant phenotype. 1058 57

CD44 is the principal cell surface receptor for extracellular matrix glycosaminoglycan hyaluronan. CD44-hyaluronan mediated cell adhesion is important in several pathophysiological processes such as inflammation and metastatic spread of cancer cells. It has been recently recognized that CD44 also functions as a signaling receptor in a variety of cell types. Cell stimulation by monoclonal anti-CD44 antibody or natural CD44 ligands activate several signaling pathways that culminate in cell proliferation, cytokine secretion, chemokine gene expression and cytolytic effector functions. One of the earliest signaling events following stimulation via CD44 is tyrosine phosphorylation of intracellular proteins substrates, and CD44 mediated cellular activation could be abolished by protein tyrosine kinase (PTK) inhibitors. The Src-family non-receptor PTKs such as Lck, Fyn, Lyn and Hck were shown to be coupled to CD44 via sphingolipid-rich microdomains (lipid rafts) of the plasma membrane. Studies on T cell receptor and IgE receptor mediated signaling in lymphocytes and mast cells have consolidated the notion that microdomains consist of signaling platforms where components of multiple signaling pathways are assembled. Co-isolation of CD44 with microdomains strongly suggests that CD44 generates cellular activation signals utilizing the signaling machinery of the plasma membrane microdomains.
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PMID:Signal transduction via CD44: role of plasma membrane microdomains. 1060 83

Monocyte chemotactic protein-1 (MCP-1, CCL2) is an important determinant of macrophage infiltration in tumors, ovarian carcinoma in particular. MCP-1 binds the chemokine receptor CCR2. Recent results indicate that proinflammatory and anti-inflammatory signals regulate chemokine receptor expression in monocytes. The present study was designed to investigate the expression of CCR2 in tumor-associated macrophages (TAM) from ovarian cancer patients. TAM isolated from ascitic or solid ovarian carcinoma displayed defective CCR2 mRNA (Northern blot and PCR) and surface expression and did not migrate in response to MCP-1. The defect was selective for CCR2 in that CCR1 and CCR5 were expressed normally in TAM. CCR2 gene expression and chemotactic response to MCP-1 were decreased to a lesser extent in blood monocytes from cancer patients. CCR2 mRNA levels and the chemotactic response to MCP-1 were drastically reduced in fresh monocytes cultured in the presence of tumor ascites from cancer patients. Ab against TNF-alpha restored the CCR2 mRNA level in monocytes cultured in the presence of ascitic fluid. The finding of defective CCR2 expression in TAM, largely dependent on local TNF production, is consistent with previous in vitro data on down-regulation of chemokine receptors by proinflammatory molecules. Receptor inhibition may serve as a mechanism to arrest and retain recruited macrophages and to prevent chemokine scavenging by mononuclear phagocytes at sites of inflammation and tumor growth. In the presence of advanced tumors or chronic inflammation, systemic down-regulation of receptor expression by proinflammatory molecules leaking in the systemic circulation may account for defective chemotaxis and a defective capacity to mount inflammatory responses associated with advanced neoplasia.
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PMID:Defective expression of the monocyte chemotactic protein-1 receptor CCR2 in macrophages associated with human ovarian carcinoma. 1062 17

As an antitumor agent, interleukin-12 (IL-12) has been revealed to be a key regulator of the immune response, particularly that involving CTL and natural killer (NK) cells. We report herein the antiangiogenesis effect of IL-12 on human as well as murine tumors in NK-depleted severe-combined immunodeficient mice using fibroblasts genetically engineered to secrete this cytokine. Although the in vitro growth of tumor cells was not affected by the presence of IL-12, coinoculation of IL-12-secreting fibroblasts strongly inhibited tumor growth in immunodeficient mice. The neovascularization surrounding the tumor was remarkably inhibited in the area in which the IL-12-secreting fibroblasts were implanted, resulting in the suppression of tumor growth. Lectin staining in tumor sample sections also showed a significant reduction in the number of vessels. The RNA expression of IFN-gamma and its inducible antiangiogenic chemokine IFN gamma-inducible protein 10 was stimulated in endothelial cells cultured with IL-12. It was also found that IL-12 down-regulated the expression of the endothelial cell mitogens vascular endothelial growth factor and basic fibroblast growth factor. The antitumor effects of IL-12 were accompanied by interesting histological changes consisting of a high degree of keratinization and apoptosis and a decrease in the proliferation rate of human tumors and extensive necrosis in the murine ones.
Cancer Res 2000 Feb 15
PMID:Direct in vitro evidence and in vivo analysis of the antiangiogenesis effects of interleukin 12. 1070 32


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