Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0007097 (carcinoma)
 152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro-activated macrophages (Mphi) co-express cytotoxicity for tumor cells and suppression of lymphocyte proliferation. These Mphi functions increase during tumor growth and are mediated by soluble molecules. Because Mphi-derived nitric oxide (NO) and TNF-alpha mediate both cytotoxicity and suppression, we determined whether fibrosarcoma (Meth-KDE) growth increased Mphi-mediated suppression of T cell proliferation by increasing Mphi NO and TNF-alpha production. Tumor-bearing host peritoneal Mphi produced more NO and TNF-alpha than normal host Mphi when activated with IFN-gamma or LPS, respectively. This tumor-induced increase in Mphi NO and TNF-alpha production mediated suppression of alloantigen-driven T cell proliferation, because treatment with either NG-monomethyl-L-arginine or anti-TNF-alpha Ab blocked tumor-bearing host Mphi-mediated suppression. TNF-alpha did not directly suppress T cells, but it induced Mphi NO production that down-regulated proliferation. When non-tumor-infiltrating peritoneal Mphi were cultured with Meth-KDE cell supernatants, Mphi production of NO and TNF-alpha was strongly down-regulated. The tumor-derived molecules responsible for this inhibition were IL-10, TGF-beta 1, and prostaglandin E2. The experimental evidence leading to this conclusion included: 1) The Meth-KDE cells produced significant levels of these cytokines. 2) Recombinant forms of these cytokines suppressed NO and TNF-alpha production. 3) Ab-mediated absorption of these cytokines from tumor cell supernatants restored NO and TNF-alpha production. 4) Anti-IL-10 and anti-TGF-beta 1 Ab addition to IFN-gamma-stimulated Mphi restored NO production. Culture supernatants of two human carcinoma cell lines and another murine fibrosarcoma suppressed Mphi NO and TNF-alpha production, which was partly mediated by TGF-beta 1 and prostaglandin E2. Collectively, these results suggest that tumor growth promotes distal Mphi suppressor activity by increasing Mphi production of cytotoxic molecules and concomitantly down-regulating the local production of these antitumor molecules.
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PMID:Tumor-induced regulation of suppressor macrophage nitric oxide and TNF-alpha production. Role of tumor-derived IL-10, TGF-beta, and prostaglandin E2. 804 39

We investigated the effects of human recombinant interferons (r-IFNs) on gelatinase production and invasion by human renal-cell carcinoma (HRCC). Incubation of KG-2 HRCC with human r-IFN-beta or -gamma (but not -alpha) suppressed transcription of the 72-kDa gelatinase gene and, hence, production of gelatinase activity. These inhibitory effects of interferons (IFNs) were independent of their antiproliferative effects. Treatment of KG-2 cell with r-IFN-beta or -gamma significantly inhibited cell invasion through reconstituted basement membrane toward chemoattractants produced by kidney fibroblasts. The inhibitory activity of r-IFNs was specific to the KG-2 cells since gelatinase activity by various fibroblasts was unaffected. These findings suggest that r-IFN-beta or IFN-gamma may be used to inhibit the invasive potential of HRCC.
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PMID:Human recombinant interferons-beta and -gamma decrease gelatinase production and invasion by human KG-2 renal-carcinoma cells. 805 Aug 21

Carcinoembryonic antigen (CEA) is a highly glycosylated cell surface protein. It is produced in large amounts in essentially all colon and several other adenocarcinomas. It has therefore been widely used as a clinical tumor marker. CEA is also a member of the immunoglobulin superfamily. Members of this family, such as ICAM-1, ICAM-2, VCAM-1 and NCAM, are known to participate in cell-cell adhesion. Similarly, the intercellular adhesion properties of CEA have been documented: it has been shown to mediate homotypic adhesion of cultured human colon adenocarcinoma cell lines. In this study we show for the first time that CEA is expressed on cultured human umbilical vein endothelial cells and on the endothelial cell line Ea.hy926. The expression of CEA on cultured endothelial cells can be enhanced by TNF-alpha or IFN-gamma, and decreased by IL-4. We demonstrate using immunohistochemistry that anti-CEA monoclonal antibody reacted with FVIII-positive endothelium in tissue sections prepared from lymph nodes. Finally, we were able to show that CEA-positive breast carcinoma cells bind to purified CEA protein, whereas CEA-negative breast carcinoma cells do not. These results reveal for the first time that endothelial cells express CEA on the cell surface and suggest that CEA-expressing adenocarcinomas could adhere to endothelial cells via CEA-CEA interaction, thus facilitating tumor cell extravasation and hematogenic metastasis.
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PMID:Carcinoembryonic antigen is expressed on endothelial cells. A putative mediator of tumor cell extravasation and metastasis. 806 3

We examined the expression of intercellular--adhesion molecule-I (ICAM-I, CD54) in 6 surgically removed pancreatic tumors and 8 pancreatic tumor cell lines. Immunohistochemistry revealed a varying percentage of ICAM-I-positive pancreas tumor cells, while normal pancreatic tissue (except for slight reactivity of endothelial cells) was not stained. The presence of the ICAM-I molecule on the cell surface and the expression of ICAM-I mRNA were investigated for 8 different pancreatic tumor cell lines. Three of these (Capan-I, Capan-2, QGP-I) expressed ICAM-I constitutively. In 4 of the ICAM-I-negative pancreas cancer cell lines, it was possible to induce a remarkable expression of ICAM-I by incubating the cells in the presence of inflammatory cytokines, whereas one cell line, 818-4, remained ICAM-I-negative. The responsiveness to either IFN-gamma, TNF-alpha, or IL-I beta treatment was shown to vary from cell line to cell line, indicating complex mechanisms that regulate the expression of ICAM-I at both, the transcriptional and the post-transcriptional level. Interestingly, ICAM-I is shed by pancreatic tumor cells, since soluble sICAM-I was detected in the cell-culture supernatants. In comparison with normal sera, the mean level of sICAM-I in sera of patients with pancreas carcinoma is elevated 2-fold.
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PMID:De novo expression of intercellular adhesion molecule 1 (ICAM-1, CD54) in pancreas cancer. 809 83

Intercellular adhesion molecule-1 (ICAM-1) is one of the cell adhesion molecules. This molecule is a glycoprotein of about 90 KDa belonging to the immunoglobulin (Ig) superfamily and is widely expressed by hematopoietic and non-hematopoietic cells which play a role in the immune system. ICAM-1 is also a ligand or counter-receptor for the leukocyte integrin lymphocyte-function associated antigen-1 (LFA-1). We investigated the expression of ICAM-1 on the surfaces of cells from fifteen head and neck squamous carcinoma cell lines and the modulation of ICAM-1 expression by IFN-gamma, using an immunohistochemical stain. We categorized four types of stain degree. (-): < 10% of cells positive (+/-): 10-40% of cells positive (+): < 40-70% of cells positive (++): > 70% of cells positive Four cell lines showed (-) type. Three cell lines: (+/-). One cell line: (+). Seven cell lines: (++). The primary site of cell lines and the degree of ICAM-1 expression were not detectable. Connection between pathological differentiation and the degreed expression were not apparent, either. IFN-gamma up-regulated the degree of ICAM-1. All cell lines, when stimulated by IFN-gamma, showed (++) type.
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PMID:[The expression of ICAM-1 on head and neck squamous cell carcinoma cell lines]. 810 Feb 70

17-1A is a murine monoclonal antibody (MAb) specific for the tumor-associated antigen CO17-1A on colorectal carcinoma cells. One of the tumor cell destruction mechanisms induced by in vivo immunotherapy with MAb17-1A has been claimed to be antibody-dependent cellular cytotoxicity (ADCC) by monocytes and NK cells. In the present study we investigated whether human neutrophils (PMN) could be involved in colorectal carcinoma cell lysis and whether IFN-gamma influences this function. We showed that neutrophils are capable of tumor lysis mediated by MAb17-1A, although to a lesser extent than are the mononuclear cells (PBMC). Neutrophil ADCC was, however, markedly increased in the presence of IFN-gamma. Enhancement by IFN-gamma was also observed for PBMC. ADCC by PMN required the binding of MAb17-1A to Fc gamma RIII (CD16) since anti-Fc gamma RIII MAbs efficiently blocked tumor cell lysis. In contrast, in the presence of IFN-gamma the neutralization of Fc gamma RIII did not affect MAb17-1A-mediated cytotoxicity, suggesting that receptors other than Fc gamma RIII were involved in the process. PBMC cytotoxicity was also inhibited by anti-CD16 antibodies but IFN-gamma did not overcome this effect. Finally, the scavenger enzymes superoxide dismutase and catalase did not block ADCC by PMN or PBMC, indicating that oxidants are not key factors in MAb17-1A-mediated lysis; however, in IFN-gamma-activated PMN the oxygen-dependent mechanism was in part involved in tumor lysis.
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PMID:Interferon-gamma enhances monoclonal antibody 17-1A-dependent neutrophil cytotoxicity toward colorectal carcinoma cell line SW11-16. 813 53

The effects of interleukin-6 (IL-6) on interferon regulatory factor 1 (IRF-1) gene expression were studied in B-hybridoma B9 cells which are growth-stimulated by IL-6 and breast carcinoma T47D cells which are growth-inhibited. IL-6 induced the production of IRF-1 mRNA and protein in both cell types, but IRF-1 binding activity to its target DNA sequence was induced only in T47D cells. With B9 cells, there was no IRF-1 binding but instead strong constitutive binding of the IRF-2 repressor, indicating that binding of IRF-1 to DNA is an important regulatory step. The IRF-1 gene promoter element, palindromic IFN-response element (pIRE), was found to respond to IL-6 with high efficiency as compared with IFN-gamma or IFN-beta. On this palindromic TTC...GAA sequence, two protein complexes (pIRE-a and pIRE-b) were induced within minutes by IL-6. pIRE-b is similar to the main complex induced by IFN-gamma and contains the Stat91 protein. pIRE-a predominantly induced by IL-6 is a slowly migrating complex which does not contain Stat91 and has low affinity for IFN-gamma activated sequence (GAS)-type sequences. Comparison of the relative effects of IL-6 and IFN-gamma shows that pIRE enhancers are differently regulated than GAS elements. Distinct transcription complexes, forming in ratios dependent on the inducer, help explain how various cytokines sharing effects through Stat91 on related enhancers can produce specific patterns of gene expression. Activation of the pIRE-a factors defines a novel transcriptional activity of IL-6 in epithelial and lymphoid cells.
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PMID:Induction by interleukin-6 of interferon regulatory factor 1 (IRF-1) gene expression through the palindromic interferon response element pIRE and cell type-dependent control of IRF-1 binding to DNA. 816 91

A human cytotoxic-T-lymphocyte (CTL) line capable of killing autologous tumor (AuTu) cell targets was established from peripheral-blood lymphocytes of a patient with squamous-cell carcinoma of the tongue. The cultured CTL were CD3+CD8+CD11b-HLA-DR+T cell receptor (TCR) alpha/beta+. When tested in 4-hr 51Cr-release assays against various lines of squamous-cell carcinoma of the head and neck (SCCHN) and a variety of non-squamous human tumor and normal cell targets, the CTL were found to lyse the autologous SCCHN cell line (PCI-50) and 7 allogeneic SCCHN lines: PCI-1, -2, -4A, -4B, -13, -30 and -38. Of these tumor cell lines, PCI-13, -30 and -38 shared HLA-A2 locus with the AuTu, PCI-50, while PCI-4A and -4B shared HLA-B44 with AuTu. Lysis of AuTu (A2+B44+), PCI-13 (A2+B44-) and PCI-4B (A2- B44+) by the CTL was efficiently inhibited by monoclonal antibodies (MAbs) to CD3, CD8, TCR alpha/beta or the major-histocompatibility-complex (MHC)-class-I antigens. MAbs to HLA-A2 antigens inhibited lysis of PCI-50 or PCI-13 targets by the CTL. In cold-target inhibition assays, unlabeled PCI-4B or PCI-13 cells inhibited CTL lysis of AuTu targets. The CTL incubated in the presence of the HLA-A2+ SCCHN PCI-50 or -13, but not an HLA-A2+ gastric carcinoma, produced TNF-alpha, IFN-gamma and GM-CSF. The CTL were tested for their TCR V beta gene expression by polymerase chain reaction (PCR). At week 10 in culture, the time of the highest AuTu cytotoxicity mediated by the CTL line, V beta 6 was expressed by 26% of T cells. Three clones, obtained by limiting dilution from 10-week CTL and selected for high cytotoxicity against AuTu, were found to be V beta6+. Further analysis of the specificity of these clones indicated lytic activity against PCI-13 (A2+B44-), but not PCI-4B (A2-B44+) targets. In 16-week cultures, which retained AuTu cytotoxicity as well as V beta 6 expression, TCR V beta 2 was also expressed at high frequency (29%), and AuTu-reactive clones were found to be V beta 2+. Our results indicate that at least 2 different CTL populations (V beta 6+ and V beta 2+) are able to recognize SCCHN-associated antigen(s) and that the V beta 6+ T cells are HLA-A2 restricted, while V beta 2+ T cells may be HLA-B44 restricted.
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PMID:HLA restriction and T-cell-receptor V beta gene expression of cytotoxic T lymphocytes reactive with human squamous-cell carcinoma of the head and neck. 816 88

Monocyte chemotactic proteins (MCP) belong to a group of structurally and functionally related factors, called chemokines. To facilitate additional characterization of the recently identified MCP-2, the 76-residue protein was chemically synthesized. The synthetic 7-kDa monomeric protein was chemotactic for monocytes at 1 nM and was biochemically similar to natural MCP-2. Sensitive radioimmunoassays for both MCP-1 and MCP-2 were developed. These RIAs were specific in that no cross-reactivity could be observed, and other chemokines or cytokines were not detected. Induction of MCP-1 and MCP-2 in human diploid fibroblasts and peripheral blood leukocytes as well as osteosarcoma, epidermal carcinoma, and melanoma cells by the cytokines IL-1 beta, IFN-beta, and IFN-gamma and cytokine inducers such as dsRNA, virus, endotoxin, mitogen, and phorbol ester was studied. In connective tissue cells, IL-1 beta was the best inducer of MCP-1, but IFN-gamma was a superior inducer of MCP-2. Mononuclear cells also proved to be a source of MCP-1 and MCP-2 when stimulated by most of the inducers tested. Granulocytes, however, were inefficient producers. Measles virus induced MCP-1 and MCP-2 in most cell types. In general, the yields of MCP-2 were at least 10-fold lower than those of MCP-1. It is concluded that, although MCP-2 is often coproduced with MCP-1, regulation of expression of the two chemokines is not identical. It remains to be studied under which pathological conditions MCP-2 is released in vivo and whether MCP-1 and MCP-2 can activate different target cells.
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PMID:Induction of monocyte chemotactic proteins MCP-1 and MCP-2 in human fibroblasts and leukocytes by cytokines and cytokine inducers. Chemical synthesis of MCP-2 and development of a specific RIA. 818 67

Compelling experimental evidence suggest that the use of differentiation-inducing agents which enhance tumor antigen expression may play a pivatal role in MAb-based approaches to tumor diagnosis and/or therapy. In particular, interferons can up-regulate CEA and TAG-72 expression on the surface of human carcinoma cells which leads to an enhanced MAb tumor localization. The ability to target additional MAb to the tumor site has subsequently been shown to augment radioimmunodetection and therapy in experimental models. Initial clinical studies reported that interferon administration to patients diagnosed with malignant melanoma improved the tumor distribution of antimelanoma MAb without an accompanying increase of antibody in normal tissues. The findings from our phase 1A trial clearly showed that intracavitary IFN-gamma administration augmented TAG-72 and CEA expression on carcinoma cells isolated from malignant ascites from patients diagnosed with ovarian or gastrointestinal cancer. Future efforts need to further investigate the molecular mechanisms involved in the regulation of these and other human tumor antigens by the interferons as well as other differentiation-inducing agents. Additional clinical studies should evaluate the overall effectiveness of combining an antigen up-regulation protocol with a conjugated MAb in the hope of improving tumor diagnosis and therapy.
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PMID:Biological response modifiers as adjuvants in monoclonal antibody-based treatment (review). 819 80


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