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)

The inhibitors of C1q biosynthesis and secretion, 3,4-dehydro-DL-proline (DHP) and 2,2'-dipyridyl, were previously shown to suppress murine macrophage FcR-dependent phagocytosis and cytolysis of IgG-opsonized RBC targets. Inasmuch as non-antibody macrophage activators also bind C1q to initiate C1 activation, we determined the effects of these same inhibitors of C1q biosynthesis on activation of macrophages for antibody-independent, nonspecific tumor cytotoxicity by lipid A and a variety of other non-antibody activators. Preexposure of mouse inflammatory peritoneal macrophages to either DHP (0.5 to 2.5 mM) or 2,2'-dipyridyl (0.1 to 0.3 mM) for 24 h produced a dose-related suppression of their response to activation by lipid A to mediate tumor cytotoxicity of L1210 mouse leukemia targets. Inhibition of C1q secretion by DHP-treated macrophages was confirmed both by a complement hemolytic assay and by autoradiographic analysis of [35S]methionine-labeled culture supernatants. DHP-treated macrophages were inhibited in their response to direct activation and triggering of IFN-gamma-primed macrophages by lipid A, Poly I:C, and cobra venom factor for tumor cytotoxicity. DHP inhibited macrophage activation for antibody-dependent cellular cytotoxicity of L1210 tumor targets mediated by antitumor target IgG. The addition of exogenous purified C1q (2 micrograms/ml) to macrophages after DHP treatment, reconstituted their response to activation for both antibody-independent and antibody-dependent tumor cytotoxicity. Our results indicate that C1q synthesis and secretion by effector macrophages is a prerequisite for the initiation of their activation by both immune complex and by non-antibody agents that also bind C1q. It now appears that macrophage-derived C1q may act as an auxiliary amplification signal for autocrine-like modulation of the initiation of macrophage activation by both the antibody-dependent and independent pathways.
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PMID:Inhibitors of C1q biosynthesis suppress activation of murine macrophages for both antibody-independent and antibody-dependent tumor cytotoxicity. 210 57

We have isolated a series of genomic and cDNA clones mapping within the boundaries of constitutional and tumor deletions that define the Wilms' tumor locus on human chromosome 11 (band p13). The transcription unit corresponding to these clones spans approximately 50 kb and encodes an mRNA approximately 3 kb long. This mRNA is expressed in a limited range of cell types, predominantly in the kidney and a subset of hematopoietic cells. The polypeptide encoded by this locus has a number of features suggesting a potential role in transcriptional regulation. These include the presence of four zinc finger domains and a region rich in proline and glutamine. The amino acid sequence of the predicted polypeptide shows significant homology to two growth regulated mammalian polypeptides, EGR1 and EGR2. The genetic localization of this gene, its tissue-specific expression, and the function predicted from its sequence lead us to suggest that it represents the 11p13 Wilms' tumor gene.
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PMID:Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. 215 35

The anticancer effects of retinoids have been recognized both in vivo and in vitro; however, little is known about their mechanism of action. Our study evaluated the effects of retinoic acid on the invasiveness of four human melanoma cell lines in vitro and showed a time-dependent inhibition of the ability of these cells to penetrate matrigel-coated filters. The possible mechanisms of action responsible for the anti-invasive effect were further investigated, and the data showed that retinoic acid-treated cells: (a) secreted lower levels of collagenolytic enzymes detected in type IV collagen-containing polyacrylamide gels compared with control cells, which was demonstrated by a decreased ability to degrade [3H]proline-labeled type IV collagen substrate; (b) showed a reduction in PA activity, primarily in the form of tPA, as demonstrated by chromogenic analysis; (c) showed a heterogeneous response with regard to c-myc, c-fos and c-jun mRNA expression, as determined by Northern blot analysis; and (d) demonstrated a decrease in B-actin levels and an increase in vimentin, as demonstrated by Northern blot analysis and SDS-PAGE transblot analysis. Collectively, these data suggest that RA causes an inhibitory effect on tumor cell invasion through a reconstituted basement basement membrane matrix by suppressing type IV collagenolytic activity and PA activity, which is probably triggered through a complex series of oncogene trans-acting factors, ultimately affecting cytoskeletal expression.
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PMID:Retinoic acid inhibits human melanoma tumor cell invasion. 216 Dec

Treatment of four A375 human melanoma sublines (A375, A375P, A375P-5, A375M), exhibiting distinct metastatic potentials in vivo, with beta-all-trans-retinoic acid in vitro caused a dose- and time-dependent inhibition of the ability of these cells to penetrate Matrigel-coated filters using a reconstituted basement membrane invasion assay. The possible mechanisms of action responsible for the antiinvasive effect were further investigated, and the data showed that compared with untreated cells the retinoic acid-treated cells: (a) secreted lower levels of collagenolytic enzymes, as demonstrated by a decreased ability of the cells to degrade [3H]proline-labeled type IV collagen substrate and by a reduction in the activity of a secreted Mr 64,000 collagenolytic enzyme detected in type IV collagen-containing polyacrylamide gels; (b) expressed lower levels of the human type IV collagenase mRNA (except in the A375P cells), as detected by Northern blot analysis; (c) exhibited decreased levels of tissue plasminogen activator activity, as demonstrated by a chromogenic assay; (d) were 10-40% less adhesive to a reconstituted basement membrane matrix, as determined by a 60-min Na2(51)CrO4-labeled cell attachment assay; (e) exhibited an increase in the high affinity metastasis-associated cell surface laminin receptor, as determined by flow cytometry after binding of fluorescently labeled laminin receptor antibody; and (f) expressed decreased amounts of gp78, a cell surface receptor for motility factor, demonstrated by immunoblotting and immunofluorescence. Collectively, these data suggest that retinoic acid inhibits tumor cell invasion through a basement membrane-like matrix by suppressing matrix degradation and by altering cell surface receptors.
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PMID:Retinoic acid inhibition of human melanoma cell invasion through a reconstituted basement membrane and its relation to decreases in the expression of proteolytic enzymes and motility factor receptor. 216 53

Monoclonal antibodies (MAbs) against human type-IV collagenase were developed and used for studies on enzyme activity and tumor-cell invasion in vitro. Fifteen MAb clones were generated against the enzyme purified form serum-free culture medium of human melanoma cells (A2058). Five clones affecting the activity of type-IV collagenase were selected for further characterization. All the selected clones could be used for a single-step purification of type-IV collagenase using IgG-Sepharose affinity columns. One of the antibodies activated the enzyme when 3H-proline-labelled type-IV collagen was used as substrate. The activation was dependent on the enzyme antibody ratio. Four clones caused more than 30% inhibition of the activity, maximal inhibition being 50%. Interestingly, the same antibody which activated the enzyme also increased the invasion of A2058 cells through a reconstituted basement membrane in an in vitro invasion assay. The 4 inhibitory antibodies decreased the penetration of A2058 cells through the reconstituted basement membrane. The results strongly support previous findings about the importance of type-IV collagenase in tumor-cell invasion.
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PMID:Modulation of type-IV collagenase activity and invasive behavior of metastatic human melanoma (A2058) cells in vitro by monoclonal antibodies to type-IV collagenase. 216 12

To test our hypothesis that supplemental vitamin A would mitigate the impaired healing that occurs in tumor-bearing animals, six groups of C3H mice, eight per group, eating a standard commercial mouse chow ad libitum that supports normal growth, reproduction, and longevity were innoculated with 200,000 C3HBA cells. When tumors measured approximately 6 mm in diameter, the mice were anesthesized and wounded (dorsal skin incisions and subcutaneous polyvinyl alcohol sponges). Twenty-four hours later, two groups (one continued on the chow and the other started on the chow supplemented with 150,000 IU vitamin A/kg chow) underwent local tumor irradiation; two groups, one ingesting the chow, the other the vitamin A supplemented chow, were started on cyclophosphamide therapy; two groups, one ingesting the chow, the other the vitamin A supplemented chow, received neither local tumor irradiation nor cyclophosphamide therapy. An additional two groups ingesting the chow, one group neither innoculated with tumor nor wounded, the other wounded by not innoculated, served as controls. Wound breaking strength and sponge reparative collagen accumulation (assessed by hydroxyproline proline measurement) were used as indicators of wound healing. The mice were killed 12 days after wounding. Tumor presence decreased wound breaking strength and sponge hydroxyproline content; these effects were largely negated by supplemental vitamin A. Local tumor irradiation diminished the adverse effect of tumor on sponge reparative collagen content but to a lesser extent than the supplemental vitamin A. Supplemental vitamin A added to the irradiation effect on healing but irradiation did not add to the vitamin A effect. Cyclophosphamide, a systemic radiomimetic anti-tumor agent, did not alter the impaired wound healing of the tumor-bearing mice. Supplemental vitamin A mitigated the impaired wound healing in the cyclophosphamide-treated tumor-bearing mice. Supplemental vitamin A also moderated the effects of wounding, tumor, and tumor therapies (local irradiation and cyclophosphamide) on the increase in adrenal size, leukopenia, thrombocytopenia, and thymic involution (except the last was not moderated in the cyclophosphamide-treated tumor-bearing rats). The splenic enlargement in the untreated tumor-bearing wounded rats and in those treated with cyclophosphamide was lessened by supplemental vitamin A. We hypothesize that these anti-stress effects of vitamin A underlie, in part, its action in mitigating the impaired wound healing of tumor-bearing mice, including those treated by local irradiation or cyclophosphamide. These findings have implications for the care of patients with malignant tumors.
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PMID:Supplemental vitamin A prevents the tumor-induced defect in wound healing. 231 Feb 37

The effects of acute administration of tumour necrosis factor-alpha (cachectin) (TNF-alpha) or of malignant tumour growth (Walker-256 carcinosarcoma) on hepatic availability and uptake of individual amino acids were compared. The results show that, in spite of lowering the hepatic availability of alanine, aspartate, serine, glycine and proline, the cytokine increased both the total amino acid hepatic uptake and the individual uptakes of alanine, glutamate, serine, threonine, proline, lysine and arginine, while decreasing those of leucine, isoleucine and phenylalanine. Tumour burden resulted in an increase in the hepatic availability of glutamine, threonine, glycine, lysine, leucine, isoleucine, valine and phenylalanine. Total liver amino acid uptake was unaffected, whereas the individual uptakes of alanine, threonine and proline were increased and those of glutamate, glutamine, serine and leucine were decreased. When effects of the cytokine are compared with those induced by tumour growth, there are similar increases in net utilization for alanine, proline and leucine, and a 3-fold difference in the increase observed for threonine. Unmatched effects are seen for glutamate, glutamine, aspartate, glycine, lysine, arginine, valine, phenylalanine and serine.
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PMID:The effects of tumour necrosis factor-alpha (cachectin) and tumour growth on hepatic amino acid utilization in the rat. 231 Mar 68

Mucins synthesized in colonic cancer are known to be different from those in the normal colon; however, the biochemical differences between these mucins have not been defined. We have purified mucins from samples of nonneoplastic (normal) human colon and colon cancer and found that the carbohydrate content of the cancer-associated mucins is 48% of that in the normal colon, including significant reductions in galactose, N-acetylglucosamine, N-acetylgalactosamine, and fucose. By subjecting the mucins to alkaline degradation, we determined that there are 19% fewer oligosaccharide chains per milligram of cancer-associated colonic mucin than there are in mucins from normal colons. We also found a reduction in mean oligosaccharide chain length in cancer-associated mucin (5.83 carbohydrate residues per chain) compared with those derived from normal colons (10.2 residues). Total and individual amino acid contents were greater in cancer-associated mucins, with the exception of three amino acids (threonine, serine, and proline), two of which represent the O-linked glycosylation sites for glycoproteins. Thus, mucins are aberrantly glycosylated in colon cancer, both in terms of the number and mean chain length of the oligosaccharide moiety. Because of their relative abundance in colonic tissue, mucins appear to be useful molecular species in the study of the derangements in protein glycosylation that occur during neoplasia.
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PMID:The carbohydrate composition of mucin in colonic cancer. 232 10

The effects of recombinant human interleukin-1 alpha (IL-1) on procollagen gene expression were examined in the clonal mouse osteoblastic cell line MC3T3-E1. Cells were grown in Dulbecco's Modified Eagle's Medium containing 10% fetal calf serum and 50 micrograms/ml ascorbic acid. Collagen synthesis was assessed as [3H]proline incorporation into collagenase-digestible protein (CDP). Procollagen mRNA levels were determined by Northern blot analysis using a 32P-labeled alpha 1(I) cDNA. Transcription rates were determined by nuclear run-off assay. IL-1 at 1-1000 pg/ml caused a concentration-dependent inhibition of CDP, which was maximally reduced by 75-80%, and a parallel reduction of procollagen alpha 1(I) mRNA levels. The effects of IL-1 were mimicked by the tumor promoter phorbol 12-myristate 13-acetate (PMA) at 1-100 nM, which inhibited CDP and reduced procollagen alpha 1(I) mRNA levels to a similar extent. The effects of IL-1 and PMA were independent of prostaglandin production, since indomethacin did not alter the inhibitory effect of either agent on CDP. Neither IL-1 (up to 10 ng/ml) nor PMA (100 nM) affected adenylate cyclase activity, while forskolin (10 microM), PTH (10 nM) and prostaglandin E2 (1 microM) stimulated adenylate cyclase activity 3- to 5-fold. However, forskolin (10 microM) and (Bu)2cAMP (100 microM) failed to alter CDP or procollagen alpha 1(I) mRNA levels. IL-1 (1 ng/ml) and PMA (100 nM) reduced transcription of the alpha 1(I) procollagen gene by 70% and 80%, respectively, while alpha 2(I) transcription was decreased by 59% and 53%. Neither IL-1 nor PMA affected transcription of the beta-actin or beta-tubulin genes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-1 alpha and phorbol ester inhibit collagen synthesis in osteoblastic MC3T3-E1 cells by a transcriptional mechanism. 232 98

To investigate the effects of extracellular matrix components on cellular function, we cultured several types of ocular cells on substrates composed of extracellular matrix materials that were layered on culture dishes either as dried films or as gels. We measured cellular proliferation on these substrates and on a series of gels composed of varying proportions of rat tail tendon type I collagen and Matrigel, a commercially available extract of a basement membrane-producing murine tumor. In addition, we studied the biosynthesis of collagens and of proteoglycans by these cultured cells using [3H]-L-proline and [35S]-sulfate. The proliferative abilities of the various types of ocular cells on the dried film substrates, on uncoated plastic culture vessels, and on pure type I collagen gel, were similar. However, proliferation of ocular cells cultured on gels composed of greater than or equal to 90% Matrigel was markedly reduced. There was little or no inhibition of growth of two types of non-ocular cells: rat C6 astrocytoma cells, and human dermal fibroblasts. Histologic studies showed that the ocular cells tested often formed long strands and capillary-like tubes, and tended to "burrow" beneath the surface of substrates containing high percentages of Matrigel. Fibroblasts infrequently formed tubes, and exhibited the burrowing property also on gels containing primarily type I collagen, while C6 cells showed neither of these behaviors on any of the matrices tested. The elution pattern of newly synthesized [3H]-labeled and [35S]-labeled macromolecules produced by all of the cultured cell types, and detected by Sepharose CL-4B chromatography in the medium and in the cell layer plus matrix fractions did not vary following culture on the different substrates. Approximately twofold more of the newly synthesized collagens and proteoglycans were deposited in the cell layer plus matrix, and proportionately less appeared in the medium, when cells were cultured on type I collagen gels and on Matrigel than on the dried film substrates. These experiments demonstrate the influence of the extracellular matrix on several aspects of cell behavior, and provide further evidence that modification of the composition of the extracellular matrix may be an important determinant of normal or pathological cell function.
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PMID:Proliferative response and macromolecular synthesis by ocular cells cultured on extracellular matrix materials. 234 Jul 48


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