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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Release reactions stimulated in human basophils by a variety of secretagogues show biochemical and morphologic differences as well as similarities. Biochemical differences include those of rate, amount, and order of mediator release, as well as mediator type released or generated. Morphologic diversity of release reactions includes prototypic anaphylactic degranulation (AND), or piecemeal degranulation (PMD), and a continuum of anatomic release comprised of PMD followed by AND that is seen when human basophils are stimulated by the bacterial peptide, formyl methionyl leucyl phenylalanine (FMLP). AND is characterized by extrusion of membrane-free granules through multiple plasma membrane pores; PMD is characterized by partially to completely empty, nonfused granule containers in the cytoplasm of basophils. AND is further characterized by diminished-to-absent granules and reduced cytoplasmic vesicles at peak histamine release intervals; PMD does not show decreases in numbers of granules, and cytoplasmic vesicles are plentiful. Smooth membrane-bound vesicles with granule particles and vesicles that appear empty comprise this organelle population. PMD is the single most evident activation change present in basophils that traffic into tissues in multiple diseases in vivo. In this study, we examined the ultrastructural kinetic morphology associated with stimulation of human basophils with tetradecanoyl phorbol acetate (TPA)--a tumor-promoting phorbol diester known to elicit histamine (but not LTC4) release. Partially purified human basophils were prepared for electron microscopy and examined either after control incubations in buffer alone or at 0 time, 1, 2, 5, 10, 30, and 45 minutes after TPA stimulation. Standard morphology and ultrastructural quantitation of vesicles and granules and contents of vesicles or alteration of granules was done and compared with previous ultrastructural kinetic analyses of human basophil release reactions stimulated by different triggers. Like biochemical studies that have determined that TPA is a unique secretogogue for human basophils, the morphology stimulated by TPA and associated with histamine release was also unique. For example, very minor images of AND were evident. Far greater amounts of PMD were imaged. PMD was associated with approximately 50% alteration of cytoplasmic granules by 45 minutes after TPA stimulation. This evidence of empty granules was associated with, and preceded by, a rapid, extensive, and sustained increase in particle-containing cytoplasmic vesicles, as compared with buffer controls (P < 0.001 for each TPA stimulation time compared with unstimulated basophils). In addition, previously undescribed interactions of releasing granules and their overlying plasma membranes characterized TPA-stimulated cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:An ultrastructural analysis of tumor-promoting phorbol diester-induced degranulation of human basophils. 146 96

This paper describes a simple and direct procedure for assaying Ca(2+)-dependent protein kinase C (PKC) activity in membrane fractions isolated from purified murine B lymphocytes (B cells) treated with phorbol 12-myristate 13-acetate (PMA). The results indicate that membrane-bound PKC in B cells, treated with PMA, can be measured directly in the presence of 0.5% Brij 58 by assaying the transfer of 32P from [gamma-32P]ATP to histone type III-S. This method obviates the need for partial purification of the protein kinase by ion-exchange chromatography prior to assaying PKC activity. The properties of membrane-associated PKC activity in B cells have been characterized, and the kinetics of PMA-induced translocation of PKC in cultured murine B cells, the rat glial tumor clone C6, and primary neonatal osteoblastic cells have been defined by this direct assay. The results obtained with B cells and the other cell lines indicate that this direct assay procedure could be useful for studies on the factors controlling PKC translocation in a variety of cultured mammalian cells.
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PMID:Direct assay of membrane-associated protein kinase C activity in B lymphocytes in the presence of Brij 58. 148 85

We have previously demonstrated that murine tumor cells transduced with a retrovirus containing the cDNA encoding wild-type human TNF regress in vivo when injected into immunocompetent mice; this regression is T cell mediated. To determine whether membrane-associated or secreted TNF was responsible for tumor regression, we transduced a cloned murine fibrosarcoma 205 F4 with retroviruses encoding modified human TNF genes. The cloned tumor lines of one retroviral transduction expressed only membrane bound 26-kDa TNF. This TNF could not be cleaved or secreted, but was present on the cell surface. A second retrovirus caused the expression of only secretory 17-kDa TNF, as the transmembrane domain of the cDNA was deleted. The TNF produced by tumor cells transduced with either retroviral vector was functional in vitro as direct lysis of the TNF-sensitive target L929 by transduced tumor cells was demonstrated. The TNF present on 26-kDa expressing tumors was membrane bound as supernatants from cultured 17-kDa TNF expressing tumor cells but not 26-kDa TNF expressing tumors mediated the lysis of L929 cells. Both tumors were injected s.c. into syngeneic mice and tumor growth was measured serially. In repeated experiments, 26-kDa TNF expressing tumors grew progressively in all mice. In contrast, 17-kDa TNF expressing tumors grew for 10 days and then regressed with all animals free of tumor at 28 days. Tumor regression was abrogated by in vivo injection of an anti-TNF antibody. Similar results were obtained in a second tumor model, 203 E4. Thus regression of TNF transduced tumors in vivo requires secretion of TNF, as membrane-bound TNF is insufficient to elicit the host response.
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PMID:In vivo activity of tumor necrosis factor (TNF) mutants. Secretory but not membrane-bound TNF mediates the regression of retrovirally transduced murine tumor. 151 71

N-Trifluoroacetyladriamycin-14-valerate (AD 32), a lipophilic, DNA non-binding analog of Adriamycin (ADR), was found to be a potent inhibitor of the membrane-bound enzyme, protein kinase C (PKC). PKC was isolated and purified from human leukemia ML-1 cells, and the enzyme activity was shown to be activated by the tumor promoters 12-O-tetradecanoylphorbol-13-acetate (TPA) and phorbol-12,13-dibutyrate (PDBu). AD 32, nevertheless, inhibited the activation of PKC by TPA or PDBu. The IC50 values for AD 32 inhibition of PKC activation were 0.85 microM for TPA and 1.25 microM for PDBu. Under the same assay conditions, ADR demonstrated much higher IC50 values: 550 microM for TPA and greater than 350 microM for PDBu. The inhibition of PKC by AD 32 was further shown to be competitive in nature; AD 32 inhibited the binding of [3H]PDBu to PKC. Therefore, AD 32 competes with the tumor promoter for the PKC binding site and prevents the latter from both interacting with the phospholipid and binding to PKC. These effects of AD 32 were reproduced in situ; incubation of human leukemia ML-1 cells with TPA showed an increased phosphorylation of cellular proteins, and the TPA-induced protein phosphorylation was inhibited by the addition of AD 32 to the cultured cells.
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PMID:Activation of human leukemia protein kinase C by tumor promoters and its inhibition by N-trifluoroacetyladriamycin-14-valerate (AD 32). 154 Feb 40

Previous studies have shown that suramin is capable of disrupting autocrine growth involving coexpression of platelet-derived growth factor and its receptors in a fibroblast model for mesenchymal oncogenesis. Suramin is currently in use as an experimental drug for the treatment of patients with epithelial cell tumors. In the present study, we have investigated the efficacy of suramin in a carcinoma model system. Our findings demonstrate that suramin enhances cell surface signaling in A431 cells by activating an autocrine loop involving the receptor for epidermal growth factor (EGFR). The mechanism of suramin action was shown to be indirect, not affecting the ability of ligand to bind and activate the EGFR. Instead, suramin induced the release of membrane-bound transforming growth factor alpha, thereby increasing its potential to activate cell surface EGFRs. Since suramin potently blocks tyrosine phosphorylation induced by platelet-derived growth factor but can activate the growth pathway regulated by the EGFR, biological responses of tumor cells to suramin treatment may differ dramatically.
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PMID:Suramin, an experimental chemotherapeutic drug, activates the receptor for epidermal growth factor and promotes growth of certain malignant cells. 155 85

Monoclonal antibody (mAb) OC125 detects the cell surface-antigen CA125, which is expressed in more than 80% of epithelial ovarian cancers but not in normal adult ovaries. Its high specificity and binding affinity makes OC125 a potential candidate for use in radioimmunotherapy (RIT) in patients with recurrent ovarian cancer. Initial biodistribution studies using radiolabelled specific mAbs have demonstrated significant increase in tumor uptake of dose as compared to radiolabelled irrelevant antibody. We report here an isodose comparison of the cytotoxicity of 131I-labelled OC125 F(ab')2, 131I-labelled nonspecific protein and external beam irradiation using a cesium-137 gamma source. Enhancement of cytotoxity due to the specific binding of the mAb could only be observed when a critical activity of 131I localized at the cell membrane. At a specific activity labelling of less than 4.1 mCi/mg, the antigen specificity of OC125 does not contribute to cell kill. Using a specific activity of 10.2 mCi/mg, the relative biological effectiveness of 131I-labelled OC125 (F(ab')2 was increased by a factor of 5 compared with external-beam X-ray therapy, and the specificity of mAb OC125 was found to enhance the cytotoxicity of the radioimmunoconjugate (RIC) by a factor of 2.7. This low value is in accordance with previously reported theoretical calculations for long range, low-LET isotopes and may be one of the reasons why RIT using 131I has severe limitations. In conclusion, it is necessary to maximize the specific activity of RICs with low-LET isotopes such as iodine-131 in order to maximize the ratio of the dose delivered specifically by membrane-bound mAb versus free-floating nonspecific protein.
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PMID:Analysis of cytotoxicity of 131I-labelled OC125 F(ab')2 on human epithelial ovarian cancer cell lines. 157 94

Among environmental pollutants, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) is one of the most potent tumor promoters and teratogens known. The molecular mechanisms responsible for the biological activity of TCDD, however, remain largely unknown. In this report, we show that the first observable effects of TCDD in cultured murine hepatoma cells are a rapid, transient increase in Ca2+ influx and a minor but significant elevation of activated, membrane-bound protein kinase C. These changes are then followed by induction of the immediate early proto-oncogenes c-fos, jun-B, c-jun, and jun-D, and by large increases in AP-1 transcription factor activity. Induction of these changes by TCDD is delayed compared with that by phorbol esters, although the magnitude of the effects caused by both treatments is similar, and both induction processes can be blocked by staurosporine, a protein kinase C inhibitor. In cultured cells, proto-oncogene induction by TCDD appears to be independent of the presence of a functional aryl hydrocarbon (Ah) receptor or nuclear translocation protein. These results reveal early events that may lead to the elucidation of the molecular basis of TCDD-induced tumor promotion.
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PMID:Dioxin induces expression of c-fos and c-jun proto-oncogenes and a large increase in transcription factor AP-1. 160 50

We report a case of intracystic papillary carcinoma of the male breast in a 70-year-old male Caucasian. Grossly, the tumor was a cystic lesion measuring 6 cm in diameter. It contained hemorrhagic fluid and a mural nodule with filiform projections. PAS stain with and without digestion revealed small clumps of diastase-resistant material in the cytoplasm of the neoplastic cells. Grimelius stain was positive. Immunoperoxidase stains were negative for neuron-specific enolase, S100 protein, cromogranin and synaptophysin and were positive for carcinoembryonic antigen and epithelial membrane antigen. On ultrastructural examination the neoplastic cells showed membrane-bound, dense-core secretory granules. We believe that this neoplasm, despite negative neuroendocrine markers, is a variant of mammary adenocarcinoma with endocrine differentiation, partly because of the positive Grimelius stain and partly because of the presence of electron-dense granules, which according to some authors represent lactational differentiation.
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PMID:Intracystic papillary carcinoma of the male breast. A case report (histochemical, immunohistochemical and ultrastructural study). 160 58

Protein kinase C (PKC), the major receptor for tumor-promoting phorbol esters, consists of a family of at least eight distinct lipid-regulated enzymes. How the various PKC isozymes are regulated in vivo and how they couple to particular cellular responses is largely unknown. We have examined the expression and regulation of PKC isoforms in R6 rat embryo fibroblasts. Northern and Western blot analyses indicate that these cells express four PKC isoforms, cPKC alpha, nPKC epsilon, nPKC delta, and nPKC zeta; of which nPKC epsilon and nPKC delta are the most abundant. In agreement with the simultaneous presence of cPKC and nPKC isozymes, both Ca(2+)-dependent and -independent PKC activities were detected in extracts of these cells. cPKC alpha and nPKC zeta were predominantly localized in the cytosol when subcellular fractionation was carried out in the presence of [ethylenebis(oxyethylenenitrilo)]tetraacetic acid. When cell lysis was carried out in the presence of Ca2+, greater than 50% of cPKC alpha redistributed to the particulate fraction, whereas nPKC zeta remained in the cytosol. In contrast to cPKC alpha and nPKC zeta, 60-80% of nPKC epsilon and nPKC delta were located in a Ca(2+)-insensitive, membrane-bound form. Treatment of R6 cells with 12-O-tetradecanoyl phorbol 13-acetate (TPA), resulted in the translocation of all four PKC isozymes to the membrane fraction, and the subsequent down-regulation of cPKC alpha, nPKC zeta, and nPKC delta, nPKC epsilon, however, was only partially down-regulated in response to long-term TPA exposure. Overproduction of exogenous cPKC beta I in R6 cells conferred partial resistance of nPKC delta to TPA-induced down-regulation and potentiated the resistance of nPKC epsilon to down-regulation. These results demonstrate that the multiple isoforms of PKC which coexist within a single cell type are differentially regulated by extra- and intracellular stimuli and may thereby influence growth control and transformation via distinct mechanisms.
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PMID:Expression of four protein kinase C isoforms in rat fibroblasts. Distinct subcellular distribution and regulation by calcium and phorbol esters. 161 87

To investigate the role of protein kinase C (PKC) in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-dependent growth of human melanocytes, we analyzed the effects of phorbol ester treatment on both PKC expression and growth control in these cells. We found that established cultures of normal melanocytes contain the PKC alpha, PKC beta, and PKC epsilon isoforms. The abilities of various phorbol ester compounds to stimulate DNA synthesis in these cultured melanocytes correlated with their known potencies for activation of PKC and tumor promotion. Dose-response studies revealed that the most effective TPA concentration for stimulation of DNA synthesis and growth of melanocytes (10 ng/ml TPA) also supported a relatively high level of PKC enzyme activity, increased membrane association of the PKC alpha and PKC epsilon isoforms, and led to a high level of phosphorylation of a major PKC substrate, the myristoylated alanine-rich C kinase substrate (MARCKS) protein. Melanocytes incubated for 48 h with TPA at a higher concentration (100 ng/ml TPA) exhibited suboptimal TPA-stimulated DNA synthesis (28% of maximal) and decreased phosphorylation of the MARCKS substrate protein (50% of maximal). Furthermore, treatment of melanocytes with 100 ng/ml TPA for 48 h resulted in a marked decrease in total PKC enzyme activity and the loss of expression of the PKC alpha and PKC epsilon isoforms in both the cytosol and membrane-bound fractions, when examined by immunoblot analysis. These results, taken together, suggest that continuous activation of PKC by TPA, rather than the loss of PKC due to TPA-induced down-regulation, is responsible for the growth-stimulatory effects of phorbol esters on normal human melanocytes. Additionally, the conditioned medium from TPA-treated human melanocytes stimulated DNA synthesis in quiescent melanocytes and human melanoma cells, thus suggesting that activation of the PKC signaling pathway in melanocytes leads to the production of an autocrine growth factor. These findings may be relevant to the autonomous growth of malignant melanomas.
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PMID:Growth of human melanocyte cultures supported by 12-O-tetradecanoylphorbol-13-acetate is mediated through protein kinase C activation. 164 43


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