Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

8-Bromo-cAMP and substances elevating cAMP levels within cells, such as forskolin, cholera toxin, and Bordetella pertussis-invasive adenylate cyclase (BPAC), suppress the growth of cultured granulosa cells cotransfected by simian virus-40 (SV40) DNA and Ha-ras oncogene concomitantly with the induction of steroidogenesis and without affecting oncogene expression. We, therefore, tested the hypothesis that cAMP can modulate tumorigenesis and metastatic spread of these cells in vivo. The cotransfected cells induced rapid development of tumors when injected sc in nude mice. Tumor development was faster in less differentiated cotransfected cells originating from preantral ovarian follicles than in those obtained from highly differentiated transformed cells originating from preovulatory follicles. Cells transfected by SV40 DNA alone produced only slow-growing small tumors. Metastatic lesions of cotransfected cells were most abundant in lung and less frequent in ovaries, kidney, and spleen. No metastatic lesions were found in the liver. However, metastatic spread was dramatically suppressed when cotransfected cells injected into nude mice were pretreated with the invasive BPAC. In contrast, no suppression of metastases was observed when the cells were pretreated with 8-bromo-cAMP, forskolin, or cholera toxin. Removal of forskolin in cultured cotransfected cells yielded a rapid decrease in cAMP levels. In contrast, high levels of cAMP persist in cell cultures even several hours after 1-h pretreatment and subsequent removal of BPAC from the medium of culture cotransfected cells. It is suggested that the inhibitory effect of BPAC on the metastatic spread of these cells is due to prolonged elevation of cAMP in vivo. The newly established granulosa cell lines transformed by SV40 and the Ha-ras oncogene can serve as a model for further studies of cAMP modulation of carcinogenesis in ovarian malignancies.
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PMID:Adenosine 3',5'-monophosphate suppresses metastatic spread in nude mice of steroidogenic rat granulosa cells transformed by simian virus-40 and Ha-ras oncogene. 131 28

A model system for testing the efficacy of chemotherapy protocols for metastatic melanoma was established using cell cultures from two brain and three lymph node metastases of melanoma from five different patients. Continuously growing cultures which were positive for tyrosinase activity were analysed regarding their proliferation rate by continuous bromodeoxyuridine (BrdU) labelling and subsequent Hoechst-33258/ethidium bromide flow cytometry. Melanoma cell cultures exhibit a strong sensitivity to BrdU: at 5% oxygen, 50% growth inhibition is attained with 360 +/- 130 microM BrdU (range: 130-520; n = 11) vs 650 +/- 50 microM BrdU (n = 3) for diploid human fibroblasts and 570 +/- 20 microM BrdU (n = 6) for human lymphoid cell lines. Moreover, BrdU sensitivity of melanoma cells is clearly oxygen dependent: 50% growth inhibition at 200 +/- 55 microM (range: 65-400 microM) for 20% oxygen vs 360 +/- 130 microM BrdU for 5% oxygen. The cell cycle kinetic mechanism of BrdU-induced growth inhibition is accumulation of cells in the first cycle G2 phase. On the basis of these results we suggest testing BrdU in chemotherapy protocols for the treatment of metastatic melanoma.
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PMID:Bromodeoxyuridine hypersensitivity of metastatic melanoma cells. 149 Jan 11

Clinical and experimental observations suggest that tumor-induced endothelial cell injury may be one of several initial events in the establishment of tumor metastases. To test this hypothesis, the authors have analyzed the interaction of malignant melanoma (ST-ML-12) multicenter tumor spheroids with endothelial cell monolayers in a three-dimensional coculture system. After 1.5 hours of interaction, the authors observed a toxic effect on endothelial cells in the perispheroid region. The latter was demonstrated by testing membrane integrity with the fluorescent probes acridine orange/ethidium bromide and resulted in sensitivity to shear stress of the damaged cells. The endothelium then underwent a regenerative cycle to replace the denuded halo. Addition of the oxygen radical-scavenging enzyme superoxide dismutase to the culture medium prevented this endothelial cell damage in a dose-dependent manner for up to 12 hours. By contrast, catalase, deferoxamine mesylate, allopurinol, and the proteinase inhibitors soybean trypsin inhibitor and aprotinin were not protective under the same conditions. The endothelial damage was dependent on the attachment of the spheroids. Medium conditioned by ST-ML-12-spheroids proved to be ineffective. A similar, but less prominent, deleterious effect was seen when human peritoneal mesothelial cells were used in place of the human umbilical vein endothelial cells. Spheroids of the uroepithelial cell line HU-609 were used as control. No toxicity was observed in these cocultures. Melanin biosynthesis is associated with the production of oxygen-derived free radicals. The results suggest a possible implication of these free radicals in metastasis formation of malignant melanoma.
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PMID:Interaction of human malignant melanoma (ST-ML-12) tumor spheroids with endothelial cell monolayers. Damage to endothelium by oxygen-derived free radicals. 151 67

The alkyllysophospholipid, racemic-l-O-octadecyl-2-O-methylglycero-3- phosphocholine (ET-18-OCH3) was previously shown to inhibit invasion of malignant cells into precultured heart fragments (PHF) in vitro. In particular, pretreatment of PHF with 10 micrograms ET-18-OCH3 for 48 h was sufficient to induce in the host tissue resistance towards invasion by mouse MO4 cells. Resistance was obvious when MO4 cells were confronted either immediately (the pretreatment experiment) or after withdrawal of the drug 7 days prior to confrontation (the reversibility experiment). In the present study, the survival of PHF cells in the pretreatment and reversibility experiments was similar to that of untreated PHF cells as determined by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) test and by the PHF explantation test. The effective anti-invasive concentration was 6 micrograms/ml in the pretreatment experiment while 3 micrograms/ml was sufficient to inhibit invasion in the reversibility experiment. Induction of resistance towards invasion in pretreated PHF was shown to occur not only with MO4 cells but also with mouse LLC-H61 Lewis lung carcinoma and mouse BW-O-Li1 T-lymphoma cells. The increase in molecular weight of N-linked cell surface glycosylpeptides (N-GP) of PHF was apparent in the pretreatment experiment and was enhanced in the reversibility experiment. This effect was completely abolished in cells obtained from pretreated PHF which were converted into a cell suspension and further cultured as a monolayer on tissue culture plastic without drug for 7 days. The results reported here provide additional evidence for the causal involvement of N-GP of the PHF host tissue in the anti-invasive activity of ET-18-OCH3 in vitro.
Clin Exp Metastasis
PMID:Role of the host tissue in the anti-invasive activity of the alkyllysophospholipid, ET-18-OCH3, in vitro. 175 86

DNA content in tumor cells from 50 patients with ovarian tumors was analysed by flow cytometry (FCM). Solid tissue samples were processed to obtain monodispersed cells. Staining for DNA analysis was achieved with ethidium bromide and mithramycin. Peripheral blood lymphocytes were used as reference diploid cell population. All benign ovarian tumors exhibited only diploid cells. DNA aneuploid cell lines were found 66.6% of serous carcinomas and in 80% of malignant granulosa cell tumors. The S-phase fraction of DNA diploid cells in benign ovarian tumors (S = 2.4 +/- 1.2%) was smaller than those of malignant tumors (S = 8.2 +/- 5.2%). DNA aneuploid cell populations in serous carcinomas display a higher S-phase fraction (S = 19.2 +/- 9.3%) than DNA diploid cells (S = 11.7 +/- 3.2%). No major differences were obtained between primary ovarian tumors and their metastases, as far as degree of aneuploidy and S-phase fraction are concerned. A high degree of correlation was established between the grade of differentiation of ovarian tumors and the DNA ploidy abnormalities.
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PMID:Flow cytometric analysis of DNA and cell proliferation in ovarian tumors. 333 38

An extract of a tumour metastases from a human medullary thyroid carcinoma contained a high concentration (at least 2.9 nmol/g wet weight) of the immunoregulatory peptide, thymosin-beta 4. The peptide was isolated as a mixture of two components with free and blocked NH2-terminal amino acid residues, the latter form predominating (approximately 98% of the total). The primary structure of the peptide was established by automated Edman degradation after cleavage with cyanogen bromide. The amino acid sequence of human thymosin-beta 4 was identical to thymosin-beta 4 previously isolated from calf thymus. Further studies are warranted to determine whether thymosin-beta 4 production is a useful marker for thyroid and other tumours.
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PMID:Isolation and structural characterization of thymosin-beta 4 from a human medullary thyroid carcinoma. 341 Dec 80

Chromatin structure, in terms of higher order nuclear-DNA condensation (scanning cytometry) and in terms of acridine orange primary binding sites (flow cytometry), is analyzed and shown to be significantly different between high (B16-F10) and low (B16-F1) metastatic variants of B16 melanoma. Furthermore, double staining of B16-F10 and B16-F1 with ethidium bromide (chromatin) and fluorescamine (membranes) provides the identification of a homogeneous subpopulation of cells with enhanced metastatic potential based on differential fluorescamine uptake. Fluorescamine uptake and poststaining viability is shown to be dependent upon the dye/cell ratio at which staining occurs. Utilizing a sterile cell sorting technique, a subpopulation of B16-F10 with increased fluorescamine uptake representing 30% of the total "intact cell" population was isolated by means of a fluorescence activated cell sorter and replated in vitro. This subpopulation when assayed in vivo produced significantly more pulmonary metastases than its parent cell line. Scanning cytometry of the Feulgen stained sorted subpopulation reveals that the cells possess a unique nuclear morphometry characterized by a 2C-3C DNA content and a large nuclear area (disperse chromatin). Finally, when we assay simultaneously for nuclear-DNA organization and cell membrane organization a progressive uncoupling between nuclear and cell morphometry is apparent if B16-F10 (versus B16-F1).
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PMID:Biophysical identification and sorting of high metastatic variants from B16 melanoma tumor. 707 1

Recognition of the carbohydrate part of cellular glycoconjugates by sugar receptors like lectins may contribute to biosignaling and interactions between normal and transformed cells. Such recognitions may be essential for establishing phenotypic characteristics in neoplastic cells, including metastasis-associated properties. To evaluate various glycoconjugates in tumor diagnosis and clinical therapy, a panel of 18 biotinylated neoglycoproteins was prepared. This included conjugates of a histochemically inert carrier protein and crucial sugar moieties such as D-glucuronic acid, alpha- and beta-N-acetyl-galactosamine, beta-N-acetyl-glucosamine, melibiose, lactose, maltose, cellobiose, mannose, mannose-6-phosphate, fucose, rhamnose, and xylose. In so doing the diazo derivative of the respective p-aminophenyl glycosides was coupled with galactose, beta-N-acetyl-galactosamine or beta-N-acetyl-glucosamine via an epoxy group-containing aliphatic spacer. Other glycoconjugates used were the proteoglycan heparin and the sulfated fucan fucoidan. Labeling was effected with cyanogen bromide activation and aminoalkylation for specific detection of endogeneous sugar receptors, especially lectins. Tissues studied were paraformaldehyde-fixed, paraffin-embedded surgical biopsies from patients with different stages of squamous cell carcinomas (SCCs) of the oral cavity (n = 16) and oropharynx (n = 17), including three lymph node metastases from oropharyngeal primary tumors. Semiquantitative binding differences of probes to tumor stages were evaluated statistically by the Mann-Whitney U-Wilcoxon rank sum W test. Specific binding of a probe to cytoplasmic and nuclear structures was detected with apparent quantitative differences. Overall, the cytoplasmic compartment revealed a higher intensity of histochemical reaction than did nuclear structures, indicating a comparatively higher density of specific carbohydrate receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of sugar receptor expression by neoglycoproteins in oral and oropharyngeal squamous cell carcinomas. 757 87

Spontaneously transformed Chinese hamster lung cells with high levels of resistance (approximately 100-fold to 70,000-fold) to actinomycin D, daunorubicin, or vincristine exhibit morphology and growth patterns characteristic of normal cells in vitro and reduced tumorigenicity in vivo. These reverse transformed, multidrug-resistant cells amplify and highly overexpress one or more genes encoding P-glycoprotein. Similarly, hydrocarbon-induced mouse sarcoma cells selected with actinomycin D, vincristine, or ethidium bromide developed high levels of resistance associated with reduced drug accumulation and suppression of malignancy. To determine whether human tumor cells would undergo similar changes and whether reverse transformation reflected an altered state of differentiation, nine multidrug-resistant sublines were selected with four agents from human neuroblastoma cells with well defined pathways of differentiation. Those five with resistance levels above about 125-fold showed a reduced tumor frequency as compared to control cells. All resistant sublines showed altered differentiation. The changes in transformation phenotype appear to be intrinsic and not the result of altered immunogenicity. Two additional consequences of high level multidrug resistance have been observed: change in ganglioside composition in the Chinese hamster cells, manifested as a block in higher ganglioside biosynthesis and/or a relative increase in GM3, and increase in epidermal growth factor receptor in all three cell systems. A tentative hypothesis links ganglioside and growth factor receptor changes to the change in transformation phenotype. The basis of the reverse transformation phenomenon is not known, but the major alterations in expression of P-glycoprotein, gangliosides, and the epidermal growth factor receptor implicate, in some way, the plasma membrane.
Cancer Metastasis Rev 1994 Jun
PMID:Reverse transformation of multidrug-resistant cells. 792 50

Invasion and metastasis may be caused by the escape of tumor cells from the negative control of growth factors. We analyzed the effects of transforming growth factor-beta 1 (TGF beta 1) on growth, migration, invasion, and adhesion in three follicular thyroid cancer cell lines (FTC133, primary; FTC236, lymph node metastasis; FTC238, lung metastasis) from one patient and in a papillary line (PTC-UC3). Cell growth was measured by dimethylthiazol-diphenyltetrazolium bromide assays, and migration (basal or epidermal growth factor stimulated) was determined by the ability of cells to penetrate 8-microns pore membranes that were covered with Matrigel for invasion assays. Moreover, we studied tumor cell adhesion to collagen type IV, fibronectin, and laminin. TGF beta 1 inhibited growth in FTC (FTC133, by 31%; FTC236, 15%; FTC238, 17%; P < 0.008), but not in PTC. Migration was inhibited in all cell lines. TGF beta 1 inhibited epidermal growth factor-stimulated migration of FTC133 by 43% vs. 29% without epidermal growth factor (P < 0.03). TGF beta 1 also inhibited invasion (FTC133, 32%; FTC236, 18%; FTC238, 16%; PTC-UC3, 32%; P < 0.02). All cell lines adhered preferably to collagen type IV and fibronectin. TGF beta 1 enhanced adhesion. Again, these effects were less pronounced in the FTC metastases. In conclusion, TGF beta 1 inhibits the growth, migration, and invasion of thyroid cancer cells in vitro. It enhances adhesion to components of the extracellular matrix. Metastatic thyroid tumors may be less responsive to the negative regulation of TGF beta 1.
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PMID:Transforming growth factor-beta 1 is a negative regulator for differentiated thyroid cancer: studies of growth, migration, invasion, and adhesion of cultured follicular and papillary thyroid cancer cell lines. 807 65


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