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

Lewis lung carcinoma and EMT6 sarcoma growing as solid tumors in mice caused a gradual increase in the susceptibility of the animals to lethal toxicity of endotoxins (lipopolysaccharides [LPS]). By day 15 following inoculation of the tumors, the 50% lethal dose of LPS, which in normal mice was approximately 400 micrograms, decreased to 2 micrograms for the sarcoma-bearing mice and 0.1 microgram for the carcinoma-bearing mice. This sensitization to endotoxin was paralleled by a high sensitization to tumor necrosis factor (TNF). Human recombinant TNF given to normal mice was lethal at about 500 micrograms. It was lethal for 50% of the animals bearing EMT6 or Lewis lung carcinoma tumors in amounts of 4 and 0.01 micrograms, respectively, on day 15 following tumor inoculation. The sensitization of tumor-bearing animals to LPS and TNF was paralleled by marked granulocytosis.
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PMID:Growing tumors induce hypersensitivity to endotoxin and tumor necrosis factor. 362 99

Tumor necrosis factors (TNFs) are a class of cytokines secreted by activated effector cells involved in host defense against tumor progression. Epidermal growth factor (EGF) and recombinant human transforming growth factor-alpha (rHuTGF-alpha) were shown to interfere with the in vitro antiproliferative effects of recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) and -beta on a human cervical carcinoma cell line, ME-180. The inhibitory effect could be observed at EGF or rHuTGF-alpha concentrations of 100 pg/ml, and was maximal between 1 and 10 ng/ml. This response was not due to down regulation of the TNF receptor or to alteration of the affinity of TNF-alpha for its receptor. Since the antiproliferative effect of recombinant human interferon-gamma was not significantly affected by the presence of EGF or rHuTGF-alpha, the inhibition was specific for recombinant TNFs and was not due solely to enhanced proliferation induced by the growth factors. Neither growth factor had a substantial protective effect on the synergistic cytotoxicity observed when tumor cells were exposed simultaneously to rHuTNF-alpha and recombinant human interferon-gamma. TGF-beta can also interfere with the antiproliferative effects of rHuTNF-alpha in vitro. At concentrations of less than 1 ng/ml, TGF-beta significantly antagonized the cytotoxic effects of rHuTNF-alpha on NIH 3T3 fibroblasts. Since EGF, platelet-derived growth factor, and TGF-beta all enhanced NIH 3T3 cell proliferation, but only TGF-beta interfered with rHuTNF-alpha cytotoxicity, the protective effects of TGF-beta were not related in a simple manner to enhanced cell proliferation. rHuTGF-alpha and TGF-beta did not have a significant protective effect against rHuTNF-alpha-mediated cytotoxicity on two other tumor cell lines, BT-20 and L-929 cells. Based upon these observations we suggest that growth factors might enhance tumor growth in vivo by a combination of distinct mechanisms: (a) by autocrine stimulation tumor cell growth; and/or (b) by interfering with normal effector mechanisms of host defense.
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PMID:Effects of growth factors on the antiproliferative activity of tumor necrosis factors. 380 82

A radioreceptor assay (RRA) capable of detecting picomolar concentrations of human recombinant tumor necrosis factor (TNF) was used to compare the relative binding affinities of genetically engineered full-length and truncated TNF proteins. The specific cell-surface receptors for TNF present on the human cervical carcinoma cell line ME-180 were characterized as having a Kd of 0.2 nM and a density of 2700 sites/cell. Conditions were then defined for an RRA that maximized the specific binding of 125I-TNF to this adherent cell line. Incubation of ME-180 cells with 125I-TNF at 37 degrees C in the presence of 0.02% sodium azide resulted in a 4-fold increase in assay sensitivity and a doubling of specific counts bound, as compared to binding done at 4 degrees C with or without sodium azide. Inhibition of receptor-ligand internalization under these conditions was a likely reason for the increases. This system was utilized to compare low concentrations of the full-length TNF protein and a genetically altered TNF protein (mutein) which lacks the 10 N-terminal amino acids and contains an N-terminal methionine. Previous studies showing the truncated TNF to be 2- to 3-fold lower in cytotoxic activity on a variety of tumor cell lines were corroborated by our findings that the mutein was also three and one-half times lower in relative affinity for the TNF receptor on ME-180 cells. These results suggest a possible role for these residues in receptor binding and illustrate the use of a highly sensitive RRA for the evaluation of TNF molecules altered by recombinant DNA technology.
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PMID:Use of a sensitive receptor binding assay to discriminate between full-length and truncated human recombinant tumor necrosis factor proteins. 380 29

The antitumor activity of tumor necrosis factor (TNF) against various primarily cultured human cancer cells (32 cases) was investigated by the 51Cr cytotoxic release assay and the tumor stem cell assay. Over 50% sensitivity (the ratio to the cytotoxicity in L929 cells) was noted in 4 of 14 cases of gastric cancer (28.6%), 7 of 9 cases of leukemic cells (77.8%), and 1 case each of pancreatic carcinoma and ovarian cancer. Scarcely any sensitivity, however, was observed in 1 case of acute promyelocytic leukemia or in some of the gastric cancer cases. No correlation was observed between the histological type of the cancer and TNF sensitivity. The above results seem to confirm that TNF has significant antitumor activity against human cancer cells.
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PMID:Antitumor effect of tumor necrosis factor against various primarily cultured human cancer cells. 393 30

The antitumor activity of tumor necrosis factor (TNA) against various human cancer cells (32 cases) was investigated by 51Cr cytotoxic release assay and tumor stem cell assay. Over 50% sensitivity (the ratio of cytotoxicity for L929 cells) was shown by 4 of 14 cases of gastric cancer (28.6%), 7 of 9 cases of leukemic cells (77.8%), and 1 case each of pancreatic carcinoma and ovarian cancer. However, scarcely any sensitivity was shown by APL, a portion of the gastric cancer cells, normal lymphocytes or colony-forming cells tested. No correspondence was observed between the histological type of the cancer and TNF sensitivity. The above results seem to confirm the significant antitumor activity of TNF against human cancer cells.
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PMID:[Antitumor effect of the tumor necrosis factor against various types of human cancer cells]. 406 18

Recent studies suggest that tumor necrosis factor-alpha (TNF-alpha), a pleiotropic cytokine, is responsible for some of the systemic and local effects, including tumor-associated cachexia and neoplastic bone destruction, seen in patients with cancer. This study was undertaken to determine if TNF-alpha is produced by human squamous cell carcinoma of the head and neck, and, if so, to determine its source and cellular distribution. Tumor specimens from nine patients with squamous cell carcinoma of the head and neck region were immunohistochemically examined for the presence of TNF-alpha. TNF-alpha was localized with antibody to human TNF-alpha by the immunoperoxidase method to the tumor and vessel endothelial cells in all nine specimens. By Western blot analysis, two protein bands recognized by anti-human TNF-alpha antibody in the soluble proteins of the tumor specimens were identified. These proteins--25 KD and 17 KD--represent the precursor and mature forms of TNF-alpha. To verify squamous cell carcinoma production of TNF-alpha, a cell culture of human head and neck squamous carcinoma was examined. The 25 KD immunoreactive protein, the TNF-alpha precursor, was found in extracts from this culture by Western blot analysis. These findings suggest that tumor cells are able to produce TNF-alpha; this production may explain some of the systemic and local effects seen in patients with squamous cell carcinoma of the head and neck.
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PMID:Tumor necrosis factor-alpha production in human head and neck squamous cell carcinoma. 751 83

CD40 was originally described as a B-cell-restricted antigen and was subsequently found to be a member of the tumor necrosis factor (TNF) receptor superfamily. CD40 is also expressed on dendritic cells, thymic epithelium, monocytes, and some carcinoma cell lines, and plays a critical role in cell contact-dependent activation. Primary and cultured Hodgkin and Reed-Sternberg (H-RS) cells, the presumed malignant cells of Hodgkin's disease (HD); were found to express high levels of cell surface CD40. We found that recombinant CD40 ligand (CD40L) induced interleukin-8 (IL-8) secretion and enhanced IL-6, TNF, and lymphotoxin-alpha (LT-alpha/TNF-beta) release from cultured H-RS cells. These cytokines play a significant role in the clinical presentation and pathology of HD, a tumor of cytokine-producing cells. CD40L had no mitogenic activity for HD-derived cell lines. In contrast, CD40L enhanced expression of costimulatory molecules intracellular adhesion molecule-T and B7-1 on cultured H-RS cells, both of which are overexpressed on primary H-RS cells. In addition, CD40L induced a 40% to 60% reduction of the expression of the HD-associated CD30 antigen, another member of the TNF receptor superfamily. Primary and cultured H-RS cells express not only CD30, but also CD40. CD40L has pleiotropic biologic activities on H-RS cells, and the CD40-CD40L interaction might be a critical element in the deregulated cytokine network and cell contact-dependent activation cascade typical for HD.
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PMID:Expression and function of CD40 on Hodgkin and Reed-Sternberg cells and the possible relevance for Hodgkin's disease. 752 24

We have previously shown that human squamous cell carcinomas (SCC) express the interleukin 2 receptor (IL2R)-alpha and -beta chains, and that the ligand, IL2, directly inhibits growth of the tumor in vitro and in vivo in the tumor xenograft-nude mice model. We now show that the alpha and beta chains of IL2R are expressed on a variety of human carcinoma cell lines and on normal human keratinocytes in early-stage cultures. While all carcinoma cells in a population expressed IL2R-alpha and -beta proteins, in keratinocytes obtained from different normal donors, variable proportions of cells were positive, as measured by flow cytometry. The carcinoma lines and 2/5 keratinocyte lines studied were also found to contain transcripts for the IL2R-gamma chain detectable by combined reverse transcription-PCR (RT-PCR) and hybridization with the specific cDNA probe. Incubation of the gastric (HR) or renal cell carcinoma (RCC) cell lines, but not of other IL2R+ carcinoma cell lines or normal keratinocytes, in the presence of IL2 resulted in dose-dependent inhibition of tumor cell growth. Monoclonal antibodies (MAbs) specific for IL2R-beta chain completely reversed this growth inhibitory effect of IL2. The ligand, IL2, also down-regulated surface expression of its own receptor and of intercellular adhesion molecule-I (ICAM-I) or class I major histocompatibility complex (MHC) antigens on IL2R+ tumor cells. All carcinoma cells studied incubated in the presence of IL2 exhibited significantly increased sensitivity to growth-inhibitory effects of other cytokines such as interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha or transforming growth factor (TGF)-beta. IL2 inhibited growth of the HR cells by arresting a significant proportion of tumor cells in the G0/G1 phase of the cell cycle. Thus, IL2 can have direct effects on IL2R+ carcinoma cells, leading to changes in growth or to increases in sensitivity of tumor cells to cytostatic activities of other cytokines.
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PMID:Expression of interleukin 2 receptors on human carcinoma cell lines and tumor growth inhibition by interleukin 2. 752 15

Cellular adhesion between sialyl Lewis a (SLea)-positive pancreas carcinoma and endothelial cells is augmented by exogenous cytokines such as interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha through an upregulated E-selectin expression on endothelial cells. Preincubation of pancreas carcinoma cells with endothelial cells for 4-6 hours at the ratio of 1:10 induced E-selectin expression on endothelial cell surface, and dramatically increased subsequent attachment of SLea-positive pancreas carcinoma with endothelial cells. Paraformaldehyde-fixed PCI cells also induced E-selectin on vascular endothelial cells upon direct contact with endothelial cells. Culture supernatants from all six pancreas carcinoma cell lines contained soluble, E-selectin-inducible factors. Antibodies against SLea and E-selectin but not SLex or ICAM-1 blocked the increased pancreas carcinoma-to-endothelial attachment. These findings suggested that SLea-positive pancreas carcinoma cells produced E-selectin-inducing cytokines, both in the soluble and the membrane bound forms, resulted in augmented attachment to endothelial cells in vitro. The soluble factor lost its activity to induce E-selectin at 70 degrees C, and was different from IL-1-beta or TNF-alpha, because the supernatants contained no measurable IL-1 beta and TNF-alpha. Moreover, pretreatment of the supernatants with specific antibodies to IL-1 beta and TNF-alpha could not neutralize the E-selectin-inducing activity. Instead, all six pancreas carcinoma cell lines produced proteins of IL-1 alpha, and preincubation of the supernatant with specific antibody to IL-1 alpha almost completely removed the E-selectin-inducing activity from the supernatants. The collecting evidence suggests that substances such as IL-1 alpha produced by pancreas carcinoma cells may contribute to hematogenous metastasis of cancers in non-inflamed distant locations.
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PMID:[Molecular mechanism in hematogenous metastasis of pancreas carcinoma--possible implication of tumor-derived cytokine in a cell-to-cell interaction of pancreas carcinoma and vascular endothelial cells]. 752 35

Nitric oxide (NO) produced by endothelial cells (EC) has been shown to exert cytotoxic activity on tumor cells. In order to analyze events involved in brain metastasis, the modulation of NO production in rat-brain-derived EC was investigated. NO release was increased by tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1 beta, lipopolysaccharide or forskolin in EC219 cells, a rat-brain-microvessel-derived EC line. Dexamethasone decreased NO release by cytokine-activated EC219 cells. Tumor cells (DHD/K12/PROb, a rat colon-carcinoma cell line) were highly adherent to EC219 cells, and adhesion was not modified by TNF-alpha plus IFN-gamma, or by dexamethasone. Addition of tumor cells or tumor-cell-conditioned medium significantly inhibited NO release induced by any of the stimuli examined, but only if added during the initial phase of endothelial-cell activation. Tumor-derived suppression of NO release was also observed in primary cultures of cerebral EC. NO synthase (NOS) activity in cytosol extracts of the cerebral EC line was Ca(2+)-independent and required both NADPH and tetrahydrobiopterin. NOS activity was increased by TNF-alpha and IFN-gamma, and significantly reduced by tumor-cell-conditioned medium. These results suggest that rat colon-carcinoma cells may have developed a protective mechanism involving the release of (a) soluble factor(s) which inhibit(s) NO production by cerebral EC.
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PMID:Tumor cells suppress cytokine-induced nitric-oxide (NO) production in cerebral endothelial cells. 752 97


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