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Sample records for ehrlich tumor cells

  1. Cancer preventive effects of whole cell type immunization against mice Ehrlich tumors.

    PubMed

    Aysan, Erhan; Bayrak, Omer Faruk; Aydemir, Esra; Telci, Dilek; Sahin, Fikrettin; Yardimci, Cem; Muslumanoglu, Mahmut

    2013-01-01

    Effects of whole cell type immunization on mice Ehrlich tumours were evaluated. After preliminary study, mice were divided two major groups; 1 x 1000 and 100 x 1000 live Ehrlich cell transferred major groups, each divided into four subgroups (n: 10). Study groups were immunized with Ehrlich cell lysates in 0, 3, 7, 14th days and after 30 days of last immunization, live Ehrlich cells were transferred. Mice were observed for six months and evaluated for total and cancer free days. Out of 100 x 1000 cell transferred solid type study group, all study group mean and tumour free periods were statistically longer than control groups. All 1 x 1000 Ehrlich cell transferred study groups survived significantly longer than 100 x 1000 Ehrlich cell transferred groups. Ehrlich mice tumours were prevented and survival prolonged with whole cell type immunization. Effects are related to the number of transferred tumor cells.

  2. Mutagenicity of alpha particles in Ehrlich ascites tumor cells

    SciTech Connect

    Iliakis, G.

    1984-07-01

    Cell killing and the induction of mutation to thioguanine resistance were measured after exposure of Ehrlich ascites tumor cells to 150-kV X rays and /sup 241/Am ..cap alpha.. particles. The curve describing the induction of mutations was almost linear after exposure to ..cap alpha.. particles but upward bending after exposure to X rays, apparently reaching a final slope similar to that obtained after exposure to ..cap alpha.. particles. The number of mutants induced per viable cell by ..cap alpha.. particles at a given level of cell killing was similar to that induced by X rays. The RBE values obtained for cell killing and the induction of mutations are compared with each other, and the possible involvement of repair processes in determining the RBE is discussed.

  3. Chronobiological organization of reproduction of Ehrlich's ascites tumor cells

    SciTech Connect

    Romanov, Qu, A.; Stepanenko, V.A.

    1986-01-01

    The rhythms of cell proliferation and DNA synthesis were studied in a hypotetraploid strain of Ehrlich's ascites tumor (EAT) and compared with data obtained previously on the hyperdiploid strain of EAT. Eighty-five noninbred male albino mice were used. An injection of tritium-thymidine, with specific radioactivity of 4.1 Ci/mmole, was given to the mice one hour before sacrifice. The results obtained are presented; it is shown that the number of DNA-synthesizing cells in the hypotetraploid strain during the 5th and 6th days of growth of EAT was 503 and 479 /sup 0//00, respectively. Fluctuations of the radioactive index during these days were not significant. Only a significant fall in the radioactive index toward noon on the seventh day of development of the hypotetraploid strain of EAT was observed.

  4. Ultraviolet Radiation Effects on Ehrlich Ascites Tumor Cells

    PubMed Central

    Freed, Jerome J.; Engle, James L.; Rudkin, George T.; Schultz, Jack

    1959-01-01

    A flying spot ultraviolet microscope, employing a fast scan and pulsed operation of the raster, has been used to induce radiation damage in ascites tumor slide cultures, and to study by time-lapse cinematography the progressive stages of cell damage. The cells observed came from a strain (EF7) of the Ehrlich ascites carcinoma. Irradiated cells were found to show a characteristic syndrome of damage, involving blebbing at the cell surface, while control cells in the adjacent areas of the preparation remained unchanged. The end of the blebbing period is marked by swelling of the cells, and the time taken for this phenomenon to occur was used as a measure of the severity of the damage. It was found that the time required for swelling is dependent on the size of the dose employed, as well as on the sensitivity of the cells. This latter sensitivity was found to decline as the physiological age of the tumor increased. If ultraviolet illumination below 255 mµ is excluded, no symptoms of damage occur, even when very large doses are used. These observations are discussed in relation to the nature of the system in the cell which is affected. PMID:13654439

  5. Inactivation of Ehrlich ascites tumor cells by heavy ions

    SciTech Connect

    Bertsche, U.; Iliakis, G.; Kraft, G.

    1983-07-01

    Exponentially growing and plateau-phase cultures of Ehrlich ascites tumor cells were irradiated with heavy ions (Z greater than or equal to 20) and assayed for loss of reproductive capacity either immediately or at delayed times after irradiation. The results indicated no modification of the exponential dose response due to conditions which usually favor the repair of potentially lethal damage at low ionization density. Postirradiation treatment of the cells with beta-arabinofuranosyladenine, a DNA synthesis inhibitor known to act on PLD repair, resulted in effects similar to those observed without this drug and confirmed the hypothesis that at such high values of ionization density only lethal, unmodifiable damage can be expressed. The inactivation cross-section values calculated from the slope of the measured survival curves showed no significant correlations with commonly used parameters of radiation quality such as LET or z/sup 2//beta 2. Instead, a functional dependence on the primary ion energy was indicated, being smaller by a factor of two at low energies (less than or equal to 2 MeV/amu) compared with values at energies above 4 MeV/amu, where agreement with the morphological nuclear cross section of the culture was found. This suggests that at higher specific ion energies energetic secondary electrons contribute to the induction of lethal damage, and that interaction of damaged sites between the primary track and the track ends of delta electrons may occur. The data are therefore also discussed in terms of the ''penumbra model'' which emphasizes the role of delta electrons in cell killing when radiations with very high ionization density are applied.

  6. Inactivation of Ehrlich ascites tumor cells by heavy ions

    SciTech Connect

    Bertsche, U.; Iliakis, G.; Kraft, G.

    1983-07-01

    Exponentially growing and plateau-phase cultures of Ehrlich ascites tumor cells were irradiated with heavy ions (Z greater than or equal to 20) and assayed for loss of reproductive capacity either immediately or at delayed times after irradiation. The results indicated no modification of the exponential dose response due to conditions which usually favor the repair of potentially lethal damage at low ionization density. Postirradiation treatment of the cells with a DNA synthesis inhibitor known to act on PLD repair resulted in effects similar to those observed without this drug and confirmed the hypothesis that at such high values of ionization density only lethal, unmodifiable damage can be expressed. The inactivation cross-section values calculated from the slope of the measured survival curves showed no significant correlations with commonly used parameters of radiation quality. Instead, a functional dependence on the primary ion energy was indicated, being smaller by a factor of two at low energies (less than or equal to 2 MeV/amu) compared with values at energies above 4 MeV/amu, where agreement with the morphological nuclear cross section of the culture was found. This suggests that at higher specific ion energies energetic secondary electrons contribute to the induction of lethal damage, and that interaction of damaged sites between the primary track and the track ends of delta electrons may occur. The data are therefore also discussed in terms of the penumbra model which emphasizes the role of delta electrons in cell killing when radiations with very high ionization density are applied.

  7. Gracilaria edulis extract induces apoptosis and inhibits tumor in Ehrlich ascites tumor cells in vivo.

    PubMed

    Patra, Satyajit; Muthuraman, Meenakshi Sundaram

    2013-11-25

    Marine environment is inestimable for their chemical and biological diversity and therefore is an extraordinary resource for the discovery of new anticancer drugs. Recent development in elucidation of the mechanism and therapeutic action of natural products helped to evaluate for their potential activity. We evaluated Gracilaria edulis J. Ag (Brown algae), for its antitumor potential against the Ehrlich ascites tumor (EAT) in vivo and in vitro. Cytotoxicity evaluation of Ethanol Extract of Gracilaria edulis (EEGE) using EAT cells showed significant activity. In vitro studies indicated that EEGE cytotoxicity to EAT cells is mediated through its ability to produce reactive oxygen species (ROS) and therefore decreasing intracellular glutathione (GSH) levels may be attributed to oxidative stress. Apoptotic parameters including Annexin-V positive cells, increased levels of DNA fragmentation and increased caspase-2, caspase-3 and caspase-9 activities indicated the mechanism might be by inducing apoptosis. Intraperitoneally administration of EEGE to EAT-bearing mice helped to increase the lifespan of the animals significantly inhibited tumor growth and increased survival of mice. Extensive hematology, biochemistry and histopathological analysis of liver and kidney indicated that daily doses of EEGE up to 300 mg/kg for 35 days are well tolerated and did not cause hematotoxicity nor renal or hepatotoxicity. Comprehensive antitumor analysis in animal model and in Ehrlich Ascites Tumor cells was done including biochemical, and pathological evaluations indicate antitumor activity of the extract and non toxic in vivo. It was evident that the mechanism explains the apoptotic activity of the algae extract.

  8. Gracilaria edulis extract induces apoptosis and inhibits tumor in Ehrlich Ascites tumor cells in vivo

    PubMed Central

    2013-01-01

    Background Marine environment is inestimable for their chemical and biological diversity and therefore is an extraordinary resource for the discovery of new anticancer drugs. Recent development in elucidation of the mechanism and therapeutic action of natural products helped to evaluate for their potential activity. Methods We evaluated Gracilaria edulis J. Ag (Brown algae), for its antitumor potential against the Ehrlich ascites tumor (EAT) in vivo and in vitro. Cytotoxicity evaluation of Ethanol Extract of Gracilaria edulis (EEGE) using EAT cells showed significant activity. In vitro studies indicated that EEGE cytotoxicity to EAT cells is mediated through its ability to produce reactive oxygen species (ROS) and therefore decreasing intracellular glutathione (GSH) levels may be attributed to oxidative stress. Results Apoptotic parameters including Annexin-V positive cells, increased levels of DNA fragmentation and increased caspase-2, caspase-3 and caspase-9 activities indicated the mechanism might be by inducing apoptosis. Intraperitoneally administration of EEGE to EAT-bearing mice helped to increase the lifespan of the animals significantly inhibited tumor growth and increased survival of mice. Extensive hematology, biochemistry and histopathological analysis of liver and kidney indicated that daily doses of EEGE up to 300 mg/kg for 35 days are well tolerated and did not cause hematotoxicity nor renal or hepatotoxicity. Conclusion Comprehensive antitumor analysis in animal model and in Ehrlich Ascites Tumor cells was done including biochemical, and pathological evaluations indicate antitumor activity of the extract and non toxic in vivo. It was evident that the mechanism explains the apoptotic activity of the algae extract. PMID:24274337

  9. [Chronobiological analysis of thyroxine action on cell proliferation in the hypotetraploid strain of Ehrlich's ascitic tumor].

    PubMed

    Romanov, Iu A; Stepanenko, V A

    1989-11-01

    Experiments on white random-bred male mice were made to study the effect of L-thyroxine on cell proliferation of the hypotetraploid strain of Ehrlich's ascites carcinoma. It was shown that prolonged thyroxine administration (during 6 days of carcinoma growth) lead to synchronization of cell proliferation and the maximum values of the mitotic index was found 3 hours earlier then in the control experiments. At the same time thyroxine did not exert any noticeable effect on the average daily magnitudes of the number of DNA-synthesizing cells and did not change the pattern of modulations in the radioactive index. The changes in the mitotic index and radioactive index were asynchronous in control and experimental animals. Analogous results were found for hyperdiploid strain of Ehrlich's ascites tumor. Ploidy of cells did not influence the tipe rhythms of the cell proliferation and its reaction on the action of thyroxine.

  10. Translocator protein (18 kDa) mediates the pro-growth effects of diazepam on Ehrlich tumor cells in vivo.

    PubMed

    Sakai, M; Ferraz-de-Paula, V; Pinheiro, M L; Ribeiro, A; Quinteiro-Filho, W M; Rone, M B; Martinez-Arguelles, D B; Dagli, M L Z; Papadopoulos, V; Palermo-Neto, J

    2010-01-25

    The Translocator Protein (TSPO), previously known as the peripheral-type benzodiazepine receptor, is a ubiquitous drug- and cholesterol-binding protein that is up regulated in several types of cancer cells. TSPO drug ligands (e.g., diazepam) induce or inhibit tumor cell proliferation, depending on the dose and tissue origin. We have previously shown that TSPO is expressed in Ehrlich tumor cells and that diazepam increases proliferation of these cells in vitro. Here, we investigated the in vivo effects of diazepam on Ehrlich tumor growth and the role of TSPO in mediating this process. Oral administration of diazepam to mice (3.0mg/kg/day for 7 days) produced plasma and ascitic fluid drug concentrations of 83.83 and 54.12 nM, respectively. Diazepam increased Ehrlich tumor growth, likely due to its ability to increase tumor cell proliferation and Reactive Oxygen Species production. Radioligand binding assays and nucleotide sequencing revealed that Ehrlich tumor cell TSPO had the same pharmacological and biochemical properties as TSPO described in other tumor cells. The estimated K(d) for PK 11195 in Ehrlich tumor cells was 0.44 nM and 8.70 nM (low and high binding site, respectively). Structurally diverse TSPO drug ligands with exclusive affinity for TSPO (i.e., 4-chlordiazepam, Ro5-4864, and isoquinoline-carboxamide PK 11195) also increased Ehrlich tumor growth. However, clonazepam, a GABA(A)-specific ligand with no affinity for TSPO, failed to do so. Taken together, these data suggest that diazepam induces in vivo Ehrlich tumor growth in a TSPO-dependent manner.

  11. Factors Influencing the Inhibitory Effect of Selenium on Mice Inoculated with Ehrlich Ascites Tumor Cells

    NASA Astrophysics Data System (ADS)

    Greeder, Glenn A.; Milner, J. A.

    1980-08-01

    Selenium, administered to mice with Ehrlich ascites tumors, effectively limited tumor growth. The response was dependent on the chemical form and dose of selenium administered. At the doses administered, there were no detectable adverse effects to the host.

  12. Ehrlich tumor inhibition using doxorubicin containing liposomes.

    PubMed

    Elbialy, Nihal Saad; Mady, Mohsen Mahmoud

    2015-04-01

    Ehrlich tumors were grown in female balb mice by subcutaneous injection of Ehrlich ascites carcinoma cells. Mice bearing Ehrlich tumor were injected with saline, DOX in solution or DOX encapsulated within liposomes prepared from DMPC/CHOL/DPPG/PEG-PE (100:100:60:4) in molar ratio. Cytotoxicity assay showed that the IC50 of liposomes containing DOX was greater than that DOX only. Tumor growth inhibition curves in terms of mean tumor size (cm(3)) were presented. All the DOX formulations were effective in preventing tumor growth compared to saline. Treatment with DOX loaded liposomes displayed a pronounced inhibition in tumor growth than treatment with DOX only. Histopathological examination of the entire tumor sections for the various groups revealed marked differences in cellular features accompanied by varying degrees in necrosis percentage ranging from 12% for saline treated mice to 70% for DOX loaded liposome treated mice. The proposed liposomal formulation can efficiently deliver the drug into the tumor cells by endocytosis (or passive diffusion) and lead to a high concentration of DOX in the tumor cells. The study showed that the formulation of liposomal doxorubicin improved the therapeutic index of DOX and had increased anti-tumor activity against Ehrlich tumor models.

  13. Role of metallothionein in the zinc metabolism of Ehrlich ascites tumor cells

    SciTech Connect

    Kraker, A.J.

    1983-01-01

    The reactions of zinc and zinc, cadmium metallothioneins with apocarbonic anhydrase have been studied. Apo-carbonic anhydrase abstracts zinc from zinc metallothionein and zinc, cadmium metallothionein in second-order processes which are two to three orders of magnitude more rapid than those of EDTA abstraction of zinc and are similar to the rate of reconstitution of the apo-enzyme by unligated Zn. In comparison with other proteins, zinc metallothionein contains unusually reactive metal binding sites suggesting this protein may be a physiological donor of Zn to zinc requiring sites in cells. When limiting amounts of dietary zinc stimulate the deficient cells to divide, zinc is not observed in metallothionein. A non-limiting amount of dietary zinc supports both proliferation and the steady state presence of zinc in this protein. Zinc metallothionein is shown to be the principal donor of zinc to added apo-carbonic anhydrase in Ehrlich cell cytosol. Treatment of cells with a copper ligand known to possess anti-tumor activity, with the toxic metal Cd, or with cis-dichlorodiamine Pt(II) which is another anti-tumor agent, all cause cells to cease proliferation at levels of each agent which result in the displacement of zinc from metallothionein. These results are used to construct a model of zinc metabolism in which Zn metallothionein is a central, biochemically active form of zinc. The finding in a number of tumors other than Ehrlich ascites carcinoma of the existence of metal binding protein with characteristics similar to metallothionein suggests that the significantly elevated levels of metallothionein-like protein may be a general feature of many tumors and that it may play a vital role in rapidly proliferating tissue in general.

  14. Chronobiological characteristics of the action of thyroxine of reproduction of Ehrlich's Ascites Tumor cells

    SciTech Connect

    Stepanenko, V.A.; Romanov, Y.A.

    1985-05-01

    This paper studies the action of thyroxine on cell proliferation in a hyperdiploid strain of Ehrlich's Ascites Tumor (EAT) depending on clock time. Five albino mice were given an injection of tritium-thymidine in a dose of 0.5 u Ci/g body weight (specific radioactivity 4.1 Ci/mmole) one hour before sacrifice. On autoradiographs from each animal, during examination of 3000-5000 cells, the number of dividing and DNA-synthesizing cells was counted and mitotic index and radioactive index were calculated and expressed in promille. Parameters method and the results were subjected to statistical analysis by the Fisher-Student method. Differences were considered significant at the P less than 0.05 level.

  15. Evaluation of combinations of drugs that inhibit Ehrlich tumor cell ribonucleotide reductase.

    PubMed

    Sato, A; Cory, J G

    1981-05-01

    The nature of the inhibition of Ehrlich tumor cell ribonucleotide reductase by combinations of agents directed at the non-heme iron-containing component and the effector-binding component was studied with the use of isobolograms. From these studies, it was determined that the combinations of pyrazoloimidazole (IMPY) and dialdehyde of inosine, IMPY and deoxyguanosine triphosphate (dGTP), IMPY and deoxyadenosine triphosphate (dATP), and IMPY and deoxythymidine triphosphate (dTTP) gave synergistic inhibition of cytidine diphosphate reductase. The combination of dATP and dGTP also gave synergistic inhibition. The combinations of hydroxyurea and IMPY, 4-methyl-5-aminoisoquinoline thiosemicarbazone (MAIQ) and IMPY, and dialdehyde of inosine and dialdehyde derivative of 5'-deoxyinosine gave antagonistic inhibition. Other combinations utilizing MAIQ and dATP, MAIQ and dGTP, MAIQ and dTTP, hydroxyurea and dGTP, and hydroxyurea and dTTP gave inhibition which was additive.

  16. Studies on the interaction between the Ehrlich ascites tumor cell and its fluid environment

    SciTech Connect

    Magnani, B.

    1984-01-01

    In this dissertation, the glycolytic nature of the Ehrlich ascites tumor (EAT) cell is disclosed both in vivo and in vitro by experiments challenging it with glucose. It is demonstrated that EAT cells can cause the extracellular pH to drop to values sufficiently acidic so as to inhibit EAT glycolysis. However, the extracellular fluid or the Ascites Supernatant Fluid (ASF) reduced the extent to which the pH dropped during EAT cell glycolysis. A comparison of the activities of the sera from tumor-bearing mice and normal mice revealed that the serumfrom the tumor-bearing mice reduced the pH fall generated by the EAT cell in the same way as did ASF; normal mouse serum had no such effect. The metabolic pathways utilized during glucose catabolism were examined by radio-respirometry and the results demonstrated that the high percentage of the glucose conversion to lactate occurred because of partial blockade of the TCA cycle. The databolism of glutamine, glutamic acid, asparagine, aspartic acid, and alanine was enhanced by ASF as determined by measuring /sup 14/CO/sub 2/ from /sup 14/C-labelled amino acids, with glutamine catabolism enhanced about three-fold. Fractionation experiments revealed that ASF contained a factor(s) responsible for this enhancement that had a molecular weight greater than 300,000 daltons and was heat-labile.

  17. An investigation of the shedding of macromolecules from the Ehrlich mouse ascites tumor cell

    SciTech Connect

    Edwards, E.H.

    1984-01-01

    The spontaneous release, or shedding, of cell surface components into the extracellular medium may be important in the determination of several features of the cancer cell phenotype. The release of macromolecules from the Erhlich mouse ascites tumor cell was studied under a variety of experimental conditions to elucidate the origin and the underlying mechanisms of release. The extrinsic macromolecules are a diverse group with apparent molecular weights ranging from 13,500 to 400,000 daltons. External labeling of the cell surface with tritiated 4,4{prime}-diisothiocyano-1,2-diphenylethane-2,2-disulfonic acid (({sup 3}H)H{sub 2}DIDS) reveals a slow loss of labeled components at 4{degrees}C, while at 21{degrees}C and 37{degrees}C an initial rapid loss is followed by a slower release. In vitro metabolic labeling with (1-{sup 14}C)-D-glucosamine hydrochloride, D-(2-{sup 3}H)-mannose and various ({sup 3}H)-L-amino acids results in the appearance of labeled macromolecules in the medium suggesting tumor, not mouse, origin. These data suggest that the extrinsic macromolecules originate from the cell surface. Macromolecules are shed by a temperature and pH sensitive process. These results suggest that a limited proteolytic digestion, or sublethal autolysis, of the cell surface may occur in this system. The macromolecules shed by the Ehrlich cell originate from the surface and are probably released by sublethal autolysis, direct secretion and a passive process.

  18. Evidence for activation of an active electrogenic proton pump in Ehrlich ascites tumor cells during glycolysis

    SciTech Connect

    Heinz, A.; Sachs, G.; Schafer, J.A.

    1981-01-01

    The addition of glucose to a suspension of Ehrlich ascites tumor cells results in rapid acidification of the extracellular medium due to lactic acid production. The nature of the H+ efflux mechanism has been studied by measuring the time course of the acidification, the rate of proton efflux, the direction and relative magnitude of the H+ concentration gradient, and the voltage across the membrane. Using the pH-sensitive dye acridine orange, we have established that after addition of 10 mM glucose an outward-directed H+ concentration gradient develops. As the rate of glycolysis slows, the continued extrusion of H+ reverses the direction of the H+ concentration gradient. Changes in absorbance of the voltage-sensitive dye diethyloxadicarbocyanine iodide (DOCC), and changes in the distribution of the lipid permeant cation tetraphenyl phosphonium, showed a dramatic and persistent hyperpolarization of the membrane voltage after glucose addition. The hyperpolarization was prevented by the protonophore tetrachlorosalicylanalide (TCS) and by valinomycin, but not by the neutral-exchange ionophore nigericin. Inhibitors of lactate efflux were found to reduce the rate of acidification after glucose addition but they had no effect on the magnitude of the resulting hyperpolarization. On the basis of these and other data we suggest that an active electrogenic pump mechanism for H+ efflux may be activated by glucose and that this mechanism operates independently of the lactate carrier system.

  19. Regulatory volume decrease in Ehrlich ascites tumor cells is not mediated by a rise in intracellular calcium.

    PubMed

    Young, R J; Smith, T C; Levinson, C

    1993-02-23

    Ehrlich ascites tumor cells suspended in hyposmotic solution initially swell and then shrink back towards normal volume, a process known as regulatory volume decrease (RVD). RVD is characterized by a specific loss of KCl, although the mechanism for this is currently unknown. The hypothesis that a rise in intracellular calcium ([Ca2+]i) activates calcium-sensitive ion conductances to initiate RVD was investigated. The results indicate that in the Ehrlich cell no rise in [Ca2+]i occurs when the extracellular osmolality is reduced from 300 mosM to 180 mosM. These findings were substantiated by the lack of sensitivity of RVD to the Ca(2+)-sensitive K+ channel blockers charybdotoxin (CTX) and nifedipine. In contrast, the ionophore ionomycin induced a cell shrinkage that was sensitive to CTX and nifedipine indicating that a rise in [Ca2+]i could play a role in cell volume reduction but that this occurred by a mechanism different from that observed in RVD. The conclusion from these experiments is that Ca2+ does not act as a second messenger for RVD in the Ehrlich cell.

  20. M3 Macrophages Stop Division of Tumor Cells In Vitro and Extend Survival of Mice with Ehrlich Ascites Carcinoma.

    PubMed

    Kalish, Sergey; Lyamina, Svetlana; Manukhina, Eugenia; Malyshev, Yuri; Raetskaya, Anastasiya; Malyshev, Igor

    2017-01-26

    BACKGROUND M1 macrophages target tumor cells. However, many tumors produce anti-inflammatory cytokines, which reprogram the anti-tumor M1 macrophages into the pro-tumor M2 macrophages. We have hypothesized that the problem of pro-tumor macrophage reprogramming could be solved by using a special M3 switch phenotype. The M3 macrophages, in contrast to the M1 macrophages, should respond to anti-inflammatory cytokines by increasing production of pro-inflammatory cytokines to retain its anti-tumor properties. Objectives of the study were to form an M3 switch phenotype in vitro and to evaluate the effect of M3 macrophages on growth of Ehrlich ascites carcinoma (EAC) in vitro and in vivo. MATERIAL AND METHODS Tumor growth was initiated by an intraperitoneal injection of EAC cells into C57BL/6J mice. RESULTS 1) The M3 switch phenotype can be programed by activation of M1-reprogramming pathways with simultaneous inhibition of the M2 phenotype transcription factors, STAT3, STAT6, and/or SMAD3. 2) M3 macrophages exerted an anti-tumor effect both in vitro and in vivo, which was superior to anti-tumor effects of cisplatin or M1 macrophages. 3) The anti-tumor effect of M3 macrophages was due to their anti-proliferative effect. CONCLUSIONS Development of new biotechnologies for restriction of tumor growth using in vitro reprogrammed M3 macrophages is very promising.

  1. M3 Macrophages Stop Division of Tumor Cells In Vitro and Extend Survival of Mice with Ehrlich Ascites Carcinoma

    PubMed Central

    Kalish, Sergey; Lyamina, Svetlana; Manukhina, Eugenia; Malyshev, Yuri; Raetskaya, Anastasiya; Malyshev, Igor

    2017-01-01

    Background M1 macrophages target tumor cells. However, many tumors produce anti-inflammatory cytokines, which reprogram the anti-tumor M1 macrophages into the pro-tumor M2 macrophages. We have hypothesized that the problem of pro-tumor macrophage reprogramming could be solved by using a special M3 switch phenotype. The M3 macrophages, in contrast to the M1 macrophages, should respond to anti-inflammatory cytokines by increasing production of pro-inflammatory cytokines to retain its anti-tumor properties. Objectives of the study were to form an M3 switch phenotype in vitro and to evaluate the effect of M3 macrophages on growth of Ehrlich ascites carcinoma (EAC) in vitro and in vivo. Material/Methods Tumor growth was initiated by an intraperitoneal injection of EAC cells into C57BL/6J mice. Results 1) The M3 switch phenotype can be programed by activation of M1-reprogramming pathways with simultaneous inhibition of the M2 phenotype transcription factors, STAT3, STAT6, and/or SMAD3. 2) M3 macrophages exerted an anti-tumor effect both in vitro and in vivo, which was superior to anti-tumor effects of cisplatin or M1 macrophages. 3) The anti-tumor effect of M3 macrophages was due to their anti-proliferative effect. Conclusions Development of new biotechnologies for restriction of tumor growth using in vitro reprogrammed M3 macrophages is very promising. PMID:28123171

  2. Morphogenesis of Influenza A Virus in Ehrlich Ascites Tumor Cells as Revealed by Thin-Sectioning and Freeze-Etching

    PubMed Central

    Bächi, T.; Gerhard, W.; Lindenmann, J.; Mühlethaler, K.

    1969-01-01

    The budding of a tumor-adapted strain of influenza A0 virus at the surface of Ehrlich ascites tumor cells was studied by electron microscopy. Thin sections of budding sites showed the formation of a fuzzy coat on the outside of the cell membrane and simultaneously the apposition of a dark layer on the inner side. The continuity of cellular and viral membrane seemed to be preserved up to the point where the virion remained attached by only a thin stalk. Freeze-etching of virus budding sites yielded pictures in which a clear differentiation between the viral membrane and the host cell membrane was visible. The breaks across the fuzzy coat revealed striations corresponding to the “spikes” seen in negative contrast, whereas tangentially broken virus particles were best interpreted by assuming that splitting occurred midway between the two outer layers of the envelope. Images PMID:5391162

  3. Characteristics of the accumulation of methotrexate polyglutamate derivatives in Ehrlich ascites tumor cells and isolated rat hepatocytes

    SciTech Connect

    Fry, D.W.; Gewirtz, D.A.; Yalowich, J.C.; Goldman, I.D.

    1983-01-01

    The intracellular synthesis and retention of polygammaglutamyl derivatives of methotrexate and their interactions with H/sub 2/ folate reductase was evaluated. Methotrexate polyglutamates were detected within 15 minutes in hepatocytes exposed to 1 microM methotrexate, and continued to accumulate for at least 60 minutes producing a large transmembrane gradient. These derivatives appeared to be preferentially retained within the cell. In studies with the Ehrlich ascites tumor accumulation of methotrexate polyglutamates was increased over 5-fold by the addition of 5 mM L-glutamine or L-glutamate and exhibited a positive correlation with the extracellular concentration of methotrexate. When Ehrlich ascites tumor cells were exposed to 10 microM methotrexate and 5 mM L-glutamine intracellular polyglutamates were detected within 10 minutes and their levels increased linearly over 4 hours. As these derivatives accumulated, there was a decline in intracellular methotrexate due at least in part to a replacement of methotrexate on H/sub 2/ folate reductase by polyglutamates and subsequent efflux of the previously bound methotrexate from the cell. When polyglutamate derivatives were in excess of the H/sub 2/ folate reductase binding capacity and extracellular methotrexate removed, methotrexate rapidly exited the cell whereas the majority of its metabolites were retained and eventually saturated the major portion of the enzyme. These studies indicate that (1) intracellular methotrexate is rapidly converted to polygammaglutamyl derivatives, (2) these metabolites effectively compete with methotrexate for binding sites on H/sub 2/ folate reductase, (3) these derivatives are retained within the cell more effectively than methotrexate, and (4) vincristine and probenecid may be potentially useful for selectively increasing methotrexate polyglutamates in tumor cells.

  4. Role of isothiocyanate conjugate of pterostilbene on the inhibition of MCF-7 cell proliferation and tumor growth in Ehrlich ascitic cell induced tumor bearing mice

    SciTech Connect

    Nikhil, Kumar; Sharan, Shruti; Chakraborty, Ajanta; Bodipati, Naganjaneyulu; Krishna Peddinti, Rama; Roy, Partha

    2014-01-15

    Naturally occurring pterostilbene (PTER) and isothiocyanate (ITC) attract great attention due to their wide range of biological properties, including anti-cancer, anti-leukemic, anti-bacterial and anti-inflammatory activities. A novel class of hybrid compound synthesized by introducing an ITC moiety on PTER backbone was evaluated for its anti-cancer efficacy in hormone-dependent breast cancer cell line (MCF-7) in vitro and Ehrlich ascitic tumor bearing mice model in vivo. The novel hybrid molecule showed significant in vitro anti-cancer activity (IC{sub 50}=25±0.38) when compared to reference compound PTER (IC{sub 50}=65±0.42). The conjugate molecule induced both S and G2/M phase cell cycle arrest as indicated by flow cytometry analysis. In addition, the conjugate induced cell death was characterized by changes in cell morphology, DNA fragmentation, activation of caspase-9, release of cytochrome-c into cytosol and increased Bax: Bcl-2 ratio. The conjugate also suppressed the phosphorylation of Akt and ERK. The conjugate induced cell death was significantly increased in presence of A6730 (a potent Akt1/2 kinase inhibitor) and PD98059 (a specific ERK inhibitor). Moreover, the conjugated PTER inhibited tumor growth in Ehrlich ascitic cell induced tumor bearing mice as observed by reduction in tumor volume compared to untreated animals. Collectively, the pro-apoptotic effect of conjugate is mediated through the activation of caspases, and is correlated with the blockade of the Akt and ERK signaling pathways in MCF-7 cells. - Highlights: • Conjugate was prepared by appending isothiocyanate moiety on pterostilbene backbone. • Conjugate showed anticancer effects at comparatively lower dose than pterostilbene. • Conjugate caused blockage of the Akt and ERK signaling pathways in MCF-7 cells. • Conjugate significantly reduced solid tumor volume as compared to pterostilbene.

  5. Selective incorporation of various C-22 polyunsaturated fatty acids in Ehrlich ascites tumor cells

    SciTech Connect

    Masuzawa, Y.; Okano, S.; Waku, K.; Sprecher, H.; Lands, W.E.

    1986-11-01

    Three /sup 14/C-labeled 22-carbon polyunsaturated fatty acids, 7,10,13,16-(/sup 14/C)docosatetraenoic acid (22:4(n-6)), 7,10,13,16,19-(/sup 14/C)docosapentaenoic acid (22:5(n-3)), and 4,7,10,13,16,19-(/sup 14/C)docosahexaenoic acid (22:6(n-3)), were compared with (/sup 3/H)arachidonic acid (20:4(n-6) and (14C)linoleic acid (18:2(n-6)) to characterize their incorporation into the lipids of Ehrlich ascites cells. The relatively rapid incorporation of the labeled 22-carbon acids into phosphatidic acid indicated that substantial amounts of these acids may be incorporated through the de novo pathway of phospholipid synthesis. In marked contrast to 20:4(n-6), the 22-carbon acids were incorporated much less into choline glycerophospholipids (CGP) and inositol glycerophospholipids (IGP). No selective preference was apparent for the (n-3) or (n-6) type of fatty acids. The amounts of the acids incorporated into diacylglycerophosphoethanolamine were in the order of: 22:6(n-3) greater than 20:4(n-6) much greater than 22:5(n-3) greater than or equal to 22:4(n-6) greater than 18:2(n-6), whereas for alkylacylglycerophosphoethanolamine they were in the order of: 22:4(n-6) greater than 22:6(n-3) greater than 22:5(n-3) much greater than 20:4(n-6) greater than 18:2(n-6). Of the mechanisms possibly responsible for the selective entry of 22-carbon acids into ethanolamine glycerophospholipids, the most reasonable explanation was that the cytidine-mediated ethanolamine phosphotransferase may have a unique double selectivity: for hexaenoic species of diacylglycerol and for 22-carbon polyunsaturated fatty acid-containing species of alkylacylglycerol. The relative distribution of fatty acids between newly incorporated and already maintained lipid classes suggested that IGP may function in Ehrlich cells as an intermediate pool for the retention of polyunsaturated fatty acids in glycerolipids.

  6. Modifying the response of Ehrlich ascites tumor cells to nitrogen mustard (HN/sub 2/) by vincristine, Ca and liposomes

    SciTech Connect

    Ritter, C.; Kutman, R.J.

    1986-03-01

    Though vincristine (0.5mg/kg) has no significant carcinostatic effect on Ehrlich ascites tumor cells, it does modify the carcinostatic effect of HN/sub 2/. Cells treated with 25 ..mu..m HN/sub 2/ in vitro, cold washed, then injected into recipient mice (1 x 10/sup 5/ cells/mouse) yielded 62% 60d mouse survival while cells treated with HN/sub 2/ and vincristine yielded approx. 30% survival. Parallel in vitro experiments using /sup 13/N HN/sub 2/ showed that vincristine did not decrease HN/sub 2/ uptake. Pretreating cells with 0.25 mM Ca before addition of drugs reversed the vincristine inhibition of HN/sub 2/ action. The action of extracellular Ca increased microtubule polymerization, decreasing vincristine action as has been reported for other systems. Cells treated with liposomes made of L(..cap alpha..) dipalmitoylphosphatidyl choline, then with HN/sub 2/ then injected into mice yielded 92% mouse survival. Liposome treatment increased HN/sub 2/ uptake only about 18% while increasing cytostatis approx. 30%. The liposome effect was removed, and cytostatis reduced to approx. 30% mouse survival by vincristine. Cells pretreated with Ca + liposomes restored HN/sub 2/ effectiveness to near that seen with liposomes alone. HN/sub 2/ distribution and tumor cell death are modified by (1) the state of microtubule polymerization and (2) by membrane phospholipid composition.

  7. Acute cholesterol depletion leads to net loss of the organic osmolyte taurine in Ehrlich Lettré tumor cells.

    PubMed

    Villumsen, Kasper Rømer; Duelund, Lars; Lambert, Ian Henry

    2010-11-01

    In mammalian cells, the organic osmolyte taurine is accumulated by the Na-dependent taurine transporter TauT and released though the volume- and DIDS-sensitive organic anion channel. Incubating Ehrlich Lettré tumor cells with methyl-β-cyclodextrin (5 mM, 1 h) reduces the total cholesterol pool to 60±5% of the control value. Electron spin resonance data indicate a concomitant disruption of cholesterol-rich micro-domains. Active taurine uptake, cellular taurine content, and cell volume are reduced by 50, 20 and 20% compared to control values, respectively, whereas the passive taurine release is increased 4.5-fold under isotonic conditions following cholesterol depletion. However, taurine release under isotonic conditions is insensitive to DIDS and inhibitors of the volume-regulated anion channel. Uptake and release of meAIB are similarly affected following cholesterol depletion. Kinetic analysis reveals that cholesterol depletion increases TauT's affinity toward taurine but reduces its maximal transport capacity. Cholesterol depletion has no impact on TauT regulation by protein kinases A and C. Phospholipase A2 activity, which is required for the activation of volume-sensitive organic anion channel (VSOAC), is increased under isotonic and hypotonic conditions following cholesterol depletion, whereas taurine release under hypotonic conditions is reduced following cholesterol depletion. Hence, acute cholesterol depletion of Ehrlich Lettré cells leads to reduced TauT and VSOAC activities and at the same time increases the release of organic osmolytes via a leak pathway different from the volume-sensitive pathways for amino acids and anions.

  8. Na+,Cl- cotransport in Ehrlich ascites tumor cells activated during volume regulation (regulatory volume increase).

    PubMed

    Hoffmann, E K; Sjøholm, C; Simonsen, L O

    1983-01-01

    Ehrlich ascites cells were preincubated in hypotonic medium with subsequent restoration of tonicity. After the initial osmotic shrinkage the cells recovered their volume within 5 min with an associated KCl uptake. The volume recovery was inhibited when NO-3 was substituted for Cl-, and when Na+ was replaced by K+, or by choline (at 5 mM external K+). The volume recovery was strongly inhibited by furosemide and bumetanide, but essentially unaffected by DIDS. The net uptake of Cl- was much larger than the value predicted from the conductive Cl- permeability. The undirectional 36Cl flux, which was insensitive to bumetanide under steady-state conditions, was substantially increased during regulatory volume increase, and showed a large bumetanide-sensitive component. During volume recovery the Cl- flux ratio (influx/efflux) for the bumetanide-sensitive component was estimated at 1.85, compatible with a coupled uptake of Na+ and Cl-, or with an uptake via a K+,Na+,2Cl- cotransport system. The latter possibility is unlikely, however, because a net uptake of KCl was found even at low external K+, and because no K+ uptake was found in ouabain-poisoned cells. In the presence of ouabain a bumetanide-sensitive uptake during volume recovery of Na+ and Cl- in nearly equimolar amounts was demonstrated. It is proposed that the primary process during the regulatory volume increase is an activation of an otherwise quiescent, bumetanide-sensitive Na+,Cl- cotransport system with subsequent replacement of Na+ by K+ via the Na+/K+ pump, stimulated by the Na+ influx through the Na+,Cl- cotransport system.

  9. Na+/H+ exchange in Ehrlich ascites tumor cells: activation by cytoplasmic acidification and by treatment with cupric sulphate.

    PubMed

    Kramhøft, B; Lambert, I H; Hoffmann, E K

    1988-04-01

    Exposure of Ehrlich cells to isotonic Na+-propionate medium induces a rapid cell swelling. This treatment is likely to impose an acid load on the cells. Cell swelling is absent in K+-propionate medium but may be induced by the ionophore nigericin, which mediates K+/H+ exchange. Cell swelling in Na+-propionate medium is blocked by amiloride, but an alternative pathway is introduced by addition of the ionophore monensin, which mediates Na+/H+ exchange. Consequently, swelling of Ehrlich cells in Na+-propionate medium is due to the operation of an amiloride-sensitive, Na+-specific mechanism. It is concluded that this mechanism is a Na+/H+ exchange system, activated by cytoplasmic acidification. We have previously demonstrated that the heavy metal salt CuSO4 in micromolar concentrations inhibits regulatory volume decrease (RVD) of Ehrlich cells following hypotonic swelling. The present work shows that CuSO4 inhibits RVD as a result of a net uptake of sodium, of which the major part is sensitive to amiloride. Measurements of intracellular pH show that CuSO4 causes significant cytoplasmic alkalinization, which is abolished by amiloride. Concomitantly, CuSO4 causes an amiloride-sensitive net proton efflux from the cells. The combined results confirm that a Na+/H+ exchange system exists in Ehrlich cells and demonstrate that the heavy metal salt CuSO4 activates this Na+/H+ exchange system.

  10. Simultaneous analysis of mitochondrial activity and DNA content in Ehrlich ascites tumor cells by dual parameter flow cytometry.

    PubMed

    Hämmerle, T; Löffler, M

    1989-01-01

    Ehrlich ascites tumor cells were permeabilized using low concentrations of digitonin, 8 micrograms/10(6) cells. Permeabilization was monitored by the assay of lactate dehydrogenase released into the incubation medium and of hexokinase partially bound to mitochondria. Integrity of the cellular organelles was unaffected as determined by assay of the mitochondrial enzyme glutamate dehydrogenase. Cells were stained with rhodamine 123 as a mitochondrial specific dye and propidium iodide/mithramycin as DNA specific dyes. The green fluorescence of bound rhodamine 123 versus red fluorescence of DNA in individual cells was analysed by dual parameter flow cytometry. Incubation of cells with inhibitors of mitochondrial energy metabolism, such as, potassium cyanide and carbonyl cyanide m-chlorophenylhydrazone abolished binding of rhodamine 123. Flow cytometric data allowed a correlation between cell position in the mitotic cycle with total mitochondrial activity. In addition, comparison of the characteristics of propidium iodide and ethidium bromide staining further elucidated the molecular basis of the staining with the positively-charged fluorescent dye rhodamine 123.

  11. THE ISOLATION OF LYSOSOMES FROM EHRLICH ASCITES TUMOR CELLS FOLLOWING PRETREATMENT OF MICE WITH TRITON WR-1339

    PubMed Central

    Horvat, Agnes; Baxandall, Jane; Touster, Oscar

    1969-01-01

    A method is described for obtaining highly purified lysosomes from Ehrlich ascites tumo cells grown in mice injected with Triton WR-1339. The isolated particles show a high specific activity for aryl sulfatase, representing an 80–90-fold purification over the homogenate, and a 15–18% yield of the total enzyme activity. Mitochondrial and microsomal marker enzymes are present in negligible amounts (0.2% of the activity of the homogenate). The biochemical evidence for a rather high degree of homogeneity of the fraction is supported by the electron microscopic examination of the purified lysosomes. The intracellular localizations of N-acetyl-β-glucosaminidase, NADH-cytochrome c reductase and NADPH-cytochrome c reductase in Ehrlich ascites cells are also reported, the first two being present in highest concentration in the combined mitochondrial-lysosomal fraction and the third in the microsomal fraction. PMID:5792335

  12. The isolation of lysosomes from Ehrlich ascites tumor cells following pretreatment of mice with Triton WR-1339.

    PubMed

    Horvat, A; Baxandall, J; Touster, O

    1969-08-01

    A method is described for obtaining highly purified lysosomes from Ehrlich ascites tumo cells grown in mice injected with Triton WR-1339. The isolated particles show a high specific activity for aryl sulfatase, representing an 80-90-fold purification over the homogenate, and a 15-18% yield of the total enzyme activity. Mitochondrial and microsomal marker enzymes are present in negligible amounts (0.2% of the activity of the homogenate). The biochemical evidence for a rather high degree of homogeneity of the fraction is supported by the electron microscopic examination of the purified lysosomes. The intracellular localizations of N-acetyl-beta-glucosaminidase, NADH-cytochrome c reductase and NADPH-cytochrome c reductase in Ehrlich ascites cells are also reported, the first two being present in highest concentration in the combined mitochondrial-lysosomal fraction and the third in the microsomal fraction.

  13. DNA damage and inhibition of akt pathway in mcf-7 cells and ehrlich tumor in mice treated with 1,4-naphthoquinones in combination with ascorbate.

    PubMed

    Ourique, Fabiana; Kviecinski, Maicon R; Felipe, Karina B; Correia, João Francisco Gomes; Farias, Mirelle S; Castro, Luiza S E P W; Grinevicius, Valdelúcia M A S; Valderrama, Jaime; Rios, David; Benites, Julio; Calderon, Pedro Buc; Pedrosa, Rozangela Curi

    2015-01-01

    The aim of this study was to enhance the understanding of the antitumor mechanism of 1,4-naphthoquinones and ascorbate. Juglone, phenylaminonaphthoquinone-7, and 9 (Q7/Q9) were evaluated for effects on CT-DNA and DNA of cancer cells. Evaluations in MCF-7 cells are DNA damage, ROS levels, viability, and proliferation. Proteins from MCF-7 lysates were immunoblotted for verifying PARP integrity, γH2AX, and pAkt. Antitumor activity was measured in Ehrlich ascites carcinoma-bearing mice. The same markers of molecular toxicity were assessed in vivo. The naphthoquinones intercalate into CT-DNA and caused oxidative cleavage, which is increased in the presence of ascorbate. Treatments caused DNA damage and reduced viability and proliferation of MCF-7 cells. Effects were potentiated by ascorbate. No PARP cleavage was observed. Naphthoquinones, combined with ascorbate, caused phosphorylation of H2AX and inhibited pAkt. ROS were enhanced in MCF-7 cells, particularly by the juglone and Q7 plus ascorbate. Ehrlich carcinoma was inhibited by juglone, Q7, or Q9, but the potentiating effect of ascorbate was reproduced in vivo only in the cases of juglone and Q7, which caused up to 60% inhibition of tumor and the largest extension of survival. Juglone and Q7 plus ascorbate caused enhanced ROS and DNA damage and inhibited pAkt also in Ehrlich carcinoma cells.

  14. DNA Damage and Inhibition of Akt Pathway in MCF-7 Cells and Ehrlich Tumor in Mice Treated with 1,4-Naphthoquinones in Combination with Ascorbate

    PubMed Central

    Ourique, Fabiana; Kviecinski, Maicon R.; Felipe, Karina B.; Correia, João Francisco Gomes; Farias, Mirelle S.; Castro, Luiza S. E. P. W.; Grinevicius, Valdelúcia M. A. S.; Valderrama, Jaime; Rios, David; Benites, Julio; Buc Calderon, Pedro; Pedrosa, Rozangela Curi

    2015-01-01

    The aim of this study was to enhance the understanding of the antitumor mechanism of 1,4-naphthoquinones and ascorbate. Juglone, phenylaminonaphthoquinone-7, and 9 (Q7/Q9) were evaluated for effects on CT-DNA and DNA of cancer cells. Evaluations in MCF-7 cells are DNA damage, ROS levels, viability, and proliferation. Proteins from MCF-7 lysates were immunoblotted for verifying PARP integrity, γH2AX, and pAkt. Antitumor activity was measured in Ehrlich ascites carcinoma-bearing mice. The same markers of molecular toxicity were assessed in vivo. The naphthoquinones intercalate into CT-DNA and caused oxidative cleavage, which is increased in the presence of ascorbate. Treatments caused DNA damage and reduced viability and proliferation of MCF-7 cells. Effects were potentiated by ascorbate. No PARP cleavage was observed. Naphthoquinones, combined with ascorbate, caused phosphorylation of H2AX and inhibited pAkt. ROS were enhanced in MCF-7 cells, particularly by the juglone and Q7 plus ascorbate. Ehrlich carcinoma was inhibited by juglone, Q7, or Q9, but the potentiating effect of ascorbate was reproduced in vivo only in the cases of juglone and Q7, which caused up to 60% inhibition of tumor and the largest extension of survival. Juglone and Q7 plus ascorbate caused enhanced ROS and DNA damage and inhibited pAkt also in Ehrlich carcinoma cells. PMID:25793019

  15. Effects of. beta. -arabinofuranosyladenine on the growth and repair of potentially lethal damage in Ehrlich ascites tumor cells

    SciTech Connect

    Iliakis, G.

    1980-09-01

    ..beta..-D-Arabinofuranosyladenine (..beta..-araA) inhibit the growth of Ehrlich ascites tumor cells by selective inhibition of DNA polymerases. RNA and protein synthesis are not significantly affected. Addition of ..beta..-araA to the cells after irradiation resulted in a concentration-dependent decrease in survival, presumably due to the inhibition of the repair of potentially lethal damage. Since ..beta..-araA selectively inhibits DNA polymerases it is suggested that repair of potentially lethal damage involves steps at the DNA level which require some polymerization. These repair steps take place in the DNA with a velocity comparable to that of the repair of potentially lethal damage. The inhibition of the repair of potentially lethal damage by ..beta..-araA was modified by the addition of deoxyadenosine; this supports the finding that ..beta..-araA acts competitively against dATP at the molecular level. The inhibition of the repair of potentially lethal damage by ..beta..-araA, which is partly reversible, resulted in a concentration-dependent modification of the survival curve. At low concentrations of ..beta..-araA a dose-modifying decrease in survival was observed. At higher concentrations (more than 12 ..mu..M) the decrease in survival resulted in a decrease of the shoulder width of the survival curve. Eventually an exponential curve was obtained. We suggest therefore that the shoulder of the survival curve results from some repair or potentially lethal damage. Preliminary information has been obtained on the time course of this repair.

  16. Characterization of the inflammatory response during Ehrlich ascitic tumor development.

    PubMed

    Fernandes, Patrícia Dias; Guerra, Fabiana S; Sales, Natália M; Sardella, Thais B; Jancar, Sonia; Neves, Josiane S

    2015-01-01

    Ehrlich tumor is a mammary adenocarcinoma with aggressive behavior. Inoculated in mice peritoneal cavity, the Ehrlich tumor grows in ascitic form (EAT). Since inflammation modulates tumor progression we further investigated the inflammatory response during EAT growth. Balb/C mice were intraperitoneal inoculated with 5×10(5) Ehrlich cells and after every 2days, blood samples were collected for hemoglobin, hematocrit, platelets and leukocytes counts. The ascitic fluid was collected for protein concentration and cell count. Phenotype analysis of the peritoneal cells was made by FACS, prostaglandin E2 (PGE2) and cytokines by ELISA, nitric oxide (NO) by nitrate conversion protocol, and cyclooxygenase-1 (COX1), COX2 and inducible nitric oxide synthase (iNOS) by immunoblotting. Following EAT inoculation into the peritoneal cavity there was a rapid increase in ascitis volume and protein concentration. The cell number in ascitis remained stable until day 8 (lag phase) followed by a sharp increase. As tumor progressed, blood leukocytes increased and erythrocyte decreased. Phenotypic analysis showed that during the lag phase the percentage of F4/80(+) cells remained similar to control levels and around 7% of this population was also positive for the GR1 marker. These double-positive cells (probably inflammatory monocytes) markedly increased at day 6. The percentage of F4/80-GR1(+)cells (probably neutrophils) was low and did not significantly vary during tumor progression. CD4(+) and CD8(+) cells were not detected in the time points analyzed. iNOS and COX1 expression increased after day 2 reaching peak levels on day 10. COX2 enzyme expression did not change significantly over time. Sustained increase in PGE2 and NO levels was observed. IL-10 and MCP-1 peaked at day 14 and IL-1β increased progressively till day 10. IFN-γ levels were low till day 10, increasing progressively after that. These data extended the characterization of the inflammatory response during Ehrlich

  17. Anticancer potential of Amaryllidaceae alkaloids evaluated by screening with a panel of human cells, real-time cellular analysis and Ehrlich tumor-bearing mice.

    PubMed

    Havelek, Radim; Muthna, Darina; Tomsik, Pavel; Kralovec, Karel; Seifrtova, Martina; Cahlikova, Lucie; Hostalkova, Anna; Safratova, Marcela; Perwein, Maria; Cermakova, Eva; Rezacova, Martina

    2017-09-25

    In this study, twenty-two Amaryllidaceae alkaloids were screened for their anticancer potential. All isolates were evaluated for antiproliferative activities on a panel of 17 human cell types of different tissue origin using WST-1 assay. In addition, we determined the antiproliferative effect with a real-time cell analysis xCELLigence system. Thereafter, to evaluate the barely known in vivo anticancer potential of the most potent molecule haemanthamine, a preliminary study was performed using an Ehrlich tumor-bearing mice model. The results showed that haemanthamine, lycorine and haemanthidine exerted the highest antiproliferative activity. The mean growth percent (GP) value after a single-dose 10 μM treatment was for haemanthamine 21%, for lycorine 21% and for haemanthidine 27% that of untreated control cells (100%). Furthermore, haemanthamine, lycorine and haemanthidine exhibited significant cytotoxicities against all the tested cell lines with individual IC50 values in the micromolar range. Dynamic real-time measures of impedance by xCELLigence indicated that these three compounds suppress cell proliferation after 10 h of treatment at a concentration of 10 μM or higher. Regrettably, in a follow-up in vivo antitumor activity study, haemanthamine showed no statistically significant reduction in the tumor size with no prolongation of survival time of Ehrlich tumor-bearing mice. Taken together, these results provide a new clue and guidance for exploiting Amaryllidaceae alkaloids as anticancer agents. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Effect of atorvastatin and methotrexate on solid Ehrlich tumor.

    PubMed

    Kabel, Ahmed M; Abdel-Rahman, Mohamed Nabih; El-Sisi, Alaa El-Din E; Haleem, Mahmoud Said; Ezzat, Nadia M; El Rashidy, Mohamed A

    2013-08-05

    Hydroxymethyl glutaryl CoA reductase is the key enzyme in cholesterol synthesis. A relationship was found between cholesterol and the development of many types of cancer. Atorvastatin is a hypolipidemic drug that may have a role in treatment of cancer. Moreover, atorvastatin was reported to decrease the resistance of cancer cells to many chemotherapeutic agents. The aim of this work was to study the effect of each of methotrexate (MTX) and atorvastatin alone and in combination on solid Ehrlich carcinoma (SEC) in mice. Fifty BALB/c mice were divided into five equal groups: control untreated group, SEC, SEC+MTX, SEC+atorvastatin, SEC+MTX+atorvastatin. Tumor volume, tissue glutathione reductase (GR), catalase, malondialdehyde (MDA), cholesterol and tumor necrosis factor alpha (TNF-α) were determined. A part of the tumor was examined for histopathological and immunohistochemical study. MTX or atorvastatin alone or in combination induced significant increase in tissue catalase and GR with significant decrease in tumor volume, tissue MDA, cholesterol and TNF-α and alleviated the histopathological changes with significant increase in p53 expression and apoptotic index compared to SEC group. In conclusion, the combination of MTX and atorvastatin had a better effect than each of MTX or atorvastatin alone against solid Ehrlich tumor in mice. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Evidence that repair and expression of potentially lethal damage cause the variations in cell survival after x irradiation observed through the cell cycle in Ehrlich ascites tumor cells

    SciTech Connect

    Iliakis, G.; Nuesse, M.

    1983-07-01

    The survival of synchronously growing Ehrlich ascites tumor cells (EAT cells) was measured after x irradiation in various stages of the cell cycle. Cells at the beginning of S or in G2 + M phase showed a high level of killing, whereas cells irradiated in G1 or in the middle of S phase were more resistant. These changes resulted from a change in the survival curve shoulder width (D/sub q/) as cells passed through the cell cycle, and the mean lethal dose (D/sub 0/) remained practically unchanged (0.8 +- 0.05 Gy). When synchronization of the cell population was further sharpened using nocodazole, exponential survival curves were obtained at the beginning of S phase and at mitosis with a D/sub 0/ = 0.8 Gy. When cells (in all stages) were incubated in balanced salt solution for 6 h after irradiation, repair of potentially lethal damage (PLD) was observed, resulting in an increase in D/sub q/, while D/sub 0/ remained constant. Treatment of the cells after irradiation with either caffeine or ..beta..-arabinofuranosyladenine (..beta..-araA) or hypertonic medium resulted in an expression of PLD and reduced the D/sub q/ of the survival curve. We measured the rate of the loss of sensitivity of these treatments that we assume reflects the rate of repair of PLD. Results indicate that the shoulder width D/sub q/ of the survival curve in cells irradiated at various stages of the cell cycle results from repair of PLD. It is suggested that the variations observed in cell survival through the cell cycle might reflect variations in the final amount of PLD either repaired or expressed as the cells progress through stages of the cell cycle.

  20. Observations on Cell Volume, Ultrastruture, Mitochondrial Conformation and Vital-Dye Uptake in Ehrlich Ascites Tumor Cells

    PubMed Central

    Laiho, Kauno U.; Shelburne, John D.; Trump, Benjamin F.

    1971-01-01

    The ultrastructure, volume, vital-dye uptake, ATP levels and amounts of intracelular water have been studied in Ehrlich ascites cells treated with two classes of inhibitors. Cell membrane injury with 10-3 M parachloromercuribenzene sulfonate (PCMBS) resulted in a rapid increase in mean cell volume to 3 times the mean zero time value. Inhibition of respiration plus glycolysis with 10-4 M iodoacetate (IAA) plus 10-4 M antimycin resulted first in a slight decrease in volume and then later a slow increase. When glucose was present in the medium, this slow increase was very slight. Intracellular water determination followed closely the volume changes. Cell populations with decreased mean volumes showed dilatations of the ER and swelling of mitochondria, indicating that expansion of some intracellular compartments can occur at the expense of others. Vital-dye uptake in metabolic injury correlated to some extent with the presence of substrate, indicating that an effect of glucose on membrane permeability might be independent of its effects on ATP levels. Mitochondrial contractions appeared with PCMBS as early as 5 minutes, with or without glucose present. With glucose present, treatment with IAA and antimycin also resulted in similar contractions as well as ring-form contractions even at 5 minutes. Without glucose, IAA plus antimycin mainly produced the usual mitochondrial contractions and these developed much later in the course of the incubation, shortly before high-amplitude swelling. The relationship of these mitochondrial conformational changes to ADP/ATP ratios and ADP levels is discussed. ImagesFig 4Fig 5Fig 1Fig 6Fig 2Fig 3Fig 11Fig 7Fig 8Fig 9Fig 10 PMID:5096366

  1. Fluorescent redox dyes. 1. Production of fluorescent formazan by unstimulated and phorbol ester- or digitonin-stimulated Ehrlich ascites tumor cells.

    PubMed

    Stellmach, J

    1984-01-01

    The reduction of a new series of tetrazolium salts to red fluorescent formazans by Ehrlich ascites tumor cells is described. The qualitative effect on this reaction of two cell surface-active compounds and of six exogenous electron carriers was investigated by varying the incubation conditions. After incubation of Ehrlich ascites cells with the new colourless, water soluble 5-cyan-2.3-ditolyltetrazolium salts, bright red water-insoluble formazan crystals on the cell surface can be observed under fluorescence microscopy. The production of formazan is enhanced by 12-0-tetradecanoyl-phorbol-13-acetate (TPA) or digitonin (DIG), two potent stimulators of oxygen consumption or by the electron carriers phenazine methosulphate (PMS), 1-methoxy-phenazine methosulphate (MPMS), meldola blue (MB), methylene blue (MTB), and 2.6-dichlorindophenol (DCIP). These results provide further evidence for the existence of redox enzymes bound to the plasma membrane of intact ascites cells and for a free radical mechanism of tetrazolium salt reduction. The fluorescence property of the new redox dyes offers the advantage of high sensitivity. Moreover, their greater homogeneity relative to the commonly used di-tetrazolium salts lowers the chances of misinterpretations due to impurities. The possible application of these new mono-tetrazolium salts to cytochemical investigations of oxidative metabolic reactions is discussed.

  2. Involvement of protein tyrosine phosphorylation and reduction of cellular sulfhydryl groups in cell death induced by 1' -acetoxychavicol acetate in Ehrlich ascites tumor cells.

    PubMed

    Moffatt, Jerry; Kennedy, David Opare; Kojima, Akiko; Hasuma, Tadayoshi; Yano, Yoshihisa; Otani, Shuzo; Murakami, Akira; Koshimizu, Koichi; Ohigashi, Hajime; Matsui-Yuasa, Isao

    2002-02-20

    Elucidation of the mechanisms underlying potential anticancer drugs continues and unraveling these mechanisms would not only provide a conceptual framework for drug design but also promote use of natural products for chemotherapy. To further evaluate the efficacy of the anticancer activity of 1'-acetoxychavicol acetate (ACA), this study investigates the underlying mechanisms by which ACA induces death of Ehrlich ascites tumor cells. ACA treatment induced loss of cell viability, and Western blotting analysis revealed that the compound stimulated tyrosine phosphorylation of several proteins with 27 and 70 kDa proteins being regulated in both dose- and time-dependent manner prior to loss of viability. Protein tyrosine kinase inhibitor herbimycin A moderately protected cells from ACA-induced toxicity. In addition, cellular glutathione and protein sulfydryl groups were also significantly reduced both dose- and time-dependently during evidence of cell death. Replenishing thiol levels by antioxidant, N-acetylcysteine (NAC), an excellent supplier of glutathione and precursor of glutathione, substantially recovered the viability loss, but the recovery being time-dependent, as late addition of NAC (at least 30 min after ACA addition to cultures) was, however, ineffective. Addition of NAC to ACA treated cultures also abolished tyrosine phosphorylation of the 27 kDa protein. These results, at least partly, identify cellular sulfhydryl groups and protein tyrosine phosphorylation as targets of ACA cytotoxicity in tumor cells.

  3. Use of raw Euphorbia tirucalli extract for inhibition of ascitic Ehrlich tumor.

    PubMed

    Santos, Orlando José Dos; Sauaia Filho, Euler Nicolau; Nascimento, Flávia Raquel Fernandes do; Júnior, Francisco Cardoso Silva; Fialho, Eder Magalhães Silva; Santos, Rayan Haquim Pinheiro; Santos, Rennan Abud Pinheiro; Serra, Izabel Cristina Portela Bogéa

    2016-02-01

    to evaluate the effect of the Euphorbia tirucalli hydroalcoholic extract (ETHE) on the development of Ehrlich Tumor, in its ascitic form. we intraperitoneally inoculated 15 Swiss mice with 10.44 x 107 cells of Ehrlich Tumor and divided them in two groups one day after: ETHE Group (eight mice), treated with a dosage of 125 mg/kg/day of EHTE for five days; and Control Group (seven mice), treated only with 0.9% isotonic saline solution over the same period. The treatment was done by gavage. Ten days after inoculation, four mice from each group were sacrificed for quantification of tumor cell number, ascitic fluid volume and bone marrow cell number. The remaining animals were maintained to evaluate survival. The ascitic fluid volume and the tumor cell number were decreased in the ETHE group when compared with the control group, but with no statistical significance. On the other hand, survival was higher in the ETHE group, as well as the number of bone marrow cells. Treatment with ETHE after inoculation of Ehrlich Tumor decreases its development and increases survival and the bone marrow cellularity, thus reducing the myelosuppression present in the Ehrlich Tumor bearing mice.

  4. Quercetin Reduces Ehrlich Tumor-Induced Cancer Pain in Mice

    PubMed Central

    Calixto-Campos, Cassia; Corrêa, Mab P.; Carvalho, Thacyana T.; Zarpelon, Ana C.; Hohmann, Miriam S. N.; Rossaneis, Ana C.; Coelho-Silva, Leticia; Pavanelli, Wander R.; Pinge-Filho, Phileno; Bernardy, Catia C. F.; Verri, Waldiceu A.

    2015-01-01

    Cancer pain directly affects the patient's quality of life. We have previously demonstrated that the subcutaneous administration of the mammary adenocarcinoma known as Ehrlich tumor induces pain in mice. Several studies have shown that the flavonoid quercetin presents important biological effects, including anti-inflammatory, antioxidant, analgesic, and antitumor activity. Therefore, the analgesic effect and mechanisms of quercetin were evaluated in Ehrlich tumor-induced cancer pain in mice. Intraperitoneal (i.p.) treatments with quercetin reduced Ehrlich tumor-induced mechanical and thermal hyperalgesia, but not paw thickness or histological alterations, indicating an analgesic effect without affecting tumor growth. Regarding the analgesic mechanisms of quercetin, it inhibited the production of hyperalgesic cytokines IL-1β and TNFα and decreased neutrophil recruitment (myeloperoxidase activity) and oxidative stress. Naloxone (opioid receptor antagonist) inhibited quercetin analgesia without interfering with neutrophil recruitment, cytokine production, and oxidative stress. Importantly, cotreatment with morphine and quercetin at doses that were ineffective as single treatment reduced the nociceptive responses. Concluding, quercetin reduces the Ehrlich tumor-induced cancer pain by reducing the production of hyperalgesic cytokines, neutrophil recruitment, and oxidative stress as well as by activating an opioid-dependent analgesic pathway and potentiation of morphine analgesia. Thus, quercetin treatment seems a suitable therapeutic approach for cancer pain that merits further investigation. PMID:26351625

  5. Quercetin reduces Ehrlich tumor-induced cancer pain in mice.

    PubMed

    Calixto-Campos, Cassia; Corrêa, Mab P; Carvalho, Thacyana T; Zarpelon, Ana C; Hohmann, Miriam S N; Rossaneis, Ana C; Coelho-Silva, Leticia; Pavanelli, Wander R; Pinge-Filho, Phileno; Crespigio, Jefferson; Bernardy, Catia C F; Casagrande, Rubia; Verri, Waldiceu A

    2015-01-01

    Cancer pain directly affects the patient's quality of life. We have previously demonstrated that the subcutaneous administration of the mammary adenocarcinoma known as Ehrlich tumor induces pain in mice. Several studies have shown that the flavonoid quercetin presents important biological effects, including anti-inflammatory, antioxidant, analgesic, and antitumor activity. Therefore, the analgesic effect and mechanisms of quercetin were evaluated in Ehrlich tumor-induced cancer pain in mice. Intraperitoneal (i.p.) treatments with quercetin reduced Ehrlich tumor-induced mechanical and thermal hyperalgesia, but not paw thickness or histological alterations, indicating an analgesic effect without affecting tumor growth. Regarding the analgesic mechanisms of quercetin, it inhibited the production of hyperalgesic cytokines IL-1β and TNFα and decreased neutrophil recruitment (myeloperoxidase activity) and oxidative stress. Naloxone (opioid receptor antagonist) inhibited quercetin analgesia without interfering with neutrophil recruitment, cytokine production, and oxidative stress. Importantly, cotreatment with morphine and quercetin at doses that were ineffective as single treatment reduced the nociceptive responses. Concluding, quercetin reduces the Ehrlich tumor-induced cancer pain by reducing the production of hyperalgesic cytokines, neutrophil recruitment, and oxidative stress as well as by activating an opioid-dependent analgesic pathway and potentiation of morphine analgesia. Thus, quercetin treatment seems a suitable therapeutic approach for cancer pain that merits further investigation.

  6. Conditions supporting repair of potentially lethal damage cause a significant reduction of ultraviolet light-induced division delay in synchronized and plateau-phase Ehrlich ascites tumor cells

    SciTech Connect

    Iliakis, G.; Nusse, M.

    1982-09-01

    Repair of potentially lethal damage (PLD) induced by uv light in synchronized and in plateau-phase cultures of Ehrlich ascites tumor cells was studied by measuring cell survival. In particlar the influence of conditions supporting repair of PLD on growth kinetics was investigated. In synchronized G/sub 1/, S, or G/sub 2/ + M cells as well as in plateau-phase cells, uv light induced, almost exclusively, delay in the next S phase. A significant decrease of this delay was observed when the cells were incubated for 24 hr in balanced salt solution. Repair of PLD after uv irradiation was found to occur in plateau-phase cells and in cells in different phases of the cell cycle provided that after irradiation these were kept under conditions inhibiting cell multiplication (incubation in balanced salt solution or in conditioned medium). The repair time constant t/sub 50/ was significantly higher than those found for X irradiation (5-10 hr compared to 2 hr), and repair was not significantly inhibited by either 20 ..mu..g/ml cycloheximide or 2 mM caffeine in 24 hr.

  7. The synergistic effect between vanillin and doxorubicin in ehrlich ascites carcinoma solid tumor and MCF-7 human breast cancer cell line.

    PubMed

    Elsherbiny, Nehal M; Younis, Nahla N; Shaheen, Mohamed A; Elseweidy, Mohamed M

    2016-09-01

    Despite the remarkable anti-tumor activity of doxorubicin (DOX), its clinical application is limited due to multiple organ toxicities. Products with less side effects are therefore highly requested. The current study investigated the anti-cancer activities of vanillin against breast cancer and possible synergistic potentiation of DOX chemotherapeutic effects by vanillin. Vanillin (100mg/kg), DOX (2mg/kg) and their combination were administered i.p. to solid Ehrlich tumor-bearing mice for 21days. MCF-7 human breast cancer cell line was treated with vanillin (1 and 2mM), DOX (100μM) or their combination. Protection against DOX-induced nephrotoxicity was studied in rats that received vanillin (100mg/kg, ip) for 10days with a single dose of DOX (15mg/kg) on day 6. Vanillin exerted anticancer effects comparable to DOX and synergesticlly potentiated DOX anticancer effects both in-vivo and in-vitro. The anticancer potency of vanillin in-vivo was mediated via apoptosis and antioxidant capacity. It also offered an in-vitro growth inhibitory effect and cytotoxicity mediated by apoptosis (increased caspase-9 and Bax:Bcl-2 ratio) along with anti-metasasis effect. Vanillin protected against DOX-induced nephrotoxicity in rats. In conclusion, vanillin can be a potential lead molecule for the development of non-toxic agents for the treatment of breast cancer either alone or combined with DOX. Copyright © 2016. Published by Elsevier GmbH.

  8. The activity against Ehrlich's ascites tumors of doxorubicin contained in self assembled, cell receptor targeted nanoparticle with simultaneous oral delivery of the green tea polyphenol epigallocatechin-3-gallate.

    PubMed

    Ray, Lipika; Kumar, Pradeep; Gupta, Kailash C

    2013-04-01

    Doxorubicin (DOX) is a well-known anticancer drug used for the treatment of a wide variety of cancers. However, undesired toxicity of DOX limits its uses. To address the issue of minimizing toxicity of DOX by making it targeted towards cancer cells, DOX was entrapped in self-assembled 6-O-(3-hexadecyloxy-2-hydroxypropyl)-hyaluronic acid (HDHA) nanoparticles. We hypothesized that by encapsulating the drug in biodegradable nanoparticles, its therapeutic efficacy would improve, if targeted against cancer cells. We synthesized cell receptor targeted, DOX loaded HDHA nanoparticles (NPs) and non-targeted DOX loaded O-hexadecylated dextran (HDD) nanoparticles (NPs) and characterized them for their entrapment efficiency, percent yield, drug load, surface morphology, particle size and in vitro drug release. The anticancer efficacy of DOX loaded HDHA-NPs was evaluated by measuring the changes in tumor volumes, tumor weights, and mean survival rate of Swiss albino mice grafted with Ehrlich's ascites carcinoma (EAC) cells. For this, the animals were given HDHA-DOX-NPs (1.5 mg/kg b.wt.) intravenously and a green tea polyphenol, Epigallocatechin-3-gallate (EGCG) (20 mg/kg b.wt.), orally through gavage. The targeted NP dose with EGCG significantly increased mean survival time of the animals and enhanced the therapeutic efficacy of the drug compared to the non-targeted NPs and free DOX. Further, we showed that these NPs (HDD and HDHA) were more active in the presence of EGCG than DOX alone in inducing apoptosis in EAC cells as evident by an increase in sub-G1 cells (percent), Annexin V positive cells and chromatin condensation along with the reduction in mitochondrial membrane potential (MMP). The study demonstrates that DOX loaded HDHA-NPs along with EGCG significantly inhibit the growth of EAC cells with ∼38-fold dose advantage compared to DOX alone and thus opens a new dimension in cancer chemotherapy.

  9. Antitumor effectiveness of different amounts of electrical charge in Ehrlich and fibrosarcoma Sa-37 tumors

    PubMed Central

    Ciria, HC; Quevedo, MS; Cabrales, LB; Bruzón, RP; Salas, MF; Pena, OG; González, TR; López, DS; Flores, JM

    2004-01-01

    Background In vivo studies were conducted to quantify the effectiveness of low-level direct electric current for different amounts of electrical charge and the survival rate in fibrosarcoma Sa-37 and Ehrlich tumors, also the effect of direct electric in Ehrlich tumor was evaluate through the measurements of tumor volume and the peritumoral and tumoral findings. Methods BALB/c male mice, 7–8 week old and 20–22 g weight were used. Ehrlich and fibrosarcoma Sa-37 cell lines, growing in BALB/c mice. Solid and subcutaneous Ehrlich and fibrosarcoma Sa-37 tumors, located dorsolaterally in animals, were initiated by the inoculation of 5 × 106 and 1 × 105 viable tumor cells, respectively. For each type of tumor four groups (one control group and three treated groups) consisting of 10 mice randomly divided were formed. When the tumors reached approximately 0.5 cm3, four platinum electrodes were inserted into their bases. The electric charge delivered to the tumors was varied in the range of 5.5 to 110 C/cm3 for a constant time of 45 minutes. An additional experiment was performed in BALB/c male mice bearing Ehrlich tumor to examine from a histolological point of view the effects of direct electric current. A control group and a treated group with 77 C/cm3 (27.0 C in 0.35 cm3) and 10 mA for 45 min were formed. In this experiment when the tumor volumes reached 0.35 cm3, two anodes and two cathodes were inserted into the base perpendicular to the tumor long axis. Results Significant tumor growth delay and survival rate were achieved after electrotherapy and both were dependent on direct electric current intensity, being more marked in fibrosarcoma Sa-37 tumor. Complete regressions for fibrosarcoma Sa-37 and Ehrlich tumors were observed for electrical charges of 80 and 92 C/cm3, respectively. Histopathological and peritumoral findings in Ehrlich tumor revealed in the treated group marked tumor necrosis, vascular congestion, peritumoral neutrophil infiltration, an acute

  10. Ascitic and solid Ehrlich tumor inhibition by Chenopodium ambrosioides L. treatment.

    PubMed

    Nascimento, Flávia R F; Cruz, Gustavo V B; Pereira, Paulo Vitor S; Maciel, Márcia C G; Silva, Lucilene A; Azevedo, Ana Paula S; Barroqueiro, Elizabeth S B; Guerra, Rosane N M

    2006-04-25

    The leaves of Chenopodium ambrosioides L. [Chenopodiaceae] ('mastruz') have been indicated for the treatment of several diseases, among which the cancer. There are no results focusing the effect of C. ambrosioides treatment on tumor development in vivo. The aim of this study was to investigate the effect of treatment with C. ambrosioides on Ehrlich tumor development. Swiss mice were treated by intraperitoneal route (i.p.) with hydroalcoholic extract from leaves of C. ambrosioides (5 mg/kg) or with PBS (control group) 48 h before or 48 h later the Ehrlich tumor implantation. The tumor cells were implanted on the left footpad (solid tumor) or in the peritoneal cavity (ascitic tumor). To determine the solid tumor growth, footpad was measured each 2 days until the fourteenth day, when the feet were weighed. Ascitic tumor development was evaluated after 8 days of tumor implantation by quantification of the ascitic fluid volume and tumor cell number. The i.p. administration of C. ambrosioides extract before or after the tumor implantation significantly inhibited the solid and ascitic Ehrlich tumor forms. This inhibition was observed in ascitic tumor cell number, in the ascitic volume, in the tumor-bearing foot size and foot weight when compared to control mice. The treatments also increased the survival of tumor-bearing mice. In conclusion, C. ambrosioides has a potent anti-tumoral effect which was evident with a small dose and even when the treatment was given two days after the tumor implantation. This effect is probably related with anti-oxidant properties of C. ambrosioides.

  11. Antineoplastic and cytogenetic effects of chlorpromazine on human lymphocytes in vitro and on Ehrlich ascites tumor cells in vivo.

    PubMed

    Lialiaris, Theodore S; Papachristou, Fotini; Mourelatos, Constantine; Simopoulou, Maria

    2009-09-01

    The inhibitory effect of phenothiazines in tumor growth and cancer cell proliferation in vitro and in vivo has been established. These reports motivated us to investigate the genotoxic, cytotoxic, and cytostatic potential of chlorpromazine, alone or in combination with mitomycin C, in vitro and in vivo. Sister chromatid exchange levels were assessed providing a quantitative index of genotoxicity. In-vitro studies were performed on human lymphocyte cultures and in-vivo studies involved Ehrilch ascites tumor (EAT) cells. An antitumour study was also conducted on the survival time and the ascitic volume in EAT-bearing Balb/C mice. The combination of chlorpromazine plus caffeine and mitomycin C exerted cytostatic and cytotoxic actions in human lymphocytes. The combination of chlorpromazine plus mitomycin C exerted cytostatic and cytotoxic actions in EAT cells, significantly increased the survival span of the mice inoculated with EAT cells, and suppressed the expected tumor growth increase. The findings of this basic study illustrate that high chlorpromazine concentrations increase chemotherapeutic effectiveness of mitomycin C. Chlorpromazine concentrations within the observed human plasma concentration range need to be tested along with antineoplastic agents in vitro for its synergistic action so as to evaluate a potential clinical application. Further investigation including other phenothiazines, biological systems, and cancer models is required.

  12. Long-Term Treatment with Aqueous Garlic and/or Tomato Suspensions Decreases Ehrlich Ascites Tumors.

    PubMed

    Bom, Jenifer; Gunutzmann, Patrícia; Hurtado, Elizabeth C Pérez; Maragno-Correa, Jussara M R; Kleeb, Silvia Regina; Lallo, Maria Anete

    2014-01-01

    We evaluated the preventive and therapeutic effects of aqueous suspensions of garlic, tomato, and garlic + tomato in the development of experimental Ehrlich tumors in mice. The aqueous suspensions (2%) were administered over a short term for 30 days before tumor inoculation and 12 days afterward, and suspensions at 6% were administered for 180 days before inoculation and for 12 days afterward. The volume, number, and characteristics of the tumor cells and AgNOR counts were determined to compare the different treatments. Aqueous 6% suspensions of garlic, tomato, and garlic + tomato given over the long term significantly reduced tumor growth but when given over the short term, they did not alter tumor growth.

  13. Synchronization of replicons in Ehrlich ascites cells

    SciTech Connect

    Gekeler, V.; Probst, H. )

    1988-03-01

    Ehrlich ascites cells, in which replication units at the beginning of the S phase started and grew synchronously, were obtained by the following protocol: (1) selection of G{sub 1} cells by zonal centrifugation, (2) hypoxia for 12 h, (3) reaeration, (4) addition of cycloheximide (30 {mu}M) within the first minute after reoxygenation. Studies on the effectiveness of the different steps revealed: (i) G{sub 1} cells reoxygenated after 12 h of hypoxia traverse two succeeding cell cycles high synchronously. This was shown by monitoring the thymidine incorporation rate, the thymidine pulse-labeling index, and the mitotic index. (ii) Cycloheximide, like hypoxia, suppresses replicon initiation in Ehrlich ascites cells without interfering with DNA chain growth and DNA maturation. The reversibility of the suppression is less complete than in the case of hypoxia. This was shown by DNA fiber autoradiography and by analyzing the length distribution of pulse- or pulse/pulse-chase-labeled daughter DNA in alkaline sucrose gradients. The alkaline sedimentation patterns of daughter-strand DNA, pulse labeled immediately after the cycloheximide addition at the end of the elaborated protocol and 1 and 2 h later, indicated synchronous initiation and growth of a homogeneous population of DNA molecules to replicon-sized lengths.

  14. Virus--tumor host cell relationships. In vivo cocultivation of adenovirus type 5 and of SV40 in mouse Ehrlich ascites carcinoma.

    PubMed

    Nastac, E; Chira, M; Hozoc, M; Athanasiu, P; Teleguţă, L; Suru, M; Stoian, M; Pirvu, C

    1982-01-01

    Mouse Ehrlich ascites carcinoma (EAC) cells proved to be a semipermissive substrate for in vivo cultivation of adenovirus 5 (Ad5) and SV40. The multiplication of SV40 in EAC cells was facilitated by the coinfection with Ad5. As demonstrated by ID and EID reactions, the virus progens isolated at the first passage after the mixed infection of EAC cells with Ad5 and SV40 possess an antigenic mosaic with fractions characteristic of the parental viruses and of the cell substrate in which they had cultivated in vitro and in vivo. The progens gave positive seroneutralization and complement fixation reactions only with antiserum to SV40.

  15. Odor cues released by Ehrlich tumor-bearing mice are aversive and induce psychological stress.

    PubMed

    Alves, Glaucie Jussilane; Palermo-Neto, João

    2015-01-01

    This study aimed to verify if odor cues released by Ehrlich tumor-bearing mice are aversive and stressful. Female mice were divided into a control group and an experimental group. One animal of each experimental pair of mice was inoculated with 5 × 10(6) Ehrlich tumor cells intraperitoneally; the other animal was kept undisturbed and was referred to as a CSP (companion of sick partner). One mouse of each control pair was treated intraperitoneally with 0.9% NaCl (1 mg/kg); the other animal (CHP, companion of healthy partner) was kept undisturbed. It was shown that, in relation to CHP, CSP mice (1) spent less time within the companion zone in a T-maze place preference test, (2) had increased levels of social interaction, (3) had increased levels of plasmatic adrenaline and noradrenaline and (4) displayed no changes in serum corticosterone levels before and after an immobilization stress challenge. It was also shown that (5) cohabitation with 2 tumor-bearing mice was more effective in decreasing neutrophil oxidative burst than cohabitation with 1 sick partner and (6) the presence of a healthy conspecific within the cage of the tumor-injected/CSP pair abrogated the effects of cohabitation on neutrophil activity. These results show that odor cues released by Ehrlich tumor-injected mice are aversive and induce psychological stress. We postulate that the aversive response induced by the chemosignals released by Ehrlich tumor-injected animals activates the sympathetic nervous system and causes the neuroimmunal changes that occur in the mice cohabiting with the sick mice. © 2014 S. Karger AG, Basel.

  16. Glycosidases of Ehrlich ascites tumor cells and ascitic fluid--purification and substrate specificity of alpha-N-acetylgalactosaminidase and alpha-galactosidase: comparison with coffee bean alpha-galactosidase.

    PubMed

    Yagi, F; Eckhardt, A E; Goldstein, I J

    1990-07-01

    Ehrlich ascites tumor cells and ascitic fluid were assayed for glycosidase activity. alpha-Galactosidase and beta-galactosidase, alpha- and beta-mannosidase, alpha-N-acetylgalactosaminidase, and beta-N-acetylglucosaminidase activities were detected using p-nitrophenyl glycosides as substrates. alpha-Galactosidase and alpha-N-acetylgalactosaminidase were isolated from Ehrlich ascites tumor cells on epsilon-aminocaproylgalactosylamine-Sepharose. alpha-Galactosidase was purified 160,000-fold and was free of other glycosidase activities. alpha-N-Acetylgalactosaminidase was also purified 160,000-fold but exhibited a weak alpha-galactosidase activity which appears to be inherent in this enzyme. Substrate specificity of the alpha-galactosidase was investigated with 12 substrates and compared with that of the corresponding coffee bean enzyme. The pH optimum of the Ehrlich cell alpha-galactosidase centered near 4.5, irrespective of substrate, whereas the pH optimum of the coffee bean enzyme for PNP-alpha-Gal was 6.0, which is 1.5 pH units higher than that for other substrates of the coffee bean enzyme. The reverse was found for alpha-N-acetylgalactosaminidase: the pH optimum for the hydrolysis of PNP-alpha-GalNAc was 3.6, lower than the pH 4.5 required for the hydrolysis of GalNAc alpha 1,3Gal. Coffee bean alpha-galactosidase showed a relatively broad substrate specificity, suggesting that it is suited for cleaving many kinds of terminal alpha-galactosyl linkages. On the other hand, the substrate specificity of Ehrlich alpha-galactosidase appears to be quite narrow. This enzyme was highly active toward the terminal alpha-galactosyl linkages of Ehrlich glycoproteins and laminin, both of which possess Gal alpha 1, 3Gal beta 1,4GlcNAc beta-trisaccharide sequences. The alpha-N-acetylgalactosaminidase was found to be active toward the blood group type A disaccharide, and trisaccharide, and glycoproteins with type A-active carbohydrate chains.

  17. Qa-2 expression levels is related with tumor-infiltrating lymphocytes profile during solid Ehrlich tumor development.

    PubMed

    da Silva, Istéfani Luciene; Veloso, Emerson Soares; Gonçalves, Ivy Nayra Nascimento; Braga, Ariadne Duarte; Lopes, Miriam Teresa Paz; Cassali, Geovanni Dantas; Quintanilla, Miguel; Simões, Renata Toscano; Ferreira, Enio

    2017-08-01

    The Qa-2 has been described as Human Leucocyte Antigen G (HLA-G) murine homolog. This homology is well accepted to gene and protein structure, in different pathology process and embryos implantation. However, in some neoplasm, this homology is questioned, where Qa-2 has been proposed as an immunogenic molecule, associated to tumor rejection. In this way, the aim of this study was to describe the pattern of Qa-2 expression and its relationship with the profile of tumor-infiltrating lymphocytes in solid Ehrlich tumor. The Ehrlich tumor growth was evaluated in Balb/c female mice in different tumor stages. The inflammatory infiltration features were determined by histopathology and, both lymphocyte type and tissue Qa-2 expression by immunohistochemistry. ELISA kit was used to determine soluble Qa-2 in the serum from the animals. We observed that Qa-2 in neoplastic cells increases in intermediate tumor development stages, while, serum Qa-2 increases in the late stage. Qa-2 increasing is correlated with CD3+ increase. Our results suggest that Qa-2 has a role opposite to HLA-G in Ehrlich solid carcinoma, and may be modulating the immune response by attracting the inflammatory infiltrate, especially T CD8+ Lymphocytes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  18. Aqueous extract from Pecan nut [Carya illinoinensis (Wangenh) C. Koch] shell show activity against breast cancer cell line MCF-7 and Ehrlich ascites tumor in Balb-C mice.

    PubMed

    Hilbig, Josiane; Policarpi, Priscila de Britto; de Souza Grinevicius, Valdelúcia Maria Alves; Santos Mota, Nádia Sandrine Ramos; Pedrosa, Rozangela Curi; Block, Jane Mara

    2017-08-11

    In Brazil, use of teas are common for the treatment of many health disorders. Shell extracts of pecan nut (Carya illinoinensis) are popularly taken as tea to prevent diverse pathologies due to their phytochemical composition presenting significant amounts of phenolic substances. Phenolic compounds from pecan nut shell extract have been associated with diverse biological effects but the effect on tumor cells has not been reported yet. The aim of the current work was to evaluate the relationship between DNA fragmentation, cell cycle arrest and apoptosis induced by pecan nut shell extract and its antitumor activity. Cytotoxicity, proliferation, cell death and cell cycle were evaluated in MCF-7 cells by MTT, colony, differential coloring and flow cytometry assays, respectively. DNA damage effects were evaluated through intercalation into CT-DNA and plasmid DNA cleavage.Tumor growth inhibition, survival time increase, apoptosis and cell cycle arrest were assessed in Ehrlich ascites tumor in Balb/C mice. In this work citotoxic effect of pecan nut shell extracts, the induction of cell death by apoptosis and also the cell cycle arrest in MCF-7 cells have been showed. Also an increase in 67% on the survival time in mice with Ehrlich ascites tumor was observed. DNA damage was shown in the CT-DNA, plasmid DNA and comet assays. The mechanism involved in the antitumor effect of pecan nut shell extracts may involve the activation of key proteins involved in apoptosis cell death (Bcl-XL, Bax and p53) and on the cell cycle regulation (cyclin A, cyclin B and CDK2). These results were attributed to the phenolic profile of the extract, which presented compounds such as gallic, 4-hydroxybenzoic, chlorogenic, vanillic, caffeic and ellagic acid, and catechin, epicatechin, epigallocatechin and epicatechin gallate. The results indicated that pecan nut shell extracts are effective against tumor cells development and may be an alternative to the treatment of cancer. Copyright © 2017

  19. Enhanced Ehrlich tumor inhibition using DOX-NP™ and gold nanoparticles loaded liposomes

    NASA Astrophysics Data System (ADS)

    Mady, M. M.; Al-Shaikh, F. H.; Al-Farhan, F. F.; Aly, A. A.; Al-Mohanna, M. A.; Ghannam, M. M.

    2016-04-01

    Treatment with doxorubicin (DOX) is a common regime in treating various types of cancer. DOX-NP™ is one of a well established marketed liposomal formulation for DOX. It offers distinct advantages over conventional DOX in reducing the cardiac toxicity and increasing the tolerability and efficacy. Gold nanoparticles (GNPs), a typical biocompatible nanomaterial, have been widely used in biomedical engineering and bioanalytical applications such as biomedical imaging and biosensors. Ehrlich tumors were grown in female balb mice by subcutaneous injection of Ehrlich ascites carcinoma cells. Mice bearing Ehrlich tumor were injected with saline, free doxorubicin (DOX) in solution, gold nanoparticles loaded liposomes and commercial liposomal encapsulated doxorubicin (DOX-NP™). The results showed that GNPs loaded liposomes could enhance the antitumor activity of commercial liposomal formulation (DOX-NP™) and displayed significantly decreased systemic toxicity compared with free DOX and commercial liposomal formulation (DOX-NP™) at the equivalent dose. So the combination of GNPs and liposomes is expected to significantly increase the likelihood of cell killing and make it a promising new approach to cancer therapy.

  20. Regulation of the Nucleolar DNA-Dependent RNA Polymerase by Amino Acids in Ehrlich Ascites Tumor Cells

    PubMed Central

    Franze-Fernández, M. T.; Pogo, A. O.

    1971-01-01

    Experiments were performed to ascertain the degree to which the amount of amino acids might be one of the regulatory factors that control the activity of the nucleolar RNA polymerase. Assays of the enzymatic activity were done with isolated nuclei from cells incubated with low and high concentrations of amino acids. Soon after the cells were exposed to a medium enriched in amino acids, a rapid increase of nucleolar RNA polymerase activity occurred. A similar result was obtained in cells incubated with lower concentrations of amino acids. However, the rate of ribosomal RNA synthesized was regularly much higher in cells incubated in a medium enriched with amino acids than in a medium low in amino acids. Apparently, the amino acids only controlled ribosomal RNA synthesis. Thus, neither maturation, processing, and transport of nuclear precursors into cytoplasmic ribosomal RNA, nor the synthesis of rapidly labeled RNA was affected. PMID:4108870

  1. Electrochemical treatment of mouse Ehrlich tumor with direct electric current.

    PubMed

    Cabrales, L B; Ciria, H C; Bruzón, R P; Quevedo, M S; Aldana, R H; De Oca, L M; Salas, M F; Peña, O G

    2001-07-01

    Electrochemical treatment of cancer utilizes direct electric current (DEC) to produce direct alterations and chemical changes in tumors. However, the DEC treatment is not established and mechanisms are not well understood. In vivo studies were conducted to evaluate the effectiveness of DEC on animal tumor models. Ehrlich tumors were implanted subcutaneously in sixty male BALB/c mice. When the tumor volumes reached 850 mm(3), four platinum electrodes were inserted into the tumors. DEC of 4 mA was applied for 21 min to the treated group; the total charge was 5 C. The healthy and sick control groups were subjected to the same conditions but without DEC. Hematological and chemical parameters as well as histopathological and peritumoral findings were studied. After the electrochemical therapy it was observed that both tumor volume decrease and necrosis percentage increase were significant in the treated group. Moreover, 24 h after treatment an acute inflammatory response, as well as sodium ion decrease, and potassium ion and spleen weight increase were observed in this group. It was concluded that both electrochemical reactions (fundamentally those in which reactive oxygen species are involved), and immune system stimulation induced by cytotoxic action of the DEC could constitute the most important antitumor mechanisms. Copyright 2001 Wiley-Liss, Inc.

  2. Immunomodulatory and anti-tumor effects of Nigella glandulifera freyn and sint seeds on ehrlich ascites carcinoma in mouse model

    PubMed Central

    Aikemu, Ainiwaer; Xiaerfuding, Xiadiya; Shiwenhui, Chengyufeng; Abudureyimu, Meiliwan; Maimaitiyiming, Dilinuer

    2013-01-01

    Aim: This study investigated the immunomodulatory and anti-tumor effects of Nigella glandulifera Freyn and Sint seeds (NGS) on Ehrlich ascites carcinoma in a mouse model. Materials and Methods: Kunming mice with transplanted Ehrlich ascites tumor cells (EAC) were treated with NGS by oral administration. On the 11th day after the EAC implant, mouse thymus, liver, spleen and kidney tumors were removed for histopathological analysis. Blood samples were taken for hematological and biochemical analyses. Results: The results indicate that NGS treatment leads to an increase in TNF-α, IL-1β, and IL-2 blood serum levels. Absence of viable EAC and presence of necrotic cells were observed in the tumor tissue of the NGS-treated animals. Conclusions: The study results indicated that a water extract of NGS had the highest anti-tumor effect. Moreover, NGS treatment also showed an increase in the immune system activity. PMID:23929999

  3. Antitumor Activity of Prosopis glandulosa Torr. on Ehrlich Ascites Carcinoma (EAC) Tumor Bearing Mice

    PubMed Central

    Senthil Kumar, Raju; Rajkapoor, Balasubramanian; Perumal, Perumal; Dhanasekaran, Thangavel; Alvin Jose, Manonmani; Jothimanivannan, Chennakesavalu

    2011-01-01

    The antitumor activity of ethanol extract of Prosopis glandulosa Torr. (EPG) was evaluated against Ehrlich ascites carcinoma (EAC) tumor model in Swiss albino mice on dose dependent manner. The activity was assessed using survival time, average increase in body weight, hematological parameters and solid tumor volume. Oral administration of EPG at the dose of 100, 200 and 400 mg/Kg, significantly (p < 0.001) increased the survival time and decreased the average body weight of the tumor bearing mice. After 14 days of inoculation, EPG was able to reverse the changes in the hematological parameters, protein and PCV consequent to tumor inoculation. Oral administration of EPG was effective in reducing solid tumor mass development induced by EAC cells. The results indicate that EPG possess significant antitumor activity on dose dependent manner. PMID:24250382

  4. The proton stoichiometry of electron transport in Ehrlich ascites tumor mitochondria.

    PubMed

    Villalobo, A; Lehninger, A L

    1979-06-10

    Initial rate measurements of the stoichiometric relationships between H+ ejection, K+ and Ca2+ uptake, and electron transport were carried out on mitochondria from Ehrlich ascites tumor cells grown in mice. With succinate as substrate and N-ethylmaleimide to prevent interfering H+ reuptake via the phosphate carrier, close to 8 H+ were ejected per oxygen atom reduced (H+/O ejection ratio = 8.0); with the NAD-linked substrates pyruvate or pyruvate + malate, the H+/O ejection ratio was close to 12. The average H+/site ratio (H+ ejected/2e-/energy-conserving site) was thus close to 4. The simultaneous uptake of charge-compensating cations, either K+ (in the presence of valinomycin) or Ca2+, was also measured, yielding average K+/site uptake ratios of very close to 4 and Ca2+/site ratios close to 2. It was also demonstrated that each calcium ion enters the respiring tumor mitochondria carrying two positive electric charges. These stoichiometric data observed in mitochondria from Ehrlich ascites tumor cells thus are in complete agreement with similar data on normal rat liver and rat heart mitochondria and suggest that the H+/site ratio of mitochondrial electron transport may be 4 generally. It was also observed that the rate of deltaH+ back-decay in anaerobic tumor mitochondria following oxygen pulses is some 6- to 8-fold greater than in rat liver mitochondria tested at equal amounts of mitochondrial protein.

  5. Transport of calcium ions by Ehrlich ascites-tumour cells.

    PubMed Central

    Landry, Y; Lehninger, A L

    1976-01-01

    Ehrlich ascites-tumour cells accumulate Ca2+ when incubated aerobically with succinate, phosphate and rotenone, as revealed by isotopic and atomic-absorption measurements. Ca2+ does not stimulate oxygen consumption by carefully prepared Ehrlich cells, but des so when the cells are placed in a hypo-osmotic medium. Neither glutamate nor malate support Ca2+ uptake in 'intact' Ehrlich cells, nor does the endogenous NAD-linked respiration. Ca2+ uptake is completely dependent on mitochondrial energy-coupling mechansims. It was an unexpected finding that maximal Ca2+ uptake supported by succinate requires rotenone, which blocks oxidation of enogenous NAD-linked substrates. Phosphate functions as co-anion for entry of Ca2+. Ca2+ uptake is also supported by extra-cellular ATP; no other nucleoside 5'-di- or tri-phosphate was active. The accumulation of Ca2+ apparently takes place in the mitochondria, since oligomycin and atractyloside inhibit ATP-supported Ca2+ uptake. Glycolysis does not support Ca2+ uptake. Neither free mitochondria released from disrupted cells nor permeability-damaged cells capable of absorbing Trypan Blue were responsible for any large fraction of the total observed energy-coupled Ca2+ uptake. The observations reported also indicate that electron flow through energy-conserving site 1 promotes Ca2+ release from Ehrlich cells and that extra-cellular ATP increase permeability of the cell membrane, allowing both ATP and Ca2+ to enter the cells more readily. PMID:988829

  6. Transport of calcium ions by Ehrlich ascites-tumour cells.

    PubMed

    Landry, Y; Lehninger, A L

    1976-08-15

    Ehrlich ascites-tumour cells accumulate Ca2+ when incubated aerobically with succinate, phosphate and rotenone, as revealed by isotopic and atomic-absorption measurements. Ca2+ does not stimulate oxygen consumption by carefully prepared Ehrlich cells, but des so when the cells are placed in a hypo-osmotic medium. Neither glutamate nor malate support Ca2+ uptake in 'intact' Ehrlich cells, nor does the endogenous NAD-linked respiration. Ca2+ uptake is completely dependent on mitochondrial energy-coupling mechansims. It was an unexpected finding that maximal Ca2+ uptake supported by succinate requires rotenone, which blocks oxidation of enogenous NAD-linked substrates. Phosphate functions as co-anion for entry of Ca2+. Ca2+ uptake is also supported by extra-cellular ATP; no other nucleoside 5'-di- or tri-phosphate was active. The accumulation of Ca2+ apparently takes place in the mitochondria, since oligomycin and atractyloside inhibit ATP-supported Ca2+ uptake. Glycolysis does not support Ca2+ uptake. Neither free mitochondria released from disrupted cells nor permeability-damaged cells capable of absorbing Trypan Blue were responsible for any large fraction of the total observed energy-coupled Ca2+ uptake. The observations reported also indicate that electron flow through energy-conserving site 1 promotes Ca2+ release from Ehrlich cells and that extra-cellular ATP increase permeability of the cell membrane, allowing both ATP and Ca2+ to enter the cells more readily.

  7. B-1 cells and concomitant immunity in Ehrlich tumour progression.

    PubMed

    Azevedo, M C; Palos, M C; Osugui, L; Laurindo, M F; Masutani, D; Nonogaki, S; Bachi, A L L; Melo, F H M; Mariano, M

    2014-05-01

    Concomitant immunity is a phenomenon in which a tumour-bearing host is resistant to the growth of an implanted secondary tumour. Metastases are considered to be secondary tumours that develop spontaneously during primary tumour growth, suggesting the involvement of concomitant immunity in controlling the rise of metastases. It has been demonstrated that B-1 cells, a subset of B-lymphocytes found predominantly in pleural and peritoneal cavities, not only increase the metastatic development of murine melanoma B16F10, but also are capable of differentiating into mononuclear phagocytes, modulating inflammatory responses in wound healing, in oral tolerance and in Paracoccidiose brasiliensis infections. Here, we studied B-1 cells' participation in concomitant immunity during Ehrlich tumour progression. Our results show that B-1 cells obtained from BALB/c mice previously injected with Ehrlich tumour in the footpad were able to protect BALB/c and BALB/Xid mice against Ehrlich tumour challenge. In addition, it was demonstrated that BALB/Xid show faster tumour growth and have lost concomitant immunity, and that this state can be partially restored by reconstituting these animals with B-1 cells. However, further researches are required to establish the mechanism involving B-1 cells in Ehrlich tumour growth. Copyright © 2014 Elsevier GmbH. All rights reserved.

  8. Anticancer effects of synthetic phosphoethanolamine on Ehrlich ascites tumor: an experimental study.

    PubMed

    Ferreira, Adilson Kleber; Meneguelo, Renato; Pereira, Alexandre; Mendonça Filho, Otaviano R; Chierice, Gilberto Orivaldo; Maria, Durvanei Augusto

    2012-01-01

    Antineoplastic phospholipids (ALPs) represent a promising class of drugs with a novel mode of action undergoes rapid turnover in the cell membrane of tumors, interfering with lipid signal transduction, inducing cell death. The aim of this study was to investigate the synthetic phosphoethanolamine (Pho-s) as a new anticancer agent. Cell viability and morphology were assessed by (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Hoechst and rhodamine staining. Apoptosis was assessed by Annexin V and propidium iodide (PI) staining, caspase-3 activity, mitochondrial membrane potential (ΔmΨ) and cell cycle analysis, combined with evaluation of tumor growth in Ehrlich Ascites Tumor (EAT) bearing mice. We found that Pho-s 2.30 mg/ml induced cytotoxicity in all tumor cell lines studied without affecting normal cells. In vitro studies with EAT cells indicated that Pho-s induced apoptosis, demonstrated by an increase in Annexin-V positive cells, loss of mitochondrial potential (ΔmΨ) and increased caspase-3 activity. It was also shown to increase the sub-G(1) apoptotic fraction and inhibit progression to the S phase of the cell cycle. Additionally, antitumor effects on the EAT-bearing mice showed that Pho-s, at a concentration of 35 and 70 mg/kg, inhibited tumor growth and increased the lifespan of animals without causing liver toxicity. These findings suggest that Pho-s is a potential anticancer candidate drug.

  9. Apoptogenic effects of black tea on Ehrlich's ascites carcinoma cell.

    PubMed

    Bhattacharyya, Arindam; Choudhuri, Tathagata; Pal, Suman; Chattopadhyay, Sreya; K Datta, Goutam; Sa, Gaurisankar; Das, Tanya

    2003-01-01

    Next to water, tea is the most ancient and widely consumed beverage in the world. Epidemiological studies have suggested a cancer protective effect, but the results obtained so far are not conclusive. In the current study, mechanisms of the apoptogenic effect of black tea extract were delineated. Black tea administration to Ehrlich's ascites carcinoma (EAC)-bearing Swiss albino mice caused a significant decrease in the tumor cell count in a dose-dependent manner. Flowcytometric analysis showed an increase in the number of cells in the sub-G(0)/G(1) population signifying tumor cell apoptosis by black tea. These results were further confirmed by nuclear staining that demonstrated distinct morphological features of apoptosis. Our data also revealed an increase in the expression of pro-apoptotic protein p53 in EAC. It is known that upon p53 induction, multiple downstream factors contribute to the decision making between growth arrest and apoptosis. Among those, pro-apoptotic gene Bax is up regulated during p53-mediated apoptosis. On the other hand, p53-mediated growth arrest involves p21 as a major effecter. In our system, increase in p53 expression was followed by moderate expression of p21/Waf-1 and high expression of Bax at protein levels. Interestingly, anti-apoptotic protein Bcl-2 was down regulated resulting in decrease in Bcl-2/Bax ratio. All these observations together signify that black tea-induced apoptogenic signals overrode the growth-arresting message of p21, thereby leading the tumor cells towards death.

  10. Synergism between propolis and hyperthermal intraperitoneal chemotherapy with cisplatin on ehrlich ascites tumor in mice.

    PubMed

    Oršolić, Nada; Car, Nikola; Lisičić, Duje; Benković, Vesna; Knežević, Anica Horvat; Dikić, Domagoj; Petrik, József

    2013-12-01

    We investigated antitumor, genotoxic, chemopreventive, and immunostimulative effects of local chemoimmunotherapy and hyperthermal intraperitoneal chemotherapy (HIPEC) in a mouse-bearing Ehrlich ascites tumor (EAT). Mice were treated with water-soluble derivative of propolis (WSDP) at a dose of 50 mg kg(-1) , 7 and 3 days before implantation of EAT cells, whereas cisplatin (5 or 10 mg kg(-1) ) was injected 3 days after implantation of EAT cells at 37°C and 43°C. The following variables were analyzed: the total number of cells, differential count of the cells present in the peritoneal cavity, functional activity of macrophages, comet assay, and micronucleus assay. The combination of WSDP + CIS 5 mg kg(-1) at 37°C resulted in tumor growth inhibition and increased the survival of mice by additional 115.25%. WSDP with HIPEC increased the survival of mice by additional 160.3% as compared with HIPEC. WSDP reduced cisplatin toxic and genotoxic effect to normal cells without affecting cisplatin cytotoxicity on EAT cells. In addition, WSDP with HIPEC increased the cytotoxic actions of macrophages to tumor cells. Water-soluble derivative of propolis increases macrophage activity and sensitivity of tumor cells to HIPEC and reduces cisplatin toxicity to normal cells. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

  11. The Ehrlich tumor induces pain-like behavior in mice: a novel model of cancer pain for pathophysiological studies and pharmacological screening.

    PubMed

    Calixto-Campos, Cassia; Zarpelon, Ana C; Corrêa, Mab; Cardoso, Renato D R; Pinho-Ribeiro, Felipe A; Cecchini, Rubens; Moreira, Estefania G; Crespigio, Jefferson; Bernardy, Catia C F; Casagrande, Rubia; Verri, Waldiceu A

    2013-01-01

    The Ehrlich tumor is a mammary adenocarcinoma of mice that can be developed in solid and ascitic forms depending on its administration in tissues or cavities, respectively. The present study investigates whether the subcutaneous plantar administration of the Ehrlich tumor cells induces pain-like behavior and initial pharmacological susceptibility characteristics. The Ehrlich tumor cells (1 × 10(4)-10(7) cells) induced dose-dependent mechanical hyperalgesia (electronic version of the von Frey filaments), paw edema/tumor growth (caliper), and flinches compared with the saline group between days 2 and 12. There was no difference between doses of cells regarding thermal hyperalgesia in the hot-plate test. Indomethacin (a cyclooxygenase inhibitor) and amitriptyline hydrochloride (a tricyclic antidepressant) treatments did not affect flinches or thermal and mechanical hyperalgesia. On the other hand, morphine (an opioid) inhibited the flinch behavior and the thermal and mechanical hyperalgesia. These effects of morphine on pain-like behavior were prevented by naloxone (an opioid receptor antagonist) treatment. None of the treatments affected paw edema/tumor growth. The results showed that, in addition to tumor growth, administration of the Ehrlich tumor cells may represent a novel model for the study of cancer pain, specially the pain that is susceptible to treatment with opioids, but not to cyclooxygenase inhibitor or to tricyclic antidepressant.

  12. Sialoadhesin expression by bone marrow macrophages derived from Ehrlich-tumor-bearing mice.

    PubMed

    Kusmartsev, S; Ruiz de Morales, J M; Rullas, J; Danilets, M G; Subiza, J L

    1999-12-01

    Sialoadhesin (sheep erythrocyte receptor, SER) is a macrophage-restricted adhesion molecule that binds certain sialylated ligands. It is borne by bone marrow stromal macrophages, promoting the interaction with developing myeloid cells, and by a subset of tissue macrophages involved in antigen presentation and activation of tumor-reactive T cells. The expression of sialoadhesin on SER+ macrophages is not constitutive but requires the continuous supply of a sialoadhesin-inducing serum factor. Tumor growth is often associated with marked alterations of myelopoiesis and impairment of T cell activation; yet the expression of sialoadhesin in macrophages derived from tumor bearers has not been addressed. The aim of this study was to assess whether Ehrlich tumor (ET) - a murine mammary carcinoma - growth may modify the sialoadhesin expression by bone marrow macrophages and/or sialoadhesin-inducing activity in ET-bearing sera. Moreover, putative functional sialoadhesin inhibitors produced by ET cells were tested. The results indicate that bone marrow cells from ET bearers show a seven- to eight-fold decrease in SER+ cells as detected by flow cytometry. This is accompanied by an overall decrease in sheep erythrocyte binding to tumor-bearer-derived bone marrow cells, but also by lower numbers of plastic-adherent cells. Functional sialoadhesin expression is preserved at the single-cell level and no inhibitors are found in ET-bearing sera or ET cell culture supernatants. Tumor progression does not impair the sialoadhesin-inducing activity of ET-bearing sera, or the ability of SER- macrophages (e.g. peritoneal macrophages) to respond to such an induction. In conclusion, while SER+ macrophages are greatly decreased in bone marrow from ET bearers, this is not due to a down-regulation of sialoadhesin expression, nor to an impairment of sialoadhesin-inducing factor or to the presence of sialoadhesin-binding moieties of tumor origin, but, more likely, to a decrease of fully mature

  13. Internucleotide protein linkers in Ehrlich ascites cell DNA.

    PubMed

    Werner, D; Krauth, W; Hershey, H V

    1980-07-29

    DNA from Ehrlich ascites tumor cells is nicked or gapped by a reaction which is induced by proteases such as autodigested pronase, proteinase K, trypsin, chymotrypsin and subtilisin. The cleavage of the protease-sensitive sites is inhibited by protease inhibitors. The nicks or gaps induced by proteases can be demonstrated by nuclease S1 sensitivity of native DNA and by a change of the sedimentation rate of alkali-denatured DNA. The limit size of denatured DNA released after optimal protease treatment is 8.5 x 10(6) daltons (27 kilo bases). The molecular weight of the native DNA pieces released after nuclease S1 degradation of DNA containing the protease-induced nicks or gaps is in the same order indicating that the protease-sensitive sites are alternatively arranged on the opposite DNA strands at an average distance of 13.5 kilo base pairs. Since the protease-induced nicks or gaps in phosphatase-treated DNA are not attacked by Escherichia coli polymerase I, one or both ends liberated by the protease treatment must be blocked by a material other than phosphate groups. The results are most compatible with peptide/protein linkers joining adjacent single-strand DNA subunits. Alternative explanations such as alkali-stable RNA linkers, protein-protected RNA linkers, site-specific nuclease contaminations in the protease preparations or cellular nucleases activated by the protease treatment are eliminated by the results presented in this paper.

  14. Utilization of ascites plasma very low density lipoprotein triglycerides by Ehrlich cells.

    PubMed

    Brenneman, D E; Spector, A A

    1974-07-01

    Much of the lipid present in the ascites plasma in which Ehrlich cells grow is contained in very low density lipoproteins (VLDL). Chemical measurements indicated that triglycerides were taken up by the cells during in vitro incubation with ascites VLDL. When tracer amounts of radioactive triolein were incorporated into the ascites VLDL, the percentage uptakes of glyceryl tri[1-(14)C]oleate and triglycerides measured chemically were similar. The cells also took up [2-(3)H]glyceryl trioleate that was added to VLDL, but the percentage of available (3)H recovered in the cell lipids was 30-40% less than that of (1 4)C from glyceryl tri[1-(1 4)C]oleate. This difference was accounted for by water-soluble (3)H that accumulated in the incubation medium, suggesting that extensive hydrolysis accompanied the uptake of VLDL triglycerides. Radioactive fatty acids derived from the VLDL triglycerides were incorporated into cell phospholipids, glycerides, and free fatty acids, and they also were oxidized to CO(2). Triglyceride utilization increased as the VLDL concentration was raised. These results suggest that one function of the ascites plasma VLDL may be to supply fatty acid to the Ehrlich cells and that the availability of fatty acid to this tumor is determined in part by the ascites plasma VLDL concentration. Although Ehrlich cells incorporate almost no free glycerol into triglycerides, considerable amounts of [2-(3)H]glyceryl trioleate radioactivity were recovered in cell triglycerides. This indicates that at least some VLDL triglycerides were taken up intact. The net uptake of VLDL protein and cholesterol was very small relative to the triglyceride uptake, suggesting that intact triglycerides are transferred from the ascites VLDL to the Ehrlich cells and that hydrolysis occurs after the triglyceride is associated with the cells.

  15. Nerve growth factor from cobra venom inhibits the growth of Ehrlich tumor in mice.

    PubMed

    Osipov, Alexey V; Terpinskaya, Tatiana I; Kryukova, Elena V; Ulaschik, Vladimir S; Paulovets, Lubov V; Petrova, Elena A; Blagun, Ekaterina V; Starkov, Vladislav G; Utkin, Yuri N

    2014-02-26

    The effects of nerve growth factor (NGF) from cobra venom (cvNGF) on growth of Ehrlich ascites carcinoma (EAC) cells inoculated subcutaneously in mice have been studied. The carcinoma growth slows down, but does not stop, during a course of cvNGF injections and restores after the course has been discontinued. The maximal anti-tumor effect has been observed at a dose of 8 nmoles cvNGF/kg body weight. cvNGF does not impact on lifespan of mice with grafted EAC cells. K252a, a tyrosine kinase inhibitor, attenuates the anti-tumor effect of cvNGF indicating the involvement of TrkA receptors in the process. cvNGF has induced also increase in body weight of the experimental animals. In overall, cvNGF shows the anti-tumor and weight-increasing effects which are opposite to those described for mammalian NGF (mNGF). However in experiments on breast cancer cell line MCF-7 cvNGF showed the same proliferative effects as mNGF and had no cytotoxic action on tumor cells in vitro. These data suggest that cvNGF slows down EAC growth via an indirect mechanism in which TrkA receptors are involved.

  16. Nerve Growth Factor from Cobra Venom Inhibits the Growth of Ehrlich Tumor in Mice

    PubMed Central

    Osipov, Alexey V.; Terpinskaya, Tatiana I.; Kryukova, Elena V.; Ulaschik, Vladimir S.; Paulovets, Lubov V.; Petrova, Elena A.; Blagun, Ekaterina V.; Starkov, Vladislav G.; Utkin, Yuri N.

    2014-01-01

    The effects of nerve growth factor (NGF) from cobra venom (cvNGF) on growth of Ehrlich ascites carcinoma (EAC) cells inoculated subcutaneously in mice have been studied. The carcinoma growth slows down, but does not stop, during a course of cvNGF injections and restores after the course has been discontinued. The maximal anti-tumor effect has been observed at a dose of 8 nmoles cvNGF/kg body weight. cvNGF does not impact on lifespan of mice with grafted EAC cells. K252a, a tyrosine kinase inhibitor, attenuates the anti-tumor effect of cvNGF indicating the involvement of TrkA receptors in the process. cvNGF has induced also increase in body weight of the experimental animals. In overall, cvNGF shows the anti-tumor and weight-increasing effects which are opposite to those described for mammalian NGF (mNGF). However in experiments on breast cancer cell line MCF-7 cvNGF showed the same proliferative effects as mNGF and had no cytotoxic action on tumor cells in vitro. These data suggest that cvNGF slows down EAC growth via an indirect mechanism in which TrkA receptors are involved. PMID:24577582

  17. Enhancement of photosensitization efficiency by various combinations with radiosensitization in an experimental Ehrlich ascites tumor

    NASA Astrophysics Data System (ADS)

    Luksiene, Zivile; Kaspariunaite, G.; Aleknavicius, E.; Valuckas, Konstantinas P.

    1996-12-01

    According to our previous results porphyrin can interact not only with visible light but with ionizing radiation also. This phenomenon gives us new possibility to combine photosensitization with radiosensitization. Data obtained on BALB/c mice with 7-day Ehrlich ascites tumors pretreated with 30 mg/kg HP dimethylether (not toxic and not mutagenic concentration) and irradiated with 60Co source (2 Gy) and visible light source (5 J/cm2) showed remarkable inhibition of tumor growth. Two Gy alone inhibited Ehrlich ascites tumor growth by 17%, whereas combination of 30 mg/kg HPde and 2 Gy (radiosensitization) -- by 38%. Photosensitization (30 mg/kg HPde plus 5 J/cm2) showed 37% tumor growth inhibition. Combination of photosensitization with radiosensitization inhibited tumor growth by 87%. It is important to note, that sequence of treatments (radiosensitization - 1 h - photosensitization or photosensitization - 1 h - radiosensitization) had no influence on tumor growth inhibition.

  18. In vivo tumor inhibitory effects of nutritional rice bran supplement MGN-3/Biobran on Ehrlich carcinoma-bearing mice.

    PubMed

    Badr El-Din, Nariman K; Noaman, Eman; Ghoneum, Mamdooh

    2008-01-01

    This study was undertaken to investigate the in vivo anti-tumor activity of MGN-3/Biobran, a modified arabinoxylan rice bran. Swiss albino mice were inoculated intramuscularly in the right thigh with Ehrlich ascites carcinoma (EAC) cells. On Day 8, mice bearing a solid Ehrlich carcinoma (SEC) tumor were treated with MGN-3 via intraperitoneal injection. Tumor growth, cytokine production, and apoptotic effect of MGN-3 were examined. MGN-3 caused a highly significant delay in both tumor volume (63.27%) and tumor weight (45.2%) as compared to controls (P < 0.01). The mechanisms by which MGN-3 exerts its antitumor effect seem to involve its ability to induce apoptosis and immune modulation. MGN-3 induced a 1.8-fold increase in the percentage of apoptotic SEC cells as determined by flow cytometry and the histopathological examination. In addition, MGN-3 influenced plasma cytokine production by increasing the levels of tumor necrosis factor-alpha and interferon-gamma, while downregulating levels of the immune suppressing cytokine interleukin-10. Data also showed that non-tumor-bearing mice intramuscularly injected with MGN-3 resulted in a twofold increase in natural killer activity. No adverse side effects due to MGN-3 treatment were observed; all animals displayed normal feeding/drinking and life activity patterns. These data may have clinical implications for the treatment of solid cancers.

  19. Evaluation of the effects of methotrexate released from polymeric implants in solid Ehrlich tumor.

    PubMed

    de Fátima Pereira, Adriana; Mara da Costa, Vivian; Cristina Magalhães Santos, Millene; Maciel de A Ribeiro, Rosy Iara; Gabriela Silva, Ana; Carmo Horta Pinto, Flávia; Vieira Teixeira Vidigal, Paula; Rodrigues Da Silva, Gisele

    2014-04-01

    In this study, the effects of the controlled and sustained release of methotrexate from poly(ɛ-caprolactone) implants were evaluated in the solid Ehrlich tumor. The drug locally leached from the implantable devices was capable of reducing the tumor growth and the necrotic areas of the tumor site. Furthermore, the methotrexate exerted its anti-tumor effect probably by the recruitment of neutrophils at the tumor site, which assisted in modulating the growth of the tumor. The polymeric implants containing methotrexate could be a chemotherapic alternative to treat locally solid tumors with lower systemic side effects. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  20. Antitumor Activity of Citrus maxima (Burm.) Merr. Leaves in Ehrlich's Ascites Carcinoma Cell-Treated Mice

    PubMed Central

    KunduSen, Sriparna; Gupta, Malaya; Mazumder, Upal K.; Haldar, Pallab K.; Saha, Prerona; Bala, Asis

    2011-01-01

    Context. The plant Citrus maxima Merr. (Rutaceae), commonly known as shaddock or pomelo is indigenous to tropical parts of Asia. The objective of present study is to evaluate the methanol extract of Citrus maxima leaves for its antitumor activity against Ehrlich's Ascites Carcinoma cell in Swiss albino mice. Experimental design. The antitumor activity of methanol extract of Citrus maxima leaves (MECM) was evaluated against Ehrlich Ascites Carcinoma (EAC) cell line in Swiss albino mice. 2 × 106 cells were inoculated in different groups of animals. MECM (200 and 400 mg/kg BW i.p.) was administered for nine consecutive days. On day 10th half the animals of different groups were sacrificed for determination of tumor and haematological parameters and the rest half were kept with sufficient food and water ad libitum for determination of increase in life span. Result and Discussions. Oral administration of the extract at the doses of 200 and 400 mg/kg significantly decreased tumor parameters such as tumor volume, viable tumor cell count and increased body weight, hematological parameters and life span in respect of the EAC control mice. Conclusion. Experimental design exhibits significant antitumor activity of the extract (MECM) in a dose dependant manner. PMID:22084708

  1. Antitumor Activity of Citrus maxima (Burm.) Merr. Leaves in Ehrlich's Ascites Carcinoma Cell-Treated Mice.

    PubMed

    Kundusen, Sriparna; Gupta, Malaya; Mazumder, Upal K; Haldar, Pallab K; Saha, Prerona; Bala, Asis

    2011-01-01

    Context. The plant Citrus maxima Merr. (Rutaceae), commonly known as shaddock or pomelo is indigenous to tropical parts of Asia. The objective of present study is to evaluate the methanol extract of Citrus maxima leaves for its antitumor activity against Ehrlich's Ascites Carcinoma cell in Swiss albino mice. Experimental design. The antitumor activity of methanol extract of Citrus maxima leaves (MECM) was evaluated against Ehrlich Ascites Carcinoma (EAC) cell line in Swiss albino mice. 2 × 10(6) cells were inoculated in different groups of animals. MECM (200 and 400 mg/kg BW i.p.) was administered for nine consecutive days. On day 10th half the animals of different groups were sacrificed for determination of tumor and haematological parameters and the rest half were kept with sufficient food and water ad libitum for determination of increase in life span. Result and Discussions. Oral administration of the extract at the doses of 200 and 400 mg/kg significantly decreased tumor parameters such as tumor volume, viable tumor cell count and increased body weight, hematological parameters and life span in respect of the EAC control mice. Conclusion. Experimental design exhibits significant antitumor activity of the extract (MECM) in a dose dependant manner.

  2. Evaluation of the effects of thalidomide-loaded biodegradable devices in solid Ehrlich tumor.

    PubMed

    Pereira, Bruno Gonçalves; Ligorio Fialho, Silvia; Maria de Souza, Cristina; Dantas Cassali, Geovanni; Silva-Cunha, Armando

    2013-03-01

    Regarding thalidomide's effects in cancer and the problems related to its physicochemical characteristics and toxic effects, we proposed a new biodegradable polymeric implant to this drug. In this paper, we evaluate the antiangiogenic activity and antitumor effect of thalidomide when incorporated in poly-lactide-co-glycolide (PLGA) implants in an animal model for Ehrlich tumor. This dosage form permits the prolonged drug release. The biodegradable implants could reduce the blood vessel in a chorioallantoic membrane (CAM) model. When applied to the Ehrlich tumor model, implant also showed to reduce the number of vessels. It was also observed to reduce areas of inflammation and increases the area of necrosis in the group of thalidomide implant. A 47% reduction in tumor volume was observed in the thalidomide implant group, which is discussed in relation to literature reported results of thalidomide conventional administration ways.

  3. (Accumulation of methyl-deficient rat liver messenger ribonucleic acid on ethionine administration). Progress report. [Methyltransferase activity in Ehrlich ascites tumor cells and effects of phorbol ester on methyltransferase activity

    SciTech Connect

    Borek, E.

    1980-01-01

    Enzyme fractions were isolated from Ehrlich ascites cells which introduced methyl groups into methyl deficient rat liver mRNA and unmethylated vaccinia mRNA. The methyl groups were incorporated at the 5' end into cap 1 structures by the viral enzyme, whereas both cap 0 and cap 1 structures were formed by the Ehrlich ascites cell enzymes. Preliminary results indicate the presence of adenine N/sup 6/-methyltransferase activity in Ehrlich ascites cells. These results indicate that mRNA deficient in 5'-cap methylation and in internal methylation of adenine accumulated in rats on exposure to ethionine. The methyl-deficient mRNA isolated from the liver of ethionine-fed rats differed in its translational properties from mRNA isolated from control animals. Preliminary experiments indicate that single topical application of 17n moles of TPA to mouse skin altered tRNA methyltransferases. The extent of methylation was increased over 2-fold in mouse skin treated with TPA for 48 hours. These changes have been observed as early as 12 hours following TPA treatment. In contrast, the application of initiating dose of DMBA had no effect on these enzymes. It should be emphasized that the changes in tRNA methyltransferases produced by TPA are not merely an increase of the concentration of the enzyme, rather that they represent alterations of specificity of a battery of enzymes. In turn the change in enzyme specificity can produce alterations in the structure of tRNA. (ERB)

  4. Integrin β1, Osmosensing, and Chemoresistance in Mouse Ehrlich Carcinoma Cells.

    PubMed

    Sørensen, Belinda Halling; Rasmussen, Line Jee Hartmann; Broberg, Bjørn Sindballe; Klausen, Thomas Kjær; Sauter, Daniel Peter Rafael; Lambert, Ian Henry; Aspberg, Anders; Hoffmann, Else Kay

    2015-01-01

    Altered expression of the integrin family of cell adhesion receptors has been associated with initiation, progression, and metastasis of solid tumors as well as in the development of chemoresistance. Here, we investigated the role of integrins, in particular integrin β1, in cell volume regulation and drug-induced apoptosis in adherent and non-adherent Ehrlich ascites cell lines. Adhesion phenotypes were verified by colorimetric cell-adhesion-assay. Quantitative real-time PCR and western blot were used to compare expression levels of integrin subunits. Small interfering RNA was used to silence integrin β1 expression. Regulatory volume decrease (RVD) after cell swelling was studied with calcein-fluorescence-self-quenching and Coulter counter analysis. Taurine efflux was estimated with tracer technique. Caspase assay was used to determine apoptosis. We show that adherent cells have stronger fibronectin binding and a significantly increased expression of integrin α5, αv, and β1 at mRNA and protein level, compared to non-adherent cells. Knockdown of integrin β1 reduced RVD of the adherent but not of the non-adherent cells. Efflux of taurine was unaffected. In contrast to non-adherent, adherent cells exhibited chemoresistance to chemotherapeutic drugs (cisplatin and gemcitabine). However, knockdown of integrin β1 promoted cisplatin-induced caspase activity in adherent cells. Our data identifies integrin β1 as a part of the osmosensing machinery and regulator of cisplatin resistance in adherent Ehrlich cells.

  5. Dual effects of indoleamine 2,3-dioxygenase inhibitors on the therapeutic effects of cyclophosphamide and cycloplatam on Ehrlich ascites tumor in mice.

    PubMed

    Bogdanova, L A; Morozkova, T S; Amitina, S A; Mazhukin, D G; Nikolin, V P; Popova, N A; Kaledin, V I

    2014-08-01

    Ethyl pyruvate, an inhibitor of indoleamine 2,3-dioxygenase, slightly suppressed the growth of transplantable Ehrlich tumor in mice and significantly potentiated the therapeutic effect of cyclophosphamide. Another inhibitor amidoxime produced a similar effect. However, both ethyl pyruvate and amidoxime significantly reduced the effect of cycloplatam therapy. The observed changes can be stipulated by different effects of cyclophosphamide and cycloplatam on the subpopulations of lymphoid cells taking part in the formation of antitumor immunity and resistance to tumors.

  6. GROWTH FACTORS AND COX2 IN WOUND HEALING: AN EXPERIMENTAL STUDY WITH EHRLICH TUMORS

    PubMed Central

    SALGADO, Flávio L. L.; ARTIGIANI-NETO, Ricardo; LOPES-FILHO, Gaspar de Jesus

    2016-01-01

    ABSTRACT Background: Healing is an innate biological phenomenon, and carcinogenesis acquired, but with common humoral and cellular elements. Carcinogenesis interferes negatively in healing. Aim: To evaluate the histological changes in laparotomy scars of healthy Balb/c mice and with an Ehrlich tumor in its various forms of presentation. Methods: Fifty-four mice were divided into three groups of 18 animals. First group was the control; the second had Ehrlich tumor with ascites; and the third had the subcutaneous form of this tumor. Seven days after tumor inoculation, all 54 mice were submitted to laparotomy. All of the animals in the experiment were operated on again on 7th day after surgery, with resection of the scar and subsequent euthanasia of the animal. The scars were sent for histological assessment using immunohistochemical techniques to evaluate Cox-2 (cyclooxygenase 2), VEGF (vascular endothelial growth factor) and FGF (fibroblast growth factor). Semi-quantitatively analysis was done in the laparotomy scars and in the abdominal walls far away from the site of the operation. Results: Assessing the weight of the animals, the correct inoculation of the tumor and weight gain in the group with tumoral ascites was observed. The histological studies showed that groups with the tumor showed a statistically significant higher presence of Cox-2 compared to the control. In the Cox-2 analysis of the abdominal wall, the ascites group showed the most significant difference. VEGF did not present any significant differences between the three groups, regardless of the site. The FGF showed a significant increase in animals with the tumor. Conclusion: Histological findings in both laparotomy scar and the abdominal wall showed that with Ehrlich's neoplasia there was an exacerbated inflammatory response, translated by more intense expression of Cox-2 and greater fibroblast proliferation, translated by more intense expression of FGF, that is, it stimulated both the immediate

  7. Growth inhibition and pro-apoptotic activity of violacein in Ehrlich ascites tumor.

    PubMed

    Bromberg, Natália; Dreyfuss, Juliana L; Regatieri, Caio V; Palladino, Marcelly V; Durán, Nelson; Nader, Helena B; Haun, Marcela; Justo, Giselle Z

    2010-06-07

    The continuing threat to biodiversity lends urgency to the need of identification of sustainable source of natural products. This is not so much trouble if there is a microbial source of the compound. Herein, violacein, a natural indolic pigment extracted from Chromobacterium violaceum, was evaluated for its antitumoral potential against the Ehrlich ascites tumor (EAT) in vivo and in vitro. Evaluation of violacein cytotoxicity using different endpoints indicated that EAT cells were twofold (IC(50)=5.0 microM) more sensitive to the compound than normal human peripheral blood lymphocytes. In vitro studies indicated that violacein cytotoxicity to EAT cells is mediated by a rapid (8-12h) production of reactive oxygen species (ROS) and a decrease in intracellular GSH levels, probably due to oxidative stress. Additionally, apoptosis was primarily induced, as demonstrated by an increase in Annexin-V positive cells, concurrently with increased levels of DNA fragmentation and increased caspase-2, caspase-9 and caspase-3 activities up to 4.5-, 6.0- and 5.5-fold, respectively, after 72 h of treatment. Moreover, doses of 0.1 and 1.0 microg kg(-1) violacein, administered intraperitoneally (i.p.) to EAT-bearing mice throughout the lifespan of the animals significantly inhibited tumor growth and increased survival of mice. In view of these results, a 35-day toxicity study was conducted in vivo. Complete hematology, biochemistry (ALT, AST and creatinine levels) and histopathological analysis of liver and kidney indicated that daily doses of violacein up to 1000 microg kg(-1) for 35 days are well tolerated and did not cause hematotoxicity nor renal or hepatotoxicity when administered i.p. to mice. Altogether, these results indicate that violacein causes oxidative stress and an imbalance in the antioxidant defense machinery of cells culminating in apoptotic cell death. Furthermore, this is the first report of its antitumor activity in vivo, which occurs in the absence of toxicity to

  8. Ursolic acid inhibits tumor angiogenesis and induces apoptosis through mitochondrial-dependent pathway in Ehrlich ascites carcinoma tumor.

    PubMed

    Saraswati, Sarita; Agrawal, S S; Alhaider, Abdulqader A

    2013-11-25

    Ursolic acid (UA) is a pentacyclic triterpene naturally occurring in many plant foods. In the present study, we investigated anti-cancer activity of UA in vivo in Ehrlich ascites carcinoma (EAC) tumor. 15 × 10(6) EAC cells were implanted intraperitoneally (i.p., ascitic tumor) and subcutaneous (s.c., solid tumor) in Swiss albino mice. Mice with established tumors received UA i.p. at 25, 50 and 100mg/kg bw for 14 d in ascitic and 100mg/kg bw in solid tumor for 30 d. On day 15, blood samples were collected for hematological assessment of hemoglobin (Hb%), RBCs, WBCs and PCV. Tumor volume, cell viability, angiogenic, anti-angiogenic, anti-inflammatory factors and antioxidant parameters were determined. Immunohistochemistry analysis for VEGF, iNOS, CD31, caspase-3 and Bax were also performed. UA significantly inhibited tumor growth, cell viability, in both ascites and solid tumor model in vivo (p<0.001). The anti-angiogenic effects were accompanied with decreased VEGF, iNOS, TNF-α and increased IL-12 levels. UA at 100mg/kg bw dose significantly increased SOD and CAT activity (p<0.01). GSH and TBARS were increased as compared to control group (p<0.001). Furthermore, UA increased total RBCs, WBCs as well as Hb% significantly (p<0.05) compared to cyclophosphamide (CP). Histopathological examination of tumor cells in the treated group demonstrated signs of apoptosis with chromatin condensation and cell shrinkage. Decreased peritoneal angiogenesis showed the anti-angiogenic potential. UA downregulated VEGF & iNOS expression whereas bax and caspase-3 expressions were upregulated suggesting drug induced tumor cell apoptosis through activating the pro-apoptotic bcl-2 family and caspase-3 and downregulation of VEGF. The present study sheds light on the potent antitumor property of the UA and can be extended further to develop therapeutic protocols for treatment of cancer. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  9. Virus - tumor cell relationships. In vivo cocultivation of para-influenza type 1 (Sendai) virus and of Rous sarcoma virus (Schmidt-Ruppin strain) in mouse Ehrlich ascites carcinoma.

    PubMed

    Nastac, E; Chira, M; Suru, M; Repanovici, R; Anghelescu, S

    1985-01-01

    Co-infection of Ehrlich ascites carcinoma (EAC)-bearing mice with Sendai virus and Rous sarcoma virus (RSV) did not result in the formation of complete RSV. Sendai virus could be, however, propagated in this system over 8 serial passages. As demonstrated by immunofluorescence and complement fixation reactions, antigens specific to each virus were synthesized in EAC cells following either single or mixed virus infection. The virus progens also contained antigenic fractions incorporated from the host cell. The incomplete progens synthesized when RSV inoculation preceded that of Sendai virus possessed three polypeptide fractions characteristic of Sendai virus and one RSV-specific fraction.

  10. Action of the antitumor and antispermatogenic agent lonidamine on electron transport in Ehrlich ascites tumor mitochondria.

    PubMed

    Floridi, A; Lehninger, A L

    1983-10-01

    The effect of lonidamine, an antispermatogenic and antitumor drug, on the oxygen consumption, ATPase activity, and redox state of the electron carriers of Ehrlich ascites tumor mitochondria has been studied. Lonidamine inhibits ADP- and uncoupler-stimulated respiration on various NAD- and FAD-linked substrates, but does not affect state 4 respiration. Experiments to determine its site of action showed that lonidamine does not significantly inhibit electron flow through cytochrome oxidase. Electron flow through site 2, the ubiquinone-cytochrome b-cytochrome c1 complex, also was unaffected by lonidamine, which failed to inhibit the oxidation of duroquinol. Moreover, inhibition of electron flow through site 2 was also excluded because of the inability of the N,N,N',N'-tetramethyl-p-phenylenediamine bypass to relieve the lonidamine inhibition of the oxidation of pyruvate + malate. The F0F1ATPase activity and vectorial H+ ejection are also unaffected by lonidamine. The inhibition of succinate oxidation by lonidamine was found to take place at a point between succinate and iron-sulfur center S3. Spectroscopic experiments demonstrated that lonidamine inhibits the reduction of mitochondrial NAD+ by pyruvate + malate and other NAD-linked substrates in the transition from state 1 to state 4. However, lonidamine does not inhibit reduction of added NAD+ by submitochondrial vesicles or by soluble purified NAD-linked dehydrogenases. These observations, together with other evidence, suggest that electron transport in tumor mitochondria is inhibited by lonidamine at the dehydrogenase-coenzyme level, particularly when the electron carriers are in a relatively oxidized state and/or when the inner membrane-matrix compartment is in the condensed state. The action of lonidamine in several respects resembles the selective inhibition of electron transport in tumor cells produced by cytotoxic macrophages (D. L. Granger and A. L. Lehninger (1982) J. Cell Biol. 95, 527).

  11. Formation and utilization of acetoin, an unusual product of pyruvate metabolism by Ehrlich and AS30-D tumor mitochondria.

    PubMed

    Baggetto, L G; Lehninger, A L

    1987-07-15

    [14C]Pyruvate was rapidly non-oxidatively decarboxylated by Ehrlich tumor mitochondria at a rate of 40 nmol/min/mg of protein in the presence or absence of ADP. A search for decarboxylation products led to significant amounts of acetoin formed when Ehrlich tumor mitochondria were incubated with 1 mM [14C] pyruvate in the presence of ATP. Added acetoin to aerobic tumor mitochondria was rapidly utilized in the presence of ATP at a rate of 65 nmol/min/mg of protein. Citrate has been found as a product of acetoin utilization and was exported from the tumor mitochondria. Acetoin has been found in the ascitic liquid of Ehrlich and AS30-D tumor-bearing animals. These unusual reactions were not observed in control rat liver mitochondria.

  12. L-lactate transport in Ehrlich ascites-tumour cells.

    PubMed Central

    Spencer, T L; Lehninger, A L

    1976-01-01

    Ehrlich ascites-tumour cells were investigated with regard to their stability to transport L-lactate by measuring either the distribution of [14C]lactate or concomitant H+ ion movements. The movement of lactate was dependent on the pH difference across the cell membrane and was electroneutral, as evidenced by an observed 1:1 antiport for OH- ions or 1:1 symport with H+ ions. 2. Kinetic experiments showed that lactate transport was saturable, with an apparent Km of approx. 4.68 mM and a Vmax. as high as 680 nmol/min per mg of protein at pH 6.2 and 37 degrees C. 3. Lactate transport exhibited a high temperature dependence (activation energy = 139 kJ/mol). 4. Lactate transport was inhibited competitively by (a) a variety of other substituted monocarboxylic acids (e.g. pyruvate, Ki = 6.3 mM), which were themselves transported, (b) the non-transportable analogues alpha-cyano-4-hydroxycinnamate (Ki = 0.5 mM), alpha-cyano-3-hydroxycinnamate (Ki = 2mM) and DL-p-hydroxyphenyl-lactate (Ki = 3.6 mM) and (c) the thiol-group reagent mersalyl (Ki = 125 muM). 5. Transport of simple monocarboxylic acids, including acetate and propionate, was insensitive to these inhibitors; they presumably cross the membrane by means of a different mechanism. 6. Experiments using saturating amounts of mersalyl as an "inhibitor stop" allowed measurements of the initial rates of net influx and of net efflux of [14C]lactate. Influx and efflux of lactate were judged to be symmetrical reactions in that they exhibited similar concentration dependence. 7. It is concluded that lactate transport in Ehrlich ascites-tumour cells is mediated by a carrier capable of transporting a number of other substituted monocarboxylic acids, but not unsubstituted short-chain aliphatic acids. PMID:7237

  13. L-lactate transport in Ehrlich ascites-tumour cells.

    PubMed

    Spencer, T L; Lehninger, A L

    1976-02-15

    Ehrlich ascites-tumour cells were investigated with regard to their stability to transport L-lactate by measuring either the distribution of [14C]lactate or concomitant H+ ion movements. The movement of lactate was dependent on the pH difference across the cell membrane and was electroneutral, as evidenced by an observed 1:1 antiport for OH- ions or 1:1 symport with H+ ions. 2. Kinetic experiments showed that lactate transport was saturable, with an apparent Km of approx. 4.68 mM and a Vmax. as high as 680 nmol/min per mg of protein at pH 6.2 and 37 degrees C. 3. Lactate transport exhibited a high temperature dependence (activation energy = 139 kJ/mol). 4. Lactate transport was inhibited competitively by (a) a variety of other substituted monocarboxylic acids (e.g. pyruvate, Ki = 6.3 mM), which were themselves transported, (b) the non-transportable analogues alpha-cyano-4-hydroxycinnamate (Ki = 0.5 mM), alpha-cyano-3-hydroxycinnamate (Ki = 2mM) and DL-p-hydroxyphenyl-lactate (Ki = 3.6 mM) and (c) the thiol-group reagent mersalyl (Ki = 125 muM). 5. Transport of simple monocarboxylic acids, including acetate and propionate, was insensitive to these inhibitors; they presumably cross the membrane by means of a different mechanism. 6. Experiments using saturating amounts of mersalyl as an "inhibitor stop" allowed measurements of the initial rates of net influx and of net efflux of [14C]lactate. Influx and efflux of lactate were judged to be symmetrical reactions in that they exhibited similar concentration dependence. 7. It is concluded that lactate transport in Ehrlich ascites-tumour cells is mediated by a carrier capable of transporting a number of other substituted monocarboxylic acids, but not unsubstituted short-chain aliphatic acids.

  14. Cohabitation with an Ehrlich tumor-bearing cagemate induces immune but not behavioral changes in male mice.

    PubMed

    Machado, Thalita R M; Alves, Glaucie J; Quinteiro-Filho, Wanderley M; Palermo-Neto, João

    2017-02-01

    Cohabitation with Ehrlich ascitic tumor-injected conspecifics induces behavioral, neurochemical, endocrine and immune changes indicative of stress and immune impairment in female mice. The present work analyzed the effects of similar cohabitation in Swiss and Balb/C male mice. At least 12 pairs of male mice were divided into a control group and an experimental group. On experimental day 1 (ED1), one animal within each experimental pair was inoculated with 5×10(6) Ehrlich tumor cells intraperitoneally (i.p.); the other animal was kept undisturbed and was referred to as the CSP (companion of a sick partner). One male mouse of each control pair was treated i.p. with 0.9% NaCl (1mL/kg); the other animal (the CHP, companion of a healthy partner) was kept undisturbed. Cohabitation with a sick partner for 11days did not induce any behavioral, hypothalamic noradrenergic, corticosterone or adrenal weight changes in the Swiss CSP male mice compared to those of the Swiss CHP group. However, impairments in neutrophil phagocytosis and oxidative burst as well as increased levels of catecholamines were observed in Swiss and Balb/C CSP mice relative to CHP male animals of the same strains on ED11 and ED14, respectively. Moreover, after a challenge with 5×10(6) Ehrlich tumor cells on ED11 of cohabitation, the number and concentration of tumor cells found in the ascitic fluid were higher in the Swiss CSP male mice than in the CHP mice. These data suggest that the immune changes observed in Swiss and Balb/C male CSP mice after cohabitation with a sick cagemate might, ultimately, depend on the changes induced by catecholamines, as previously reported for CSP female mice. However, contrary to that reported in Swiss CSP female mice, changes in behavioral and hypothalamic noradrenaline activity were not found in the Swiss CSP male mice analyzed in this work. This fact suggests that male and female CSP mice might use similar immune but different CNS strategies against the threats posed

  15. Magnetite Nanoparticles Inhibit Tumor Growth and Upregulate the Expression of P53/P16 in Ehrlich Solid Carcinoma Bearing Mice

    PubMed Central

    Bassiony, Heba; Sabet, Salwa; Salah El-Din, Taher A.; Mohamed, Mona M.; El-Ghor, Akmal A.

    2014-01-01

    Background Magnetite nanoparticles (MNPs) have been widely used as contrast agents and have promising approaches in cancer treatment. In the present study we used Ehrlich solid carcinoma (ESC) bearing mice as a model to investigate MNPs antitumor activity, their effect on expression of p53 and p16 genes as an indicator for apoptotic induction in tumor tissues. Method MNPs coated with ascorbic acid (size: 25.0±5.0 nm) were synthesized by co-precipitation method and characterized. Ehrlich mice model were treated with MNPs using 60 mg/Kg day by day for 14 injections; intratumorally (IT) or intraperitoneally (IP). Tumor size, pathological changes and iron content in tumor and normal muscle tissues were assessed. We also assessed changes in expression levels of p53 and p16 genes in addition to p53 protein level by immunohistochemistry. Results Our results revealed that tumor growth was significantly reduced by IT and IP MNPs injection compared to untreated tumor. A significant increase in p53 and p16 mRNA expression was detected in Ehrlich solid tumors of IT and IP treated groups compared to untreated Ehrlich solid tumor. This increase was accompanied with increase in p53 protein expression. It is worth mentioning that no significant difference in expression of p53 and p16 could be detected between IT ESC and control group. Conclusion MNPs might be more effective in breast cancer treatment if injected intratumorally to be directed to the tumor tissues. PMID:25375144

  16. Magnetite nanoparticles inhibit tumor growth and upregulate the expression of p53/p16 in Ehrlich solid carcinoma bearing mice.

    PubMed

    Bassiony, Heba; Sabet, Salwa; Salah El-Din, Taher A; Mohamed, Mona M; El-Ghor, Akmal A

    2014-01-01

    Magnetite nanoparticles (MNPs) have been widely used as contrast agents and have promising approaches in cancer treatment. In the present study we used Ehrlich solid carcinoma (ESC) bearing mice as a model to investigate MNPs antitumor activity, their effect on expression of p53 and p16 genes as an indicator for apoptotic induction in tumor tissues. MNPs coated with ascorbic acid (size: 25.0±5.0 nm) were synthesized by co-precipitation method and characterized. Ehrlich mice model were treated with MNPs using 60 mg/Kg day by day for 14 injections; intratumorally (IT) or intraperitoneally (IP). Tumor size, pathological changes and iron content in tumor and normal muscle tissues were assessed. We also assessed changes in expression levels of p53 and p16 genes in addition to p53 protein level by immunohistochemistry. Our results revealed that tumor growth was significantly reduced by IT and IP MNPs injection compared to untreated tumor. A significant increase in p53 and p16 mRNA expression was detected in Ehrlich solid tumors of IT and IP treated groups compared to untreated Ehrlich solid tumor. This increase was accompanied with increase in p53 protein expression. It is worth mentioning that no significant difference in expression of p53 and p16 could be detected between IT ESC and control group. MNPs might be more effective in breast cancer treatment if injected intratumorally to be directed to the tumor tissues.

  17. Role of N-6-isopentenyl adenine in tumor cell growth

    SciTech Connect

    Adair, W.L. Jr. Brennan, S.L.

    1986-05-29

    When cell extracts from Ehrlich ascites tumor cells were assayed for isopentenyl adenine content and correlation with cell growth stage by radioimmunoassay, concentrations of low statistical significance, were obtained. High performance liquid chromatographic analysis of cell extracts showed undetectable levels of isopentenyl adenine of 8-hydroxy-isopentenyl adenine, a known metabolite. Thus these substances do not seem to be required for cell division in Ehrlich ascites tumor cells.

  18. Analysis of the inhibitory effects of VP-16-213 (etoposide) and podophyllotoxin on thymidine transport and metabolism in Ehrlich ascites tumor cells in vitro

    SciTech Connect

    Yalowich, J.C.; Goldman, I.D.

    1984-03-01

    Uptake of /sup 3/H after exposure of cells to (/sup 3/H)-thymidine is characterized by a rapid initial velocity that approximates membrane transport followed by a slower rate of uptake that parallels the accumulation of phosphorylated derivatives of thymidine, primarily thymidine triphosphate, within the cell. The high rate of thymidine transport relative to thymidine metabolism to the triphosphate within the cell decreases as the extracellular nucleoside concentration is reduced due to a much greater decrease in membrane transport than the subsequent metabolic step. Hence, as extracellular thymidine is decreased, transport becomes increasingly rate limiting to metabolism within the cell. VP-16-213 (etoposide) or podophyllotoxin inhibits the initial uptake rate for thymidine and, as a consequence, inhibits the intracellular formation of thymidine triphosphate. When extracellular thymidine is high, inhibitory effects on transport are transient, and the net rate of thymidine triphosphate accumulation within drug-treated cells rapidly approaches a velocity comparable to that of control cells, indicating no direct VP-16-213 or podophyllotoxin effect on nucleoside and nucleotide phosphorylation. When extracellular thymidine is reduced so that transport is rate limiting to metabolism, the duration of the inhibitory effects of VP-16-213 on thymidine triphosphate formation is prolonged. A secondary effect of VP-16-213 becomes manifest beyond 10 min of incubation with (3H)thymidine with the virtual complete cessation of thymidine incorporation into the acid precipitate without any change in the thymidine triphosphate level. This late effect is not observed with podophyllotoxin and indicates a direct effect of VP-16-213 on DNA synthesis that is distinct from the earlier inhibitory effect on thymidine phosphorylation, which is secondary to membrane transport.

  19. Trichosanthes dioica root extract induces tumor proliferation and attenuation of antioxidant system in albino mice bearing Ehrlich ascites carcinoma

    PubMed Central

    Bhattacharya, Sanjib; Haldar, Pallab Kanti

    2011-01-01

    Trichosanthes dioica Roxb. (Cucurbitaceae), called pointed gourd in English, is a dioecious climber grown widely in the Indian subcontinent. The present study assessed the influence of treatment of hydroalcoholic extract of Trichosanthes dioica root (TDA) on Ehrlich ascites carcinoma (EAC) in Swiss albino mice with effects on antioxidant systems. Twenty-four hours after intraperitoneal inoculation of tumor (EAC) cells in mice, TDA was administered at 25 and 50 mg/kg for 8 consecutive days. On the 9th day, half of the mice were sacrificed for estimation of tumor proliferation, hematological, and hepatic antioxidative parameters. The rest were kept for assessment of survival parameters. TDA exhibited dose dependent and significant increase in tumor weight, tumor volume, packed cell volume and viable cells and reduced non-viable cells and life span of EAC bearing animals. Hematological parameters were significantly worsened in TDA-treated mice. TDA treatment significantly aggravated the hepatic antioxidative parameters. The present study demonstrated that T. dioica root possessed tumor promoting activity in EAC bearing albino mice, plausibly mediated by attenuation of endogenous antioxidant systems. PMID:22319252

  20. The neuroimmune changes induced by cohabitation with an Ehrlich tumor-bearing cage mate rely on olfactory information.

    PubMed

    Alves, Glaucie J; Ribeiro, Alison; Palermo-Neto, João

    2012-01-01

    Cohabitation for 14 days with Ehrlich tumor-bearing mice was shown to increase locomotor activity, to decrease hypothalamic noradrenaline (NA) levels, to increase NA turnover and to decrease innate immune responses and decrease the animals' resistance to tumor growth. Cage mates of a B16F10 melanoma-bearer mice were also reported to show neuroimmune changes. Chemosignals released by Ehrlich tumor-bearing mice have been reported to be relevant for the neutrophil activity changes induced by cohabitation. The present experiment was designed to further analyze the effects of odor cues on neuroimmune changes induced by cohabitation with a sick cage mate. Specifically, the relevance of chemosignals released by an Ehrlich tumor-bearing mouse was assessed on the following: behavior (open-field and plus maze); hypothalamic NA levels and turnover; adrenaline (A) and NA plasmatic levels; and host resistance induced by tumor growth. To comply with such objectives, devices specifically constructed to analyze the influence of chemosignals released from tumor-bearing mice were employed. The results show that deprivation of odor cues released by Ehrlich tumor-bearing mice reversed the behavioral, neurochemical and immune changes induced by cohabitation. Mice use scents for intraspecies communication in many social contexts. Tumors produce volatile organic compounds released into the atmosphere through breath, sweat, and urine. Our results strongly suggest that volatile compounds released by Ehrlich tumor-injected mice are perceived by their conspecifics, inducing the neuroimmune changes reported for cohabitation with a sick companion. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. Genetic constraints in the induction of the immune response to Ehrlich ascites tumor in mice. [X ray

    SciTech Connect

    Marusic, M.; Perkins, E.H.

    1981-07-15

    A single injection of irradiated Ehrlich ascites tumor (EAT) cells induces immunity in normal mice but fails to do so in T-cell-deficient-thymectomized, lethally irradiated, bone marrow-reconstituted (TIR) mice. TIR mice injected with normal syngeneic T cells develop an immune response to EAT when injected with irradiated EAT cells and reject a subsequent tumor cell challenge. In the present studies allogeneic T cells were unable to protect against EAT in TIR recipients even if harvested from donors tolerant to the recipient's transplantation antigens and injected into the TIR mice tolerant to the transplantation antigens of the injected T cells. Tolerance was produced by establishing long-term radiation chimeras of the P ..-->.. F/sub 1/ type. Semiallogeneic T cells also failed to afford protection against EAT in TIR recipients. Whereas tolerance to other parental-strain transplantation antigens did not reverse the inability of parental T cells (cells from P ..-->.. F/sub 1/ chimeric donors) to protect against EAT in F/sub 1/ TIR mice, it did enable F/sub 1/ T cells to afford protection in P ..-->.. F/sub 1/ TIR mice.

  2. The effects of silibin administration for different time periods on mouse liver with Ehrlich ascites carcinoma.

    PubMed

    Beydogan, Alisa Bahar; Bolkent, Sema

    2016-06-01

    Ehrlich ascites carcinoma is the one of the animal cancer models having high malignancy and rapid growth resistance. Silibin has reported to be an antioxidant in previous studies. We aimed to investigate the effects of silibin on mouse liver with Ehrlich ascites tumor (EAT) cells in different time periods. Balb/c mice were divided into five groups. Group I (Control): The saline buffer (sb) was injected intraperitoneally (ip) to the mice for 15 days. Group II (Silibin): 150mg/kg silibin was injected ip for 15 days. Group III (Ehrlich): 2×10(5) cells were transferred from the donor mouse to healthy mice on first day. Group IV (Ehrlich+Silibin): Silibin was given between 5th and 15th days to mice inoculated with EAT. Group V (Silibin+Ehrlich): Silibin was injected for 15 days after EAT cells. The liver sections were stained with matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), caspase 3, caspase 8, and proliferating cell nuclear antigen (PCNA) antibodies by the streptavidin-biotin-peroxidase technique. Biochemical analysis and Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) method were performed in the liver. Superoxide dismutase levels of liver increased in Ehrlich+Silibin group compared with Ehrlich group. Malondialdehyde levels significantly decreased in Silibin+Ehrlich group compared with Ehrlich+Silibin. MMP-2 and MMP-9 immunopositive cells increased in Silibin+Ehrlich compared with Ehrlich group. Caspase 3 and TUNEL signals significantly increased in Silibin+Ehrlich group compared with Ehrlich group. PCNA positive signals significantly increased in Ehrlich+Silibin group compared with Ehrlich group. According to our findings, we suggest that silibin treatment after EAT cells inoculation has more effective than concurrently EAT and silibin treatment. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  3. Immunotherapy of BALB/c mice bearing Ehrlich ascites tumor with vitamin D-binding protein-derived macrophage activating factor.

    PubMed

    Yamamoto, N; Naraparaju, V R

    1997-06-01

    Vitamin D3-binding protein (DBP; human DBP is known as Gc protein) is the precursor of macrophage activating factor (MAF). Treatment of mouse DBP with immobilized beta-galactosidase or treatment of human Gc protein with immobilized beta-galactosidase and sialidase generated a remarkably potent MAF, termed DBPMAF or GcMAF, respectively. The domain of Gc protein responsible for macrophage activation was cloned and enzymatically converted to the cloned MAF, designated CdMAF. In Ehrlich ascites tumor-bearing mice, tumor-specific serum alpha-N-acetylgalactosaminidase (NaGalase) activity increased linearly with time as the transplanted tumor cells grew in the peritoneal cavity. Therapeutic effects of DBPMAF, GcMAF, and CdMAF on mice bearing Ehrlich ascites tumor were assessed by survival time, the total tumor cell count in the peritoneal cavity, and serum NaGalase activity. Mice that received a single administration of DBPMAF or GcMAF (100 pg/mouse) on the same day after transplantation of tumor (1 x 10(5) cells) showed a mean survival time of 35 +/- 4 days, whereas tumor-bearing controls had a mean survival time of 16 +/- 2 days. When mice received the second DBPMAF or GcMAF administration at day 4, they survived more than 50 days. Mice that received two DBPMAF administrations, at days 4 and 8 after transplantation of 1 x 10(5) tumor cells, survived up to 32 +/- 4 days. At day 4 posttransplantation, the total tumor cell count in the peritoneal cavity was approximately 5 x 10(5) cells. Mice that received two DBPMAF administrations, at days 0 and 4 after transplantation of 5 x 10(5) tumor cells, also survived up to 32 +/- 4 days, while control mice that received the 5 x 10(5) ascites tumor cells only survived for 14 +/- 2 days. Four DBPMAF, GcMAF, or CdMAF administrations to mice transplanted with 5 x 10(5) Ehrlich ascites tumor cells with 4-day intervals showed an extended survival of at least 90 days and an insignificantly low serum NaGalase level between days 30 and 90.

  4. GROWTH FACTORS AND COX2 IN WOUND HEALING: AN EXPERIMENTAL STUDY WITH EHRLICH TUMORS.

    PubMed

    Salgado, Flávio L L; Artigiani-Neto, Ricardo; Lopes-Filho, Gaspar de Jesus

    2016-01-01

    Healing is an innate biological phenomenon, and carcinogenesis acquired, but with common humoral and cellular elements. Carcinogenesis interferes negatively in healing. To evaluate the histological changes in laparotomy scars of healthy Balb/c mice and with an Ehrlich tumor in its various forms of presentation. Fifty-four mice were divided into three groups of 18 animals. First group was the control; the second had Ehrlich tumor with ascites; and the third had the subcutaneous form of this tumor. Seven days after tumor inoculation, all 54 mice were submitted to laparotomy. All of the animals in the experiment were operated on again on 7th day after surgery, with resection of the scar and subsequent euthanasia of the animal. The scars were sent for histological assessment using immunohistochemical techniques to evaluate Cox-2 (cyclooxygenase 2), VEGF (vascular endothelial growth factor) and FGF (fibroblast growth factor). Semi-quantitatively analysis was done in the laparotomy scars and in the abdominal walls far away from the site of the operation. Assessing the weight of the animals, the correct inoculation of the tumor and weight gain in the group with tumoral ascites was observed. The histological studies showed that groups with the tumor showed a statistically significant higher presence of Cox-2 compared to the control. In the Cox-2 analysis of the abdominal wall, the ascites group showed the most significant difference. VEGF did not present any significant differences between the three groups, regardless of the site. The FGF showed a significant increase in animals with the tumor. Histological findings in both laparotomy scar and the abdominal wall showed that with Ehrlich's neoplasia there was an exacerbated inflammatory response, translated by more intense expression of Cox-2 and greater fibroblast proliferation, translated by more intense expression of FGF, that is, it stimulated both the immediate inflammatory reactions, observed with Cox-2 reactions, and

  5. Antitumor effect of vitamin D-binding protein-derived macrophage activating factor on Ehrlich ascites tumor-bearing mice.

    PubMed

    Koga, Y; Naraparaju, V R; Yamamoto, N

    1999-01-01

    Cancerous cells secrete alpha-N-acetylgalactosaminidase (NaGalase) into the blood stream, resulting in deglycosylation of serum vitamin D3-binding protein (known as Gc protein), which is a precursor for macrophage activating factor (MAF). Incubation of Gc protein with immobilized beta-galactosidase and sialidase generates the most potent macrophage activating factor (designated GcMAF). Administration of GcMAF to cancer-bearing hosts can bypass the inactivated MAF precursor and act directly on macrophages for efficient activation. Therapeutic effects of GcMAF on Ehrlich ascites tumor-bearing mice were assessed by survival time and serum NaGalase activity, because serum NaGalase activity was proportional to tumor burden. A single administration of GcMAF (100 pg/mouse) to eight mice on the same day after transplantation of the tumor (5 x 10(5) cells) showed a mean survival time of 21 +/- 3 days for seven mice, with one mouse surviving more than 60 days, whereas tumor-bearing controls had a mean survival time of 13 +/- 2 days. Six of the eight mice that received two GcMAF administrations, at Day 0 and Day 4 after transplantation, survived up to 31 +/- 4 days whereas, the remaining two mice survived for more than 60 days. Further, six of the eight mice that received three GcMAF administrations with 4-day intervals showed an extended survival of at least 60 days, and serum NaGalase levels were as low as those of control mice throughout the survival period. The cure with subthreshold GcMAF-treatments (administered once or twice) of tumor-bearing mice appeared to be a consequence of sustained macrophage activation by inflammation resulting from the macrophage-mediated tumoricidal process. Therefore, a protracted macrophage activation induced by a few administrations of minute amounts of GcMAF eradicated the murine ascites tumor.

  6. Effect of various doses of chalone-containing alcohol precipitate from Ehrlich's ascites tumor on mitotic activity and DNA synthesis in that tumor

    SciTech Connect

    Matsak, N.Ya.; Romanov, Yu.A.; Antokhin, A.I.

    1987-06-01

    Experiments were carried out on noninbred male albino mice to assess the effects of varying doses of chalone-containing alcohol precipitates on mitotic activity and DNA synthesis in Ehrlich ascites tumor. Histological preparations of the tumor and small intestine were made by standard methods. Hydrolysis of the tumor in HCl was carried out before application of the nuclear photographic emulsion in order to prepare autoradiographs of the tumor. Tritium-labelled thymidine was injected as the radioactive marker.

  7. Efficiency of calcium phosphate composite nanoparticles in targeting Ehrlich carcinoma cells transplanted in mice

    PubMed Central

    Abdel-Gawad, Eman I.; Hassan, Amal I.; Awwad, Sameh A.

    2015-01-01

    The present study aimed to investigate the mode of action of nano-CaPs in vivo as a therapy for solid tumor in mice. To achieve this goal, Ehrlich Ascites Carcinoma (EAC) was transplanted into 85 Swiss male albino mice. After nine days, the mice were divided into 9 groups. Groups 1 and 2 were allocated as the EAC control. Groups 3 and 4 were injected once intratumorally (IT) by nano-calcium phosphate (nano-CaP). Groups 5 and 6 received once intraperitoneal injection (IP) of nano-CaP. Groups 7, 8, and 9 received nano-CaP (IP) weekly. Blood samples and thigh skeletal muscle were collected after three weeks from groups 1, 3, 5, and 7 and after four weeks from groups 2, 4, 6, and 8. On the other hand, group 9 received nano-CaP (IP) for four weeks and lasted for three months to follow up the recurrence of tumor and to ensure the safety of muscle by histopathological analysis. Tumor growth was monitored twice a week throughout the experiment. DNA fragmentation of tumor cells was evaluated. In thigh tissue, noradrenaline, dopamine, serotonin (5HT), and gamma-aminobutyric acid (GABA) were measured. In serum, 8-Hydroxy-deoxyguanosine (8-OHDG), adenosine triphosphate (ATP), and vascular endothelial growth factor (VEGF) were analyzed. Histopathological and biochemical results showed a significant therapeutic effect of nano-CaP on implanted solid tumor and this effect was more pronounced in the animals treated IP for four weeks. This improvement was evident from the repair of fragmented DNA, the significant decrease of caspase-3, 8-OHDG, myosin, and VEGF, and the significant increase of neurotransmitters (NA, DA, 5HT, and GABA). Additionally, histopathological examination showed complete recovery of cancer cells in the thigh muscle after three months. PMID:26843980

  8. Nickel(II) diacetyl monoxime-2-pyridyl hydrazone complex can inhibit Ehrlich solid tumor growth in mice: A potential new antitumor drug.

    PubMed

    Saad, Entsar A; Hassanien, Mohamed M; El-Lban, Faten W

    2017-03-11

    The chief chemotherapeutic drug, cisplatin had common bad effects such as nephrotoxicity, ototoxicity and bone marrow depression. This led us to develop a new potential anticancer drug based on nickel metal ion that may be less toxic. Nickel(II) diacetyl monoxime-2-pyridyl hydrazone complex cytoprotective effect, superoxide dismutase (SOD)-like activity and anticancer activities were studied. In vitro, the complex showed SOD-like activity of 86.62%. It was capable to kill 90.2% of Ehrlich ascites carcinoma (EAC) cells and to protect 92.48% of human RBCs. In vivo, the complex lowered the tumor burden markedly in a concentration-dependent manner. Noticeably, solid tumor growth was suppressed; tumor volume and weight were reduced and mice life span was lengthened. The hematological indices were improved, catalase activity was re-elevated and malondialdehyde (MDA) level was reversed towards normal. Nucleic acids, cholesterol, triglycerides, liver enzymes, urea and creatinine contents were reduced to near normal ranges. Glutathione (GSH), SOD, albumin and total protein levels were increased. In conclusion, our results revealed that the complex has the ability to suppress Ehrlich solid tumor growth in mice with minimal side effects. This may possibly via its redox activity. Surprisingly, nickel complex antitumor activities were more potent than those of cisplatin. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Transport and metabolism of thiamine in Ehrlich ascites-carcinoma cells

    PubMed Central

    Menon, I. A.; Quastel, J. H.

    1966-01-01

    1. Aerobic or anaerobic incubation at 37° of Ehrlich ascites-carcinoma cells in Krebs–Ringer bicarbonate medium containing glucose and labelled thiamine results in accumulation in the cell of labelled thiamine, so that the concentration of total labelled thiamine in the cells greatly exceeds (by a factor 7) that in the medium. This concentration ratio is approximately constant for small initial external concentrations of labelled thiamine but diminishes when the latter exceed 0·4μm. 2. All the labelled thiamine in the tumour cells is present as thiamine phosphates. 3. The uptake of labelled thiamine is markedly diminished by decrease of temperature. At 9° concentration ratio (cells/medium) 0·5 is observed whereas at 37° the concentration ratio is 8·6. 4. The extent of phosphorylation of labelled thiamine depends on the period of incubation. 5. The influx of labelled thiamine is diminished by the presence of its analogues, pyrithiamine and Amprol, and also by the presence of thiamine monophosphate and thiamine diphosphate, which are potent inhibitors of thiamine phosphorylation in Ehrlich ascites cells. 6. Labelled thiamine phosphates leak from the cell into the medium, so that eventually all the labelled thiamine, both in the cell and medium, is converted into thiamine phosphates. However, in the presence of 2,4-dinitrophenol (0·1mm) and iodoacetate (1mm) thiamine phosphorylation is diminished, the concentration ratio for labelled thiamine (cells/medium) falls to half its normal value and little or no labelled thiamine phosphates leaks into the medium. 7. In the presence of thiamine phosphates, free labelled thiamine accumulates in Ehrlich ascites cells against a concentration gradient, concentration ratios (cells/medium) greater than unity being evident. 8. The evidence supports the conclusion that thiamine is transferred into the Ehrlich ascites cell by a carrier-mediated energy-assisted process. PMID:5964972

  10. Antitumor activity of Pleurotus ostreatus polysaccharide fractions on Ehrlich tumor and Sarcoma 180.

    PubMed

    Facchini, Jean Mary; Alves, Endi Pricila; Aguilera, Charlise; Gern, Regina Maria Miranda; Silveira, Marcia Luciane Lange; Wisbeck, Elisabeth; Furlan, Sandra Aparecida

    2014-07-01

    The medicinal properties of fungi of the genus Pleurotus have attracted great interest due to their therapeutic properties. Polysaccharides synthesized by Pleurotus, including the β-glucans are considered the main responsible for its therapeutic properties. This study aimed to evaluate the efficacy of polysaccharidic fractions extracted from mycelial biomass of Pleurotus ostreatus DSM 1833 in inhibiting the development of Ehrlich Tumor (ET) and Sarcoma 180 (S-180). FC, FI and FII fractions provided 60.6, 76.5 and 73.6% of ET inhibition, respectively (mean value of about 70%) while FS, FIII-1 and FIII-2 showed no inhibition against ET. FII and FIII-2 resulted in 85.6 and 93.6% (mean value of about 90%) while FIII-1, FC and FS resulted in 54.1 and 0%, respectively, of S-180 inhibition. The yields of the fractions FS, FI, FII, FIII-1 and FIII-2 obtained from P. ostreatus mycelial biomass were 11.6, 1.3, 0.4, 0.65 and 0.35%, respectively. FII fraction (30mg/kg) apparently had no toxic effect on healthy animals, since no difference between the body weights of animals in substance control (SC) and negative control (NC) groups was observed. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Dextran-functionalized magnetic fluid mediating magnetohyperthermia for treatment of Ehrlich-solid-tumor-bearing mice: toxicological and histopathological evaluations.

    PubMed

    Miranda-Vilela, Ana Luisa; Yamamoto, Kelly Reis; Miranda, Kely Lopes Caiado; Matos, Breno Noronha; de Almeida, Marcos Célio; Longo, João Paulo Figueiró; de Souza Filho, José; Fernandes, Juliana Menezes Soares; Sartoratto, Patrícia Pommé Confessori; Lacava, Zulmira Guerrero Marques

    2014-04-01

    Dextran-functionalized maghemite fluid (DexMF) has been tested to treat Ehrlich-solid-tumor-bearing mice, evidencing its potential use in mediating magnetohyperthermia in breast cancer treatment. However, although magnetic nanoparticles tend to accumulate in tumor tissues, part of the nanomaterial can reach the blood stream, and then the organism. The aim of this study was to investigate the acute systemic effects of the intratumoral injection of DexMF mediating magnetohyperthermia in the treatment of an advanced clinical Ehrlich-solid-tumor, assessed through histopathological analyses of liver, kidneys, heart and spleen, comet assay, micronucleus test, hemogram, and serum levels of bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, creatinine, and urea. The tumor's histopathology and morphometry were used to assess its aggressiveness and regression. DexMF mediating hyperthermia was effective in containing tumor aggressiveness and in inducing tumor regression, besides showing no toxic effects. Its physical characteristics also suggest that it is safe to use in other biomedical applications.

  12. Boric acid enhances in vivo Ehrlich ascites carcinoma cell proliferation in Swiss albino mice.

    PubMed

    Qureshi, S; Al-Shabanah, O A; Al-Harbi, M M; Al-Bekairi, A M; Raza, M

    2001-08-13

    The influence of boric acid, a boron carrier, on Ehrlich ascites carcinoma (EAC) cell-bearing mice was investigated in view of its importance in the boron neutron capture therapy and the influence of boron on proliferation and progression of cancer cells mediated by proteoglycans and collagen. The present study included the evaluation of boric acid for the effects on total count and viability of EAC cells in addition to their non-protein sulfhydryls (NP-SH) and malondialdehyde (MDA) contents as parameters for conjugative detoxication potency and possible oxidative damage. The EAC cell-bearing animals were also observed for the effect on survival, body weight changes, and histopathological evaluation of the tumors grown at the site of inoculation. The treatment with boric acid significantly increased the total number of peritoneal EAC cells and their viability. A significant increase in the body weight was observed that dose-dependently reached plateau levels by 20 days of treatment. Conversely, a reduction in the duration of survival of these animals was evident with the same protocol. Boric acid treatment resulted in a decrease in NP-SH contents with a concomitant increase in MDA levels in EAC cells as revealed by the results of the biochemical analysis. These data are supported by our results on histopathological investigations, which apparently showed fast growth, in addition to several mitotic figures and mixed inflammatory reaction, after treatment with boric acid. It seems likely that a particular combination of properties of boric acid, rather than a single characteristic alone, will provide useful information on the use of this boron carrier in neutron capture therapy.

  13. Interactions between 7-hydroxymethotrexate and methotrexate at the cellular level in the Ehrlich ascites tumor in vitro.

    PubMed

    Fabre, G; Matherly, L H; Fabre, I; Cano, J P; Goldman, I D

    1984-03-01

    Studies were undertaken to characterize the cellular pharmacology of 7-hydroxymethotrexate (7-OH-MTX) in Ehrlich ascites tumor cells, compare it to that of methotrexate (MTX), and define the interactions between the parent compound and its catabolite. Transport of 7-OH-MTX is mediated by the MTX-tetrahydrofolate cofactor carrier, with a Km of 9 microM in comparison to the MTX Km of 5 microM. Both compounds mutually inhibit their influx and steady-state levels of free drug accumulated. While influx of 7-OH-MTX is slower than influx of MTX, 7-OH-MTX efflux is likewise slower, so that the steady-state level of 7-OH-MTX achieved is comparable to that of MTX. Influx of 7-OH-MTX is inhibited by extracellular 5-formyltetrahydrofolate and trans-stimulated in cells preloaded with this tetrahydrofolate cofactor. The energetics of 7-OH-MTX transport is similar to that of MTX in the influx and net transport are stimulated by sodium azide, while net transport is reduced by glucose. As observed for MTX, 7-OH-MTX transport is sensitive to the anionic composition of the extracellular compartment and was shown to be inhibited by organic and inorganic phosphates. 7-OH-MTX does not, alone, inhibit [3H]deoxyuridine incorporation into DNA at concentrations of up to 50 microM. However, the catabolite reduces MTX inhibition of deoxyuridine metabolism, presumably due to the reduction in the free level of intracellular MTX achieved. These findings support the possibility that when 7-OH-MTX accumulates to high levels relative to MTX in clinical regimens, it may modulate the pharmacological effects of MTX.

  14. Identity-based High-performance thin Layer Chromatography Fingerprinting Profile and Tumor Inhibitory Potential of Anisochilus carnosus (L.f.) wall Against Ehrlich Ascites Carcinoma

    PubMed Central

    Gupta, Nilesh; Lobo, Richard; Kumar, Nimmy; Bhagat, Jay Kumar; Mathew, Jessy Elizabeth

    2015-01-01

    Context: Anisochilus carnosus (L.f.) wall belonging to the family Lamiaceae is a plant that is widely used in folk medicine for treating eczema, cold, cough, and fever. Objective: In the present study, we explored the anticancer potential of A. carnosus leaves against Ehrlich ascites carcinoma (EAC) and estimated the quantity of luteolin present in various extracts and fractions of A. carnosus by high-performance thin layer chromatography (HPTLC) fingerprinting. Materials and Methods: Various factors such as tumor volume, tumor cell viability, tumor weight, prolongation of lifespan, and hematological parameters were assessed. Result: We observed a significant lowering in tumor volume, tumor weight, and cell viability in EAC-induced mice following intervention with A. carnosus extracts. Also, there was a considerable prolongation of host lifespan and restoration of hematological parameters to almost normal levels with A. carnosus treatment. HPTLC fingerprinting of various extracts and fractions of A. carnosus along with luteolin as the reference standard revealed the occurrence of luteolin in all tested extracts and fractions of A. carnosus with the highest concentration being reported in the ethanol fraction. Conclusion: A. carnosus exhibits potent anti-tumor potential which can most likely be attributed to the occurrence of different phytochemicals such as phytosterols, terpenoids, and flavonoids in the plant. Further studies to isolate compounds from A. carnosus and understand the mechanism of anti-tumor activity would be worthwhile. SUMMARY EAC induced mice that received A. carnosus treatment exhibited significant reduction in tumor volume, tumor weight and tumor cell viability. Their life span was considerably prolonged. We detected luteolin in A. carnosus aqueous and ethanol extract using HPTLC. Hence, anticancer activity of A. carnosus can be partly attributed to the presence of luteolin. PMID:26929584

  15. Experimental study of simultaneous photodynamic and hyperthermic treatment of Ehrlich ascites carcinoma and A22 hepatoma

    NASA Astrophysics Data System (ADS)

    Luksiene, Zivile

    1997-12-01

    Combined treatment of PDT and hyperthermia was examined on Ehrlich ascites tumor cell viability and A22 hepatoma tumor growth inhibition. Histological evaluations of tumors after different treatments have shown tumor necrosis, congestion of blood vessels and hemorrhage. The most drastic damages were observed after simultaneous PDT and hyperthermia action. At these experimental conditions tumor growth for 5 days was absolutely inhibited.

  16. Inhibition by 2,5-anhydromannitol of glycolysis in isolated rat hepatocytes and in Ehrlich ascites cells.

    PubMed Central

    Riquelme, P T; Kneer, N M; Wernette-Hammond, M E; Lardy, H A

    1985-01-01

    2,5-Anhydromannitol decreases lactate formation and 3H2O formation from [5-3H]glucose in isolated rat hepatocytes metabolizing high concentrations of glucose. The inhibition of glycolysis is accompanied by a slight decrease in the cellular content of fructose-6-P and a more substantial decrease in the cellular content of fructose-1,6-P2, with no change in the content of glucose-6-P. The 3H2O release data and changes in hexosephosphate distribution indicate possible inhibitions at phosphofructokinase-1 and phosphoglucose isomerase. 2,5-Anhydromannitol also inhibits glycolysis in Ehrlich ascites cells, but the tumor cells, unlike hepatocytes, must be treated with 2,5-anhydromannitol prior to exposure to glucose to obtain the inhibition. The decrease in 3H2O formation from [5-3H]glucose and the metabolite pattern that results from the addition of low concentrations (less than or equal to 0.25 mM) of 2,5-anhydromannitol indicate an inhibition at phosphofructokinase-1 that cannot be attributed to a decrease in the cellular content of fructose-2,6-P2. Higher concentrations (greater than or equal to 0.5 mM) of 2,5-anhydromannitol cause a substantial decrease in the cellular content of ATP that is accompanied by decreases in the content of glucose-6-P and fructose-6-P and transient increases in fructose-1,6-P2. In Ehrlich ascites cells, 2,5-anhydromannitol is metabolized to 2,5-anhydromannitol mono- and bisphosphate. The inhibition of glycolysis caused by 2,5-anhydromanitol decreases with time, because the phosphorylated metabolites formed during the preliminary incubation in the absence of glucose are rapidly dephosphorylated during the incubation in the presence of glucose. PMID:3155858

  17. Bioassay of Eucalyptus extracts for anticancer activity against Ehrlich ascites carcinoma (eac) cells in Swiss albino mice

    PubMed Central

    Islam, Farhadul; Khatun, Hasina; Ghosh, Soby; Ali, MM; Khanam, JA

    2012-01-01

    Objective To evaluate the antineoplastic activity of Eucalyptus extract (EuE) against Ehrlich ascites carcinoma (EAC) in Swiss albino mice. Methods Preliminary examination of four plant extracts (namely Eucalyptus, Costus, Azadirachta, Feronia) has been done by observing the reduction ability of number of EAC cells in previously inoculated Swiss albino mice. Among them as EuE showed maximum capability, the whole study has been conducted with EuE only. Important parameters viz. enhancement of life span, reduction of average tumor weight etc. have been studied. In addition the effects of EuE on hematological parameters in both normal and EAC inoculated mice have been measured. Effect of EuE on normal peritoneal cells has also been studied. Results : EuE reduced tumor burden remarkably. It reduced the tumor growth rate and enhanced the life span of EAC bearing mice noticeably. It reversed back the hematological parameters towards normal, reduced the trasplantability of EAC cells and enhanced the immunomodulatory effects in mice. The host toxic effect of EuE in mice is minimum and mostly reversible with time. All such data have been compared with those obtained by running parallel experiments with bleomycin at dose 0.3 mg/kg (i.p.). Conclusions The Eucalyptus extract may be considered as a potent anticancer agent for advanced researches. PMID:23569937

  18. Tissue Distribution and Efficacy of Gold Nanorods Coupled with Laser Induced Photoplasmonic Therapy in Ehrlich Carcinoma Solid Tumor Model

    PubMed Central

    El-Sayed, Mostafa A.; Shabaka, Ali A.; El-Shabrawy, Osama A.; Yassin, Nemat A.; Mahmoud, Sawsan S.; El-Shenawy, Siham M.; Al-Ashqar, Emad; Eisa, Wael H.; Farag, Niveen M.; El-Shaer, Marwa A.; Salah, Nabila; Al-Abd, Ahmed M.

    2013-01-01

    Gold nanorods (GNR) within tumor microregions are characterized by their ability to absorb near IR light and emit heat in what is called photoplasmonic effect. Yet, the efficacy of nanoparticles is limited due to intratumoral tissue distribution reasons. In addition, distribution of GNRs to normal tissue might result in non specific toxicity. In the current study, we are assessing the intratumoral and tissue distribution of PEGylated GNRs on the top of its antitumor characteristics when given intravenously or intratumoral to solid tumor bearing mice and coupled with laser photoplasmonic sessions. PEGylated GNRs with a longitudinal size of less than 100 nm were prepared with aspect ratio of 4.6 showing strong surface plasmon absorption at wavelength 800 nm. Pharmacokinetics of GNR after single I.V. administration (0.1 mg/kg) showed very short systemic circulating time (less than 3 h). On the other hand, tissue distribution of I.V. GNR (0.1 mg/kg) to normal animals showed preferential deposition in spleen tissue. Repeated administration of I.V. GNR resulted in preferential accumulation in both liver and spleen tissues. In addition, I.V. administration of GNR to Ehrlich carcinoma tumor bearing mice resulted in similar tissue distribution; tumor accumulation and anti-tumor effect compared to intratumoral administration. In conclusion, the concentration of GNR achieved within tumors microregions after I.V. administration was comparable to I.T. administration and sufficient to elicit tumoral growth arrest when coupled with laser-aided photoplasmonic treatment. PMID:24098446

  19. Beta-Adrenergic Blockade Decreases the Neuroimmune Changes in Mice Induced by Cohabitation with an Ehrlich Tumor-Bearing Cage Mate.

    PubMed

    Margatho, Rafael O; Massoco, Cristina de O; Calefi, Atilio S; Cruz, Daniel S G; Sandini, Thaisa M; Alves, Glaucie Jussilane; Florio, Jorge C; Palermo-Neto, João

    2017-01-01

    Cohabitation with Ehrlich tumor-bearing (ETB) mice induced behavioral, neurochemical, hormonal, and immune effects in the conspecifics as a consequence of stress-induced activation of the sympathetic nervous system (SNS) with catecholamine release. In the current study, the nonspecific β-AR blocker d,l-propranolol and the specific β2-AR blocker ICI-118.551 were employed as pharmacological tools to assess the extent to which catecholamines participated in the effects induced by cohabitation with ETB mice. Two experiments were performed, 1 with d,l-propranolol treatment and the other with ICI-118.551. One mouse in the experimental group was called the "companion of the sick partner" (CSP) since it was forced to live in the same cage with 2 (experiment 1) or 1 (experiment 2) cage mate that had been i.p. injected with 5 × 106 Ehrlich tumor cells. The d,l-propranolol treatment, but not the ICI-118.551 treatment, attenuated the effects of cohabitation with 2 ETB mice on both open-field behavior and the hypothalamic levels and turnover rate of norepinephrine. The 2 β-AR blockers were unable to change the serum corticosterone levels and adrenal weights of the CSP mice; however, these drugs abrogated the effects of cohabitation on neutrophil oxidative burst and phagocytosis. Finally, an increase in the 5-HT turnover rate was observed in the olfactory bulb of CSP mice compared to their respective controls, an effect that was not modified by β-AR blockade. These results confirm and strengthen our hypothesis that the SNS is involved in the effects induced by cohabitation with ETB mice and point towards β2-AR participation in the immune effects analyzed. © 2017 S. Karger AG, Basel.

  20. Paul Ehrlich's mastzellen: a historical perspective of relevant developments in mast cell biology.

    PubMed

    Ghably, Jack; Saleh, Hana; Vyas, Harsha; Peiris, Emma; Misra, Niva; Krishnaswamy, Guha

    2015-01-01

    Following the discovery of mast cells (or mastzellen) by the prolific physician researcher, Paul Ehrlich, many advances have improved our understanding of these cells and their fascinating biology. The discovery of immunoglobulin E and receptors for IgE and IgG on mast cells heralded further in vivo and in vitro studies, using molecular technologies and gene knockout models. Mast cells express an array of inflammatory mediators including tryptase, histamine, cytokines, chemokines, and growth factors. They play a role in many varying disease states, from atopic diseases, parasitic infections, hematological malignancies, and arthritis to osteoporosis. This review will attempt to summarize salient evolving areas in mast cell research over the last few centuries that have led to our current understanding of this pivotal multifunctional cell.

  1. Unexpected additional mode of energization of amino-acid transport into Ehrlich cells.

    PubMed Central

    Garcia-Sancho, J; Sanchez, A; Handlogten, M E; Christensen, H N

    1977-01-01

    Ehrlich cells treated with dinitrophenol and iodoacetate rapidly recover their 30-sec uptake of 2-(methyl-amino)-isobutyrate on treatment with 0.1 mM phenazine methosulfate + 20 mM sodium ascorbate before they begin to recover from the severely depressed ATP levels and alkali-ion gradients. Addition of 10 mM pyruvate also restores uptake of methylaminoisobutyrate before the alkali-ion gradients rise. This restoration is prevented by rotenone, but rotenone does not handicap restoration by phenazine methosulfate/ascorbate. Na+-independent uptake of 2-aminonorbornane-2-carboxylate by Ehrlich cells is affected the same way. Quinacrine almost completely suppresses uptake of methylaminoisobutyrate within the 30-sec uptake test, even when ATP levels are sustained by pyruvate and alkali-ion gradients are not depressed. Ouabain prevents restoration of both Na+-dependent and Na+-independent amino-acid transport by phenazine methosulfate/ascorbate or pyruvate. We interpret these results to indicate that amino-acid transport can be energized not only by known means, but also by reducing equivalents, which presumably reach the plasma membrane in the form of NADH from the mitochondria when the source of energy is pyruvate. In support of this hypothesis, the distribution of methylaminoisobutyrate between plasma membrane vesicles and their supporting media was influenced in the predictable way by NADH, quinacrine, and an uncoupling agent, proceeding on the assumption that more of the vesicles had the everted rather than the natural orientation. PMID:266189

  2. Computer simulation study of hexokinase II from Ehrlich ascites cells.

    PubMed

    Garfinkel, L

    1975-02-21

    A study of the mechanism of hexokinase II from ascites cells the effects of its binding to mitochondrial membranes has been carried out by computer simulation. This is based on experimental data of Kosow and Rose and of Gumaa and McLean, and the theoretical methods of cleveland. For the soluble enzyme the mechanism is random with ternary produce-inhibition complexes; when bound to mitochondria, the mechanism becomes ordered-on, random-off, as the binding of ATP to the free enzymes becomes negligibly slow. The requirements of experimental data for mechanistic studies are discussed.

  3. K+/H+-antiporter nigericin arrests DNA synthesis in Ehrlich ascites carcinoma cells.

    PubMed Central

    Margolis, L B; Novikova I, Y u; Rozovskaya, I A; Skulachev, V P

    1989-01-01

    Acidification of the cytoplasm of Ehrlich ascites carcinoma cells to pH 6.3 arrests DNA synthesis in these cells. Such an effect can be achieved by incubating the cells at pH 6.2 or by adding low concentrations of the K+/H+ antiporter, the antibiotic nigericin, at neutral pH. Glucose and anaerobiosis potentiate the nigericin effect. The inhibition of DNA synthesis by nigericin occurs without any significant decrease in the ATP concentration and in the mitochondrial membrane potential. The DNA synthesis inhibition is caused neither by a decrease in the intracellular [K+] nor by an increase in the intracellular [Na+] accompanying the nigericin effect (at least at low concentrations of the antibiotic). Nigericin should thus be regarded as a type of a cytostatic primarily affecting intracellular pH. PMID:2771947

  4. K+/H+-antiporter Nigericin Arrests DNA Synthesis in Ehrlich Ascites Carcinoma Cells

    NASA Astrophysics Data System (ADS)

    Margolis, Leonid B.; Novikova, Irina Yu.; Rozovskaya, Irina A.; Skulachev, Vladimir P.

    1989-09-01

    Acidification of the cytoplasm of Ehrlich ascites carcinoma cells to pH 6.3 arrests DNA synthesis in these cells. Such an effect can be achieved by incubating the cells at pH 6.2 or by adding low concentrations of the K+/H+ antiporter, the antibiotic nigericin, at neutral pH. Glucose and anaerobiosis potentiate the nigericin effect. The inhibition of DNA synthesis by nigericin occurs without any significant decrease in the ATP concentration and in the mitochondrial membrane potential. The DNA synthesis inhibition is caused neither by a decrease in the intracellular [K+] nor by an increase in the intracellular [Na+] accompanying the nigericin effect (at least at low concentrations of the antibiotic). Nigericin should thus be regarded as a type of a cytostatic primarily affecting intracellular pH.

  5. [FUNCTIONAL ACTIVITY OF EHRLICH CARCINOMA CELLS AFTER TREATMENT WITH HYBRID NANOCOMPLEXES CONTAINING ORTHOVANADATES OF RARE-EARTH ELEMENTS, CHOLESTEROL AND LUMINESCENT DYE].

    PubMed

    Goltsev, A N; Babenko, N N; Gaevskaya, A; Chelombitko, O V; Bondarovich, N A; Dubrava, T G; Ostankov, M V; Klochkov, V K; Kavok, N S; Malyukin, Yu V

    2015-01-01

    Tumor development is the consequence of expanding the population of low differentiated cells with unlimited self-maintenance potential, i.e. cancer stem cells (CSCs). Application of new forms of nanocomposites capable of binding to CSCs and inducing the tumor destruction is perspective direction for treating this pathology. There have been developed the methods of obtaining hybrid nanocomplexes containing rare-earth orthovanadates GdYVO4:Eu³⁺, cholesterol and luminescent dye Dil. By immune fluorescence method using monoclonal antibodies to CD44, CD24, CD117 and Sca-1 markers there has been established the change in the ratio of tumor progenitors of various differentiation levels in a general pool of Ehrlich carcinoma (EC) after treatment with hybrid nanocomplexes. Essential reduction in the concentration of the most tumorogenic CD44high cells with simultaneous rise in the number of CD117⁺-cells resulted in an increased index of CD44high/CD117⁺ ratio. It has been demonstrated that application of hybrid nanocomplexes suppressed the tumor growth almost by 80%. The value of cooperative interactions of the cells with different phenotype signs in tumor sites has been proved. The index of CD44high/CD117⁺ ratio can be used as one of diagnostic and prognostic parameters of development and inactivation rate of tumor process when using different types of anti-tumor therapy.

  6. Experimental evaluation of the glucose antimetabolite, 2-deoxy-D-glucose (2-DG) as a possible adjuvant to radiotherapy of tumors: I. Kinetics of growth and survival of ehrlich ascites tumor cells (EATC) in vitro and of growth of solid tumors after 2-DG and x-irradiation

    SciTech Connect

    Purohit, S.C.; Pohlit, W.

    1982-03-01

    Modifications of cell proliferation and survival induced by 2-DG and X-irradiation alone or in combination were studied under both aerobic and hypoxic conditions and for cells both in exponential and plateau phase. The degree of inhibition of cell proliferation was found to be dependent on absorbed dose of X rays and on the 2-DG/Glucose Molar ratio in the medium. At an equimolar ratio (2-DG/Glucose = 1) in nutrient medium the growth of euoxic EATC was ihibited by 80% relative to the control (without 2-DG). This inhibition was fully reversible up to 48 hours of the culture inoculation if 2-DG was removed from the medium, demonstrating the importance of glucose and glycolysis for tumor growth. The inhibitory effects of 2-DG on the viability of cultured cells when applied alone or in combination with radiation was found to be more pronounced in hypoxic cells than in euoxic cells. The combined effect of both noxae (2-DG and X-irradiation) on the growth inhibition of euoxic EATC in cultures was slightly more than additive, while they were clearly snyergistic on the growth inhibition of solid tumors in vivo. As tumors are known to have a fraction of hypoxic cells, it seems likely that synergistic action of 2-DG results from the stronger effect of 2-DG on these cells. The reason for the stronger effect may be a result of inhibition of their glycolytic energy supply limiting repair processes. Our results suggest that 2-DG could be used to advantage as an adjuvant in radiotherapy of human tumors.

  7. Boswellic acid disables signal transduction of IL-6-STAT-3 in Ehrlich ascites tumor bearing irradiated mice.

    PubMed

    Moustafa, Enas Mahmoud; Thabet, Noura Magdy; Azab, Khaled Shaaban

    2016-08-01

    Boswellic acid (BA) is known for its ability to trigger apoptosis as well as to inhibit angiogenesis in tumor tissue. In this study, we investigated the effect of BA on the IL-6-STAT-3 signalling pathway in irradiated mice bearing solid tumors of Ehrlich ascites carcinoma (EAC). For this, we administered BA (25 mg·(kg body mass)(-1)·day(-1), by intraperitoneal injection) to mice with EAC, and then exposed them to 4 Gy of gamma radiation. Data analyses of the results revealed a specific impact from BA on IL-6R mRNA and survivin mRNA in EACs and irradiated EAC-bearing mice. Also, significant improvements were observed in the protein expression of JAK-1, P-JAK-1, STAT-3, P-STAT-3, and caspase-3, as well as VEGF and IL-6 levels. We propose that BA interfered with IL-6-STAT-3 signal transduction, thereby preventing the activation of caspase-3 and subsequently triggering the process of apoptosis. However, the alternative angiogenesis pathway, which includes the over-expression of VEGF and which depends on IL-6-STAT-3 signalling, was inhibited by the action of BA. Thus, we recommend that therapeutic strategies for cancer should include treatment with BA.

  8. Cellular uptake of {sup 212}BiOCl by Ehrlich ascites cells: A dosimetric analysis

    SciTech Connect

    Roeske, J.C.; Whitlock, J.L.; Harper, P.V.; Rotmensch, J.; Stinchcomb, T.G.; Schwartz, J.L.; Hines, J.J.

    1999-01-01

    Bi-212 is an alpha-emitting radionuclide being investigated as a therapeutic agent in the intraperitoneal treatment of micrometastatic ovarian carcinoma. In evaluating a new therapeutic modality, cell-survival studies are often used as a means of quantifying the biological effects of radiation. In this analysis, Ehrlich ascites cells were irradiated under conditions similar to therapy in various concentrations of Bi-212. Immediately following irradiation, a cell survival assay was performed in which cells were plated and colonies were counted after 10--14 days. Both a macrodosimetric and a microdosimetric approach were used in analyzing these data. These models used as input the fraction of activity within the cell and in solution, the distribution of cell sizes, and the variation of LET along individual alpha-particle tracks. The results indicate that the energy deposited within the nucleus varies significantly among individual cells. There is a small fraction of cell nuclei which receive no hits, while the remaining cells receive energy depositions which can differ significantly from the mean value. These dosimetric parameters are correlated with measured cell survival and will be a useful predictor of outcome for therapeutic doses.

  9. Effect of electromagnetic microwave radiation on the growth of Ehrlich ascites carcinoma.

    PubMed

    Kryukova, O V; Pyankov, V F; Kopylov, A F; Khlebopros, R G

    2016-09-01

    Daily exposure of mouse recipients of Ehrlich ascites carcinoma to electromagnetic radiation of the microwave range leads to a change in the dynamics of tumor growth by decreasing the total number of cells. The number of tumor cells with blebbing morphological signs after microwave radiation increases gradually with tumor growth. The maximum content of tumor cells in the state of blebbing is observed during active proliferation in tumor-recipient mice of the control group (without irradiation).

  10. Solid Ehrlich carcinoma reproduces functional and biological characteristics of cancer cachexia.

    PubMed

    Frajacomo, Fernando Tadeu Trevisan; de Souza Padilha, Camila; Marinello, Poliana Camila; Guarnier, Flávia Alessandra; Cecchini, Rubens; Duarte, José Alberto R; Deminice, Rafael

    2016-10-01

    Well-characterized animal tumor models of cancer cachexia are warranted to elucidate underlying mechanisms and provide a better approach to the human scenario. We aimed to investigate whether solid Ehrlich carcinoma reproduces clinical, functional and biological conditions of tumor-induced cachexia in mice. Eight-week old female Swiss mice were subcutaneously inoculated with Ehrlich tumor cells (tumor-bearing, TB group) or vehicle (sham) into the right flank and monitored for 28days. Tumor histopathological features and tumor-host interaction, including tissue weight, muscle structure, strength and biochemical parameters were carried out. Tumor growth curve demonstrated a linear pattern with no difference in final carcass weight between groups. A well-defined capsule composed by connective tissue infiltrated by inflammatory and neoplastic cells surrounded the tumors. The TB group had reduced handgrip strength, aside from lower cross sectional area (CSA) and critically reduced parametrial fat pads. Plasma parameters of lactate dehydrogenase (LDH), creatine kinase (CK) and tumor necrosis factor-α (TNF-α) were higher in the TB group, suggesting predominance of catabolic and pro-inflammatory activities. Conversely, food intake and tissue weight did not differ between groups. Our data elucidated that the solid Ehrlich tumor model is feasible and effective in reproducing some of the relevant issues experienced by cancer patients with cachexia. The solid Ehrlich carcinoma emerges as an alternative tool against more aggressive cancer cachexia models during preclinical research. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Interactions of lectins with plasma membrane glycoproteins of the Ehrlich ascites carcinoma cell.

    PubMed

    Nachbar, M S; Oppenheim, J D; Aull, F

    1976-02-06

    Several aspects of the interaction of various lectins with the surface of Ehrlich ascites carcinoma cells are described. The order of agglutinating activity for various lectins is Ricinus communis greater than wheat germ greater than or equal to concanavalin A greater than or equal to soybean greater than Limulus polyphemus. No agglutination was noted for Ulex europaeus. Using 125I-labeled lectins it was determined that there are 1.6 and 7 times as many Ricinus communis lectin binding sites for concanavalin A and soybean lectins. Sodium deoxycholate-solubilized plasma membrane material was subjected to lectin affinity chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The lectin receptors of the plasma membrane appeared to be heterogeneous and some qualitative differences could be discerned among the electrophoretically analyzed material, which bound to and was specifically eluted from the various lectin affinity columns. The characteristics of elution of bound material from individual lectin columns indicated secondary hydrophobic interactions between concanavalin A or wheat germ agglutinin and their respective lectin receptor molecules.

  12. Dinucleosidetetraphosphatase from Ehrlich ascites tumour cells: inhibition by adenosine, guanosine and uridine 5'-tetraphosphates.

    PubMed

    Moreno, A; Lobatón, C D; Sillero, M A; Sillero, A

    1982-01-01

    1. An enzyme has been partially purified from Ehrlich ascites tumour cells which specifically hydrolyses dinucleosidetetraphosphates, with Km values of around 2 microM. The products of the hydrolysis are the corresponding nucleoside tri- and monophosphates. Dinucleoside Tri- and diphosphates were not substrates of the reaction. 2. The enzyme requires Mg2+ or Mn2+, is maximally active at a pH value of approx. 7.5 and has a mol, wt of 19,800 as estimated by filtration on Sephadex G-75. Nucleoside mono-, di- and triphosphates were competitive inhibitors of the reaction with Ki values in the 0.1 mM range. 3. Particularly relevant is the inhibition of this enzyme by adenosine and guanosine 5'tetraphosphates. In the course of this investigation, the presence of uridine 5'-tetraphosphate was detected in a commercial preparation of UTP. Adenosine, guanosine and uridine 5'-tetraphosphates were very strong inhibitors of the reaction with Ki values in the nM range.

  13. The influence of 1-10 kD fraction from brains of the hibernating ground squirrel and the Yakut horse on proliferation and protein synthesizing system of Ehrlich ascitic carcinoma cells.

    PubMed

    Gulevsky, A K; Grischenko, V I; Tereschenko, O S; Shchenyavcky, I J

    2005-01-01

    The experimental data presented in the work testify to the cytostatic activity of 1-10 kD polypeptide fractions from brains of the hibernating ground squirrel and the Yakut horse towards Ehrlich ascitic carcinoma (EAC) cells. The experiments on the investigation of the inhibiting influence of 1-10 kD fractions from tissues of the hibernating and cold-adapted animals on protein-synthesizing system of EAC cells allow us to conclude that the cytostatic effect of the fractions is effected at the genetic level in the tumor cells.

  14. Antibacterial activity of Kaempferia rotunda rhizome lectin and its induction of apoptosis in Ehrlich ascites carcinoma cells.

    PubMed

    Kabir, Syed Rashel; Reza, Md Abu

    2014-03-01

    The tuberous rhizome Kaempferia rotunda Linn. has been used as food and traditional medicinal plant, and the purified K. rotunda lectin (KRL) showed antiproliferative activity against Ehrlich ascites carcinoma cells [1]. In the present study, KRL showed agglutination activity against Escherichia coli and Staphylococcus aureus, with partial inhibition of their growth. MTT assay was used to investigate the effect of KRL on EAC cells in vitro in RPMI-1640 medium, and it was found that lectin inhibited 6.2-50.5% cell growth at the range of 7.5-120 μg/ml protein concentration. The cell cycle arrest at G0/G1 phase of EAC cells was also determined by flow cytometry after treatment with lectin. The apoptotic cell morphological changes of the treated EAC cells were confirmed by fluorescence and optical microscope. In the presence of caspase-3 inhibitor, the cell growth inhibition of the lectin was reduced significantly. RT-PCR was used to evaluate the expression of apoptosis-related genes, bcl-2, bcl-X, and bax. Bax gene expression was intensively increased with the despaired of bcl-X gene expression and significant decrease of bcl-2 gene expression in the cells treated with KRL. Thus, lectin induced apoptotic cell death in Ehrlich ascites carcinoma cells.

  15. Kinetic analysis of ligand binding to the Ehrlich cell nucleoside transporter: Pharmacological characterization of allosteric interactions with the sup 3 Hnitrobenzylthioinosine binding site

    SciTech Connect

    Hammond, J.R. )

    1991-06-01

    Kinetic analysis of the binding of {sup 3}Hnitrobenzylthioinosine ({sup 3}H NBMPR) to Ehrlich ascites tumor cell plasma membranes was conducted in the presence and absence of a variety of nucleoside transport inhibitors and substrates. The association of {sup 3}H NBMPR with Ehrlich cell membranes occurred in two distinct phases, possibly reflecting functional conformation changes in the {sup 3}HNBMPR binding site/nucleoside transporter complex. Inhibitors of the equilibrium binding of {sup 3}HNBMPR, tested at submaximal inhibitory concentrations, generally decreased the rate of association of {sup 3}HNBMPR, but the magnitude of this effect varied significantly with the agent tested. Adenosine and diazepam had relatively minor effects on the association rate, whereas dipyridamole and mioflazine slowed the rate dramatically. Inhibitors of nucleoside transport also decreased the rate of dissociation of {sup 3}HNBMPR, with an order of potency significantly different from their relative potencies as inhibitors of the equilibrium binding of {sup 3}HNBMPR. Dilazep, dipyridamole, and mioflazine were effective inhibitors of both {sup 3}HNBMPR dissociation and equilibrium binding. The lidoflazine analogue R75231, on the other hand, had no effect on the rate of dissociation of {sup 3}HNBMPR at concentrations below 300 microM, even though it was one of the most potent inhibitors of {sup 3}HNBMPR binding tested (Ki less than 100 nM). In contrast, a series of natural substrates for the nucleoside transport system enhanced the rate of dissociation of {sup 3}HNBMPR with an order of effectiveness that paralleled their relative affinities for the permeant site of the transporter. The most effective enhancers of {sup 3}HNBMPR dissociation, however, were the benzodiazepines diazepam, chlordiazepoxide, and triazolam.

  16. Prooxidative effect of copper--metallothionein in the acute cytotoxicity of hydrogen peroxide in Ehrlich ascites tumour cells.

    PubMed

    Suntres, Zacharias E; Lui, Edmund M K

    2006-01-16

    This study was concerned with the role of copper (Cu) and Cu-metallothionein (Cu-MT) in oxidative stress. Hydrogen peroxide (H(2)O(2))-induced oxidative injury was examined in Ehrlich ascites tumour cells isolated from host mice pretreated with 0, 1 or 2mg of CuSO(4) (ip) 24h earlier. Control Ehrlich cells contained low levels of Cu and Cu treatment produced dose-related increases in cellular Cu and Cu-MT levels and corresponding increases in sensitivity to oxidative toxicity of H(2)O(2) (LC(50), cell blebbing, lipid peroxidation, GSH depletion, and increase in intracellular free [Ca(2+)](i)). Hydrogen peroxide treatment also resulted in the oxidation of MT thiolates, reduction in the binding of Cu to MT resulting in translocation of Cu to other subcellular sites. d-penicillamine, a Cu-chelating agent, obliterated the sensitization effect of Cu-pretreatment and reduced the redistribution of MT-bound Cu, suggesting the participation of Cu ions derived from MT in promoting oxidant stress. Additional experiments with desferoxamine and mannitol have revealed the involvement of a Cu-dependent Fenton reaction in the mediation of the prooxidative effect of Cu-MT. These data suggest that cells with high levels of Cu-MT may be particularly susceptible to oxidative stress.

  17. The in vivo effect of a Brassica oleracea var. capitata extract on Ehrlich ascites tumors of MUS musculus BALB/C mice.

    PubMed

    Yurtsever, E; Yardimci, K T

    1999-01-01

    An extract of Brassica oleracea var. capitata juice was prepared using petroleum ether, ether, ethanol and an Al2O3 column. The healing and tumor protecting effects of this extract were tested on Ehrlich ascites (EA) solid tumors of Mus musculus BALB/C mice. Complete disappearance of the tumors was observed in 54.5% of the animals in the experimental group (n = 22) which received 20 mg/day of the extract i.p. for 28 days. Regression of the tumors (27%), fixation of tumor size (4%) and an increase in tumor size (18%) were also recorded. Neither tumor size fixation nor regression was recorded in the control group which received physiological serum (0.5 ml/day). The healing effect was found to be related to the starting tumor size. The healed animals in the experimental group were followed for 6-7 months and no tumor recurrence was recorded. The protective effect of this extract on tumor formation was also tested. Experimental animals (n = 35) received 20 mg/day of the extract i.p. for 20 days. Physiological serum was administered to a control group (n = 30). Transplantation of solid tumors was performed on the 20th day and extract administration was discontinued. Transplantation success was recorded 20 days after transplantation. In the experimental group, only three out of 35 mice showed tumor development, whereas in the control group the number was 23 out of 35 mice. It was also observed that the extract prevented the development of liquid EA tumors. This extract was also found to be nontoxic. Brassica oleracea var. capitata had a healing effect as well as a protective effect on EA solid tumors of mice. These results are in agreement with our previous results obtained from a liquid Brassica oleracea var. acephala juice extract.

  18. Molecular size of a Na sup + -dependent amino acid transporter in Ehrlich ascites cell plasma membranes estimated by radiation inactivation

    SciTech Connect

    McCormick, J.I.; Johnstone, R.M. ); Jette, M.; Beliveau, R. ); Potier, M. )

    1991-04-16

    Radiation inactivation was used to estimate the molecular size of a Na{sup +}-dependent amino acid transport system in Ehrlich ascites cell plasma membrane vesicles. Na{sup +}-dependent {alpha}-aminoisobutyric acid uptake was measured after membranes were irradiated at {minus}78.5C in a cryoprotective medium. Twenty-five percent of the transport activity was lost at low radiation doses (<0.5 Mrad), suggesting the presence of a high molecular weight transport complex. The remaining activity ({approximately}75% of total) decreased exponentially with increasing radiation dose, and a molecular size of 347 kDa was calculated for the latter carrier system. Radiation doses 2-3 fold higher than those required to inactivate amino acid transport were needed to cause significant volume changes. The relationship between the fragmentation of a 120-130-kDapeptide, a putative component of the Na{sup +}-dependent amino acid carrier and loss of transport activity in irradiated membranes was also examined. Peptide loss was quantitated by Western blot analysis. The data support the conclusion that fragmentation of the 120-130-kDa peptide is related to loss of amino acid transport in irradiation Ehrlich cell plasma membranes.

  19. In vitro and in vivo anti-proliferative evaluation of bis(4'-(4-tolyl)-2,2':6',2″-terpyridine)copper(II) complex against Ehrlich ascites carcinoma tumors.

    PubMed

    Mahendiran, Dharmasivam; Kumar, Raju Senthil; Viswanathan, Vijayan; Velmurugan, Devadasan; Rahiman, Aziz Kalilur

    2017-09-07

    The bis(4'-(4-tolyl)-2,2':6',2″-terpyridine)copper(II) complex [Cu(ttpy)2]Cl2 was synthesized and authenticated by single crystal analysis, which shows distorted octahedral geometry around copper(II) ion. The crystal packing is stabilized by C-H···π inter and intramolecular interactions. The complex was found to be lipophilic as determined by shake-flask method. In vitro cytotoxicity of the complex was tested against Ehrlich ascites carcinoma (EAC) and L6 myotube cell lines. The complex exhibit potent cytotoxicity with respect to the commercially available anticancer drug cisplatin. Hoechst 33258, AO/EB and PI (flow cytometry) staining methods suggest that the complex can induce apoptosis in EAC cells. Cell cycle analyses also support the induced apoptosis. Cellular uptake studies revealed that the complex can go into the cytoplasm and accumulate in the cell nuclei. The complex induces EAC cell apoptosis through a ROS-mediated mitochondrial pathway by activating caspase 3 and caspase 7 and regulates the Bcl-2 family proteins. In vivo study of the complex was validated against the animal tumor growth (EAC) cell in Swiss albino mice. The bis(4'-(4-tolyl)-2,2':6',2″-terpyridine)copper(II) complex induces EAC cell apoptosis through a ROS-mediated mitochondrial pathway and significantly reduced the body weight and solid tumor volume in Swiss albino mice.

  20. Immunogenicity of ascites tumor cells following in vitro hyperthermia

    SciTech Connect

    Dickson, J.A.; Jasiewicz, M.L.; Simpson, A.C.

    1982-06-01

    The concept that host immunization may be achieved by heat-induced antigenic modifications of cancer cells and/or the release of immunogenic products by dead or dying tumor cells following in vitro heating was examined. Ehrlich ascites cells were used, inasmuch as it was claimed that in vitro hyperthermia increased the immunogenicity of these cells. Tumor cell populations of different viability were obtained by heating Ehrlich cells at 42.5 degrees, 45 degrees, or 60 degrees C. Viable and nonviable cells were separated by Ficoll-Hypaque density centrifugation; viable nonreplicating cells were obtained by treatment with mitomycin C. Cell populations of different viability after heating were left to die slowly over 3 days at 37 degrees C. Swiss TO mice were then given injections of the treated cells and/or medium. No survival benefit occurred in mice inoculated with any of these different components and then challenged with viable tumor cells. Injection of irradiated cells, however, did produce host immunity. Similarly, D23 rat hepatoma ascites cells produced host immunity after 15,000 rad but not after heating. The claim that in vitro hyperthermia increases the immunogenicity of tumor cells was not confirmed.

  1. Effect of infrared and X-ray radiation on thymus cells and the rate of growth of Ehrlich carcinoma.

    PubMed

    Dyukina, A R; Zaichkina, S I; Rozanova, O M; Aptikaeva, G F; Romanchenko, S P; Sorokina, S S

    2012-09-01

    We studied the effect of infrared light with a wavelength of 850 nm and modulated frequency of 101 Hz and X-ray radiation on the induction of cross-adaptive and radiation responses in the thymus and on the rate of tumor growth in mice in vivo. Preliminary exposure to infrared and X-ray radiation was shown to result in recovery in thymus weight after irradiation in a dose of 1.5 Gy and also inhibited the growth rate of Ehrlich carcinoma. These data attest to common mechanisms of the adaptive response induced by infrared and X-ray radiation in mice. Infrared light can be used as an adaptogen to adapt the animals to adverse factors.

  2. Solanum tuberosum lectin inhibits Ehrlich ascites carcinoma cells growth by inducing apoptosis and G2/M cell cycle arrest.

    PubMed

    Kabir, Syed Rashel; Rahman, Md Musfikur; Amin, Ruhul; Karim, Md Rezaul; Mahmud, Zahid Hayat; Hossain, M Tofazzal

    2016-06-01

    Recently, a lectin was purified from the potato cultivated in Bangladesh locally known as Sheel. In the present study cytotoxicity of the lectin against Ehrlich ascites carcinoma (EAC) cells was studied by MTT assay in vitro in RPMI-1640 medium and 8.0-36.0 % cell growth inhibition was observed at the range of 2.5-160 μg/ml protein concentration when incubated for 24 h. The lectin-induced apoptosis in EAC cells was confirmed by fluorescence and optical microscope. The apoptotic cell death was also confirmed by using caspase inhibitors. Cells growth inhibition caused by the lectin (36 %) was remarkably decreased to 7.6 and 22.3 % respectively in the presence of caspase-3 and -8 inhibitors. RT-PCR was used to evaluate the expression of apoptosis-related genes Bcl-X, p53, and Bax. An intensive expression of Bcl-X gene was observed in untreated control EAC cells with the disappeared of the gene in Sheel-treated EAC cells. At the same time, Bax gene expression appeared only in Sheel-treated EAC cells and the expression level of the p53 gene was increased remarkable after the treatment of EAC cells with the lectin. The lectin showed strong agglutination activity against EAC cells. Flow cytometry was used to study the cell cycle phases of EAC cells and it was observed that the lectin arrested the G2/M phase. In conclusion, Sheel lectin inhibited EAC cells growth by inducing apoptosis.

  3. Identification of a Zn(2+)-sensitive component of Ehrlich cell plasma membrane redox system by CHAPS-agarose-polyacrylamide electrophoresis and in situ staining of activity.

    PubMed

    Rodríguez-Caso, L; Rodríguez-Agudo, D; del Castillo-Olivares, A; Márquez, J; Núñez de Castro, I; Medina, M A

    1997-01-01

    A procedure based on CHAPS-agarose-polyacrylamide electrophoresis and in situ staining of activity was used to detect a Zn(2+)-sensitive component of Ehrlich cell plasma membrane redox system. The procedure is so powerful that it allows to use crude plasma membrane fractions and can be easily adapted for use in an electrophoretic approach to the purification of this protein.

  4. Inhibition of Na-K-Cl cotransport in Ehrlich ascites cells by antiserum against purified proteins of the cotransporter

    SciTech Connect

    Dunham, P.B. ); Jessen, F.; Hoffmann, E.K. )

    1990-09-01

    Two proteins were purified earlier from solubilized membranes of Ehrlich ascites cells by using a bumetanide-Sepharose affinity column. These proteins were proposed to be constituents of the Na-K-Cl cotransporter. However, the specificity of binding of bumetanide to the cotransporter was insufficient evidence for this proposal. The authors now have direct evidence that the purified protein contains components of the cotransporter. Antiserum raised against the bumetanide-binding proteins strongly inhibits Na-K-Cl cotransport measured by two independent methods. Cotransport was induced by hypertonic challenge and was measured as the bumetanide-sensitive portion of unidirectional Cl influx and as regulatory cell volume increase. In both assays, contransport was strongly inhibited by antiserum. Fab fragments of the antibodies inhibited cotransport to a similar extent.

  5. Ultrastructural changes produced in Ehrlich ascites carcinoma cells by ultraviolet-visible radiation in the presence of melanins

    SciTech Connect

    Lea, P.J.; Pawlowski, A.; Persad, S.D.; Menon, I.A.; Haberman, H.F.

    1988-01-01

    Irradiation of Ehrlich ascites carcinoma (EAC) cells in the presence of pheomelanin, i.e., red hair melanin (RHM), has been reported to produce extensive cell lysis. Irradiation in the presence of eumelanin, i.e., black hair melanin (BHM), or irradiation in the absence of either type of melanin did not produce this effect. We observed that RHM particles penetrated the cell membrane without apparent structural damage to the cell or the cell membrane. Irradiation of the cells in the absence of melanin did not produce any changes in the ultrastructure of the cells. Incubation of the cells in the dark in the presence of RHM produced only minor structural, mainly cytoplasmic changes. Irradiation of the cells in the presence of RHM produced extensive ultrastructural changes prior to complete cell lysis; these changes were more severe than the effects of incubation of the cells in the dark in the presence of RHM. When the cells incubated in the dark or irradiated in the presence of latex particles or either one of the eumelanins particles, viz. BHM or synthetic dopa melanin, these particles did not penetrate into the cells or produce any ultrastructural changes. These particles were in fact not even ingested by the cells.

  6. Modulation of the volume-sensitive K+ current in Ehrlich ascites tumour cells by pH.

    PubMed

    Hougaard, C; Jørgensen, F; Hoffmann, E K

    2001-07-01

    The effects of extracellular and intracellular pH (pHo and pHi respectively) on the regulatory volume decrease (RVD) response and on the volume-sensitive K+ and Cl- currents (IK,vol and ICl,vol respectively) were studied in Ehrlich ascites tumour cells. Alkaline pHo accelerated and acidic pHo decelerated the RVD response significantly. Intra- and extracellular alkalinisation increased the amplitude of IK,vol whereas acidification had an inhibitory effect. The magnitude of ICl,vol was not affected by changes in pHi or pHo. A significant reduction in the activation time for IK,vol after hypotonic cell swelling was observed upon moderate intracellular alkalinisation (to pHi 7.9). A further increase in pHi to 8.4 resulted in the spontaneous activation of an IK under isotonic conditions which resembled IK,vol with respect to its pharmacological profile and current/voltage (I/V) relation. Noise analysis demonstrated that the increased amplitude of IK,vol at alkaline pH resulted mainly from an increase in the number of channels (N) contributing to the current. The channel open probability, Po, was largely unaffected by pH. The pH dependence and the biophysical and pharmacological properties of IK,vol are similar to those of the cloned tandem pore-domain acid-sensitive K+ (TASK) channels, and in the current study the presence of TASK-1 was confirmed in Ehrlich cells.

  7. Cell content of phosphatidylinositol (4,5)bisphosphate in Ehrlich mouse ascites tumour cells in response to cell volume perturbations in anisotonic and in isosmotic media.

    PubMed

    Nielsen, Doris K; Jensen, Annelie Kolbjørn; Harbak, Henrik; Christensen, Søren C; Simonsen, Lars Ole

    2007-08-01

    The labelling pattern of cellular phosphoinositides (PtdInsP(n)) was studied in Ehrlich ascites cells labelled in vivo for 24 h with myo-[2-(3)H]- or l-myo-[1-(3)H]inositol and exposed to anisotonic or isosmotic volume perturbations. In parallel experiments the cell volume ([(14)C]3-OMG space) was monitored. In hypotonic media the cells initially swelled osmotically and subsequently as expected showed a regulatory volume decrease (RVD) response. Concurrently, the cell content of PtdInsP(2) showed a marked, transient decrease and the content of PtdInsP a small, transient increase. The changes in PtdInsP(2) and PtdInsP content increased progressively with the extent of hypotonicity (in the range 1.00-0.50 relative osmolarity). No evidence was found for either hydrolysis of PtdInsP(2) or formation of PtdInsP(3). In hypertonic medium (relative osmolarity 1.50), cells initially shrank osmotically and subsequently as expected showed a small regulatory volume increase (RVI) response. Concurrently, the cell content of PtdInsP(2) showed a marked increase and the content of PtdInsP a small decrease, i.e. changes in the opposite direction of those seen in hypotonic media. In isosmotic media with high (100 mm) or low (0.8 mm) K(+) concentration, cells slowly swelled or shrank due to uptake or loss of isosmotic KCl. Under these conditions, with largely unchanged intracellular ionic strength, the cell content of PtdInsP(2) and PtdInsP remained constant. Our results show that PtdInsP(2) is not volume sensitive per se, and moreover that the regulatory volume adjustments in Ehrlich ascites cells are not mediated by PtdInsP(2) hydrolysis and its subsequent production of second messengers. The simplest interpretation of the observed effects would be that PtdInsP(2) is controlled by ionic strength, probably via activation/inhibition of phosphoinositide-specific phosphatases/kinases. In Ehrlich ascites cells, as shown previously, the opposing ion channels and transporters activated

  8. Damage effects of protoporphyrin IX - sonodynamic therapy on the cytoskeletal F-actin of Ehrlich ascites carcinoma cells.

    PubMed

    Zhao, Xia; Liu, Quanhong; Tang, Wei; Wang, Xiaobing; Wang, Pan; Gong, Liyan; Wang, Yuan

    2009-01-01

    In this study, we report evidence of the damage effects of sonodynamic therapy (SDT) on a novel intracellular target, cytoskeletal F-actin, that has great importance for cancer treatment. Ehrlich ascites carcinoma (EAC) cells suspended in PBS were exposed to ultrasound at 1.34 MHz for up to 60s in the presence and absence of protoporphyrin IX (PPIX). To evaluate the polymeric state and distribution of actin filaments (AF) we employed FITC-Phalloidin staining. The percentage of cells with intact AF was decreased with 10-80 microM PPIX after ultrasonic exposure, while only few cells with disturbed F-actin were observed with 80 microM PPIX alone. The fluorescence intensity of FITC-Phalloidin labeled cells was detected by flow cytometry. The morphological changes of EAC cells were observed by scanning electron microscope (SEM). The nuclei were stained with Hoechst 33258 to determine apoptosis. Cytoskeletal F-actin and cell morphological changes were dependent on the time after SDT. Some cells suffered deformations of plasma membrane as blebs that reacted positively to FITC-Phalloidin at 2h after SDT treatment. Many of the cells showed the typically apoptotic chromatin fragmentation. The alterations were more significant 4h later. Our results showed that cytoskeletal F-actin might represent an important target for the SDT treatment and the observed effect on F-actin and the subsequent bleb formation mainly due to apoptosis formation due to the treatment.

  9. Inhibition of electron flow through complex I of the mitochondrial respiratory chain of Ehrlich ascites carcinoma cells by methylglyoxal.

    PubMed

    Ray, S; Dutta, S; Halder, J; Ray, M

    1994-10-01

    The effect of methylglyoxal on the oxygen consumption of Ehrlich-ascites-carcinoma (EAC)-cell mitochondria was tested by using different respiratory substrates, electron donors at different segments of the mitochondrial respiratory chain and site-specific inhibitors to identify the specific respiratory complex which might be involved in the inhibitory effect of methylglyoxal on the oxygen consumption by these cells. The results indicate that methylglyoxal strongly inhibits ADP-stimulated alpha-oxo-glutarate and malate plus pyruvate-dependent respiration, whereas, at a much higher concentration, methylglyoxal fails to inhibit succinate-dependent respiration. Methylglyoxal also fails to inhibit respiration which is initiated by duroquinol, an artificial electron donor. Moreover, methylglyoxal cannot inhibit oxygen consumption when the NNN'N'-tetramethyl-p-phenylenediamine by-pass is used. The inhibitory effect of methylglyoxal is identical on both ADP-stimulated and uncoupler-stimulated respiration. Lactaldehyde, a catabolite of methylglyoxal, can exert a protective effect on the inhibition of EAC-cell mitochondrial respiration by methylglyoxal. We suggest that methylglyoxal possibly inhibits the electron flow through complex I of the EAC-cell mitochondrial respiratory chain.

  10. C57BL/6N Mice Are More Resistant to Ehrlich Ascites Tumors Than C57BL/6J Mice: The Role of Macrophage Nitric Oxide.

    PubMed

    Kalish, Sergey; Lyamina, Svetlana; Chausova, Svetlana; Kochetova, Lada; Malyshev, Yuri; Manukhina, Eugenia; Malyshev, Igor

    2015-10-20

    BACKGROUND Effectiveness of the immune defense formed by the genotype often determines the predisposition to cancer. Nitric oxide (NO) produced by macrophages is an important element in this defense. MATERIAL AND METHODS We hypothesized that genetic characteristics of NO generation systems can predetermine the vulnerability to tumor development. The study was conducted on mice of 2 genetic substrains - C57BL/6J and C57BL/6N - with Ehrlich ascites carcinoma (EAC). NO production in the tumor was changed using ITU, an iNOS inhibitor; c-PTIO, a NO scavenger; and SNP, a NO donor. Macrophage NO production was estimated by nitrite concentration in the culture medium. iNOS content was measured by Western blot analysis. Macrophage phenotype was determined by changes in NO production, iNOS level, and CD markers of the phenotype. RESULTS The lifespan of C57BL/6N mice (n=10) with EAC was 25% longer (p<0.01) than in C57BL/6J mice (n=10). Decreased NO production 23% reduced the survival duration of C57BL/6N mice (p<0.05), which were more resistant to tumors. Elevated NO production 26% increased the survival duration of C57BL/6J mice (p<0.05), which were more susceptible to EAC. Both the NO production and the iNOS level were 1.5 times higher in C57BL/6N than in C57BL/6J mice (p<0.01). CD markers confirmed that C57BL/6N macrophages had the M1 and C57BL/6J macrophages had the M2 phenotype. CONCLUSIONS The vulnerability to the tumor development can be predetermined by genetic characteristics of the NO generation system in macrophages. The important role of NO in anti-EAC immunity should be taken into account in elaboration of new antitumor therapies.

  11. Influence of metronidazole and some electron acceptors on the chlorin e6 photosensitized killing of Ehrlich carcinoma cells

    NASA Astrophysics Data System (ADS)

    Chekulayev, V.; Shevchuk, Igor; Mihkelsoo, Virgo T.; Kallikorm, A. P.

    1992-06-01

    A decrease in the effectiveness of photosensitized killing of neoplasm cells was observed in the presence of chlorin-e6 at a reduced concentration of oxygen. But when metronidazole (MZ) was injected in vitro as well as in vivo, a significant increase in the photosensitized killing of Ehrlich carcinoma cells by chlorin-e6 was observed. Moreover, contrary to the hematoporphyrin derivative (HpD), MZ increases the effectiveness of photodynamic therapy (PDT) by using chlorin-e6 not only in the hypoxic but also in the aerobic conditions. The interaction between MZ and the excited photosensitizer may account for an increased phototoxicity of chlorin-e6. The formation of cytotoxic nitroimidazole radicals as a result of photochemical processes of type 1 is discussed. This property of the photosensitizer may be successfully used in working out a method of potentiating PDT in combination not only with nitroimidazoles, but also with other electron acceptor compounds (EACp), e.g., quinone antitumor antibiotics.

  12. Paul Ehrlich: pathfinder in cell biology. 1. Chronicle of his life and accomplishments in immunology, cancer research, and chemotherapy.

    PubMed

    Kasten, F H

    1996-01-01

    The paper reviews the life of Paul Ehrlich and his biomedical accomplishments in immunology, cancer research, and chemotherapy. Ehrlich achieved renown as an organic chemist, histologist, hematologist, immunologist, and pharmacologist. He disliked the formality of school but managed to excel in Latin and mathematics. His role model was an older cousin, Carl Weigert, who became a lifelong friend. Ehrlich studied medicine at Breslau, Strasbourg, Freiburg, and Leipzig, coming under the influence of Wilhelm Waldeyer, Julius Cohnheim, Rudolf Heidenhein, and Ferdinand Cohn. As a medical student, Ehrlich was captivated by structural organic chemistry and dyes. When he was 23, his first paper was published on selective staining. His doctoral thesis, "Contribution to the Theory and Practice of Histological Staining" contained most of the germinal ideas that would guide his future career. Most of his early work was centered in Berlin at Charite Hospital, where he did pioneering studies on blood and intravital staining, and at Robert Koch's Institute for Infectious Diseases, where he undertook important investigations in immunology. Ehrlich became an authority on antitoxin standardization and developed the "side-chain theory" of antibody formation for which he was later awarded the Nobel Prize. He became director of an Institute for Experimental Therapy in Frankfurt where he continued research in immunology and carried out routine serum testing. He developed new lines of investigation in cancer research and originated the field of chemotherapy. Using principles developed in his early work with dyes, he successfully treated certain experimental trypanosomal infections with azo dyes. His crowning accomplishment was discovering that the compound Salvarsan could control human syphilis. Ehrlich's legacy in immunology and chemotherapy is discussed and an intimate portrait is drawn of Ehrlich the person.

  13. Anticancer effect and immunologic response to xenogeneic embryonic proteins in mice bearing Ehrlich solid carcinoma.

    PubMed

    Symchych, T V; Fedosova, N I; Karaman, О М; Yevstratieva, L M; Potebnia, H P

    2017-03-01

    To investigate anticancer and immunologic effects of chicken embryonic proteins (CEP) in mice bearing Ehrlich solid carcinoma. The study was carried out on male Balb/c mice bearing Ehrlich solid carcinoma. The immunizations were performed after the tumor transplantation. The immune status was assessed on days 7, 14, 21 and 28 after the tumor challenge. Cytotoxic activity (CAT) of macrophages (Mph), natural killer cells (NK), cytotoxic T-lymphocytes (CTL) and blood serum, as well as the influence of the blood serum on immune cells activity was checked in MTT-assay; Mph's cytochemical activity was tested in NBT-assay; Ehrlich antigen-specific or CEP-specific antibodies were detected in ELISA-assay; medium size circulating immune complexes (CIC) were detected in reaction of 4.5% polyethylene glycol precipitation. The immunization resulted in tumor growth suppression and significant 25.64% prolongation of the survival time. In both control and immunized mice with transplanted tumors antibodies specific to Ehrlich carcinoma antigens and to CEP were detected, but antibody response was more balanced in the treatment group. In the treatment group both cytochemical and CAT of Mph was moderately activated and well preserved until late stages of tumor development; CAT of NK and CTL remained in the range of the intact mice until day 28 after the tumor transplantation. The immunized mice were well protected from accumulation of CIC and suppressive activity of autologous blood serum. Collectively, our data indicate that CEP can elicit immunomodulating and immunoprotecting effects sufficient to provide tumor growth inhibition. The further elaboration of a xenogeneic anticancer vaccine based on CEP is warranted.

  14. Apigenin potentiates the antitumor activity of 5-FU on solid Ehrlich carcinoma: Crosstalk between apoptotic and JNK-mediated autophagic cell death platforms.

    PubMed

    Gaballah, Hanaa H; Gaber, Rasha A; Mohamed, Darin A

    2017-02-01

    Although 5- Fluorouracil (5-FU) has exhibited effectiveness against cancer, novel therapeutic strategies are needed to enhance its antitumor efficiency and modulate its cytotoxity. Apigenin, a flavonoid present in fruits and vegetables, is a potent dietary phytochemical effective in cancer chemoprevention. This study was undertaken to investigate the potential synergistic antitumor activity of apigenin and 5-FU on Solid Ehrlich carcinoma (SEC). Eighty Swiss albino male mice were divided into four equal groups: vehicle treated control SEC, SEC+5-FU, SEC+apigenin, SEC+ 5-FU+apigenin. Beclin-1 and caspases 3, 9 and JNK activities were estimated by ELISA; mRNA expression levels of the antiapoptotic gene Mcl-1 were estimated using quantitative real-time RT-PCR, while tissue malondialdehyde (MDA), glutathione peroxidase and total antioxidant capacity were evaluated spectrophotometrically. A part of the tumor was examined for histopathological and Ki-67 immunohistochemistry analysis. 5-FU and/or apigenin caused significant increase in tissue levels of Beclin-1, caspases 3, 9 and JNK activities, MDA with significant decrease in tumor volume, Mcl-1expression, tissue glutathione peroxidase and total antioxidant capacity and alleviated the histopathological changes with significant decrease of Ki-67 proliferation index compared to vehicle treated SEC control group. The combination of 5-FU and apigenin had a greater effect than each of 5-FU or apigenin alone against solid Ehrlich carcinoma in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Biodistribution and antitumoral effect of long-circulating and pH-sensitive liposomal cisplatin administered in Ehrlich tumor-bearing mice.

    PubMed

    Araújo, José Geraldo Coimbra; Mota, Luciene das Graças; Leite, Elaine Amaral; Maroni, Laís de Carvalho; Wainstein, Alberto Julius Alves; Coelho, Luiz Gonzaga Vaz; Savassi-Rocha, Paulo Roberto; Pereira, Márcio Tadeu; de Carvalho, Andréa Teixeira; Cardoso, Valbert Nascimento; De Oliveira, Mônica Cristina

    2011-07-01

    Cisplatin (CDDP) is one of the most active cytotoxic agents and has been widely used in the treatment of peritoneal carcinomatosis by the intraperitoneal (i.p.) route. However, CDDP, a low-molecular-weight compound, is rapidly absorbed by the capillaries in the i.p. serosa and transferred to the bloodstream, inducing the appearance of systemic side-effects, such as nephrotoxicity. Furthermore, the i.p. CDDP chemotherapy is limited to patients whose residual tumor nodules are less than 0.5 cm in diameter after surgical debulking. The failure of i.p. therapy is attributed to the poor penetration of CDDP into larger tumors. One strategy to improve drug delivery in the peritoneal region and reduce toxicity is the use of drug delivery systems. The objective of the present work was to evaluate the biodistribution and antitumoral effect of long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP), as compared with free CDDP, after their i.p. administration in Ehrlich ascitic tumor-bearing mice. After administering a 6 mg/kg single i.p. bolus injection of either free CDDP or SpHL-CDDP, ascitic fluid (AF), blood and organs (kidneys, liver, spleen and lungs) were collected and analyzed for CDDP content. The area under the CDDP concentration-time curve (AUC) obtained for AF and blood after SpHL-CDDP administration was 3.3-fold larger and 1.3-fold lower, respectively, when compared with free CDDP treatment, thus indicating its high retention within the peritoneal cavity. The determination of the ratio between AUC in each tissue and that in blood (Kp) showed a lower accumulation of CDDP in kidneys after SpHL-CDDP treatment. The SpHL-CDDP treatment demonstrated a significant uptake by the liver and spleen. SpHL-CDDP treatment led to a higher survival rate of mice with initial or disseminated peritoneal carcinomatosis than CDDP treatment. These results indicate that SpHL-CDDP may be useful for i.p. chemotherapy due to their greater concentration in the peritoneal

  16. Effects of 2,4-dinitrophenol and other metabolic inhibitors on the thermograms of Ehrlich ascites carcinoma cells registered with a microcalorimeter.

    PubMed

    Ito, E; Sakihama, H; Toyama, K; Matsui, K

    1984-05-01

    The heat produced by Ehrlich ascites carcinoma cells was measured microcalorimetrically to investigate the characteristics of the energetics of these cells. 2,4-Dinitrophenol and other inhibitors were used to obtain the standard thermograms. The heat level of starved Ehrlich ascites carcinoma cells (endogenous) was almost constant and linear and depended on the cell number used in the experiments (about 1 cal/1 X 10(8) cells/hr). The endogenous heat generation was suppressed strongly by potassium cyanide but not by iodoacetic acid or 2,4-dinitrophenol. On the other hand, heat evolution was directly related to the amount of glucose added to the medium but not to the number of cells (19 cal/mmol of glucose). The addition of iodoacetic acid markedly suppressed heat generation, but potassium cyanide did not. In contrast, glucose with dinitrophenol increased heat production markedly to about 10% higher than that of the control, possibly due to the uncoupled energy from oxidative phosphorylation. Malonic acid (1 mM) suppressed slightly the endogenous heat but caused a 15% reduction in exogenous heat. The amount of heat produced by the addition of glucose (19 cal/mmol) was equivalent to 40% of the theoretical value of energy released through glycolysis (47 cal/mmol). Thus, the heat produced by exogenous glucose appears to be mainly dependent on glycolysis.

  17. Nonfunctioning Juxtaglomerular Cell Tumor

    PubMed Central

    Sakata, Ryoko; Shimoyamada, Hiroaki; Yanagisawa, Masahiro; Murakami, Takayuki; Makiyama, Kazuhide; Nakaigawa, Noboru; Inayama, Yoshiaki; Ohashi, Kenichi; Nagashima, Yoji; Yao, Masahiro; Kubota, Yoshinobu

    2013-01-01

    The juxtaglomerular cell tumor (JGCT) is a rare renal tumor characterized by excessive renin secretion causing intractable hypertension and hypokalemia. However, asymptomatic nonfunctioning JGCT is extremely rare. Here, we report a case of nonfunctioning JGCT in a 31-year-old woman. The patient presented with a left renal tumor without hypertension or hypokalemia. Under a clinical diagnosis of renal cell carcinoma, radical nephrectomy was performed. The tumor was located in the middle portion adjacent to the renal pelvis, measuring 2 cm in size. Pathologically, the tumor was composed of cuboidal cells forming a solid arrangement, immunohistochemically positive for renin. Based on these findings, the tumor was diagnosed as JGCT. In cases with hyperreninism, preoperative diagnosis of JGCT is straightforward but difficult in nonfunctioning case. Generally, JGCT presents a benign biological behavior. Therefore, we should take nonfunctioning JGCT into the differential diagnoses for renal tumors, especially in younger patients to avoid excessive surgery. PMID:23607027

  18. Tumor cell metabolism

    PubMed Central

    Romero-Garcia, Susana; Lopez-Gonzalez, Jose Sullivan; B´ez-Viveros, José Luis; Aguilar-Cazares, Dolores

    2011-01-01

    Cancer is a genetic disease that is caused by mutations in oncogenes, tumor suppressor genes and stability genes. The fact that the metabolism of tumor cells is altered has been known for many years. However, the mechanisms and consequences of metabolic reprogramming have just begun to be understood. In this review, an integral view of tumor cell metabolism is presented, showing how metabolic pathways are reprogrammed to satisfy tumor cell proliferation and survival requirements. In tumor cells, glycolysis is strongly enhanced to fulfill the high ATP demands of these cells; glucose carbons are the main building blocks in fatty acid and nucleotide biosynthesis. Glutaminolysis is also increased to satisfy NADPH regeneration, whereas glutamine carbons replenish the Krebs cycle, which produces metabolites that are constantly used for macromolecular biosynthesis. A characteristic feature of the tumor microenvironment is acidosis, which results from the local increase in lactic acid production by tumor cells. This phenomenon is attributed to the carbons from glutamine and glucose, which are also used for lactic acid production. Lactic acidosis also directs the metabolic reprogramming of tumor cells and serves as an additional selective pressure. Finally, we also discuss the role of mitochondria in supporting tumor cell metabolism. PMID:22057267

  19. [Retroperitoneal germ cell tumor].

    PubMed

    Borrell Palanca, A; García Garzón, J; Villamón Fort, R; Domenech Pérez, C; Martínez Lorente, A; Gunthner, S; García Sisamón, F

    1999-03-01

    We report a case of retroperitoneal extragonadal germ-cell tumor in an 17 years old patient who presented with aedema and pain in left inferior extremity asociated with hemopthysis caused by pulmonar metastasis, who was treated with chemotherapy and resection of residual mass and pulmonary nodes. Dyagnosis was stableshed by fine neadle aspiration biopsy of the wass. We comment on the difficult of stableshing differential dyagnosis between retroperitoneal extragonadal germ-cell tumor and metastasis of a testicular tumor. Dyagnosis is stableshed by the finding of a histologically malignant germ-cell tumor with normal testis. We considered physical examination and ecographyc exploration enough for a correct dyagnosis.

  20. Merkel cell tumor.

    PubMed

    Kitazawa, M; Watanabe, H; Kobayashi, H; Ohnishi, Y; Shitara, A; Nitto, H

    1987-06-01

    A Merkel cell tumor appeared on the left cheek of an 83-year-old female was reported. The tumor was located mainly in the dermis and infiltrated to the subcutaneous adipose tissue with an involvement of the blood vessels and lymphatics at the periphery. Electron-microscopically, few of the dense-cored granules and the single globular aggregates of intermediate filaments at the nuclear indentations were observed. Electron-microscopic uranaffin reaction proved positive reaction on the dense-cored granules. Half of the cytoplasmic border was smooth, while the rest had short projections. Desmosomes or junctional complexes were not detected among the tumor cells. Immunohistochemically, the cytoplasm of tumor cell showed positive reaction to both neuron-specific enolase (NSE) and keratin. The single globular positive spots of the latter were localized in accordance with the aggregates of intermediate filaments. These findings suggested a neurogenic origin with double differentiation, epithelial and neuroendocrine, of the Merkel cell tumor.

  1. A p-menth-1-ene-4,7-diol (EC-1) from Eucalyptus camaldulensis Dhnh. triggers apoptosis and cell cycle changes in Ehrlich ascites carcinoma cells.

    PubMed

    Islam, Farhadul; Khanam, Jahan Ara; Khatun, Mahbuba; Zuberi, Natasha; Khatun, Laboni; Kabir, Syed Rashel; Reza, Md Abu; Ali, M M; Rabbi, M A; Gopalan, Vinod; Lam, Alfred King-Yin

    2015-04-01

    Anticancer activities of p-menth-1-ene-4,7-diol (EC-1) isolated from Eucalyptus camaldulensis Dhnh. were studied on Ehrlich ascites carcinoma (EAC) cells by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. Anticancer activities also analyzed in EAC-bearing mice by assessment of cancer growth inhibition, changes in cancer volume, changes in life span, and hematological parameters. Apoptosis was analyzed by fluorescence microscope, DNA fragmentation assay, and flow cytometry. The expression of apoptosis-related genes, Bcl-2, Bcl-X, PARP-1, p53, and Bax, were analyzed using polymerase chain reaction (PCR). EC-1 significantly inhibited proliferation of EAC cells in vivo and restored the altered hematological parameters of EAC-bearing mice. Cytological observation by fluorescence microscope showed apoptosis of EAC cells upon treatment with EC-1. Also, DNA fragmentation assay revealed EAC cells' apoptosis following EC-1 treatment. Increased mRNA expressions of p53 and Bax genes and negative expressions of Bcl-2 and Bcl-X were observed in cells treated with EC-1. These findings confirmed the induction of apoptosis by EC-1. In addition, MTT assay showed dose-dependent anticancer activity of EC-1 against EAC cell. Cell cycle analysis revealed that EC-1 treatment caused suppression of EAC cells at S phase. To conclude, EC-1 is a novel anticancer compound and showed antiproliferative and apoptotic activities in cellular and mice models.

  2. [Testicular germ cell tumors].

    PubMed

    Dourthe, L M; Ouachet, M; Fizazi, K; Droz, J P

    1998-09-01

    Testicle germ cells tumors are the most common young men neoplasm. The incidence is maximal in Scandinavian countries. Cryptorchidism is a predisposing factor. Diagnosis is clinic, first treatment is radical orchidectomy by inguinal incision, after study of tumor markers. Histology shows seminoma or non seminomatous tumor. Carcinoma in situ is the precursor of invasive germ cell tumors. Germ cell tumors have no p53 mutation, and have isochrome of the short arm of chromosome 12 as a specific marker. With the results of histological, biochemical and radiographic evaluation, patient are classified as follows: good, intermediate and poor risk prognosis. Standard treatment of stage I seminoma is prophylactic irradiation. Stage II with less than 3 cm lymph node too. Other situations need a cisplatin based chemotherapy. In case of metastatic residuals masses more than 3 cm, surgery need to be discussed. Stage I non seminomatous germ cell tumors are treated by retroperitoneal lymphadenectomy, by surveillance or by two cycles of adjuvant chemotherapy with cisplatin, etoposide and bleomycin (BEP). Standard treatment of good prognosis stage II and III is three cycles of BEP, four for poor prognosis. Residual mass need surgery, adjuvant chemotherapy is necessary in presence of viable germ cell. Standard treatment for relapses is chemotherapy with cisplatin, ifosfamide and vinblastine with a 30% remission rate. The place of high dose chemotherapy with autologous stem cell transplantation is not yet standardised. New drugs, as paclitaxel, are under studies.

  3. Antitumor Properties of Modified Detonation Nanodiamonds and Sorbed Doxorubicin on the Model of Ehrlich Ascites Carcinoma.

    PubMed

    Medvedeva, N N; Zhukov, E L; Inzhevatkin, E V; Bezzabotnov, V E

    2016-01-01

    We studied antitumor properties of modified detonation nanodiamonds loaded with doxorubicin on in vivo model of Ehrlich ascites carcinoma. The type of tumor development and morphological characteristics of the liver, kidneys, and spleen were evaluated in experimental animals. Modified nanodiamonds injected intraperitoneally produced no antitumor effect on Ehrlich carcinoma. However, doxorubicin did not lose antitumor activity after sorption on modified nanodiamonds.

  4. Membrane potential, chloride exchange, and chloride conductance in Ehrlich mouse ascites tumour cells.

    PubMed Central

    Hoffmann, E K; Simonsen, L O; Sjøholm, C

    1979-01-01

    ) may indicate that the chloride exchange and conductance pathways are not completely separate and distinct modes of transport, but may involve common elements. The reduced chloride permeability in the presence of phloretin is estimated to be two orders of magnitude larger than the ground permeability of the cell membrane. PMID:529133

  5. In vitro conversion of MVM parvovirus single-stranded DNA to the replicative form by DNA polymerase alpha from Ehrlich ascites tumour cells.

    PubMed Central

    Faust, E A; Rankin, C D

    1982-01-01

    A partially purified preparation of DNA polymerase alpha, obtained from the cytosol of Ehrlich ascites tumour cells, has been found to catalyze the conversion of MVM parvovirus, SS DNA (5 kilobases) to RF in vitro. The reaction initiates at a natural 55 base pair hairpin which exists at the 3' terminus of MVM SS DNA. The SS leads to RF conversion is sensitive to aphidicolin, resistant to ddTTP and is promoted by purine ribonucleoside 5' triphosphates, a phenomenon which could not be explained simply by stabilization effects on the in vitro deoxynucleotide precursor pool. In the absence of rNTPs, nascent complementary strands frequently terminate prematurely at a preferred location, between 1300 and 1700 nucleotides from the initiating 3' hairpin terminus. This in vitro system, involving self-primed parvovirus DNA synthesis, provides a convenient assay for those components of the mammalian replicative DNA polymerase complex which are required for the elongation of nascent DNA chains. Images PMID:6812024

  6. Altered glycosylation in tumor cells

    SciTech Connect

    Reading, C.L. ); Hakomori, S. ); Marcus, D.M. )

    1988-01-01

    This book contains the proceeding on the following: Glycoconjugates of normal and tumor cells; Glycosyltransferases in normal and neoplastic cells; Mammalian lectins of normal tissues and tumor cells; and Immune recognition of carbohydrates and clinical applications.

  7. Effect of Balanites aegyptiaca on Ehrlich Ascitic carcinoma growth and metastasis in Swiss mice.

    PubMed

    Issa, N M; Mansour, F K; El-Safti, F A; Nooh, H Z; El-Sayed, I H

    2015-09-01

    The role of Balanites aegyptiaca (B. aegyptiaca) on development and growth of Ehrlich Ascitic carcinoma (EAC) and metastasis (liver and spleen) was evaluated. Balanite (400mg/kg; 10mg in 0.1ml/mouse) was given daily over a period of two weeks started 24h before intraperitoneal injection of EAC (2×10(6)/once). The present study deals with the effect of B. aegyptiaca on the growth of transplantable ascetic tumor, life span of EAC-bearing mice, hepatocellular and splenic histology. Antioxidant and biochemical changes as well as p53 genes expression were recorded. B. aegyptiaca extracts inhibited tumor growth and proliferation in ascetic fluid through a significant decrease in tumor volume, total cell volume, and viable cell count and prolonged the life span of mice. Also, it significantly decreased the levels of lipid peroxidation and increased SOD, CAT levels and P53 expression. Also, balanite inhibited either tumor invaded/or affected hepatic and splenic tissue. This result gives a new insight on beneficial effect of B. aegyptiaca in primary and secondary loci of Ehrlich Ascitic tumor through its antioxidant effect. Copyright © 2015 Elsevier GmbH. All rights reserved.

  8. Ghost Cell Tumors.

    PubMed

    Sheikh, Jason; Cohen, Molly D; Ramer, Naomi; Payami, Ali

    2017-04-01

    Ghost cell tumors are a family of lesions that range in presentation from cyst to solid neoplasm and in behavior from benign to locally aggressive or metastatic. All are characterized by the presence of ameloblastic epithelium, ghost cells, and calcifications. This report presents the cases of a 14-year-old girl with a calcifying cystic odontogenic tumor (CCOT) and a 65-year-old woman with a peripheral dentinogenic ghost cell tumor (DGCT) with dysplastic changes, a rare locally invasive tumor of odontogenic epithelium. The first patient presented with a 1-year history of slowly progressing pain and swelling at the left body of the mandible. Initial panoramic radiograph displayed a mixed radiolucent and radiopaque lesion. An incisional biopsy yielded a diagnosis of CCOT. Decompression of the mass was completed; after 3 months, it was enucleated and immediately grafted with bone harvested from the anterior iliac crest. The second patient presented with a 3-month history of slowly progressing pain and swelling at the left body of the mandible. Initial panoramic radiograph depicted a mixed radiolucent and radiopaque lesion with saucerization of the buccal mandibular cortex. An incisional biopsy examination suggested a diagnosis of DGCT because of the presence of ghost cells, dentinoid, and islands of ameloblastic epithelium. Excision of the mass with peripheral ostectomy was completed. At 6 and 12 months of follow-up, no evidence of recurrence was noted.

  9. Pediatric brain tumor cell lines.

    PubMed

    Xu, Jingying; Margol, Ashley; Asgharzadeh, Shahab; Erdreich-Epstein, Anat

    2015-02-01

    Pediatric brain tumors as a group, including medulloblastomas, gliomas, and atypical teratoid rhabdoid tumors (ATRT) are the most common solid tumors in children and the leading cause of death from childhood cancer. Brain tumor-derived cell lines are critical for studying the biology of pediatric brain tumors and can be useful for initial screening of new therapies. Use of appropriate brain tumor cell lines for experiments is important, as results may differ depending on tumor properties, and can thus affect the conclusions and applicability of the model. Despite reports in the literature of over 60 pediatric brain tumor cell lines, the majority of published papers utilize only a small number of these cell lines. Here we list the approximately 60 currently-published pediatric brain tumor cell lines and summarize some of their central features as a resource for scientists seeking pediatric brain tumor cell lines for their research.

  10. Circulating tumor cells

    PubMed Central

    Raimondi, Cristina; Nicolazzo, Chiara; Gradilone, Angela; Giannini, Giuseppe; De Falco, Elena; Chimenti, Isotta; Varriale, Elisa; Hauch, Siegfried; Plappert, Linda; Cortesi, Enrico; Gazzaniga, Paola

    2014-01-01

    The hypothesis of the “liquid biopsy” using circulating tumor cells (CTCs) emerged as a minimally invasive alternative to traditional tissue biopsy to determine cancer therapy. Discordance for biomarkers expression between primary tumor tissue and circulating tumor cells (CTCs) has been widely reported, thus rendering the biological characterization of CTCs an attractive tool for biomarkers assessment and treatment selection. Studies performed in metastatic colorectal cancer (mCRC) patients using CellSearch, the only FDA-cleared test for CTCs assessment, demonstrated a much lower yield of CTCs in this tumor type compared with breast and prostate cancer, both at baseline and during the course of treatment. Thus, although attractive, the possibility to use CTCs as therapy-related biomarker for colorectal cancer patients is still limited by a number of technical issues mainly due to the low sensitivity of the CellSearch method. In the present study we found a significant discordance between CellSearch and AdnaTest in the detection of CTCs from mCRC patients. We then investigated KRAS pathway activating mutations in CTCs and determined the degree of heterogeneity for KRAS oncogenic mutations between CTCs and tumor tissues. Whether KRAS gene amplification may represent an alternative pathway responsible for KRAS activation was further explored. KRAS gene amplification emerged as a functionally equivalent and mutually exclusive mechanism of KRAS pathway activation in CTCs, possibly related to transcriptional activation. The serial assessment of CTCs may represent an early biomarker of treatment response, able to overcome the intrinsic limit of current molecular biomarkers represented by intratumor heterogeneity. PMID:24521660

  11. A fluorescent redox dye. Influence of several substrates and electron carriers on the tetrazolium salt-formazan reaction of Ehrlich ascites tumour cells.

    PubMed

    Stellmach, J; Severin, E

    1987-01-01

    This study was performed to elaborate the best conditions for measuring the redox activity of Ehrlich ascites tumour cells by using a new tetrazolium salt, cyantolyl tetrazolium chloride (CTC). This tetrazolium salt forms a fluorescent water-insoluble formazan on reduction on the surface of intact vital cells. The influences of fixation and of various substrates and electron carriers on the cellular reduction of CTC were investigated quantitatively using an elution technique. The amount of formazan obtained after incubating vital cells with Meldola Blue as electron carrier was greater than that obtained with Methylene Blue, menadione, 2,6-dichloroindophenol, 1-methoxyphenazine methosulphate or phenazine methosulphate. Using flow cytometry, the formazan production per cell and, after staining the nuclear DNA, the distribution of the redox activity in the cell population can be visualized with satisfactory resolution. We conclude from our findings that dehydrogenases are only partially involved in the reduction of tetrazolium salts by intact cells and that a redox activity, probably related to a cell membrane-bound NAD(P)H-oxidase system, is mainly measured.

  12. Benign notochordal cell tumors.

    PubMed

    Martínez Gamarra, C; Bernabéu Taboada, D; Pozo Kreilinger, J J; Tapia Viñé, M

    2017-08-01

    Benign notochordal cell tumors (TBCN) are lesions with notochordal differentiation which affect the axial skeleton. They are characterized by asymptomatic or non-specific symptomatology and are radiologically unnoticed because of their small size, or because they are mistaken with other benign bone lesions, such as vertebral hemangiomas. When they are large, or symptomatic, can be differential diagnosis with metastases, primary bone tumors and chordomas. We present a case of a TBCN in a 50-year-old woman, with a sacral lesion seen in MRI. A CT-guided biopsy was scheduled to analyze the lesion, finding that the tumor was not clearly recognizable on CT, so the anatomical references of MRI were used to select the appropriate plane. The planning of the approach and the radio-pathological correlation were determinant to reach the definitive diagnosis. Copyright © 2017 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

  13. Enhanced photodynamic efficacy of PLGA-encapsulated 5-ALA nanoparticles in mice bearing Ehrlich ascites carcinoma

    NASA Astrophysics Data System (ADS)

    Shaker, Maryam N.; Ramadan, Heba S.; Mohamed, Moustafa M.; El khatib, Ahmed M.; Roston, Gamal D.

    2014-10-01

    Nanoparticles (NPs) fabricated from the biodegradable copolymer poly(lactic- co-glycolic acid) (PLGA) were investigated as a drug delivery system to enhance the photodynamic efficacy of 5-aminolevulinic acid (5-ALA) in mice bearing Ehrlich ascites carcinoma. The PLGA-encapsulated 5-ALA NPs were prepared using binary organic solvent diffusion method and characterized in terms of shape and particle size. The in vivo photodynamic efficiency in Ehrlich ascites-bearing mice was studied. The obtained particles were uniform in size with spherical shape of mean size of 249.5 nm as obtained by particle size analyzer and the in vitro release studies demonstrated a controlled release profile of 5-ALA. Tumor-bearing mice injected with PLGA-encapsulated 5-ALA NPs exhibited significantly smaller mean tumor volume, increased tumor growth delay compared with the control group and the group injected with free 5-ALA during the time course of the experiment. Histopathological examination of tumor from mice treated with PLGA-encapsulated 5-ALA NPs showed regression of tumor cells, in contrast to those obtained from mice treated with free 5-ALA. The results indicate that PLGA-encapsulated 5-ALA NPs are a successful delivery system for improving photodynamic activity in the target tissue.

  14. Juxtaglomerular cell tumor: MR findings.

    PubMed

    Agrawal, R; Jafri, S Z; Gibson, D P; Bis, K G; Ali-Reza

    1995-01-01

    Juxtaglomerular (JG) cell tumor is a rare benign neoplasm of the kidney that typically presents with hypertension, secondary hyperaldosteronism, hypocalcemia, and hyperreninism. We describe a case of JG cell tumor diagnosed with MRI.

  15. Ovarian Germ Cell Tumors Treatment

    MedlinePlus

    ... Tube, & Primary Peritoneal Cancer Screening Research Ovarian Germ Cell Tumors Treatment (PDQ®)–Patient Version General Information About Ovarian Germ Cell Tumors Go to Health Professional Version Key Points ...

  16. Induction of apoptosis in Ehrlich ascites tumour cells via p53 activation by a novel small-molecule MDM2 inhibitor - LQFM030.

    PubMed

    da Mota, Mariana F; Cortez, Alane P; Benfica, Polyana L; Rodrigues, Bruna Dos S; Castro, Thalyta F; Macedo, Larissa M; Castro, Carlos H; Lião, Luciano M; de Carvalho, Flávio S; Romeiro, Luiz A S; Menegatti, Ricardo; Verli, Hugo; Villavicencio, Bianca; Valadares, Marize C

    2016-09-01

    The activation of the p53 pathway through the inhibition of MDM2 has been proposed as a novel therapeutic strategy against tumours. A series of cis-imidazoline analogues, termed nutlins, were reported to displace the recombinant p53 protein from its complex with MDM2 by binding to MDM2 in the p53 pocket, and exhibited an antitumour activity both in vitro and in vivo. Thus, the purpose of this study was to evaluate the antitumour properties of LQFM030 (2), a nutlin analogue created by employing the strategy of molecular simplification. LQFM030 (2) cytotoxicity was evaluated in Ehrlich ascites tumour (EAT) cells, p53 wild type, by the trypan blue exclusion test, and the mechanisms involved in EAT cell death were investigated by light and fluorescence microscopy, flow cytometry, real-time PCR and Western blotting. Our results demonstrate that LQFM030 has dose-dependent antiproliferative activity and cytotoxic activity on EAT cells, induces the accumulation of p53 protein and promotes cell cycle arrest and apoptosis. p53 gene transcription was unaffected by LQFM030 (2); however, MDM2 mRNA increased and MDM2 protein decreased. These results suggest that the small-molecule p53 activator LQFM030 (2) has the potential for further development as a novel cancer therapeutic agent. © 2016 Royal Pharmaceutical Society.

  17. Effects of ultraviolet-visible irradiation in the presence of melanin isolated from human black or red hair upon Ehrlich ascites carcinoma cells

    SciTech Connect

    Menon, I.A.; Persad, S.; Ranadive, N.S.; Haberman, H.F.

    1983-07-01

    The present study is an attempt to investigate the possibility that ultraviolet irradiation in the presence of pheomelanin may be more harmful to cells than the irradiation in the presence of eumelanin. The effects of UV-visible irradiation upon Ehrlich ascites carcinoma cells in the presence of the melanin isolated from human black hair (eumelanin) or from red hair (pheomelanin) were investigated. Irradiation of these cells was found to produce cell lysis, as observed by leakage of 51Cr from labeled cells and intracellular lactic dehydrogenase from the cells and decrease in cell viability demonstrated by the trypan blue exclusion test. The three parameters were quantitatively parallel to one another under various experimental conditions, namely different periods of irradiation and irradiation in the presence of different concentrations of melanin. The above effects were more pronounced when the irradiation was carried out in the presence of melanin from red hair than in the presence of black-hair melanin. In the absence of either melanin, the irradiation did not produce any significant effect in cell viability or cell lysis. Irradiation of the cells in the presence of red-hair melanin also decreased the transplantability of these cells. These observations clearly show that irradiation of cells in the presence of pheomelanin could produce cytotoxic effects. The present experimental design may have application in the development of in vitro models for the study of UV radiation-induced cutaneous carcinogenesis. The reactions of pheomelanin may be related to the susceptibility of ''Celtic'' skin to UV radiation-induced skin damage and carcinogenesis.

  18. Probing of Ehrlich ascites carcinoma cell using in situ aggregates of Au-NPs as SERS label created by plasmon exciting hybrid- TEM*11 laser mode

    NASA Astrophysics Data System (ADS)

    Kumar, R.; Mehta, D. S.; Saraswati, S.; Shakher, C.

    2012-02-01

    Apart from commonly employed target-specific labeling/adsorption of antibodies over Au-NPs surface for the creation of localized aggregates, an alternative approach using optical tweezers (OT) driven by hybrid-TEM*11 mode has been devised and exploited for in vitro detection of Ehrlich ascites carcinoma cells (EAC) relying on enhanced scattering. Intra-cavity generated spatially featured asymmetric (SFA) laser beam (λ = 532 nm) has effected simultaneous trapping of mice-EAC cells and in-situ crowd/assembly of incubated Au-NPs/small gold nano-aggregates (created from two or more individual Au-NPs). Relatively larger focus spot created by tightly focused SFA beam than frequently employed Gaussian-mode in OT has offered an extended working area and hence dilute heating has taken care of EAC cells. GNA improves significantly the sensitivity of diagnostics relying on scattered light and the safety and efficacy of therapeutic nanotechnologies for the diseases of cancer and vascular system in medicine.

  19. Granular cell tumor of trachea.

    PubMed

    Bekteshi, Edgar; Toth, Jennifer W; Benninghoff, Michael G; Kang, Jason; Betancourt, Manuel

    2009-01-01

    Granular cell tumors of the tracheobronchial tree are rare benign lesions of neurogenic origin. These benign tumors mostly involve the skin, oral cavity, or esophagus. There is no consensus regarding treatment of granular cell tumors. Treatment varies from simple observation to different bronchoscopic interventions, such as laser therapy or fulguration to surgical resection.

  20. Inhibition of oxidative phosphorylation in ascites tumor mitochondria and cells by intramitochondrial Ca2+.

    PubMed

    Villalobo, A; Lehninger, A L

    1980-03-25

    Accumulation of Ca2+ (+ phosphate) by respiring mitochondria from Ehrlich ascites or AS30-D hepatoma tumor cells inhibits subsequent phosphorylating respiration in response to ADP. The respiratory chain is still functional since a proton-conducting uncoupler produces a normal stimulation of electron transport. The inhibition of phosphorylating respiration is caused by intramitochondrial Ca2+ (+ phosphate). ATP + Mg2+ together, but not singly, prevents the inhibitory action of Ca2+. Neither AMP, GTP, GDP, nor any other nucleoside 5'-triphosphate or 5'-diphosphate could replace ATP in this effect. Phosphorylating respiration on NAD(NADP)-linked substrates was much more susceptible to the inhibitory effect of intramitochondrial Ca2+ than succinate-linked respiration. Significant inhibition of oxidative phosphorylation is given by the endogenous Ca2+ present in freshly isolated tumor mitochondria. The phosphorylating respiration of permeabilized Ehrlich ascites tumor cells is also inhibited by Ca2+ accumulated by the mitochondria in situ. Possible causes of the Ca2+-induced inhibition of oxidative phosphorylation are considered.

  1. Saccharomyces cerevisiae, the Baker's Yeast, suppresses the growth of Ehrlich carcinoma-bearing mice.

    PubMed

    Ghoneum, Mamdooh; Badr El-Din, Nariman K; Noaman, Eman; Tolentino, Lucilene

    2008-04-01

    This study was undertaken to evaluate the effectiveness and mechanisms of anti-tumor activity of Baker's yeast, Saccharomyces cerevisiae, in immunocompetent mice. Swiss albino mice were inoculated intramuscularly in the right thigh with Ehrlich Ascites Carcinoma (EAC) cells. At day 8, mice bearing Solid Ehrlich Carcinoma tumor (SEC) were intratumorally (IT) injected with killed S. cerevisiae (10 x 10(6) and 20 x 10(6) cells) for 35 days. Histopathology of yeast-treated mice showed extensive tumor degeneration, apoptosis, and ischemic (coagulative) and liquefactive necrosis. These changes are associated with a tumor growth curve that demonstrates a significant antitumor response that peaked at 35 days. Yeast treatment (20 x 10(6) cells) three times a week resulted in a significant decrease in tumor volume (TV) (67.1%, P < 0.01) as compared to PBS-treated mice. The effect was determined to be dependent on dose and frequency. Yeast administered three and two times per week induced significant decrease in TV as early as 9 and 25 days post-treatment, respectively. Administration of yeast significantly enhanced the recruitment of leukocytes, including macrophages, into the tumors and triggered apoptosis in SEC cells as determined by flow cytometry (78.6%, P < 0.01) at 20 x 10(6) cells, as compared to PBS-treated mice (42.6%). In addition, yeast treatment elevated TNF-alpha and IFN-gamma plasma levels and lowered the elevated IL-10 levels. No adverse side effects from the yeast treatment were observed, including feeding/drinking cycle and life activity patterns. Indeed, yeast-treated mice showed significant final body weight gain (+21.5%, P < 0.01) at day 35. These data may have clinical implications for the treatment of solid cancer with yeast, which is known to be safe for human consumption.

  2. The return of Ehrlich's 'Therapia magna sterilisans' and other Ehrlich concepts?. Series of papers honoring Paul Ehrlich on the occasion of his 150th birthday.

    PubMed

    Sörgel, F

    2004-04-01

    On March 14th of this year, the birthday of Paul Ehrlich, the great German researcher and 'founder of chemotherapy', returned for the 150th time. Interestingly, his later colleague Emil von Behring was born one day later in 1854. Both were coworkers in Robert Koch's laboratory and became Nobel Prize laureates (for their work in immunology), making great contributions to antiinfectious treatments. Emil von Behring's approach was through the use of immunological agents, while Ehrlich favored an approach of antiinfectious treatment by chemical agents. Through an ingenious concept that was a clear continuation of his early days in research with dyes, he found the first chemotherapeutic agents. From his dye work, he had concluded the following: if there are dyes that one can use to stain cells, why not develop pharmacological agents that, like stains, also attach to a structure in the living pathogen and kill them. He gave these agents the emotionally charged name 'magic bullets'. This introductory review will initiate a series of papers on the occasion of Ehrlich's 150th birthday and the 'World Conference on Dosing of Antiinfectives: Dosing the Magic Bullets', which is going to be held in Nürnberg, Germany, from September 9 to 11, 2004 (see www.ehrlich2004.org). Apart from the conference topic, this conference will also commemorate a real science giant of the last century and yet a modest human being whom, as Robert Koch put it, 'one had to like'. This article recalls Ehrlich's ingenious concepts, including modern syphilis treatment, one-dose treatment ('therapia magna sterilisans') of Helicobacter pylori infections and introduction of an arsenic compound, arsenic trioxide, as well as experiments and new exciting data on Congo red, a well-known 'non-Ehrlich dye'.

  3. Cholesterol modulates the volume-regulated anion current in Ehrlich-Lettre ascites cells via effects on Rho and F-actin.

    PubMed

    Klausen, Thomas Kjaer; Hougaard, Charlotte; Hoffmann, Else K; Pedersen, Stine F

    2006-10-01

    The mechanisms controlling the volume-regulated anion current (VRAC) are incompletely elucidated. Here, we investigate the modulation of VRAC by cellular cholesterol and the potential involvement of F-actin, Rho, Rho kinase, and phosphatidylinositol-(4,5)-bisphosphate [PtdIns(4,5)P(2)] in this process. In Ehrlich-Lettre ascites (ELA) cells, a current with biophysical and pharmacological properties characteristic of VRAC was activated by hypotonic swelling. A 44% increase in cellular cholesterol content had no detectable effects on F-actin organization or VRAC activity. A 47% reduction in cellular cholesterol content increased cortical and stress fiber-associated F-actin content in swollen cells. Cholesterol depletion increased VRAC activation rate and maximal current after a modest (15%), but not after a severe (36%) reduction in extracellular osmolarity. The cholesterol depletion-induced increase in maximal VRAC current was prevented by F-actin disruption using latrunculin B (LB), while the current activation rate was unaffected by LB, but dependent on Rho kinase. Rho activity was decreased by approximately 20% in modestly, and approximately 50% in severely swollen cells. In modestly swollen cells, this reduction was prevented by cholesterol depletion, which also increased isotonic Rho activity. Thrombin, which stimulates Rho and causes actin polymerization, potentiated VRAC in modestly swollen cells. VRAC activity was unaffected by inclusion of a water-soluble PtdIns(4,5)P(2) analogue or a PtdIns(4,5)P(2)-blocking antibody in the pipette, or neomycin treatment to sequester PtdIns(4,5)P(2). It is suggested that in ELA cells, F-actin and Rho-Rho kinase modulate VRAC magnitude and activation rate, respectively, and that cholesterol depletion potentiates VRAC at least in part by preventing the hypotonicity-induced decrease in Rho activity and eliciting actin polymerization.

  4. Effect of propranolol on IL-10, visfatin, Hsp70, iNOS, TLR2, and survivin in amelioration of tumor progression and survival in Solid Ehrlich Carcinoma-bearing mice.

    PubMed

    Abdin, Amany A; Soliman, Nema A; Saied, Eman M

    2014-12-01

    β-Adrenergic signaling could contribute to initiation and progression of breast cancer. This research investigated some potential mechanisms of propranolol in amelioration of progression and survival in breast cancer. Solid Ehrlich Carcinoma (SEC) xenograft model was induced in 30 mice divided into 3 groups; where group I served as untreated SEC group. In groups II and III, propranolol treatment i.p. in low (5mg/kg) and high dose (10mg/kg) caused significant increase in interleukin-10 (IL-10) and decrease in heat shock protein 70 (Hsp70) and inducible nitric oxide synthase (iNOS) activity with non significant change in visfatin in tumor tissues compared to untreated SEC. In untreated SEC, tumor volume (V) exhibited significant negative correlation with IL-10 levels and toll like receptor 2 (TLR2) expression with significant positive correlation with Hsp70 levels and iNOS activity. While propranolol in either doses caused reduction of tumor volume (V), and improved percentage tumor growth inhibition (% TGI) only its high dose exhibited significant impact on survival rate. Propranolol dose-dependent effect was evident for IL-10 and Hsp70, and even only the high dose significantly increased and decreased TLR2 and survivin, respectively. This comes in favor of recommending high dose of propranolol in cancer therapy. Nonetheless, use of low dose cannot be ignored when benefit to risk balance have to be considered. Propranolol could provide palliative effects in progression and survival of breast cancer that are mainly mediated via direct immunomodulatory and apoptotic mechanisms and probably associated with indirect anti-angiogenic activity. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  5. Pancreatic islet cell tumor

    MedlinePlus

    ... functions. These include blood sugar level and the production of stomach acid. Tumors that arise from islet ... try and shrink the tumors. If the abnormal production of hormones is causing symptoms, you may receive ...

  6. The effect of atebrine and an acridine analog (BCMA) on the coenzyme fluorescence spectra of cultured melanoma and Ehrlich ascites (EL2) cells.

    PubMed

    Viallet, P; Kohen, E; Schachtschabel, D O; Marty, A; Salmon, J M; Kohen, C; Leising, H B; Thorell, B

    1978-09-15

    Coenzyme fluorescence spectra of single living cells are due to free pyridine nucleotides (folded configuration), bound pyridine nucleotides (unfolded configuration) and a third component, possibly a mixture or flavins. Such spectra can be used to recognize possible differences in coenzyme composition between cell lines or changes of metabolic pathways due to chemicals acting at levels below or above cytotoxicity, by high resolution spectrofluorometry. A study of spectra recorded from cultured Ehrlich ascites (EL2), and Harding Passey melanoma cells (HPM-67 and HPM-73 line) grown under comparable conditions, shows that free NAD(P)H predominates in HPM-67 and EL2, while this coenzyme is bound in HPM-73. The free/bound ratio may be profoundly modifed by chemicals, e.g. in the HPM-73 increase of free and decrease of bound NAD(P)H occurred upon treatment with 10(-6) oligomycin. When atebrine at levels (10(-6) M) below cytotoxicity was added, there was a decrease of the free NAD(P)H spectrum possibly through energy transfer from NAD(P)H to atebrine. Consideration of long range energy transfer i.e., excitation of atebrine by fluorescence of NAD(P)H vs. short range transfer of excitation energy from free NAD(P)H to atebrine, favors the latter mechanism. A transient (reversible) increase in atebrine fluorescence is seen following intracellular microinjection of substrate (e.g. glucose-6-P) leading to an increase in free NAD(P)H. At cytotoxic levels of atebrine (e.g 2 x 10(-5) M) an irreversible increase of atebrine fluorescence is seen. The microspectrofluorometric technique appears therefore well suited to study physiological processes at the level of intracellular coenzymes, as well as possible processes of intermolecular energy transfer in the microenvironment.

  7. Detection of Circulating Tumor Cells

    PubMed Central

    Terstappen, Leon W. M. M.

    2014-01-01

    The increasing number of treatment options for patients with metastatic carcinomas has created an accompanying need for methods to determine if the tumor will be responsive to the intended therapy and to monitor its effectiveness. Ideally, these methods would be noninvasive and provide quantitative real-time analysis of tumor activity in a variety of carcinomas. Assessment of circulating tumor cells shed into the blood during metastasis may satisfy this need. Here we review the CellSearch technology used for the detection of circulating tumor cells and discuss potential future directions for improvements. PMID:25133014

  8. Paul Ehrlich and the Early History of Granulocytes.

    PubMed

    Kay, A Barry

    2016-08-01

    Paul Ehrlich's techniques, published between 1879 and 1880, for staining blood films using coal tar dyes, and his method of differential blood cell counting, ended years of speculation regarding the classification of white cells. Acidic and basic dyes had allowed him to recognize eosinophil and basophil granules, respectively, work that was a direct continuation of his discovery of the tissue mast cell described in his doctoral thesis. Ehrlich went on to develop neutral dyes that identified epsilon granules in neutrophils ("cells with polymorphous nuclei"). He also speculated, for the most part correctly, on the formation, function, and fate of blood neutrophils and eosinophils. Before Ehrlich, a number of important observations had been made on white cells and their role in health and disease. Among the most notable were William Hewson's studies of blood and lymph; the early descriptions of leukemia by Alfred Donné, John Hughes Bennett, Rudolf Virchow, and others; as well as seminal observations on inflammation by William Addison, Friedrich von Recklinghausen, and Julius Cohnheim. Eosinophils were almost certainly recognized previously by others. In 1846, Thomas Wharton Jones (1808-1891) described "granule blood-cells" in several species including humans. The term "granule cell" had also been used by Julius Vogel (1814-1880), who had previously observed similar cells in inflammatory exudates. Vogel, in turn, was aware of the work of Gottlieb Gluge (1812-1898), who had observed "compound inflammatory globules" in pus and serum that resembled eosinophils. Almost 20 years before Ehrlich developed his staining methods, Max Johann Schultze (1825-1874) performed functional experiments on fine and coarse granular cells using a warm stage microscopic technique and showed they had amoeboid movement and phagocytic abilities. Despite these earlier observations, it was Ehrlich's use of stains that heralded the modern era of studies of leukocyte biology and pathology.

  9. Metformin enhancing the antitumor efficacy of carboplatin against Ehrlich solid carcinoma grown in diabetic mice: Effect on IGF-1 and tumoral expression of IGF-1 receptors.

    PubMed

    Abo-Elmatty, Dina M; Ahmed, Eman A; Tawfik, Mona K; Helmy, Seham A

    2017-03-01

    Diabetes has been listed as a risk factor for various types of cancer. Cancer cell development can be promoted by increased levels of IGF-1 and hyperinsulinemia that are associated with diabetes type II. Metformin is an anti-diabetic agent and its potential antitumor impact has become the objective of numerous studies. In this vein, we hypothesize that using metformin in diabetes type II mice may synergistic with carboplatin for reducing the risk of cancer. Therefore, the study aimed to evaluate the in vivo antitumor activity of metformin against solid EAC tumor growth in female diabetic mice and its potential pro-apoptotic and anti-proliferative effects with clarification of its inconclusive biological mechanisms. Mice were assigned into nine groups; normal control, diabetic control, diabetic plus EAC control, EAC control, and treated groups received carboplatin and/or metformin (100, 200mg/kg). Metformin administration especially with high dose potentiated the antitumor activity of carboplatin displayed by increased pro-apoptotic activators "caspase-3 and bax" and reduced anti-apoptotic protein bcl-2. This was confirmed by the histopathological scores. Moreover, the combination therapy was effective in attenuating the expression of the pro-angiogenic mediator "VEGF" and the microvessel density as revealed by the CD34. Additionally, this combination down-regulated the high levels of the mutagenic element "IGF-1" and its receptor expression, and attenuated the intensity of inflammatory mediators. In conclusion, it was found that metformin therapy could enhance apoptotic marker, and suppress the neovascularization and proliferation process. This clarified the ability of metformin to support carboplatin activity in reducing tumor progression in type II diabetes. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Tumor Endothelial Cells

    PubMed Central

    Dudley, Andrew C.

    2012-01-01

    The vascular endothelium is a dynamic cellular “organ” that controls passage of nutrients into tissues, maintains the flow of blood, and regulates the trafficking of leukocytes. In tumors, factors such as hypoxia and chronic growth factor stimulation result in endothelial dysfunction. For example, tumor blood vessels have irregular diameters; they are fragile, leaky, and blood flow is abnormal. There is now good evidence that these abnormalities in the tumor endothelium contribute to tumor growth and metastasis. Thus, determining the biological basis underlying these abnormalities is critical for understanding the pathophysiology of tumor progression and facilitating the design and delivery of effective antiangiogenic therapies. PMID:22393533

  11. Antitumor Activity of the Methanol Extract of Hypericum hookerianum Stem Against Ehrlich Ascites Carcinoma in Swiss Albino Mice.

    PubMed

    Dongre, Santoshkumar H; Badami, Shrishailappa; Natesan, Senthilkumar; H, Raghu Chandrashekhar

    2007-04-01

    A large number of plants belonging to the Hypericum family are known to possess strong antitumor properties. The methanol extract of H. hookerianum Wight and Arnott stem (MEHH) exhibited potent in vitro cytotoxic activity against various cancerous cell lines. In the present study, the high performance liquid chromatography (HPLC) standardized MEHH was tested for in vivo antitumor properties against Ehrlich ascites carcinoma (EAC) tumor bearing mice at 100, 200, and 400 mg/kg body weight doses given orally once daily for 14 days. The results indicate that administration of the extract not only increased the survival of animals with ascites tumor, decreased the body weight induced by the tumor burden, and reduced packed cell volume and viable tissue cell count, but also altered many hematological parameters changed during tumor progression, indicating the potent antitumor nature of the extract. Among the three doses tested, the 200 mg/kg body weight dose was found to be the most potent.

  12. Deformability of Tumor Cells versus Blood Cells

    PubMed Central

    Shaw Bagnall, Josephine; Byun, Sangwon; Begum, Shahinoor; Miyamoto, David T.; Hecht, Vivian C.; Maheswaran, Shyamala; Stott, Shannon L.; Toner, Mehmet; Hynes, Richard O.; Manalis, Scott R.

    2015-01-01

    The potential for circulating tumor cells (CTCs) to elucidate the process of cancer metastasis and inform clinical decision-making has made their isolation of great importance. However, CTCs are rare in the blood, and universal properties with which to identify them remain elusive. As technological advancements have made single-cell deformability measurements increasingly routine, the assessment of physical distinctions between tumor cells and blood cells may provide insight into the feasibility of deformability-based methods for identifying CTCs in patient blood. To this end, we present an initial study assessing deformability differences between tumor cells and blood cells, indicated by the length of time required for them to pass through a microfluidic constriction. Here, we demonstrate that deformability changes in tumor cells that have undergone phenotypic shifts are small compared to differences between tumor cell lines and blood cells. Additionally, in a syngeneic mouse tumor model, cells that are able to exit a tumor and enter circulation are not required to be more deformable than the cells that were first injected into the mouse. However, a limited study of metastatic prostate cancer patients provides evidence that some CTCs may be more mechanically similar to blood cells than to typical tumor cell lines. PMID:26679988

  13. Natural killer cell activity, lymphocyte proliferation, and cytokine profile in tumor-bearing mice treated with MAPA, a magnesium aggregated polymer from Aspergillus oryzae.

    PubMed

    Justo, G Z; Durán, N; Queiroz, M L S

    2003-08-01

    The present study examined the effects of MAPA, an antitumor aggregated polymer of protein magnesium ammonium phospholinoleate-palmitoleate anhydride, isolated from Aspergillus oryzae, on concanavalin A (Con A)-induced spleen cell proliferation, cytokine production and on natural killer (NK) cell activity in Ehrlich ascites tumor-bearing mice. The Ehrlich ascites tumor (EAT) growth led to diminished mitogen-induced expansion of spleen cell populations and total NK activity. This was accompanied by striking spleen enlargement, with a marked increase in total cell counts. Moreover, a substantial enhancement in IL-10 levels, paralleled by a significant decrease in IL-2 was observed, while production of IL-4 and interferon-gamma (IFN-gamma) was not altered. Treatment of mice with 5 mg/kg MAPA for 7 days promoted spleen cell proliferation, IL-2 production and NK cell activity regardless of tumor outgrowth. In addition, MAPA treatment markedly enhanced IFN-gamma levels and reduced IL-10 production relative to EAT mice. A 35% reduction in splenomegaly with normal number of nucleated cells was also found. Altogether, our results suggest that MAPA directly and/or indirectly modulates immune cell activity, and probably disengages tumor-induced suppression of these responses. Clearly, MAPA has an impact and may delay tumor outgrowth through immunotherapeutic mechanisms.

  14. Comparison of hypoxic cell radiosensitizers, KIN-804, KIN-844, KIN-806 and TX-1877, on brain and liver metabolizing capacities in mice bearing Ehrlich ascites carcinoma.

    PubMed

    Abou-Bedair, Farid Ahmed; Hori, Hitoshi; Nagasawa, Hideko; Uto, Yoshihiro; Abu-Zeid, Medhat; Inayama, Seiichi

    2002-05-01

    The biochemical effects of the 2-nitroimidazole hypoxic cell radiosensitizers KIN-804, KIN-806, and their analogues KIN-844 and TX-1877 on brain acetylcholinesterase (AChE) and hepatic free radical scavenging systems, such as reduced glutathione (GSH) and glucose-6-phosphate dehydrogenase (G-6-PDH) levels, and hepatic antioxidants, such as superoxide dismutase (SOD) and catalase, were evaluated in Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. The assay of brain AChE revealed nonsignificant changes with all drugs examined. To evaluate the hepatic metabolic capacity, groups of mice were divided into control, EAC-inoculated, 10-Gy local gamma-irradiated, and KIN-804, KIN-844, KIN-806, or TX-1877 (50 mg/kg body weight, i.p.) groups, and gamma-irradiation was combined with each drug. EAC inoculation markedly suppressed GSH, G-6-PDH, SOD, and catalase levels. On the other hand, treatment with gamma-irradiation significantly enhanced them. The treatment of EAC-bearing mice with each drug alone in the absence of gamma-irradiation revealed that KIN-806 and its derivative TX-1877 showed antitumor activity through their significant recovery of GSH and SOD levels, respectively, in the EAC-bearing mice group. Similarly, the combined treatment of EAC-bearing mice with gamma-irradiation with each of the drugs tested showed that KIN-806 and TX-1877 significantly increased GSH and SOD, and to a lesser extent G-6-PDH and catalase levels. On the other hand, KIN-804 and KIN-844 had only a nonsignificant effect on all parameters examined. In conclusion, these data reveal that the administration of KIN-806 and TX-1877 with or without subsequent gamma-irradiation, resulted in significant recovery of GSH and SOD activities that were inhibited by EAC inoculation.

  15. Nanotechniques Inactivate Cancer Stem Cells

    NASA Astrophysics Data System (ADS)

    Goltsev, Anatoliy N.; Babenko, Natalya N.; Gaevskaya, Yulia A.; Bondarovich, Nikolay A.; Dubrava, Tatiana G.; Ostankov, Maksim V.; Chelombitko, Olga V.; Malyukin, Yuriy V.; Klochkov, Vladimir K.; Kavok, Nataliya S.

    2017-06-01

    One of the tasks of current oncology is identification of cancer stem cells and search of therapeutic means capable of their specific inhibition. The paper presents the data on phenotype characteristics of Ehrlich carcinoma cells as convenient and easy-to-follow model of tumor growth. The evidence of cancer stem cells as a part of Ehrlich carcinoma and significance of CD44+ and CD44- subpopulations in maintaining the growth of this type of tumor were demonstrated. A high (tenfold) tumorigenic activity of the Ehrlich carcinoma CD44+ cells if compared to CD44- cells was proven. In this pair of comparison, the CD44+ cells had a higher potential of generating in peritoneal cavity of CD44high, CD44+CD24-, CD44+CD24+ cell subpopulations, highlighting the presence of cancer stem cells in a pool of CD44+ cells.

  16. Treatment Option Overview (Extragonadal Germ Cell Tumors)

    MedlinePlus

    ... Professional Extragonadal Germ Cell Tumors Treatment Extragonadal Germ Cell Tumors Treatment (PDQ®)–Patient Version General Information About Extragonadal Germ Cell Tumors Go to Health Professional Version Key Points ...

  17. General Information about Extragonadal Germ Cell Tumors

    MedlinePlus

    ... Professional Extragonadal Germ Cell Tumors Treatment Extragonadal Germ Cell Tumors Treatment (PDQ®)–Patient Version General Information About Extragonadal Germ Cell Tumors Go to Health Professional Version Key Points ...

  18. [Changes in clonogenic properties of bone marrow and transplantable mice tumor cells during combined use of cyclophosphane and biological response modifiers of adaptogenic origin].

    PubMed

    Udintsev, S N; Shakhov, V P

    1990-01-01

    The clonogenic activity of tumors and blood marrow cells has been studied in experiments on CBA, BALB/C and C57B1/6 mice with the Ehrlich adenocarcinoma and Lewis lung carcinosarcoma treated with adaptogenic drugs of Rhodiola Rosea extract, a synthetic analog of Rhodiola phenol derivative, methyluracil and their combinations with cyclophosphamide. The extract and derivative are shown to protect the myelopoietic tissue from the toxic action of cyclophosphamide, retaining or increasing the suppressive effect of the latter towards clonogenic tumors cells. These data can be the reason for using the extract and derivative during the antitumor chemotherapy as biological response modifiers.

  19. Inhibitory effect of yoghurt and soya yoghurt containing bifidobacteria on the proliferation of Ehrlich ascites tumour cells in vitro and in vivo in a mouse tumour model.

    PubMed

    Abd el-Gawad, I A; el-Sayed, E M; Hafez, S A; el-Zeini, H M; Saleh, F A

    2004-07-01

    The effect of yoghurt and soya yoghurt containing Bifidobacterium lactis Bb-12 or B. longum Bb-46 on Ehrlich ascites tumour cell proliferation was investigated in vitro and in vivo. Tumour cells were incubated with B. lactis Bb-12 or B. longum Bb-46 cultivated in de Mann Rogosa Sharpe (MRS) broth medium, or with their centrifuged supernatant fractions or sediments, for 2 h at 37 degrees C. Treatment resulted in the inhibition of tumour cell proliferation by 85.42 (SD 0.78) and 85.10 (SD 1.28) % by intact micro-organisms, 77.61 (SD 0.29) and 71.43 (SD 1.75) % by their supernatant fractions, but only 4.00 (SD 0.19) and 9.09 (SD 1.24) % by the two sedimented bacteria, respectively. The incubation of tumour cells with yoghurt and soya yoghurt containing Bb-12 for 2 h resulted in 83.01 (SD 0.11) and 88.23 (SD 0.06) % inhibition, respectively, while it was 83.82 (SD 0.24) and 86.36 (SD 0.06) %, respectively for the same products containing Bb-46. Corresponding values for plain yoghurt and soya milk (without bifidobacteria) were 32.81 (SD 0.14) and 5.55 (SD 0.12) %, respectively. The differences between yoghurt or soya yoghurt containing Bb-12 or Bb-46 and plain yoghurt, soya milk or control treatments were statistically significant (n 3; P<0.05). Female Swiss albino mice were injected intraperitoneally with the same tumour cells. The lifespan of mice fed diets supplemented with yoghurt or soya yoghurt containing Bb-12 or Bb-46 was prolonged by 16, 23, 34 and 39 %, respectively compared with that of the positive control group (n 6; P<0.05). The lifespan of groups fed plain yoghurt or soya milk was prolonged by 15 and 8 %, respectively. Prolongation of lifespan was positively correlated with faeces bifidobacterial count in the groups fed yoghurt or soya yoghurt containing bifidobacteria (r 0.917; P<0.05).

  20. Evaluation of antitumor activity of Mimusops elengi leaves on Ehrlich's ascites carcinoma-treated mice.

    PubMed

    Kar, Biswakanth; Kumar, R B Suresh; Bala, Asis; Dolai, Narayan; Mazumder, Upal Kanti; Haldar, Pallab Kanti

    2012-09-01

    Mimusops elengi (M. elengi) Linn. (Sapotaceae) has been used as a folk medicine in wound healing, and the treatment of pain, and inflammation in many parts of India. The purpose of this investigation was to explore the antitumor activity of methanol extract of M. elengi (MEME) in Swiss albino mice against Ehrlich ascites carcinoma (EAC) cell line. Twenty-four hours after intraperitoneal (i.p.) inoculation of tumor (EAC) cells in mice (n = 12), MEME was administered at 200 and 300 mg/kg body weight daily for 9 consecutive days. On day 10, half of the mice were dissected and the rest were kept alive for assessment of increase in life span. The antitumor effect of MEME was assessed by evaluating tumor volume, viable and nonviable tumor cell count, tumor weight, hematological parameter, and biochemical estimations. In vivo antioxidant parameters were assayed by estimating liver tissue enzyme. In vitro cytotoxicity assay of MEME was measured by using trypan blue exclusion method. MEME showed significant (p < .001) decrease in tumor volume, packed cell volume, and viable cell count, and increased the life span of EAC bearing mice. Hematological, biochemical profile, and in vivo antioxidant parameters were significantly restored toward normal levels in MEME-treated mice as compared to EAC control. MEME also showed direct cytotoxicity on EAC cell line in a dose-dependent manner. The present study demonstrates that M. elengi leaves exhibited antitumor activity in Swiss mice, which may be due to its cytotoxic effect and antioxidant properties.

  1. Escape from Tumor Cell Dormancy

    DTIC Science & Technology

    2012-10-01

    3 ESCAPE FROM TUMOR CELL DORMANCY An Organotypic Liver System to Study Tumor Cell Dormancy Alan Wells and Donna Stolz (UPitt), Linda Griffith (MIT...insights into dormancy and the transition that heralds metastatic emergenceis due mainly to the lack of tractable experimental systems with which to... systems are being optimized in others. The main efforts during the first year of this two-year project have been focused on the establishing the

  2. Simulating Heterogeneous Tumor Cell Populations

    PubMed Central

    Bar-Sagi, Dafna; Mishra, Bud

    2016-01-01

    Certain tumor phenomena, like metabolic heterogeneity and local stable regions of chronic hypoxia, signify a tumor’s resistance to therapy. Although recent research has shed light on the intracellular mechanisms of cancer metabolic reprogramming, little is known about how tumors become metabolically heterogeneous or chronically hypoxic, namely the initial conditions and spatiotemporal dynamics that drive these cell population conditions. To study these aspects, we developed a minimal, spatially-resolved simulation framework for modeling tissue-scale mixed populations of cells based on diffusible particles the cells consume and release, the concentrations of which determine their behavior in arbitrarily complex ways, and on stochastic reproduction. We simulate cell populations that self-sort to facilitate metabolic symbiosis, that grow according to tumor-stroma signaling patterns, and that give rise to stable local regions of chronic hypoxia near blood vessels. We raise two novel questions in the context of these results: (1) How will two metabolically symbiotic cell subpopulations self-sort in the presence of glucose, oxygen, and lactate gradients? We observe a robust pattern of alternating striations. (2) What is the proper time scale to observe stable local regions of chronic hypoxia? We observe the stability is a function of the balance of three factors related to O2—diffusion rate, local vessel release rate, and viable and hypoxic tumor cell consumption rate. We anticipate our simulation framework will help researchers design better experiments and generate novel hypotheses to better understand dynamic, emergent whole-tumor behavior. PMID:28030620

  3. Antioxidant potential by arabinoxylan rice bran, MGN-3/biobran, represents a mechanism for its oncostatic effect against murine solid Ehrlich carcinoma.

    PubMed

    Noaman, Eman; Badr El-Din, Nariman K; Bibars, Mona A; Abou Mossallam, Ahlam A; Ghoneum, Mamdooh

    2008-09-18

    We have recently examined the oncolytic effect of arabinoxylan rice bran, MGN-3/biobran, against solid Ehrlich carcinoma (SEC)-bearing mice via immune-modulation and apoptosis [N.K. Badr El-din, E. Noaman, M. Ghoneum, In vivo tumor inhibitory effects of nutritional rice bran supplement MGN-3/biobran on Ehrlich carcinoma-bearing mice, Nutr. Cancer 60 (2) (2008) 235-244]. In the present study, we examined the antioxidant system as another possible mechanism through which MGN-3 exerts its oncostatic potential. Female albino mice were inoculated intramuscularly in the right thigh with Ehrlich ascites carcinoma (EAC) cells. MGN-3 (25 mg/kg body weight) was injected intraperitoneally (i.p.) six times a week for 25 days into mice at either day 4 or day 11 post-EAC cell inoculation. Tumor growth, lipid peroxidation (LPx), glutathione (GSH) contents, the activity of the antioxidant scavenger enzymes, and alterations in gene expression were examined. MGN-3 efficiently suppressed the growth of tumors, which was associated with normalization of the LPx levels and augmentation of GSH contents. MGN-3 enhanced the activity of the endogenous antioxidant scavenging enzymes -- superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and glutathione-S-transferase (GST) -- in blood, liver, and tumor tissue. Similarly it up-regulated the expression of GPx, SOD1 and CAT mRNA in the liver. The effect of MGN-3 was more pronounced when treated early, at day 4 of tumor cell inoculation, as compared to later treatment at 11 days. In conclusion, MGN-3-induced oncostatic activity by modulating lipid peroxidation, augmenting the antioxidant defense system and protecting against oxidative stress.

  4. Effect of hypolipidemic drugs on basal and stimulated adenylate cyclase activity in tumor cells

    SciTech Connect

    Bershtein, L.M.; Kovaleva, I.G.; Rozenberg, O.A.

    1986-02-01

    This paper studies adenylate cyclase acticvity in Ehrlich's ascites carcinoma (EAC) cells during administration of drugs with a hypolipidemic action. Seven to eight days before they were killed, male mice ingested the antidiabetic biguanide phenformin, and the phospholipid-containing preparation Essentiale in drinking water. The cAMP formed was isolated by chromatography on Silufol plates after incubation of the enzyme preparation with tritium-ATP, or was determined by the competitive binding method with protein. It is shown that despite the possible differences in the concrete mechanism of action of the hypolipidemic agents chosen for study on the cyclase system, the use of such agents, offers definite prospects for oriented modification of the hormone sensitivity of tumor cells.

  5. Magnitude of malate-aspartate reduced nicotinamide adenine dinucleotide shuttle activity in intact respiring tumor cells.

    PubMed

    Greenhouse, W V; Lehninger, A L

    1977-11-01

    Measurements of respiration, CO2 and lactate production, and changes in the levels of various key metabolites of the glycolytic sequence and tricarboxylic acid cycle were made on five lines of rodent ascites tumor cells (two strains of Ehrlich ascites tumor cells, Krebs II carcinoma, AS-30D carcinoma, and L1210 cells) incubated aerobically in the presence of uniformly labeled D-[14C]glucose. From these data, as well as earlier evidence demonstrating that the reduced nicotinamide adenine dinucleotide (NADH) shuttle in these cells requires a transaminase step and is thus identified as the malate-aspartate shuttle (W.V.V. Greenhouse and A.L. Lehninger, Cancer Res., 36: 1392-1396, 1976), metabolic flux diagrams were constructed for the five cell lines. These diagrams show the relative rates of glycolysis, the tricarboxylic acid cycle, electron transport, and the malate-aspartate shuttle in these tumors. Large amounts of cytosolic NADH were oxidized by the mitochondrial respiratory chain via the NADH shuttle, comprising anywhere from about 20 to 80% of the total flow of reducing equivalents to oxygen in these tumors. Calculations of the sources of energy for adenosine triphosphate synthesis indicated that on the average about one-third of the respiratory adenosine triphosphate is generated by electron flow originating from cytosolic NADH via the malate-aspartate shuttle.

  6. Tumor cell differentiation

    SciTech Connect

    Aarbakke, J.; Chiang, P.K.; Koeffler, H.P

    1987-01-01

    This book contains four sections, each consisting of several papers. Some of the paper titles are: Studies of Gene Expression During Granulocyte Maturation; Proliferation and Differentiation of Human Leukemic Cells in Culture; Sequence-Specific DNA Methylation: Promoter Inactivation and Release of the Expression Block; Retinoic Acid-Induced Differentiation of HL-60: Studies In Vitro and In Vivo; and Differentiation of Human Leukemia Cells by Nucleoside Analogues.

  7. Metastasis and Circulating Tumor Cells

    PubMed Central

    van Dalum, Guus; Holland, Linda

    2012-01-01

    Cancer is a prominent cause of death worldwide. In most cases, it is not the primary tumor which causes death, but the metastases. Metastatic tumors are spread over the entire human body and are more difficult to remove or treat than the primary tumor. In a patient with metastatic disease, circulating tumor cells (CTCs) can be found in venous blood. These circulating tumor cells are part of the metastatic cascade. Clinical studies have shown that these cells can be used to predict treatment response and their presence is strongly associated with poor survival prospects. Enumeration and characterization of CTCs is important as this can help clinicians make more informed decisions when choosing or evaluating treatment. CTC counts are being included in an increasing number of studies and thus are becoming a bigger part of disease diagnosis and therapy management. We present an overview of the most prominent CTC enumeration and characterization methods and discuss the assumptions made about the CTC phenotype. Extensive CTC characterization of for example the DNA, RNA and antigen expression may lead to more understanding of the metastatic process. PMID:27683421

  8. Acute inflammation induces immunomodulatory effects on myeloid cells associated with anti-tumor responses in a tumor mouse model

    PubMed Central

    Salem, Mohamed L.; Attia, Zeinab I.; Galal, Sohaila M.

    2015-01-01

    Given the self nature of cancer, anti-tumor immune response is weak. As such, acute inflammation induced by microbial products can induce signals that result in initiation of an inflammatory cascade that helps activation of immune cells. We aimed to compare the nature and magnitude of acute inflammation induced by toll-like receptor ligands (TLRLs) on the tumor growth and the associated inflammatory immune responses. To induce acute inflammation in tumor-bearing host, CD1 mice were inoculated with intraperitoneal (i.p.) injection of Ehrlich ascites carcinoma (EAC) (5 × 105 cells/mouse), and then treated with i.p. injection on day 1, day 7 or days 1 + 7 with: (1) polyinosinic:polycytidylic (poly(I:C)) (TLR3L); (2) Poly-ICLC (clinical grade of TLR3L); (3) Bacillus Calmette Guerin (BCG) (coding for TLR9L); (4) Complete Freund’s adjuvant (CFA) (coding for TLR9L); and (5) Incomplete Freund’s Adjuvant (IFA). Treatment with poly(I:C), Poly-ICLC, BCG, CFA, or IFA induced anti-tumor activities as measured by 79.1%, 75.94%, 73.94%, 71.88% and 47.75% decreases, respectively in the total number of tumor cells collected 7 days after tumor challenge. Among the tested TLRLs, both poly(I:C) (TLR3L) and BCG (contain TLR9L) showed the highest anti-tumor effects as reflected by the decrease in the number of EAc cells. These effects were associated with a 2-fold increase in the numbers of inflammatory cells expressing the myeloid markers CD11b+Ly6G+, CD11b+Ly6G−, and CD11b+Ly6G−. We concluded that Provision of the proper inflammatory signal with optimally defined magnitude and duration during tumor growth can induce inflammatory immune cells with potent anti-tumor responses without vaccination. PMID:26966565

  9. Interaction of MSC with tumor cells.

    PubMed

    Melzer, Catharina; Yang, Yuanyuan; Hass, Ralf

    2016-09-08

    Tumor development and tumor progression is not only determined by the corresponding tumor cells but also by the tumor microenvironment. This includes an orchestrated network of interacting cell types (e.g. immune cells, endothelial cells, fibroblasts, and mesenchymal stroma/stem cells (MSC)) via the extracellular matrix and soluble factors such as cytokines, chemokines, growth factors and various metabolites. Cell populations of the tumor microenvironment can interact directly and indirectly with cancer cells by mutually altering properties and functions of the involved partners. Particularly, mesenchymal stroma/stem cells (MSC) play an important role during carcinogenesis exhibiting different types of intercellular communication. Accordingly, this work focusses on diverse mechanisms of interaction between MSC and cancer cells. Moreover, some functional changes and consequences for both cell types are summarized which can eventually result in the establishment of a carcinoma stem cell niche (CSCN) or the generation of new tumor cell populations by MSC-tumor cell fusion.

  10. Microenvironments Dictating Tumor Cell Dormancy

    PubMed Central

    Bragado, Paloma; Sosa, Maria Soledad; Keely, Patricia; Condeelis, John

    2012-01-01

    The mechanisms driving dormancy of disseminated tumor cells (DTCs) remain largely unknown. Here, we discuss experimental evidence and theoretical frameworks that support three potential scenarios contributing to tumor cell dormancy. The first scenario proposes that DTCs from invasive cancers activate stress signals in response to the dissemination process and/or a growth suppressive target organ microenvironment inducing dormancy. The second scenario asks whether therapy and/or micro-environmental stress conditions (e.g. hypoxia) acting on primary tumor cells carrying specific gene signatures prime new DTCs to enter dormancy in a matching target organ microenvironment that can also control the timing of DTC dormancy. The third and final scenario proposes that early dissemination contributes a population of DTCs that are unfit for immediate expansion and survive mostly in an arrested state well after primary tumor surgery, until genetic and/or epigenetic mechanisms activate their proliferation. We propose that DTC dormancy is ultimately a survival strategy that when targeted will eradicate dormant DTCs preventing metastasis. For these non-mutually exclusive scenarios we review experimental and clinical evidence in their support. PMID:22527492

  11. Paullinia cupana Mart. var. sorbilis, guarana, increases survival of Ehrlich ascites carcinoma (EAC) bearing mice by decreasing cyclin-D1 expression and inducing a G0/G1 cell cycle arrest in EAC cells.

    PubMed

    Fukumasu, Heidge; Latorre, Andreia Oliveira; Zaidan-Dagli, Maria Lucia

    2011-01-01

    The objective of this work is to report the antiproliferative effect of P. cupana treatment in Ehrlich Ascites Carcinoma (EAC)-bearing animals. Female mice were treated with three doses of powdered P. cupana (100, 1000 and 2000 mg/kg) for 7 days, injected with 10(5) EAC cells and treated up to day 21. In addition, a survival experiment was carried out with the same protocol. P. cupana decreased the ascites volume (p = 0.0120), cell number (p = 0.0004) and hemorrhage (p = 0.0054). This occurred through a G1-phase arrest (p < 0.01) induced by a decreased gene expression of Cyclin D1 in EAC cells. Furthermore, P. cupana significantly increased the survival of EAC-bearing animals (p = 0.0012). In conclusion, the P. cupana growth control effect in this model was correlated with a decreased expression of cyclin D1 and a G1 phase arrest. These results reinforce the cancer therapeutic potential of this Brazilian plant. Copyright © 2010 John Wiley & Sons, Ltd.

  12. Implication of Tumor Microenvironment in Chemoresistance: Tumor-Associated Stromal Cells Protect Tumor Cells from Cell Death

    PubMed Central

    Castells, Magali; Thibault, Benoît; Delord, Jean-Pierre; Couderc, Bettina

    2012-01-01

    Tumor development principally occurs following the accumulation of genetic and epigenetic alterations in tumor cells. These changes pave the way for the transformation of chemosensitive cells to chemoresistant ones by influencing the uptake, metabolism, or export of drugs at the cellular level. Numerous reports have revealed the complexity of tumors and their microenvironment with tumor cells located within a heterogeneous population of stromal cells. These stromal cells (fibroblasts, endothelial or mesothelial cells, adipocytes or adipose tissue-derived stromal cells, immune cells and bone marrow-derived stem cells) could be involved in the chemoresistance that is acquired by tumor cells via several mechanisms: (i) cell–cell and cell–matrix interactions influencing the cancer cell sensitivity to apoptosis; (ii) local release of soluble factors promoting survival and tumor growth (crosstalk between stromal and tumor cells); (iii) direct cell-cell interactions with tumor cells (crosstalk or oncologic trogocytosis); (iv) generation of specific niches within the tumor microenvironment that facilitate the acquisition of drug resistance; or (v) conversion of the cancer cells to cancer-initiating cells or cancer stem cells. This review will focus on the implication of each member of the heterogeneous population of stromal cells in conferring resistance to cytotoxins and physiological mediators of cell death. PMID:22949815

  13. Palifosfamide in Treating Patients With Recurrent Germ Cell Tumors

    ClinicalTrials.gov

    2015-06-11

    Adult Central Nervous System Germ Cell Tumor; Adult Teratoma; Malignant Extragonadal Germ Cell Tumor; Malignant Extragonadal Non-Seminomatous Germ Cell Tumor; Extragonadal Seminoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Ovarian Germ Cell Tumor; Stage IV Extragonadal Non-Seminomatous Germ Cell Tumor; Stage IV Extragonadal Seminoma; Stage IV Ovarian Germ Cell Tumor

  14. Willow leaves' extracts contain anti-tumor agents effective against three cell types.

    PubMed

    El-Shemy, Hany A; Aboul-Enein, Ahmed M; Aboul-Enein, Khalid Mostafa; Fujita, Kounosuke

    2007-01-31

    Many higher plants contain novel metabolites with antimicrobial, antifungal and antiviral properties. However, in the developed world almost all clinically used chemotherapeutics have been produced by in vitro chemical synthesis. Exceptions, like taxol and vincristine, were structurally complex metabolites that were difficult to synthesize in vitro. Many non-natural, synthetic drugs cause severe side effects that were not acceptable except as treatments of last resort for terminal diseases such as cancer. The metabolites discovered in medicinal plants may avoid the side effect of synthetic drugs, because they must accumulate within living cells. The aim here was to test an aqueous extract from the young developing leaves of willow (Salix safsaf, Salicaceae) trees for activity against human carcinoma cells in vivo and in vitro. In vivo Ehrlich Ascites Carcinoma Cells (EACC) were injected into the intraperitoneal cavity of mice. The willow extract was fed via stomach tube. The (EACC) derived tumor growth was reduced by the willow extract and death was delayed (for 35 days). In vitro the willow extract could kill the majority (75%-80%) of abnormal cells among primary cells harvested from seven patients with acute lymphoblastic leukemia (ALL) and 13 with AML (acute myeloid leukemia). DNA fragmentation patterns within treated cells inferred targeted cell death by apoptosis had occurred. The metabolites within the willow extract may act as tumor inhibitors that promote apoptosis, cause DNA damage, and affect cell membranes and/or denature proteins.

  15. Myeloid Cells in the Tumor Microenvironment: Modulation of Tumor Angiogenesis and Tumor Inflammation

    PubMed Central

    Schmid, Michael C.; Varner, Judith A.

    2010-01-01

    Myeloid cells are a heterogeneous population of bone marrow-derived cells that play a critical role during growth and metastasis of malignant tumors. Tumors exhibit significant myeloid cell infiltrates, which are actively recruited to the tumor microenvironment. Myeloid cells promote tumor growth by stimulating tumor angiogenesis, suppressing tumor immunity, and promoting metastasis to distinct sites. In this review, we discuss the role of myeloid cells in promoting tumor angiogenesis. Furthermore, we describe a subset of myeloid cells with immunosuppressive activity (known as myeloid-derived suppressor cells). Finally, we will comment on the mechanisms regulating myeloid cell recruitment to the tumor microenvironment and on the potential of myeloid cells as new targets for cancer therapy. PMID:20490273

  16. Patient-Derived Antibody Targets Tumor Cells

    Cancer.gov

    An NCI Cancer Currents blog on an antibody derived from patients that killed tumor cells in cell lines of several cancer types and slowed tumor growth in mouse models of brain and lung cancer without evidence of side effects.

  17. Treatment Option Overview (Ovarian Germ Cell Tumors)

    MedlinePlus

    ... Tube, & Primary Peritoneal Cancer Screening Research Ovarian Germ Cell Tumors Treatment (PDQ®)–Patient Version General Information About Ovarian Germ Cell Tumors Go to Health Professional Version Key Points ...

  18. General Information about Ovarian Germ Cell Tumors

    MedlinePlus

    ... Tube, & Primary Peritoneal Cancer Screening Research Ovarian Germ Cell Tumors Treatment (PDQ®)–Patient Version General Information About Ovarian Germ Cell Tumors Go to Health Professional Version Key Points ...

  19. Hepatic perivascular epithelioid cell tumor

    PubMed Central

    Tang, Da; Wang, Jianmin; Tian, Yuepeng; Li, Qiuguo; Yan, Haixiong; Wang, Biao; Xiong, Li; Li, Qinglong

    2016-01-01

    Abstract Rational: Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm which expresses both myogenic and melanocytic markers. PEComas are found in a variety locations in the body, but up to now only approximately 30 cases about hepatic perivascular epithelioid cell tumor are reported in English language worldwide. Patient concerns: A 32-year-old woman was admitted in our hospital with intermittent right upper quadrant pain for 1 month and recent (1 day) progressive deterioration. Diagnoses: Based on the results of the laboratory examinations and the findings of the computed tomography, the diagnosis of hepatic hamartoma or the hepatocecullar carcinoma with hemorrhage was made. Interventions: The patient underwent a segmentectomy of the liver, and the finally diagnosis of hepatic PEComa was made with immunohistochemical confirmation with HMB-45 and SMA. Outcomes: There is no clinical or radiographic evidence of recurrence 9 months after surgery. Lessons: This kind of tumor is extremely rare and the natural history of PEComa is uncertain, as the treatment protocol for hepatic PEComa has not reached a consensus. But the main treatment of the disease may be surgical resection. Only after long term follow-up can we know whether the tumor is benign or malignant. It appears that longer clinical follow-up is necessary in all patients with hepatic PEComas. PMID:28002331

  20. Dorzolamide synergizes the antitumor activity of mitomycin C against Ehrlich's carcinoma grown in mice: role of thioredoxin-interacting protein.

    PubMed

    Ali, Belal M; Zaitone, Sawsan A; Shouman, Samia A; Moustafa, Yasser M

    2015-12-01

    The antitumor activity of carbonic anhydrase (CA) inhibitors is attributed to their ability to induce a state of intracellular acidification. In fact, acidic intracellular pH was demonstrated to upregulate several tumor suppressor proteins and increase the activity of many chemotherapies. The present study aimed to investigate the antitumor activity of the CA inhibitor, dorzolamide, in combination with mitomycin C and to study the effect of these drugs on tumoral thioredoxin-interacting protein (TXNIP) as well as tumor cell proliferation and apoptosis. Solid tumors were induced by subcutaneous inoculation of Ehrlich's ascites carcinoma (EAC) cells in female mice. Mice were treated with dorzolamide (3, 10, or 30 mg/kg/day, i.p.) and/or mitomycin C (1 mg/kg, i.p.) weekly for 3 weeks. Treatment with mitomycin C increased TXNIP level in EAC solid tumors in mice. Likewise, treatment with dorzolamide upregulated TXNIP and p53 while downregulated bcl-2. Both drug therapies increased tumoral caspase 9, caspase 3, and PARP-1 cleavage in addition to decreasing the proliferative Ki-67-stained nuclear fraction. Indeed, a synergistic effect was detected between mitomycin C and dorzolamide. The current data demonstrated that the antitumor activity of mitomycin C and dorzolamide was, at least in part, mediated through stimulating tumoral expression of TXNIP and enhancing tumor apoptosis.

  1. Cancer stem cells in nervous system tumors.

    PubMed

    Singh, Sheila K; Clarke, Ian D; Hide, Takuichiro; Dirks, Peter B

    2004-09-20

    Most current research on human brain tumors is focused on the molecular and cellular analysis of the bulk tumor mass. However, evidence in leukemia and more recently in solid tumors such as breast cancer suggests that the tumor cell population is heterogeneous with respect to proliferation and differentiation. Recently, several groups have described the existence of a cancer stem cell population in human brain tumors of different phenotypes from both children and adults. The finding of brain tumor stem cells (BTSCs) has been made by applying the principles for cell culture and analysis of normal neural stem cells (NSCs) to brain tumor cell populations and by identification of cell surface markers that allow for isolation of distinct tumor cell populations that can then be studied in vitro and in vivo. A population of brain tumor cells can be enriched for BTSCs by cell sorting of dissociated suspensions of tumor cells for the NSC marker CD133. These CD133+ cells, which also expressed the NSC marker nestin, but not differentiated neural lineage markers, represent a minority fraction of the entire brain tumor cell population, and exclusively generate clonal tumor spheres in suspension culture and exhibit increased self-renewal capacity. BTSCs can be induced to differentiate in vitro into tumor cells that phenotypically resembled the tumor from the patient. Here, we discuss the evidence for and implications of the discovery of a cancer stem cell in human brain tumors. The identification of a BTSC provides a powerful tool to investigate the tumorigenic process in the central nervous system and to develop therapies targeted to the BTSC. Specific genetic and molecular analyses of the BTSC will further our understanding of the mechanisms of brain tumor growth, reinforcing parallels between normal neurogenesis and brain tumorigenesis.

  2. The contributions of Paul Ehrlich to infectious disease.

    PubMed

    Gensini, Gian Franco; Conti, Andrea Alberto; Lippi, Donatella

    2007-03-01

    Paul Ehrlich (1854-1915) is nowadays considered a pioneer in a number of medical fields, and in the course of time his role in the establishment and development of disciplines such as histology, immunology, oncology and haematology has been acknowledged. Aim of this historical note is to illustrate, in the area of chemotherapy, the special importance of this brilliant scientist whose 150th anniversary of birth occurred in 2004. Already as a medical student, Ehrlich was obsessed by structural organic chemistry and dyes, and, continually studying these issues, he elaborated his theory regarding the discovery of a "magic bullet", able to specifically destroy tumour cells and micro-organisms. In practice he applied methylene blue to the treatment of malaria patients, following his intuition that such a dye could destroy parasites. However, his culminating achievements in the chemotherapic field, reached even at the expense of his health, were the concept of the one-dose treatment of Helicobacter pylori infection, and the creation of arsphenamine (compound 606, or Salvarsan), the first really effective compound in controlling human syphilis. Within the many and various contributions of Ehrlich to the development of experimental and clinical medicine, a special mention of his experimental studies and clinical applications in the area of chemotherapy is essential, since his achievements in this biomedical area remain a paramount legacy in the history of the therapy of infections.

  3. An experimental study on the anti-Ehrlich ascites carcinoma effect of purified toad venom extract.

    PubMed

    Wang, Ying

    2013-01-01

    The objective of this paper was to study the anti-Ehrlich ascites carcinoma effect of purified toad venom extract and its mechanism. Mouse model of Ehrlich ascites carcinoma was established with cisplatin as the control to observe the inhibitory effect of purified toad venom extract on malignant peritoneal effusion in mice. The results showed that compared with the control group, ascites volume, number of tumour cells and tumour cell viability decreased and ascites inhibition rate reached over 50% in each treatment group, and with the increase of the dose, incidence of ascites showed a downward trend. The number of tumour cells in ascites and tumour cell viability in the purified toad venom high-dose group were lower than those of the cisplatin group. Compared with the model group, survival time was prolonged in varying degrees in the purified toad venom groups and cisplatin group. The study concluded that purified extract of toad venom has an anti-Ehrlich ascites carcinoma effect.

  4. The antitumor effects of tetrodotoxin and/or doxorubicin on Ehrlich ascites carcinoma-bearing female mice.

    PubMed

    El-Dayem, Samiha M Abd; Fouda, Fatma M; Ali, Elham H A; Motelp, Bosy A Abd El

    2013-06-01

    The study aimed to investigate the antitumor effect of tetrodotoxin (TTX) and/or doxorubicin (DOX) on Ehrlich ascites carcinoma (EAC)-bearing mice through the investigated biochemical parameters. TTX and/or DOX with or without N-acetylcystiene were administrated after 10 days into EAC-female mice for a period of 2 weeks in six equal doses. Treatment with TTX or DOX caused a significant decrease in the mean tumor weight and an increase in the cumulative mean survival time when compared with EAC group. All the treatments reduced the elevated liver tumor markers and increased liver antioxidant enzymes under investigation in comparison with EAC. Hepatic cells, suffered severely from degeneration and karriolysis in EAC group, revealed some improvement as appearance of healthy hepatocytes by TTX treatment. The present results suggested that TTX had a more powerful inhibitor effect on EAC growth than DOX and TTX plus DOX treatments reflected by antitumor biochemical and histological studies.

  5. Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice.

    PubMed

    Lu, Tangying; Ramakrishnan, Rupal; Altiok, Soner; Youn, Je-In; Cheng, Pingyan; Celis, Esteban; Pisarev, Vladimir; Sherman, Simon; Sporn, Michael B; Gabrilovich, Dmitry

    2011-10-01

    Cancer immunotherapeutic approaches induce tumor-specific immune responses, in particular CTL responses, in many patients treated. However, such approaches are clinically beneficial to only a few patients. We set out to investigate one possible explanation for the failure of CTLs to eliminate tumors, specifically, the concept that this failure is not dependent on inhibition of T cell function. In a previous study, we found that in mice, myeloid-derived suppressor cells (MDSCs) are a source of the free radical peroxynitrite (PNT). Here, we show that pre-treatment of mouse and human tumor cells with PNT or with MDSCs inhibits binding of processed peptides to tumor cell-associated MHC, and as a result, tumor cells become resistant to antigen-specific CTLs. This effect was abrogated in MDSCs treated with a PNT inhibitor. In a mouse model of tumor-associated inflammation in which the antitumor effects of antigen-specific CTLs are eradicated by expression of IL-1β in the tumor cells, we determined that therapeutic failure was not caused by more profound suppression of CTLs by IL-1β-expressing tumors than tumors not expressing this proinflammatory cytokine. Rather, therapeutic failure was a result of the presence of PNT. Clinical relevance for these data was suggested by the observation that myeloid cells were the predominant source of PNT in human lung, pancreatic, and breast cancer samples. Our data therefore suggest what we believe to be a novel mechanism of MDSC-mediated tumor cell resistance to CTLs.

  6. Tumor-suppressing effects of microRNA-429 in human renal cell carcinoma via the downregulation of Sp1

    PubMed Central

    Wu, Deyao; Niu, Xiaobing; Pan, Huixing; Zhou, Yunfeng; Zhang, Zichun; Qu, Ping; Zhou, Jian

    2016-01-01

    MicroRNA (miR)-429 has been frequently reported to be downregulated in various tumors, including renal cell carcinoma (RCC), nasopharyngeal carcinoma, Ehrlich ascites tumor cells, gastric cancer, non-small cell lung cancer and endometrial endometrioid carcinoma. The present study investigated the effects of miR-429 on human RCC A498 and 786-O cells. Following transfection of cells with miR-429 mimics and scrambled control, MTT, cell migration, cell invasion and luciferase assays were performed. In addition, western blotting was performed in order to assess the expression of specificity protein 1 (Sp1), which was predicted to be a target of miR-429 by TargetScan. The present results revealed that miR-429 inhibited cell proliferation, migration and invasion of 786-O and A498 cells. In addition, the present results demonstrated that miR-429 overexpression downregulated Sp1 protein expression, which provides evidence that miR-429 may directly target Sp1 in RCC. These results suggest that miR-429 may be investigated for use as a predictive marker for early detection of tumor metastasis and blocking RCC cells from becoming invasive. PMID:27698878

  7. Study of Antitumor Activity of Sodium Phenylbutyrate, Histon Deacetylase Inhibitor, on Ehrlich Carcinoma Model.

    PubMed

    Fadeev, N P; Kharisov, R I; Kovan'ko, E G; Pustovalov, Yu I

    2015-09-01

    Antitumor activity of sodium phenylbutyrate was studied on 120 outbred female mice with transplanted Ehrlich ascites carcinoma. The animals received the drug in doses of 400, 800, and 1200 mg/kg with drinking water daily for 21 days. The antitumor effect was evaluated by tumor growth inhibition and lifespan prolongation. Phenylbutyrate in the dose of 800 mg/kg was most effective. The drug inhibited the tumor growth by 71%, prolonged the lifespan of animals by 28, and was low-toxic.

  8. Intracranial granular cell tumor in a dog.

    PubMed

    Liu, Chen-Hsuan; Liu, Chen-I; Liang, Sao-Ling; Cheng, Chiung-Hsiang; Huang, Sun-Chau; Lee, Chin-Cheng; Hsu, Wei-Chih; Lin, Yung-Chang

    2004-01-01

    A 12-year-old female miniature poodle showed a 3-month history of neurological signs. Magnetic resonance imaging disclosed a high intensity tumor mass in the right cerebral hemisphere with compression of the lateral ventricle. At necropsy, a 2 x 3 cm white, friable mass was found in the right ventral pyriform lobe. Microscopically, the tumor cells were large, polygonal to round cells supported by a sparse fibrovascular stroma. The tumor cells typically possessed finely granular, pale eosinophilic cytoplasm with strongly positive periodic acid-Schiff (PAS) reaction. The tumor cells were immunopositive for vimentin, NSE and S-100. Ultrastructurally, the tumor cells showed large amounts of granules in the cytoplasm, and absence of basement membrane. Based on the above-mentioned findings, the intracranial granular cell tumor was diagnosed.

  9. Isolation by Size of Epithelial Tumor Cells

    PubMed Central

    Vona, Giovanna; Sabile, Abdelmajid; Louha, Malek; Sitruk, Veronique; Romana, Serge; Schütze, Karin; Capron, Frédérique; Franco, Dominique; Pazzagli, Mario; Vekemans, Michel; Lacour, Bernard; Bréchot, Christian; Paterlini-Bréchot, Patrizia

    2000-01-01

    We have developed a new assay, ISET (isolation by size of epithelial tumor cells), which allows the counting and the immunomorphological and molecular characterization of circulating tumor cells in patients with carcinoma, using peripheral blood sample volumes as small as 1 ml. Using this assay, epithelial tumor cells can be isolated individually by filtration because of their larger size when compared to peripheral blood leukocytes. ISET parameters were defined using peripheral blood spiked with tumor cell lines (HepG2, Hep3B, MCF-7, HeLa, and LNCaP). ISET can detect a single, micropipetted tumor cell, added to 1 ml of blood. We also demonstrate that fluorescence in situ hybridization can be used to perform chromosomal analyses on tumor cells collected using ISET. Polymerase chain reaction-based genetic analyses can be applied to ISET-isolated cells, and, as an example, we demonstrate homozygous p53 deletion in single Hep3B cells after filtration and laser microdissection. Finally, we provide evidence for the in vivo feasibility of ISET in patients with hepatocellular carcinoma undergoing tumor resection. ISET, but not reverse transcriptase-polymerase chain reaction, allowed analysis of cell morphology, counting of tumor cells, and demonstration of tumor microemboli spread into peripheral blood during surgery. Overall, ISET constitutes a novel approach that should open new perpectives in molecular medicine. PMID:10623654

  10. Robo-Enabled Tumor Cell Extrusion.

    PubMed

    Richardson, Helena E; Portela, Marta

    2016-12-19

    How aberrant cells are removed from a tissue to prevent tumor formation is a key question in cancer biology. Reporting in this issue of Developmental Cell, Vaughen and Igaki (2016) show that a pathway with an important role in neural guidance also directs extrusion of tumor cells from epithelial tissues.

  11. Evolution of cooperation among tumor cells.

    PubMed

    Axelrod, Robert; Axelrod, David E; Pienta, Kenneth J

    2006-09-05

    The evolution of cooperation has a well established theoretical framework based on game theory. This approach has made valuable contributions to a wide variety of disciplines, including political science, economics, and evolutionary biology. Existing cancer theory suggests that individual clones of cancer cells evolve independently from one another, acquiring all of the genetic traits or hallmarks necessary to form a malignant tumor. It is also now recognized that tumors are heterotypic, with cancer cells interacting with normal stromal cells within the tissue microenvironment, including endothelial, stromal, and nerve cells. This tumor cell-stromal cell interaction in itself is a form of commensalism, because it has been demonstrated that these nonmalignant cells support and even enable tumor growth. Here, we add to this theory by regarding tumor cells as game players whose interactions help to determine their Darwinian fitness. We marshal evidence that tumor cells overcome certain host defenses by means of diffusible products. Our original contribution is to raise the possibility that two nearby cells can protect each other from a set of host defenses that neither could survive alone. Cooperation can evolve as by-product mutualism among genetically diverse tumor cells. Our hypothesis supplements, but does not supplant, the traditional view of carcinogenesis in which one clonal population of cells develops all of the necessary genetic traits independently to form a tumor. Cooperation through the sharing of diffusible products raises new questions about tumorigenesis and has implications for understanding observed phenomena, designing new experiments, and developing new therapeutic approaches.

  12. Effect of tumor cells and tumor microenvironment on NK-cell function.

    PubMed

    Vitale, Massimo; Cantoni, Claudia; Pietra, Gabriella; Mingari, Maria Cristina; Moretta, Lorenzo

    2014-06-01

    The ability of tumors to manage an immune-mediated attack has been recently included in the "next generation" of cancer hallmarks. In solid tumors, the microenvironment that is generated during the first steps of tumor development has a pivotal role in immune regulation. An intricate net of cross-interactions occurring between tumor components, stromal cells, and resident or recruited immune cells skews the possible acute inflammatory response toward an aberrant ineffective chronic inflammatory status that favors the evasion from the host's defenses. Natural killer (NK) cells have powerful cytotoxic activity, but their activity may be eluded by the tumor microenvironment. Immunosubversion, immunoediting or immunoselection of poorly immunogenic tumor cells and interference with tumor infiltration play a major role in evading NK-cell responses to tumors. Tumor cells, tumor-associated fibroblasts and tumor-induced aberrant immune cells (i.e. tolerogenic or suppressive macrophages, dendritic cells (DCs) and T cells) can interfere with NK-cell activation pathways or the complex receptor array that regulate NK-cell activation and antitumor activity. Thus, the definition of tumor microenvironment-related immunosuppressive factors, along with the identification of new classes of tissue-residing NK-like innate lymphoid cells, represent key issues to design effective NK-cell-based therapies of solid tumors.

  13. Therapeutic Trial for Patients With Ewing Sarcoma Family of Tumor and Desmoplastic Small Round Cell Tumors

    ClinicalTrials.gov

    2017-04-11

    Desmoplastic Small Round Cell Tumor; Ewing Sarcoma of Bone or Soft Tissue; Localized Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor

  14. Photodynamic therapy and knocking out of single tumor cells by multiphoton excitation processes

    NASA Astrophysics Data System (ADS)

    Riemann, Iris; Fischer, Peter; Koenig, Karsten

    2004-09-01

    Near infrared (NIR) ultrashort laser pulses of 780 nm have been used to induce intracellular photodynamic reactions by nonlinear excitation of porphyrin photosensitizers. Intracellular accumulation and photobleaching of the fluorescent photosensitizers protoporphyrin IX and Photofrin (PF) have been studied by non-resonant two-photon fluorescence excitation of PF and aminolevulinic acid (ALA)-labeled Chinese hamster ovary (CHO) cells. To testify the efficacy of both substrates to induce irreversible destructive effects, the cloning efficiency (CE) of cells exposed to femtosecond pulses of a multiphoton laser scanning microscope (40x/1.3) was determined. In the case of Photofrin accumulation, CEs of 50% and 0% were obtained after 17 laserscans (2 mW?, 16 s/ frame) and 50 scans, respectively. All cells exposed to 50 scans died within 48h after laser exposure. 100 scans were required to induce lethal effects in ALA labeled cells. Sensitizer-free control cells could be scanned 250 times (1.1 h) and more without impact on the reproduction behavior, morphology, and vitality. In addition to the slow phototoxic effect by photooxidation processes, another destructive but immediate effect based on optical breakdown was induced when employing high intense NIR femtosecond laser beams. This was used to optically knock out single tumor cells in living mice (solid Ehrlich-Carcinoma) in a depth of 10 to 100 μm.

  15. Tumor cell metabolism: an integral view.

    PubMed

    Romero-Garcia, Susana; Lopez-Gonzalez, Jose Sullivan; Báez-Viveros, José Luis; Aguilar-Cazares, Dolores; Prado-Garcia, Heriberto

    2011-12-01

    Cancer is a genetic disease that is caused by mutations in oncogenes, tumor suppressor genes and stability genes. The fact that the metabolism of tumor cells is altered has been known for many years. However, the mechanisms and consequences of metabolic reprogramming have just begun to be understood. In this review, an integral view of tumor cell metabolism is presented, showing how metabolic pathways are reprogrammed to satisfy tumor cell proliferation and survival requirements. In tumor cells, glycolysis is strongly enhanced to fulfill the high ATP demands of these cells; glucose carbons are the main building blocks in fatty acid and nucleotide biosynthesis. Glutaminolysis is also increased to satisfy NADPH regeneration, whereas glutamine carbons replenish the Krebs cycle, which produces metabolites that are constantly used for macromolecular biosynthesis. A characteristic feature of the tumor microenvironment is acidosis, which results from the local increase in lactic acid production by tumor cells. This phenomenon is attributed to the carbons from glutamine and glucose, which are also used for lactic acid production. Lactic acidosis also directs the metabolic reprogramming of tumor cells and serves as an additional selective pressure. Finally, we also discuss the role of mitochondria in supporting tumor cell metabolism.

  16. Sickle red blood cells accumulate in tumor.

    PubMed

    Brown, S L; Ewing, J R; Nagaraja, T N; Swerdlow, P S; Cao, Y; Fenstermacher, J D; Kim, J H

    2003-12-01

    The preferential accumulation of sickle blood cells in tumor vasculature is demonstrated noninvasively using MRI and sickle red blood cells loaded with Gd-DTPA and invasively by two other techniques. The distribution of red blood cells in rat brain tumors relative to normal brains were measured using three separate techniques: MRI of Gd-DTPA loaded cells, fluorescent microscopy detection of Oregon Green 488 fluorescence conjugated to a streptavidin-biotin complex that binds to red blood cell surface proteins, and autoradiography using a technetium (99m)Tc-labeling kit. Labeled red cells were infused intravenously in rats with brain tumors. Sickle cells preferentially accumulated in tumor relative to normal brain, with highest concentrations near the tumor / normal tissue boundary, whereas control normal red cells did not preferentially aggregate at the tumor periphery. This demonstrates the potential of sickle red blood cells to accumulate in the abnormal tumor vessel network, and the ability to detect their aggregation noninvasively and at high spatial resolution using MRI. The application of the noninvasive measurement of sickle cells for imaging tumor neovasculature, or as a delivery tool for therapy, requires further study. Copyright 2003 Wiley-Liss, Inc.

  17. Altered Tumor-Cell Glycosylation Promotes Metastasis

    PubMed Central

    Häuselmann, Irina; Borsig, Lubor

    2014-01-01

    Malignant transformation of cells is associated with aberrant glycosylation presented on the cell-surface. Commonly observed changes in glycan structures during malignancy encompass aberrant expression and glycosylation of mucins; abnormal branching of N-glycans; and increased presence of sialic acid on proteins and glycolipids. Accumulating evidence supports the notion that the presence of certain glycan structures correlates with cancer progression by affecting tumor-cell invasiveness, ability to disseminate through the blood circulation and to metastasize in distant organs. During metastasis tumor-cell-derived glycans enable binding to cells in their microenvironment including endothelium and blood constituents through glycan-binding receptors – lectins. In this review, we will discuss current concepts how tumor-cell-derived glycans contribute to metastasis with the focus on three types of lectins: siglecs, galectins, and selectins. Siglecs are present on virtually all hematopoietic cells and usually negatively regulate immune responses. Galectins are mostly expressed by tumor cells and support tumor-cell survival. Selectins are vascular adhesion receptors that promote tumor-cell dissemination. All lectins facilitate interactions within the tumor microenvironment and thereby promote cancer progression. The identification of mechanisms how tumor glycans contribute to metastasis may help to improve diagnosis, prognosis, and aid to develop clinical strategies to prevent metastasis. PMID:24592356

  18. PLGA-encapsulated tea polyphenols enhance the chemotherapeutic efficacy of cisplatin against human cancer cells and mice bearing Ehrlich ascites carcinoma

    PubMed Central

    Singh, Madhulika; Bhatnagar, Priyanka; Mishra, Sanjay; Kumar, Pradeep; Shukla, Yogeshwer; Gupta, Kailash Chand

    2015-01-01

    The clinical success of the applicability of tea polyphenols awaits efficient systemic delivery and bioavailability. Herein, following the concept of nanochemoprevention, which uses nanotechnology for enhancing the efficacy of chemotherapeutic drugs, we employed tea polyphenols, namely theaflavin (TF) and epigallocatechin-3-gallate (EGCG) encapsulated in a biodegradable nanoparticulate formulation based on poly(lactide-co-glycolide) (PLGA) with approximately 26% and 18% encapsulation efficiency, respectively. It was observed that TF/EGCG encapsulated PLGA nanoparticles (NPs) offered an up to ~7-fold dose advantage when compared with bulk TF/EGCG in terms of exerting its antiproliferative effects and also enhanced the anticancer potential of cisplatin (CDDP) in A549 (lung carcinoma), HeLa (cervical carcinoma), and THP-1 (acute monocytic leukemia) cells. Cell cycle analysis revealed that TF/EGCG-NPs were more efficient than bulk TF/EGCG in sensitizing A549 cells to CDDP-induced apoptosis, with a dose advantage of up to 20-fold. Further, TF/EGCG-NPs, alone or in combination with CDDP, were more effective in inhibiting NF-κB activation and in suppressing the expression of cyclin D1, matrix metalloproteinase-9, and vascular endothelial growth factor, involved in cell proliferation, metastasis, and angiogenesis, respectively. EGCG and TF-NPs were also found to be more effective than bulk TF/EGCG in inducing the cleavage of caspase-3 and caspase-9 and Bax/Bcl2 ratio in favor of apoptosis. Further, in vivo evaluation of these NPs in combination with CDDP showed an increase in life span (P<0.05) in mice bearing Ehrlich’s ascites carcinoma cells, with apparent regression of tumor volume in comparison with mice treated with bulk doses with CDDP. These results indicate that EGCG and TF-NPs have superior cancer chemosensitization activity when compared with bulk TF/EGCG. PMID:26586942

  19. SYNOVIAL GIANT CELL TUMOR OF THE KNEE.

    PubMed

    Abdalla, Rene Jorge; Cohen, Moisés; Nóbrega, Jezimar; Forgas, Andrea

    2009-01-01

    Synovial giant cell tumor is a benign neoplasm, rarely reported in the form of malignant metastasis. Synovial giant cell tumor most frequently occurs on the hand, and, most uncommon, on the ankle and knee. In the present study, the authors describe a rare case of synovial giant cell tumor on the knee as well as the treatment approach. Arthroscopy has been shown, in this case, to be the optimal method for treating this kind of lesion, once it allowed a less aggressive approach, while providing good visualization of all compartments of knee joint and full tumor resection.

  20. SYNOVIAL GIANT CELL TUMOR OF THE KNEE

    PubMed Central

    Abdalla, Rene Jorge; Cohen, Moisés; Nóbrega, Jezimar; Forgas, Andrea

    2015-01-01

    Synovial giant cell tumor is a benign neoplasm, rarely reported in the form of malignant metastasis. Synovial giant cell tumor most frequently occurs on the hand, and, most uncommon, on the ankle and knee. In the present study, the authors describe a rare case of synovial giant cell tumor on the knee as well as the treatment approach. Arthroscopy has been shown, in this case, to be the optimal method for treating this kind of lesion, once it allowed a less aggressive approach, while providing good visualization of all compartments of knee joint and full tumor resection. PMID:27004193

  1. [Granular cell tumor of the larynx].

    PubMed

    Modrzyński, M; Wróbel, B; Zawisza, E; Drozd, K

    1999-09-01

    Granular cell tumor is an unusual growth of probably neuroectodermal histogenesis, first reported by Abrikossoff in 1926 with the name of myoblastenmyoma. Authors described a case of a 54 year man with laryngeal seat of granular-cell myoblastoma. In this case Abrikossoff tumor was located in the right vocal chord. The tumor was treated successfully surgically by microlaryngoscopy. The etiology, clinical features and diagnostic difficulties are discussed.

  2. Contractile forces in tumor cell migration.

    PubMed

    Mierke, Claudia Tanja; Rösel, Daniel; Fabry, Ben; Brábek, Jan

    2008-09-01

    Cancer is a deadly disease primarily because of the ability of tumor cells to spread from the primary tumor, to invade into the connective tissue, and to form metastases at distant sites. In contrast to cell migration on a planar surface where large cell tractions and contractile forces are not essential, tractions and forces are thought to be crucial for overcoming the resistance and steric hindrance of a dense three-dimensional connective tissue matrix. In this review, we describe recently developed biophysical tools, including 2-D and 3-D traction microscopy to measure contractile forces of cells. We discuss evidence indicating that tumor cell invasiveness is associated with increased contractile force generation.

  3. Immune Cells in Blood Recognize Tumors

    Cancer.gov

    NCI scientists have developed a novel strategy for identifying immune cells circulating in the blood that recognize specific proteins on tumor cells, a finding they believe may have potential implications for immune-based therapies.

  4. Circulating tumor cells in germ cell tumors: are those biomarkers of real prognostic value? A review

    PubMed Central

    CEBOTARU, CRISTINA LIGIA; OLTEANU, ELENA DIANA; ANTONE, NICOLETA ZENOVIA; BUIGA, RARES; NAGY, VIORICA

    2016-01-01

    Analysis of circulating tumor cells from patients with different types of cancer is nowadays a fascinating new tool of research and their number is proven to be useful as a prognostic factor in metastatic breast, colon and prostate cancer patients. Studies are going beyond enumeration, exploring the circulating tumor cells to better understand the mechanisms of tumorigenesis, invasion and metastasis and their value for characterization, prognosis and tailoring of treatment. Few studies investigated the prognostic significance of circulating tumor cells in germ cell tumors. In this review, we examine the possible significance of the detection of circulating tumor cells in this setting. PMID:27152069

  5. PGE from Octopus aegina Induces Apoptosis in Ehrlich's Ascites Carcinoma of Mice.

    PubMed

    Karthigayan, S; Balasubashini, M Sri; Balasubramanian, T; Somasundaram, S T

    2007-01-01

    ABSTRACT The present study was carried out to assess the antitumor effect of venomous peptide from the cephalopod Octopus aegina on Ehrlich's ascites carcinoma (EAC). Male albino Swiss mice were used in the present study. Four groups of animals were treated with three doses of the sublethal dose of venom, 15, 75, and 150 mug/kg body weight (intraperitoneal injection), along with the standard drug 5-fluorouracil (20 mg/kg b.w.). After 10 days of treatment, six animals from each group were sacrificed for the biochemical analysis and the rest were left to calculate the mean survival time. In EAC-bearing mice, mean lifespan, tumor volume, hemoglobin, red blood cells, and lymphocytes were significantly decreased when compared to the normal animals. While body weight, neutrophils, and viable tumor cell count were increased in the EAC-bearing mice, these changes were brought back to near normal levels in different treatment groups. The macromolecule concentration of peritoneal cells, such as DNA, RNA, and protein, were altered in the EAC-bearing mice and observed to be near normal in the treatment groups. The caspase-3 activity was significantly increased in the peritoneal cells of the treatment groups when compared to the EAC-bearing mice. The role of apoptotic cascade in EAC cell death was confirmed by the DNA fragmentation on agarose gel. Apart from the antitumor effect, octopus venom reduced the tumor burden on the liver and altered the changes in the activities of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP). Therefore, the venom from O. aegina has a potential antitumor effect on the EAC-bearing mice.

  6. Imaging Tumor Cell Movement In Vivo

    PubMed Central

    Entenberg, David; Kedrin, Dmitriy; Wyckoff, Jeffrey; Sahai, Erik; Condeelis, John; Segall, Jeffrey E.

    2013-01-01

    This unit describes the methods that we have been developing for analyzing tumor cell motility in mouse and rat models of breast cancer metastasis. Rodents are commonly used both to provide a mammalian system for studying human tumor cells (as xenografts in immunocompromised mice) as well as for following the development of tumors from a specific tissue type in transgenic lines. The Basic Protocol in this unit describes the standard methods used for generation of mammary tumors and imaging them. Additional protocols for labeling macrophages, blood vessel imaging, and image analysis are also included. PMID:23456602

  7. Tumor's other immune targets: dendritic cells.

    PubMed

    Esche, C; Lokshin, A; Shurin, G V; Gastman, B R; Rabinowich, H; Watkins, S C; Lotze, M T; Shurin, M R

    1999-08-01

    The induction of apoptosis in T cells is one of several mechanisms by which tumors escape immune recognition. We have investigated whether tumors induce apoptosis in dendritic cells (DC) by co-culture of murine or human DC with different tumor cell lines for 4-48 h. Analysis of DC morphological features, JAM assay, TUNEL, caspase-3-like and transglutaminase activity, Annexin V binding, and DNA fragmentation assays revealed a time- and dose-dependent induction of apoptosis in DC by tumor-derived factors. This finding is both effector and target specific. The mechanism of tumor-induced DC apoptosis involved regulation of Bcl-2 and Bax expression. Double staining of both murine and human tumor tissues confirmed that tumor-associated DC undergo apoptotic death in vivo. DC isolated from tumor tissue showed significantly higher levels of apoptosis as determined by TUNEL assay when compared with DC isolated from spleen. These findings demonstrate that tumors induce apoptosis in DC and suggest a new mechanism of tumor escape from immune recognition. DC protection from apoptosis will lead to improvement of DC-based immunotherapies for cancer and other immune diseases.

  8. [Circulating tumor cells: liquid biopsy].

    PubMed

    Alix-Panabières, Catherine; Pierga, Jean-Yves

    2014-01-01

    The detection and molecular characterization of circulating tumor cells (CTCs) are one of the most active areas of translational cancer research, with more than 400 clinical studies having included CTCs as a biomarker. The aims of research on CTCs include: a) estimation of the risk for metastatic relapse or metastatic progression (prognostic information); b) stratification and real-time monitoring of therapies; c) identification of therapeutic targets and resistance mechanisms; and d) understanding metastasis development in cancer patients. This review focuses on the technologies used for the enrichment and detection of CTCs. We outline and discuss the current technologies that are based on exploiting the physical and biological properties of CTCs. A number of innovative technologies to improve methods for CTC detection have recently been developed, including CTC microchips, filtration devices, quantitative reverse-transcription PCR assays, and automated microscopy systems. Molecular characterization studies have indicated, however, that CTCs are very heterogeneous, a finding that underscores the need for multiplex approaches to capture all of the relevant CTC subsets. We therefore emphasize the current challenges of increasing the yield and detection of CTCs that have undergone an epithelial-mesenchymal transition. Increasing assay analytical sensitivity may lead, however, to a decrease in analytical specificity (e.g., through the detection of circulating normal epithelial cells). A considerable number of promising CTC detection techniques have been developed in recent years. The analytical specificity and clinical utility of these methods must be demonstrated in large prospective multicenter studies to reach the high level of evidence required for their introduction into clinical practice.

  9. Antitumor efficacy and amelioration of oxidative stress by Trichosanthes dioica root against Ehrlich ascites carcinoma in mice.

    PubMed

    Bhattacharya, Sanjib; Prasanna, Angelene; Majumdar, Piyali; Kumar, R B Suresh; Haldar, Pallab K

    2011-09-01

    Trichosanthes dioica Roxb. (Cucurbitaceae) is a dioecious climber, traditionally used in India for several medicinal purposes. The present study assessed the hydroalcoholic extract of T. dioica root (TDA) for antitumor effect and antioxidant influence against Ehrlich ascites carcinoma (EAC) in Swiss albino mice. Twenty four hours after intraperitoneal inoculation of tumor (EAC) cells in mice, TDA was administered at 5 and 10 mg/kg body weight daily for 9 consecutive days. On the 10th day, half of the mice were sacrificed for estimation of tumor proliferation, hematological, and liver antioxidant parameters viz. lipid peroxidation, reduced glutathione (GSH), glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT); and the rest were kept alive for assessment of increase in life span. The antitumor effect of TDA was assessed by evaluating tumor weight, tumor volume, packed cell volume, viable and non-viable tumor cell counts, median survival time and percentage increase in life span of EAC bearing mice. TDA exhibited dose dependent and significant (p < 0.001) decrease in tumor weight, tumor volume, packed cell volume and viable cell count and extended the life span of EAC bearing hosts. Hematological profiles were significantly (p < 0.001) restored near to normal in TDA treated mice as compared to EAC control. TDA treatment significantly (p < 0.001) modulated the aforesaid liver antioxidant parameters as compared to EAC control. The present study demonstrated that TDA possessed promising antitumor efficacy in mice, plausibly mediated by amelioration of oxidative stress by multiple mechanisms.

  10. Tumor-infiltrating immune cells: triggers for tumor capsule disruption and tumor progression?

    PubMed

    Jiang, Bin; Mason, Jeffrey; Jewett, Anahid; Liu, Min-ling; Chen, Wen; Qian, Jun; Ding, Yijiang; Ding, Shuqing; Ni, Min; Zhang, Xichen; Man, Yan-gao

    2013-01-01

    Our previous studies of human breast and prostate cancer have shown that aberrant immune cell infiltration is associated with focal tumor capsule disruption and tumor cell budding that facilitate invasion and metastasis. Our current study attempted to determine whether aberrant immune cell infiltration would have similar impact on colorectal cancer (CRC). Tissue sections from 100 patients with primary CRC were assessed for the frequencies of focal basement membrane (BM) disruption, muscularis mucosa (MM) fragmentation, and tumor cell dissemination in epithelial structures adjacent and distal to infiltrating lymphoid aggregates using a panel of biomarkers and quantitative digital imaging. Our study revealed: (1) epithelial structures adjacent to lymphoid follicles or aggregates had a significantly higher (p<0.001) frequency of focally disrupted BM, dissociated epithelial cells in the stroma, disseminated epithelial cells within lymphatic ducts or blood vessels, and fragmented MM than their distal counterparts, (2) a majority of dissociated epithelial cells within the stroma or vascular structures were immediately subjacent to or physically associated with infiltrating immune cells, (3) the junctions of pre-invasive and invasive lesions were almost exclusively located at sites adjacent to lymphoid follicles or aggregates, (4) infiltrating immune cells were preferentially associated with epithelial capsules that show distinct degenerative alterations, and (5) infiltrating immune cells appeared to facilitate tumor stem cell proliferation, budding, and dissemination. Aberrant immune cell infiltration may have the same destructive impact on the capsule of all epithelium-derived tumors. This, in turn, may selectively favor the proliferation of tumor stem or progenitor cells overlying these focal disruptions. These proliferating epithelial tumor cells subsequently disseminate from the focal disruption leading to tumor invasion and metastasis.

  11. Aconitine-containing agent enhances antitumor activity of dichloroacetate against Ehrlich carcinoma.

    PubMed

    Pyaskovskaya, O N; Boychuk, I V; Fedorchuk, A G; Kolesnik, D L; Dasyukevich, O I; Solyanik, G I

    2015-09-01

    Significant variability of anticancer efficacy of dichloroacetate (DCA) stimulated an active search for the agents capable to enhance it antitumor action. Therefore, the aim of this work is the study of capability of aconitine-containing antiangiogenic agent BC1 to enhance anticancer activity of DCA against Ehrlich carcinoma. DCA (total dose was 1.3 g/kg of b.w.) and BC1 (total dose was 0.9 mg/kg of b.w.) were administered per os starting from the 2(nd) and 3(rd) days, respectively (8 admini-strations for each agent). Antitumor efficacy of agents was estimated. Lactate level, LDH activity and the state of mitochondrial electron transport chain in tumor cells as well as phagocytic activity and reactive oxygen species (ROS) production of tumor-associated macrophages (TAM) were studied. Combined administration of DCA and ВС1 resulted in 89.8% tumor growth inhibition (p < 0.001), what is by 22.5% (p < 0.05) higher that that of DCA alone. This combined treatment was accompanied with a decrease of lactate level in tumor tissue by 30% (p < 0.05) and significant elevation of LDH activity by 70% (p < 0.01). Increased level of NO-Fe-S clusters and 2-fold reduction of Fe-S cluster content were revealed in tumor tissue of mice after DCA and BC1 administration. It was shown that combined therapy did not effect TAM quantity and their phagocytic activity but stimulated ROS production by TAMs by 78% (p < 0.05) compared to this index in control animals. Antiangiogenic agent ВС1 in combination with DCA considerably enhances antitumor activity of DCA via significant decrease of Fe-S-containing protein level resulted from substantial elevation of nitrosylation of these proteins.

  12. Tumor-associated macrophages (not tumor cells) are the determinants of photosensitizer tumor localization

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Krosl, Gorazd

    1995-03-01

    The distribution of Photofrin and several other photosensitizers among major cellular populations contained in solid mouse tumors was examined using flow cytometry. Seven tumor models were included in the analysis: sarcomas EMT6, KHT, RIF, FsaR and FsaN, Lewis lung carcinoma and squamous cell carcinoma SCCVII. In all these tumors, the highest photosensitizer levels were found in a subpopulation of tumor associated macrophages consisting of activated cells (as suggested by their increased size, granularity, and the number of interleukin 2 receptors). There was no evidence of selective photosensitizer accumulation in malignant tumor cells. Results consistent with these observations were also obtained with the carcinogen induced squamous cell carcinoma growing in hamster cheek pouch.

  13. Giant cell tumor in adipose package Hoffa

    PubMed Central

    Etcheto, H. Rivarola; Escobar, G.; Blanchod, C. Collazo; Palanconi, M.; Zordan, J.; Salinas, E. Alvarez; Autorino₁, Carlos

    2017-01-01

    Tumors of adipose Hoffa package are very uncommon, with isolated cases reported in the literature. His presentation in pediatric patients knee is exceptional. The most frequently described tumors are benign including vellonodular synovitis. The extra-articular localized variant there of is known as giant cell tumor of the tendon sheath. It is characterized by locally aggressive nature, and has been described in reports of isolated cases. Objective: A case of giant cell tumor of the tendon sheath in adipose presentation package Hoffa in pediatric patients is presented in this paper. Methods: male patient eleven years with right knee pain after sports practice was evaluated. Physical examination, showed limited extension -30º, joint effusion, stable negative Lachman maneuver without peripheral knee laxity. MRI hyperintense on tumor is observed in T2 and hypointense on T1 homogeneous and defined edges content displayed prior to LCA related to adipose Hoffa package. Results: The tumor specimen was obtained and histopathology is defined as densely cellular tissue accumulation of xantomisados fibrocollagenous with histiocytes and multinucleated giant cells, compatible with giant cell tumor of tendon sheath. Conclusion: The presentation of giant cell tumors of the tendon sheath in Hoffa fat pad is exceptional. However, his suspicion allows adequate preoperative surgical planning, as a whole resection is the only procedure that has been shown to decrease the rate of recurrence of this disease.

  14. Inhibition of uncoupled respiration in tumor cells. A possible role of mitochondrial Ca2+ efflux.

    PubMed

    Gabai, V L

    1993-08-23

    Uncouplers CCCP (2-4 microM) or DNP (200-400 microM) when added to EL-4 thymoma or Ehrlich carcinoma ascites cells initially stimulated endogenous respiration about 2-fold but then inhibited it to a first-order rate 20-25% of controls. This inhibition was accelerated by intracellular acidification or by A23187, a Ca2+/H(+)-antiporter (i.e. when mitochondrial Ca2+ efflux was stimulated) whereas Ruthenium red, an inhibitor of uniporter-driven Ca2+ efflux, significantly slowed down the effect of uncouplers. The respiratory inhibition was associated with NAD(P)H oxidation and was partially reversed by exogenous substrates (glutamine or glucose). In the permeabilized cells, endogenous and glutamine-supported respiration was inhibited by EGTA, while succinate-supported respiration was Ca2+ independent. It is suggested that mitochondrial Ca2+ is necessary for NADH-dependent respiration of tumor cells, and uncouplers inhibit it by activation of mitochondrial Ca2+ efflux.

  15. Herceptin Conjugates Linked by EDC Boost Direct Tumor Cell Death via Programmed Tumor Cell Necrosis

    PubMed Central

    Hughes, Dennis; Esteva, Francisco J.; Liu, Bolin; Chandra, Joya; Li, Shulin

    2011-01-01

    Tumor-targeted antibody therapy is one of the safest biological therapeutics for cancer patients, but it is often ineffective at inducing direct tumor cell death and is ineffective against resistant tumor cells. Currently, the antitumor efficacy of antibody therapy is primarily achieved by inducing indirect tumor cell death, such as antibody-dependent cell cytotoxicity. Our study reveals that Herceptin conjugates, if generated via the crosslinker EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride), are capable of engendering human epidermal growth factor receptor 2 (Her2) positive tumor cells death. Using a high-performance liquid chromatography (HPLC) system, three peaks with estimated molecular weights of antibody monomer, dimer, and trimer were isolated. Both Herceptin trimer and dimer separated by HPLC induced significant levels of necrotic tumor cell death, although the trimer was more effective than the dimer. Notably, the Herceptin trimer also induced Herceptin-resistant tumor cell death. Surprisingly different from the known cell death mechanism that often results from antibody treatment, the Herceptin trimer elicited effective and direct tumor cell death via a novel mechanism: programmed cell necrosis. In Her2-positive cells, inhibition of necrosis pathways significantly reversed Herceptin trimer-induced cell death. In summary, the Herceptin trimer reported herein harbors great potential for overcoming tumor cell resistance to Herceptin treatment. PMID:21853100

  16. Perioperative circulating tumor cell detection: Current perspectives

    PubMed Central

    Kaifi, Jussuf T.; Li, Guangfu; Clawson, Gary; Kimchi, Eric T.; Staveley-O'Carroll, Kevin F.

    2016-01-01

    ABSTRACT Primary cancer resections and in selected cases surgical metastasectomies significantly improve survival, however many patients develop recurrences. Circulating tumor cells (CTCs) function as an independent marker that could be used in the prognostication of different cancers. Sampling of blood and bone marrow compartments during cancer resections is a unique opportunity to increase individual tumor cell capture efficiency. This review will address the diagnostic and therapeutic potentials of perioperative tumor isolation and highlight the focus of future studies on characterization of single disseminated cancer cells to identify targets for molecular therapy and immune escape mechanisms. PMID:27045201

  17. Destruction of solid tumors by immune cells

    NASA Astrophysics Data System (ADS)

    López, Álvaro G.; Seoane, Jesús M.; Sanjuán, Miguel A. F.

    2017-03-01

    The fractional cell kill is a mathematical expression describing the rate at which a certain population of cells is reduced to a fraction of itself. In order to investigate the fractional cell kill that governs the rate at which a solid tumor is lysed by a cell population of cytotoxic CD8+ T cells (CTLs), we present several in silico simulations and mathematical analyses. When the CTLs eradicate efficiently the tumor cells, the models predict a correlation between the morphology of the tumors and the rate at which they are lysed. However, when the effectiveness of the immune cells is decreased, the mathematical function fails to reproduce the process of lysis. This limit is thoroughly discussed and a new fractional cell kill is proposed.

  18. DNA Tumor Viruses and Cell Metabolism.

    PubMed

    Mushtaq, Muhammad; Darekar, Suhas; Kashuba, Elena

    2016-01-01

    Viruses play an important role in cancerogenesis. It is estimated that approximately 20% of all cancers are linked to infectious agents. The viral genes modulate the physiological machinery of infected cells that lead to cell transformation and development of cancer. One of the important adoptive responses by the cancer cells is their metabolic change to cope up with continuous requirement of cell survival and proliferation. In this review we will focus on how DNA viruses alter the glucose metabolism of transformed cells. Tumor DNA viruses enhance "aerobic" glycolysis upon virus-induced cell transformation, supporting rapid cell proliferation and showing the Warburg effect. Moreover, viral proteins enhance glucose uptake and controls tumor microenvironment, promoting metastasizing of the tumor cells.

  19. Surgery for germ cell tumors.

    PubMed

    Sagae, S; Kudo, R

    2000-01-01

    We performed a review of the current modalities of surgical treatment of malignant ovarian germ cell tumors by clinical stages and histological types. Stage IA dysgerminoma is performed with a unilateral salpingo-oophorectomy (USO) without chemotherapy. However, for Stage IB or IC patients with dysgerminoma, USO plus chemotherapy as a primary treatment may or may not be followed with a second-look operation (SLO). For non-dysgerminomas, USO is indicated only for Stage IA immature teratoma grade 1. The treatment for Stage IA immature teratoma grade 2 or 3 and other histological types is USO plus chemotherapy. Patients with Stage IB, IC or higher with non-dysgerminoma are treated with USO plus chemotherapy or USO with contralateral partial ovariectomy plus chemotherapy. For patients who require non-conservative surgery, a total abdominal hysterectomy (TAH) and a bilateral salpingo-oophorectomy (BSO) plus chemotherapy are performed. For patients with Stage II of all histological types, conservative surgery consists of USO and a cytoreductive operation plus chemotherapy, followed by SLO or a second cytoreductive operation. For non-conservative surgery, TAH+BSO with or without a cytoreductive operation plus chemotherapy is followed by SLO. Conservative surgery for patients with Stage III and IV is USO and a cytoreductive operation plus chemotherapy followed by a second cytoreductive operation. Non-conservative surgery is TAH+BSO with a cytoreductive operation plus chemotherapy, followed by SLO or a second cytoreductive operation. However, primary or secondary cytoreductive surgery with or without lymphadenectomy and SLO are still controversial in terms of improving patient survival. Copyright 2000 Wiley-Liss, Inc.

  20. Mesenchymal stem cells in tumor development

    PubMed Central

    Cuiffo, Benjamin G.; Karnoub, Antoine E.

    2012-01-01

    Mesenchymal stem cells (MSCs) are multipotent progenitor cells that participate in the structural and functional maintenance of connective tissues under normal homeostasis. They also act as trophic mediators during tissue repair, generating bioactive molecules that help in tissue regeneration following injury. MSCs serve comparable roles in cases of malignancy and are becoming increasingly appreciated as critical components of the tumor microenvironment. MSCs home to developing tumors with great affinity, where they exacerbate cancer cell proliferation, motility, invasion and metastasis, foster angiogenesis, promote tumor desmoplasia and suppress anti-tumor immune responses. These multifaceted roles emerge as a product of reciprocal interactions occurring between MSCs and cancer cells and serve to alter the tumor milieu, setting into motion a dynamic co-evolution of both tumor and stromal tissues that favors tumor progression. Here, we summarize our current knowledge about the involvement of MSCs in cancer pathogenesis and review accumulating evidence that have placed them at the center of the pro-malignant tumor stroma. PMID:22863739

  1. Sertoli-Leydig cell tumor

    MedlinePlus

    ... produce and release a male sex hormone called testosterone. Causes The exact cause of this tumor is ... the levels of female and male hormones, including testosterone . An ultrasound or another imaging test will likely ...

  2. Cell trafficking of endothelial progenitor cells in tumor progression.

    PubMed

    de la Puente, Pilar; Muz, Barbara; Azab, Feda; Azab, Abdel Kareem

    2013-07-01

    Blood vessel formation plays an essential role in many physiologic and pathologic processes, including normal tissue growth and healing, as well as tumor progression. Endothelial progenitor cells (EPC) are a subtype of stem cells with high proliferative potential that are capable of differentiating into mature endothelial cells, thus contributing to neovascularization in tumors. In response to tumor-secreted cytokines, EPCs mobilize from the bone marrow to the peripheral blood, home to the tumor site, and differentiate to mature endothelial cells and secrete proangiogenic factors to facilitate vascularization of tumors. In this review, we summarize the expression of surface markers, cytokines, receptors, adhesion molecules, proteases, and cell signaling mechanisms involved in the different steps (mobilization, homing, and differentiation) of EPC trafficking from the bone marrow to the tumor site. Understanding the biologic mechanisms of EPC cell trafficking opens a window for new therapeutic targets in cancer.

  3. Characterization of cell suspensions from solid tumors

    SciTech Connect

    Pallavicini, M.

    1985-07-10

    The desirable features of cells in suspension will necessarily be dependent upon the use for which the cells were prepared. Adequate cell yield or recovery is defined by the measurement to be performed. Retention of cellular morphology is important for microscopic identification of cell types in a heterogenous cell suspension, and may be used to determine whether the cells in suspension are representative of those in the tumor in situ. Different dispersal protocols may yield cells with different degrees of clonogenicity, as well as altered biochemical features, such as loss of cellular proteins, surface antigens, nucleotide pools, etc. The quality of the cell suspension can be judged by the degree of cell clumping and level of cellular debris, both of which impact on flow cytometric measurements and studies in which the number of cells be known accurately. Finally, if the data measured on the cells in suspension are to be extrapolated to phenomena occurring in the tumor in situ, it is desirable that the cells in suspension are representative of those in the solid tumor in vivo. This report compares characteristics of tumor cell suspensions obtained by different types of selected disaggregation methods. 33 refs., 2 figs., 4 tabs.

  4. Hemagglutinin protease secreted by V. cholerae induced apoptosis in breast cancer cells by ROS mediated intrinsic pathway and regresses tumor growth in mice model.

    PubMed

    Ray, Tanusree; Chakrabarti, Monoj Kumar; Pal, Amit

    2016-02-01

    Conventional anticancer therapies are effective but have side effects, so alternative targets are being developed. Bacterial toxins that can kill cells or alter the cellular processes like proliferation, apoptosis and differentiation have been reported for cancer treatment. In this study we have shown antitumor activity of hemagglutinin protease (HAP) secreted by Vibrio cholerae. One µg of HAP showed potent antitumor activity when injected into Ehrlich ascites carcinoma (EAC) tumors in Swiss albino mice. Weekly administration of this dose is able to significantly diminish a large tumor volume within 3 weeks and increases the survival rates of cancerous mice. HAP showed apoptotic activity on EAC and other malignant cells. Increased level of pro-apoptotic p53 with increased ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2 signify that HAP induced apoptogenic signals lead to death of the tumor cells. In vivo and ex vivo studies suggest that mitochondrial dependent intrinsic pathway is responsible for this apoptosis. The level of ROS in malignant cells is reported to be higher than the normal healthy cells. HAP induces oxidative stress and increases the level of ROS in malignant cells which is significantly higher than the normal healthy cells. As a result the malignant cells cross the threshold level of ROS for cell survival faster than normal healthy cells. This mechanism causes HAP mediated apoptosis in malignant cells, but normal cells remain unaltered in the same environment. Our study suggests that HAP may be used as a new candidate drug for cancer therapy.

  5. CAR T Cell Therapy for Solid Tumors.

    PubMed

    Newick, Kheng; O'Brien, Shaun; Moon, Edmund; Albelda, Steven M

    2017-01-14

    The field of cancer immunotherapy has been re-energized by the application of chimeric antigen receptor (CAR) T cell therapy in cancers. These CAR T cells are engineered to express synthetic receptors that redirect polyclonal T cells to surface antigens for subsequent tumor elimination. Many CARs are designed with elements that augment T cell persistence and activity. To date, CAR T cells have demonstrated tremendous success in eradicating hematologic malignancies (e.g., CD19 CARs in leukemias). However, this success has yet to be extrapolated to solid tumors, and the reasons for this are being actively investigated. We characterize some of the challenges that CAR T cells have to surmount in the solid tumor microenvironment and new approaches that are being considered to overcome these hurdles.

  6. Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses

    PubMed Central

    Chiba, Shiho; Ikushima, Hiroaki; Ueki, Hiroshi; Yanai, Hideyuki; Kimura, Yoshitaka; Hangai, Sho; Nishio, Junko; Negishi, Hideo; Tamura, Tomohiko; Saijo, Shinobu; Iwakura, Yoichiro; Taniguchi, Tadatsugu

    2014-01-01

    The eradication of tumor cells requires communication to and signaling by cells of the immune system. Natural killer (NK) cells are essential tumor-killing effector cells of the innate immune system; however, little is known about whether or how other immune cells recognize tumor cells to assist NK cells. Here, we show that the innate immune receptor Dectin-1 expressed on dendritic cells and macrophages is critical to NK-mediated killing of tumor cells that express N-glycan structures at high levels. Receptor recognition of these tumor cells causes the activation of the IRF5 transcription factor and downstream gene induction for the full-blown tumoricidal activity of NK cells. Consistent with this, we show exacerbated in vivo tumor growth in mice genetically deficient in either Dectin-1 or IRF5. The critical contribution of Dectin-1 in the recognition of and signaling by tumor cells may offer new insight into the anti-tumor immune system with therapeutic implications. DOI: http://dx.doi.org/10.7554/eLife.04177.001 PMID:25149452

  7. Histopathology of pineal germ cell tumors.

    PubMed

    Vasiljevic, A; Szathmari, A; Champier, J; Fèvre-Montange, M; Jouvet, A

    2015-01-01

    Germ cell tumors (GCTs) classically occur in gonads. However, they are the most frequent neoplasms in the pineal region. The pineal location of GCTs may be caused by the neoplastic transformation of a primordial germ cell that has mismigrated. The World Health Organization (WHO) recognizes 5 histological types of intracranial GCTs: germinoma and non-germinomatous tumors including embryonal carcinoma, yolk sac tumor, choriocarcinoma and mature or immature teratoma. Germinomas and teratomas are frequently encountered as pure tumors whereas the other types are mostly part of mixed GCTs. In this situation, the neuropathologist has to be able to identify each component of a GCT. When diagnosis is difficult, use of recent immunohistochemical markers such as OCT(octamer-binding transcription factor)3/4, Glypican 3, SALL(sal-like protein)4 may be required. OCT3/4 is helpful in the diagnosis of germinomas, Glypican 3 in the diagnosis of yolk sac tumors and SALL4 in the diagnosis of the germ cell nature of an intracranial tumor. When the germ cell nature of a pineal tumor is doubtful, the finding of an isochromosome 12p suggests the diagnosis of GCT. The final pathological report should always be confronted with the clinical data, especially the serum or cerebrospinal fluid levels of β-human chorionic gonadotropin (HCG) and alpha-fetoprotein.

  8. Pancreastatin producing cell line from human pancreatic islet cell tumor.

    PubMed

    Funakoshi, A; Tateishi, K; Tsuru, M; Jimi, A; Wakasugi, H; Ikeda, Y; Kono, A

    1990-04-30

    It has been characterized that cell line QGP-1 derived from human non-functioning pancreatic islet cell tumor produces human pancreastatin. Exponentially growing cultures produced 5.7 fmol of pancreastatin/10(6) cells/hr. Human pancreastatin immunoreactivities in plasma and tumor after xenografting with QGP-1 into nude mouse were 92.7 fmol/ml and 160.2 pmol/g wet weight, respectively. Immunocytochemical study revealed both chromogranin A and pancreastatin immunoreactive cells in the tumor. Gel filtrations of culture medium and tumor extract identified heterogenous molecular forms of PST-LI which eluted as large and smaller molecular species. These results suggest that plasma pancreastatin levels may be useful as a tumor marker of endocrine tumor of the pancreas, and the pancreastatin producing cell line may be useful for studies of the mechanism of secretions and processing of chromogranin A and pancreastatin.

  9. Energy and Redox Homeostasis in Tumor Cells

    PubMed Central

    de Oliveira, Marcus Fernandes; Amoêdo, Nívea Dias; Rumjanek, Franklin David

    2012-01-01

    Cancer cells display abnormal morphology, chromosomes, and metabolism. This review will focus on the metabolism of tumor cells integrating the available data by way of a functional approach. The first part contains a comprehensive introduction to bioenergetics, mitochondria, and the mechanisms of production and degradation of reactive oxygen species. This will be followed by a discussion on the oxidative metabolism of tumor cells including the morphology, biogenesis, and networking of mitochondria. Tumor cells overexpress proteins that favor fission, such as GTPase dynamin-related protein 1 (Drp1). The interplay between proapoptotic members of the Bcl-2 family that promotes Drp 1-dependent mitochondrial fragmentation and fusogenic antiapoptotic proteins such as Opa-1 will be presented. It will be argued that contrary to the widespread belief that in cancer cells, aerobic glycolysis completely replaces oxidative metabolism, a misrepresentation of Warburg's original results, mitochondria of tumor cells are fully viable and functional. Cancer cells also carry out oxidative metabolism and generally conform to the orthodox model of ATP production maintaining as well an intact electron transport system. Finally, data will be presented indicating that the key to tumor cell survival in an ROS rich environment depends on the overexpression of antioxidant enzymes and high levels of the nonenzymatic antioxidant scavengers. PMID:22693511

  10. [Sertoli cell tumor of the testis].

    PubMed

    Hita Rosino, E; López Hidalgo, J; Mellado Mesa, P; Olivar Buera, M

    2001-01-01

    Sertoli cell tumors (TCS) derivated from sex-cord estroma cells, are an uncommon variety of testicles neoplasms. A 66 year-old patient that came to the consultation for an increased scrotum of size present. Ultrasound viewed a hipoecoic nodule capable with testicular tumor, more secondary hidrocele. After undergoing the standard treatment, by means of groin radical orchiectomy, its pathologic analysis identified the lesion as Sertoli cell tumor conventional. The pathologic features that best correlate with a clinically benign course are as follows: a lower size tumor to 5 cm, mild nuclear atypia, a mitotic rate of less than 5 mitosis per 10 high power fields, and absent necrosis. Our case presented with these features. Follow-up of these neoplasms should be prolonged by the unusual of its presentation and a small percentage of cases are clinically malignant.

  11. Nuclisome--targeting the tumor cell nucleus.

    PubMed

    Gedda, Lars; Edwards, Katarina

    2012-06-01

    The Nuclisome concept builds on a novel two-step targeting strategy with the aim to deliver short-range Auger-electron-emitting radionuclides to nuclear DNA of tumor cells. The concept is based on the use of Nuclisome-particles, i.e., tumor-targeted PEG-stabilized liposomes loaded with a unique DNA-intercalating compound that enables specific and effective delivery of radionuclides to DNA. The specific and potent two-step targeting leads to eradication of tumor cells while toxicity to normal organs is reduced to a minimum. Results of in vitro and in vivo studies point towards the Nuclisome concept as a promising strategy for the treatment of small tumor masses and, in particular, for the elimination of spread single cells and micrometastases.

  12. Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles

    PubMed Central

    Ma, Jingwei; Zhang, Yi; Tang, Ke; Zhang, Huafeng; Yin, Xiaonan; Li, Yong; Xu, Pingwei; Sun, Yanling; Ma, Ruihua; Ji, Tiantian; Chen, Junwei; Zhang, Shuang; Zhang, Tianzhen; Luo, Shunqun; Jin, Yang; Luo, Xiuli; Li, Chengyin; Gong, Hongwei; Long, Zhixiong; Lu, Jinzhi; Hu, Zhuowei; Cao, Xuetao; Wang, Ning; Yang, Xiangliang; Huang, Bo

    2016-01-01

    Developing novel approaches to reverse the drug resistance of tumor-repopulating cells (TRCs) or stem cell-like cancer cells is an urgent clinical need to improve outcomes of cancer patients. Here we show an innovative approach that reverses drug resistance of TRCs using tumor cell-derived microparticles (T-MPs) containing anti-tumor drugs. TRCs, by virtue of being more deformable than differentiated cancer cells, preferentially take up T-MPs that release anti-tumor drugs after entering cells, which in turn lead to death of TRCs. The underlying mechanisms include interfering with drug efflux and promoting nuclear entry of the drugs. Our findings demonstrate the importance of tumor cell softness in uptake of T-MPs and effectiveness of a novel approach in reversing drug resistance of TRCs with promising clinical applications. PMID:27167569

  13. Epigenetic states of cells of origin and tumor evolution drive tumor-initiating cell phenotype and tumor heterogeneity.

    PubMed

    Chow, Kin-Hoe; Shin, Dong-Mi; Jenkins, Molly H; Miller, Emily E; Shih, David J; Choi, Seungbum; Low, Benjamin E; Philip, Vivek; Rybinski, Brad; Bronson, Roderick T; Taylor, Michael D; Yun, Kyuson

    2014-09-01

    A central confounding factor in the development of targeted therapies is tumor cell heterogeneity, particularly in tumor-initiating cells (TIC), within clinically identical tumors. Here, we show how activation of the Sonic Hedgehog (SHH) pathway in neural stem and progenitor cells creates a foundation for tumor cell evolution to heterogeneous states that are histologically indistinguishable but molecularly distinct. In spontaneous medulloblastomas that arise in Patched (Ptch)(+/-) mice, we identified three distinct tumor subtypes. Through cell type-specific activation of the SHH pathway in vivo, we determined that different cells of origin evolved in unique ways to generate these subtypes. Moreover, TICs in each subtype had distinct molecular and cellular phenotypes. At the bulk tumor level, the three tumor subtypes could be distinguished by a 465-gene signature and by differential activation levels of the ERK and AKT pathways. Notably, TICs from different subtypes were differentially sensitive to SHH or AKT pathway inhibitors, highlighting new mechanisms of resistance to targeted therapies. In summary, our results show how evolutionary processes act on distinct cells of origin to contribute to tumoral heterogeneity, at both bulk tumor and TIC levels.

  14. Targeting extracellular ROS signaling of tumor cells.

    PubMed

    Bauer, Georg

    2014-04-01

    Expression of membrane-associated NADPH oxidase (NOX1) represents a characteristic feature of malignant cells. NOX1-derived extracellular superoxide anions are the basis for autocrine stimulation of proliferation, but also drive the HOCl and the NO/peroxynitrite signaling pathways. This may cause the elimination of transformed cells. Tumor cells express membrane-associated catalase that efficiently protects the cells against apoptosis-inducing reactive oxygen species (ROS) signaling. Membrane-associated superoxide dismutase (SOD) plays a co-modulatory protective role that is functionally interrelated with the protective effect mediated by catalase. Due to the co-localization of NOX1, catalase and SOD on the outer membrane of tumor cells, specific inhibition of membrane-associated SOD causes superoxide anion-dependent inhibition of catalase. This establishes a strong apoptotic signaling through the NO/peroxynitrite pathway. In parallel, it causes a drastic decrease in the concentration of proliferation-stimulating H2O2. Knowledge of the biochemical network on the surface of tumor cells should, therefore, allow development of specific novel strategies for tumor therapy, based on the specific features of tumor cell-specific extracellular ROS interactions.

  15. Spirulina platensis Lacks Antitumor Effect against Solid Ehrlich Carcinoma in Female Mice

    PubMed Central

    Barakat, Waleed; Elshazly, Shimaa M.; Mahmoud, Amr A. A.

    2015-01-01

    Spirulina is a blue-green alga used as a dietary supplement. It has been shown to possess anti-inflammatory, antioxidant, and hepatoprotective properties. This study was designed to evaluate the antitumor effect of spirulina (200 and 800 mg/kg) against a murine model of solid Ehrlich carcinoma compared to a standard chemotherapeutic drug, 5-fluorouracil (20 mg/kg). Untreated mice developed a palpable solid tumor after 13 days. Unlike fluorouracil, spirulina at the investigated two dose levels failed to exert any protective effect. In addition, spirulina did not potentiate the antitumor effect of fluorouracil when they were administered concurrently. Interestingly, their combined administration resulted in a dose-dependent increase in mortality. The present study demonstrates that spirulina lacks antitumor effect against this model of solid Ehrlich carcinoma and increased mortality when combined with fluorouracil. However, the implicated mechanism is still elusive. PMID:26366170

  16. Spirulina platensis Lacks Antitumor Effect against Solid Ehrlich Carcinoma in Female Mice.

    PubMed

    Barakat, Waleed; Elshazly, Shimaa M; Mahmoud, Amr A A

    2015-01-01

    Spirulina is a blue-green alga used as a dietary supplement. It has been shown to possess anti-inflammatory, antioxidant, and hepatoprotective properties. This study was designed to evaluate the antitumor effect of spirulina (200 and 800 mg/kg) against a murine model of solid Ehrlich carcinoma compared to a standard chemotherapeutic drug, 5-fluorouracil (20 mg/kg). Untreated mice developed a palpable solid tumor after 13 days. Unlike fluorouracil, spirulina at the investigated two dose levels failed to exert any protective effect. In addition, spirulina did not potentiate the antitumor effect of fluorouracil when they were administered concurrently. Interestingly, their combined administration resulted in a dose-dependent increase in mortality. The present study demonstrates that spirulina lacks antitumor effect against this model of solid Ehrlich carcinoma and increased mortality when combined with fluorouracil. However, the implicated mechanism is still elusive.

  17. Contractile forces in tumor cell migration

    PubMed Central

    Mierke, Claudia Tanja; Rösel, Daniel; Fabry, Ben; Brábek, Jan

    2008-01-01

    Cancer is a deadly disease primarily because of the ability of tumor cells to spread from the primary tumor, to invade into the connective tissue, and to form metastases at distant sites. In contrast to cell migration on a planar surface where large cell tractions and contractile forces are not essential, tractions and forces are thought to be crucial for overcoming the resistance and steric hindrance of a dense 3-dimensional connective tissue matrix. In this review, we describe recently developed biophysical tools including 2-D and 3-D traction microscopy to measure contractile forces of cells. We discuss evidence indicating that tumor cell invasiveness is associated with increased contractile force generation. PMID:18295931

  18. One cell, multiple roles: contribution of mesenchymal stem cells to tumor development in tumor microenvironment.

    PubMed

    Yang, Xue; Hou, Jing; Han, Zhipeng; Wang, Ying; Hao, Chong; Wei, Lixin; Shi, Yufang

    2013-01-21

    The discovery of tissue reparative and immunosuppressive abilities of mesenchymal stem cells (MSCs) has drawn more attention to tumor microenvironment and its role in providing the soil for the tumor cell growth. MSCs are recruited to tumor which is referred as the never healing wound and altered by the inflammation environment, thereby helping to construct the tumor microenvironment. The environment orchestrated by MSCs and other factors can be associated with angiogenesis, immunosuppression, inhibition of apoptosis, epithelial-mesenchymal transition (EMT), survival of cancer stem cells, which all contribute to tumor growth and progression. In this review, we will discuss how MSCs are recruited to the tumor microenvironment and what effects they have on tumor progression.

  19. Whole tumor antigen vaccination using dendritic cells: Comparison of RNA electroporation and pulsing with UV-irradiated tumor cells

    PubMed Central

    Benencia, Fabian; Courrèges, Maria C; Coukos, George

    2008-01-01

    Because of the lack of full characterization of tumor associated antigens for solid tumors, whole antigen use is a convenient approach to tumor vaccination. Tumor RNA and apoptotic tumor cells have been used as a source of whole tumor antigen to prepare dendritic cell (DC) based tumor vaccines, but their efficacy has not been directly compared. Here we compare directly RNA electroporation and pulsing of DCs with whole tumor cells killed by ultraviolet (UV) B radiation using a convenient tumor model expressing human papilloma virus (HPV) E6 and E7 oncogenes. Although both approaches led to DCs presenting tumor antigen, electroporation with tumor cell total RNA induced a significantly higher frequency of tumor-reactive IFN-gamma secreting T cells, and E7-specific CD8+ lymphocytes compared to pulsing with UV-irradiated tumor cells. DCs electroporated with tumor cell RNA induced a larger tumor infiltration by T cells and produced a significantly stronger delay in tumor growth compared to DCs pulsed with UV-irradiated tumor cells. We conclude that electroporation with whole tumor cell RNA and pulsing with UV-irradiated tumor cells are both effective in eliciting antitumor immune response, but RNA electroporation results in more potent tumor vaccination under the examined experimental conditions. PMID:18445282

  20. Cell Motility in Tumor Invasion

    DTIC Science & Technology

    2004-07-01

    lines ( Dondi et al. 1994; Dondi et al. 1998; Limonta et al. 2001). In line with these observations, the LHRH analog Cetrorelix has been shown to have...Stone et al. 1978); it retains the androgen independence of the original tumor and does not express a functional androgen receptor ( Dondi et al. 1998...goserelin ( Dondi et al. 1994; Jungwirth et al. 1997A; Jungwirth et al. 1997B; Limonta et al. 1998; Wells et al. 2002), and one that inhibits DU-145 WT

  1. Retrotransposon Targeting of Tumor Cells

    DTIC Science & Technology

    2005-10-01

    with 10% fetal bovine serum (Hyclone, Logan, UT), 2 mM L-glutamine, 1 mM sodium pyruvate, at 370 C, 5% CO 2 in air. -7- Transfection of vector into tumor...The reaction was terminated by adding 100 ul of 0.1M EDTA (pH 8.0) and extracting the RNA twice with phenol chloroform. RNA was ethano l-precipitated

  2. Molecular biology of testicular germ cell tumors.

    PubMed

    Gonzalez-Exposito, R; Merino, M; Aguayo, C

    2016-06-01

    Testicular germ cell tumors (TGCTs) are the most common solid tumors in young adult men. They constitute a unique pathology because of their embryonic and germ origin and their special behavior. Genetic predisposition, environmental factors involved in their development and genetic aberrations have been under study in many works throughout the last years trying to explain the susceptibility and the transformation mechanism of TGCTs. Despite the high rate of cure in this type of tumors because its particular sensitivity to cisplatin, there are tumors resistant to chemotherapy for which it is needed to find new therapies. In the present work, it has been carried out a literature review on the most important molecular aspects involved in the onset and development of such tumors, as well as a review of the major developments regarding prognostic factors, new prognostic biomarkers and the possibility of new targeted therapies.

  3. Cancer stem cell plasticity and tumor hierarchy.

    PubMed

    Cabrera, Marina Carla; Hollingsworth, Robert E; Hurt, Elaine M

    2015-01-26

    The origins of the complex process of intratumoral heterogeneity have been highly debated and different cellular mechanisms have been hypothesized to account for the diversity within a tumor. The clonal evolution and cancer stem cell (CSC) models have been proposed as drivers of this heterogeneity. However, the concept of cancer stem cell plasticity and bidirectional conversion between stem and non-stem cells has added additional complexity to these highly studied paradigms and may help explain the tumor heterogeneity observed in solid tumors. The process of cancer stem cell plasticity in which cancer cells harbor the dynamic ability of shifting from a non-CSC state to a CSC state and vice versa may be modulated by specific microenvironmental signals and cellular interactions arising in the tumor niche. In addition to promoting CSC plasticity, these interactions may contribute to the cellular transformation of tumor cells and affect response to chemotherapeutic and radiation treatments by providing CSCs protection from these agents. Herein, we review the literature in support of this dynamic CSC state, discuss the effectors of plasticity, and examine their role in the development and treatment of cancer.

  4. ADAM12 produced by tumor cells rather than stromal cells accelerates breast tumor progression.

    PubMed

    Fröhlich, Camilla; Nehammer, Camilla; Albrechtsen, Reidar; Kronqvist, Pauliina; Kveiborg, Marie; Sehara-Fujisawa, Atsuko; Mercurio, Arthur M; Wewer, Ulla M

    2011-11-01

    Expression of ADAM12 is low in most normal tissues but is markedly increased in numerous human cancers, including breast carcinomas. We have previously shown that overexpression of ADAM12 accelerates tumor progression in a mouse model of breast cancer (PyMT). In this study, we found that ADAM12 deficiency reduces breast tumor progression in the PyMT model. However, the catalytic activity of ADAM12 seems to be dispensable for its tumor-promoting effect. Interestingly, we show that ADAM12 endogenously expressed in tumor-associated stroma in the PyMT model does not influence tumor progression, but that ADAM12 expression by tumor cells is necessary for tumor progression in these mice. This finding is consistent with our observation that in human breast carcinoma, ADAM12 is almost exclusively located in tumor cells and, only rarely, seen in the tumor-associated stroma. We hypothesized, however, that the tumor-associated stroma may stimulate ADAM12 expression in tumor cells, on the basis of the fact that TGF-β1 stimulates ADAM12 expression and is a well-known growth factor released from tumor-associated stroma. TGF-β1 stimulation of ADAM12-negative Lewis lung tumor cells induced ADAM12 synthesis, and growth of these cells in vivo induced more than 200-fold increase in ADAM12 expression. Our observation that ADAM12 expression is significantly higher in the terminal duct lobular units (TDLU) adjacent to human breast carcinoma compared with TDLUs found in normal breast tissue supports our hypothesis that tumor-associated stroma triggers ADAM12 expression.

  5. Olmesartan Potentiates the Anti-Angiogenic Effect of Sorafenib in Mice Bearing Ehrlich's Ascites Carcinoma: Role of Angiotensin (1–7)

    PubMed Central

    Abd-Alhaseeb, Mohammad M.; Zaitone, Sawsan A.; Abou-El-Ela, Soad H.; Moustafa, Yasser M.

    2014-01-01

    Local renin-angiotensin systems exist in various malignant tumor tissues; this suggests that the main effector peptide, angiotensin II, could act as a key factor in tumor growth. The underlying mechanisms for the anti-angiogenic effect of angiotensin II type 1 receptor blockers need to be further evaluated. The present study was carried out to investigate the anti-angiogenic effect of olmesartan alone or in combination with sorafenib, an angiotensin (1–7) agonist or an angiotensin (1–7) antagonist in Ehrlich's ascites carcinoma-bearing mice. The tumor was induced by intradermal injection of Ehrlich's ascites carcinoma cells into mice. Tumor discs were used to evaluate the microvessel density; the serum levels of vascular endothelial growth factor (VEGF) and serum insulin-like growth factor I (IGF-I); and their intratumoral receptors, VEGF receptor-2 and IGF-I receptor, respectively. All parameters were determined following the treatment course, which lasted for 21 days post-inoculation. Monotherapy with olmesartan and its combination with sorafenib resulted in a significant reduction in microvessel density and serum levels of VEGF and IGF-I, as well as their intratumoral receptors. In addition, the combination of olmesartan (30 mg/kg) with an angiotensin (1–7) agonist reduced the microvessel density, IGF-I serum levels and the levels of its intratumoral receptor. In conclusion, olmesartan reduced the levels of the angiogenesis markers IGF-I and VEGF and down-regulated the intratumoral expression of their receptors in a dose-dependent manner, and these effects were dependent on the angiotensin (1–7) receptor. These results suggest that olmesartan is a promising adjuvant to sorafenib in the treatment of cancer. PMID:24465768

  6. Cell-ECM Interactions in Tumor Invasion.

    PubMed

    He, Xiuxiu; Lee, Byoungkoo; Jiang, Yi

    2016-01-01

    The cancer cells obtain their invasion potential not only by genetic mutations, but also by changing their cellular biophysical and biomechanical features and adapting to the surrounding microenvironments. The extracellular matrix, as a crucial component of the tumor microenvironment, provides the mechanical support for the tissue, mediates the cell-microenvironment interactions, and plays a key role in cancer cell invasion. The biomechanics of the extracellular matrix, particularly collagen, have been extensively studied in the biomechanics community. Cell migration has also enjoyed much attention from both the experimental and modeling efforts. However, the detailed mechanistic understanding of tumor cell-ECM interactions, especially during cancer invasion, has been unclear. This chapter reviews the recent advances in the studies of ECM biomechanics, cell migration, and cell-ECM interactions in the context of cancer invasion.

  7. Circulating tumor cells in colorectal cancer patients.

    PubMed

    Torino, Francesco; Bonmassar, Enzo; Bonmassar, Laura; De Vecchis, Liana; Barnabei, Agnese; Zuppi, Cecilia; Capoluongo, Ettore; Aquino, Angelo

    2013-11-01

    The availability of sensitive methods has allowed the detailed study of circulating tumor cells only recently. Evolving evidence support the prognostic and predictive role of these cells in patients affected by several solid tumors, including colorectal cancer. Ongoing studies are aimed at confirming that the molecular characterization of circulating tumor cells in peripheral blood and in bone marrow of patients is a powerful tool to improve the patient risk-stratification, to monitor activity of the drugs, to develop more appropriate targeted therapies and tailored treatments. In parallel, results from these correlative studies promise to gain a better biological understanding of the metastatic process. The clinical utility of the detection of circulating tumor cells in patients affected by colorectal cancer is still hampered by a number of specific hurdles. Improvement in sensitivity and specificity of the available methods of detection, standardization of these methods and functional characterization of circulating tumor cells in well designed and statistically well powered studies are the key steps to reach these ambitious objectives in colorectal cancer patients as well. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Surgery and Combination Chemotherapy in Treating Children With Extracranial Germ Cell Tumors

    ClinicalTrials.gov

    2016-05-06

    Childhood Embryonal Tumor; Childhood Extracranial Germ Cell Tumor; Childhood Extragonadal Germ Cell Tumor; Childhood Malignant Ovarian Germ Cell Tumor; Childhood Malignant Testicular Germ Cell Tumor; Childhood Teratoma; Ovarian Embryonal Carcinoma; Ovarian Yolk Sac Tumor; Stage II Malignant Testicular Germ Cell Tumor; Stage IIA Ovarian Germ Cell Tumor; Stage IIB Ovarian Germ Cell Tumor; Stage IIC Ovarian Germ Cell Tumor; Stage III Malignant Testicular Germ Cell Tumor; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIC Ovarian Germ Cell Tumor; Testicular Choriocarcinoma and Yolk Sac Tumor; Testicular Embryonal Carcinoma

  9. Giant cell tumor of bone: Multimodal approach

    PubMed Central

    Gupta, AK; Nath, R; Mishra, MP

    2007-01-01

    Background: The clinical behavior and treatment of giant cell tumor of bone is still perplexing. The aim of this study is to clarify the clinico-pathological correlation of tumor and its relevance in treatment and prognosis. Materials and Methods: Ninety -three cases of giant cell tumor were treated during 1980-1990 by different methods. The age of the patients varied from 18-58 yrs with male and female ratio as 5:4. The upper end of the tibia was most commonly involved (n=31), followed by the lower end of the femur(n=21), distal end of radius(n=14), upper end of fibula (n=9), proximal end of femur(n=5), upper end of the humerus(n=3), iliac bone(n=2), phalanx (n=2) and spine(n=1). The tumors were also encountered on uncommon sites like metacarpals (n=4) and metatarsal(n=1). Fifty four cases were treated by curettage and bone grafting. Wide excision and reconstruction was performed in twenty two cases. Nine cases were treated by wide excision while primary amputation was performed in four cases. One case required only curettage. Three inaccessible lesions of ilium and spine were treated by radiotherapy. Results: 19 of 54 treated by curettage and bone grafting showed a recurrence. The repeat curettage and bone grafting was performed in 18 cases while amputation was done in one. One each out of the cases treated by wide excision and reconstruction and wide excision alone recurred. In this study we observed that though curettage and bone grafting is still the most commonly adopted treatment, wide excision of tumor with reconstruction has shown lesser recurrence. Conclusion: For radiologically well-contained and histologically typical tumor, curettage and autogenous bone grafting is the treatment of choice. The typical tumors with radiologically deficient cortex, clinically aggressive tumors and tumors with histological Grade III should be treated by wide excision and reconstruction. PMID:21139762

  10. Proline oxidase promotes tumor cell survival in hypoxic tumor microenvironments

    PubMed Central

    Liu, Wei; Glunde, Kristine; Bhujwalla, Zaver M.; Raman, Venu; Sharma, Anit; Phang, James M.

    2012-01-01

    Proline is a readily released stress substrate that can be metabolized by proline oxidase (POX) to generate either reactive oxygen species to induce apoptosis or autophagy or ATP during times of nutrient stress. However, the contribution of proline metabolism to tumorigenesis in hypoxic microenvironments has not been explored. In this study, we investigated the different functions of POX under hypoxia and glucose depletion. We found that hypoxia induced POX expression in cancer cells in vitro and that POX upregulation co-localized with hypoxic tissues in vivo. In addition, the combination of hypoxia and low-glucose showed additive effects on POX expression. Similar to conditions of low glucose, hypoxia-mediated POX induction was dependent on AMP-activated protein kinase (AMPK) activation, but was independent of HIF-1α and HIF-2α. Under low-glucose and combined low-glucose and hypoxic conditions, proline catabolized by POX was used preferentially for ATP production, whereas under hypoxia, POX mediated autophagic signaling for survival by generating ROS. Although the specific mechanism was different for hypoxia and glucose deprivation, POX consistently contributed to tumor cell survival under these conditions. Together, our findings offer new insights into the metabolic reprogramming of tumor cells present within a hostile microenvironment and suggest that proline metabolism is a potential target for cancer therapeutics. PMID:22609800

  11. In vivo photolabeling of tumor-infiltrating cells reveals highly regulated egress of T-cell subsets from tumors.

    PubMed

    Torcellan, Tommaso; Hampton, Henry R; Bailey, Jacqueline; Tomura, Michio; Brink, Robert; Chtanova, Tatyana

    2017-05-30

    Immune therapy is rapidly gaining prominence in the clinic as a major weapon against cancer. Whereas much attention has been focused on the infiltration of tumors by immune cells, the subsequent fate of these infiltrates remains largely unexplored. We therefore established a photoconversion-based model that allowed us to label tumor-infiltrating immune cells and follow their migration. Using this system, we identified a population of tumor-experienced cells that emigrate from primary tumors to draining lymph nodes via afferent lymphatic vessels. Although the majority of tumor-infiltrating cells were myeloid, T cells made up the largest population of tumor-egressing leukocytes. Strikingly, the subset composition of tumor-egressing T cells was greatly skewed compared with those that had infiltrated the tumor and those resident in the draining lymph node. Some T-cell subsets such as CD8(+) T cells emigrated more readily; others including CD4(-)CD8(-) T cells were preferentially retained, suggesting that specific mechanisms guide immune cell egress from tumors. Furthermore, tumor-egressing T cells were more activated and displayed enhanced effector function in comparison with their lymph node counterparts. Finally, we demonstrated that tumor-infiltrating T cells migrate to distant secondary tumors and draining lymph nodes, highlighting a mechanism whereby tumor-experienced effector T cells may mediate antitumor immunity at metastatic sites. Thus, our results provide insights into migration and function of tumor-infiltrating immune cells and the role of these cells in tumor immunity outside of primary tumor deposits.

  12. Giant Cell Tumor of Bone - An Overview

    PubMed Central

    Sobti, Anshul; Agrawal, Pranshu; Agarwala, Sanjay; Agarwal, Manish

    2016-01-01

    Giant Cell tumors (GCT) are benign tumors with potential for aggressive behavior and capacity to metastasize. Although rarely lethal, benign bone tumors may be associated with a substantial disturbance of the local bony architecture that can be particularly troublesome in peri-articular locations. Its histogenesis remains unclear. It is characterized by a proliferation of mononuclear stromal cells and the presence of many multi- nucleated giant cells with homogenous distribution. There is no widely held consensus regarding the ideal treatment method selection. There are advocates of varying surgical techniques ranging from intra-lesional curettage to wide resection. As most giant cell tumors are benign and are located near a joint in young adults, several authors favor an intralesional approach that preserves anatomy of bone in lieu of resection. Although GCT is classified as a benign lesion, few patients develop progressive lung metastases with poor outcomes. Treatment is mainly surgical. Options of chemotherapy and radiotherapy are reserved for selected cases. Recent advances in the understanding of pathogenesis are essential to develop new treatments for this locally destructive primary bone tumor. PMID:26894211

  13. Circulating tumor cells: getting more from less.

    PubMed

    Lang, Joshua M; Casavant, Benjamin P; Beebe, David J

    2012-07-04

    Recent insights into circulating tumor cells (CTCs) have been driven by numerous technological innovations aimed at isolating, purifying, and analyzing these rare cells. However, the information density within these cells has yet to be truly accessed and exploited for patient benefit. A device reported by Issadore et al. in this issue of Science Translational Medicine proposes a highly sensitive methodology that may both extend CTC capture to a broader patient population and provide greater understanding of biological targets for personalized medical therapies.

  14. Tumor invasion as dysregulated cell motility.

    PubMed

    Kassis, J; Lauffenburger, D A; Turner, T; Wells, A

    2001-04-01

    Investigations across a range of disciplines over the past decade have brought the study of cell motility and its role in invasion to an exciting threshold. The biophysical forces proximally involved in generating cell locomotion, as well as the underlying signaling and genomic regulatory processes, are gradually becoming elucidated. We now appreciate the intricacies of the many cellular and extracellular events that modulate cell migration. This has enabled the demonstration of a causal role of cell motility in tumor progression, with various points of 'dysregulation' of motility being responsible for promoting invasion. In this paper, we describe key fundamental principles governing cell motility and branch out to describe the essence of the data that describe these principles. It has become evident that many proposed models may indeed be converging into a tightly-woven tapestry of coordinated events which employ various growth factors and their receptors, adhesion receptors (integrins), downstream molecules, cytoskeletal components, and altered genomic regulation to accomplish cell motility. Tumor invasion occurs in response to dysregulation of many of these modulatory points; specific examples include increased signaling from the EGF receptor and through PLC gamma, altered localization and expression of integrins, changes in actin modifying proteins and increased transcription from specific promoter sites. This diversity of alterations all leading to tumor invasion point to the difficulty of correcting causal events leading to tumor invasion and rather suggest that the underlying common processes required for motility be targeted for therapeutic intervention.

  15. High-Dose Thiotepa Plus Peripheral Stem Cell Transplantation in Treating Patients With Refractory Solid Tumors

    ClinicalTrials.gov

    2013-03-06

    Brain and Central Nervous System Tumors; Childhood Germ Cell Tumor; Extragonadal Germ Cell Tumor; Ovarian Cancer; Retinoblastoma; Testicular Germ Cell Tumor; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific

  16. Management of desmoplastic small round cell tumor.

    PubMed

    Hayes-Jordan, Andrea; LaQuaglia, Michael P; Modak, Shakeel

    2016-10-01

    Desmoplastic small round cell tumor (DSRCT) is a soft tissue sarcoma of mesenchymal cell origin that typically presents with multiple intra-abdominal tumors and exhibits a multi-phenotypic pattern of immunohistochemical staining. The specific organ or tissue type of origin has yet to be identified. DSRCT rarely arises as a singular tumor in the abdomen; in most cases, there are dozens to hundreds of abdominal peritoneal tumors that are detected on diagnosis. One very large dominant mass is usually present in the omentum, with an additional one or two large conglomerates of tumors in the pelvis and right peritoneum, respectively. Despite an often overwhelmingly large number of abdominal tumors, symptoms of bowel obstruction are rare. Ascites may be present. In late stages, pleural effusions, pleural implants, mediastinal adenopathy, supraclavicular adenopathy, or bone metastasis may be present. With this challenging disease, multidisciplinary therapy, including aggressive surgery, is warranted. This review will address DSRCT biology and treatment options and discuss outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Intracardiac metastasis from germ cell testicular tumor.

    PubMed

    Jonjev, Z S; Rajić, J; Majin, M; Donat, D

    2012-09-01

    Intracardiac metastases of germ cell testicular tumors are not commonly seen in clinical practice. The clinical presentation of right-sided heart metastases ranges widely. Depending upon its size and intracardiac location, it could be highly symptomatic, leading to a congestive heart failure, pulmonary embolism, and death, or completely asymptomatic. Improved imaging techniques and treatment strategies demonstrate that right-sided heart metastasis should be considered a potentially dangerous but treatable disease. Presented is the case of a 24-year-old man with a testicular nonseminomatous germ cell tumor, which after metastasizing in the right atrium differentiated into a teratoma and resulted in an inflow obstruction of the right ventricle.

  18. Antitumoral effect of a selective Rho-kinase inhibitor Y-27632 against Ehrlich ascites carcinoma in mice.

    PubMed

    Isler, Derya; Ozaslan, Mehmet; Karagoz, Isik Didem; Kilic, Ibrahim Halil; Karakok, Metin; Taysi, Seyithan; Guler, Izzettin; Cakmak, Ahmet; Demiryurek, Abdullah Tuncay

    2014-02-01

    The Rho proteins and Rho-kinase (ROCK) enzymes are responsible for signal transduction, and cause cell permeability, contractility, differentiation, migration, proliferation or apoptosis depending on cell types. All of these functions are vital for cancer initiation and progression. In this study, the preventive and protective effects of a selective ROCK inhibitor Y-27632 against Ehrlich ascites carcinoma in Swiss albino mice were investigated. Adult male albino mice were divided into five equal groups, and Y-27632 (0.1, 1, and 10 mg/kg) was given to groups as two steps; before (pre-carcinoma) and after inoculation of carcinoma cell suspensions (post-carcinoma). At the end of the experiments (at day 15), cardiac blood samples, the ascitic fluid, and intestinal specimens were collected for histopathology and biochemical investigation. Significant decreases in the body weight and immunostaining scores in small and large intestine for ROCK2, preservation of serum glutathione (GSH) levels, and an increase in tumor level of nitric oxide were recorded in groups pretreated with Y-27632. However, treatment with Y-27632 after tumor inoculation did not affect body weight and ROCK2 immunostaining scores, increased serum MDA levels, and decreased GSH levels. This is the first study on the effectiveness of Y-27632 in this experimental tumor model. Our findings provided direct evidence for ROCK involvement in tumor development. These data suggest that pretreatment with Y-27632 has a protective effect against tumor formation. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  19. Escape from Tumor Cell Dormancy

    DTIC Science & Technology

    2012-10-01

    prostate cancer cells increases chemoresistance. Clinical and Experimental Metastasis 29, 39-50. PMID: 21964676. YL Chao, Q Wu, M Acquafondata, R...Dhir, A Wells (2012). Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases. Cancer Microenvironment 5, 19- 28... cancer is its propensity to recur in metastatic sites even over a decade after all evidence of cancer has passed. It is obvious that these cells had

  20. Innate Lymphoid Cells in Tumor Immunity

    PubMed Central

    van Beek, Jasper J. P.; Martens, Anne W. J.; Bakdash, Ghaith; de Vries, I. Jolanda M.

    2016-01-01

    Innate lymphoid cells (ILCs) are a group of immune cells of the lymphoid lineage that do not possess antigen specificity. The group includes natural killer (NK) cells, lymphoid tissue inducer (LTi) cells and the recently identified ILC1s, ILC2s and ILC3s. Although the role of NK cells in the context of cancer has been well established, the involvement of other ILC subsets in cancer progression and resistance is just emerging. Here, we review the literature on the role of the different ILC subsets in tumor immunity and discuss its implications for cancer treatment and monitoring. PMID:28536374

  1. Innate Lymphoid Cells in Tumor Immunity.

    PubMed

    van Beek, Jasper J P; Martens, Anne W J; Bakdash, Ghaith; de Vries, I Jolanda M

    2016-02-25

    Innate lymphoid cells (ILCs) are a group of immune cells of the lymphoid lineage that do not possess antigen specificity. The group includes natural killer (NK) cells, lymphoid tissue inducer (LTi) cells and the recently identified ILC1s, ILC2s and ILC3s. Although the role of NK cells in the context of cancer has been well established, the involvement of other ILC subsets in cancer progression and resistance is just emerging. Here, we review the literature on the role of the different ILC subsets in tumor immunity and discuss its implications for cancer treatment and monitoring.

  2. CDC20 maintains tumor initiating cells

    PubMed Central

    Xie, Qi; Wu, Qiulian; Mack, Stephen C.; Yang, Kailin; Kim, Leo; Hubert, Christopher G.; Flavahan, William A.; Chu, Chengwei; Bao, Shideng; Rich, Jeremy N.

    2015-01-01

    Glioblastoma is the most prevalent and lethal primary intrinsic brain tumor. Glioblastoma displays hierarchical arrangement with a population of self-renewing and tumorigenic glioma tumor initiating cells (TICs), or cancer stem cells. While non-neoplastic neural stem cells are generally quiescent, glioblastoma TICs are often proliferative with mitotic control offering a potential point of fragility. Here, we interrogate the role of cell-division cycle protein 20 (CDC20), an essential activator of anaphase-promoting complex (APC) E3 ubiquitination ligase, in the maintenance of TICs. By chromatin analysis and immunoblotting, CDC20 was preferentially expressed in TICs relative to matched non-TICs. Targeting CDC20 expression by RNA interference attenuated TIC proliferation, self-renewal and in vivo tumor growth. CDC20 disruption mediated its effects through induction of apoptosis and inhibition of cell cycle progression. CDC20 maintains TICs through degradation of p21CIP1/WAF1, a critical negative regulator of TICs. Inhibiting CDC20 stabilized p21CIP1/WAF1, resulting in repression of several genes critical to tumor growth and survival, including CDC25C, c-Myc and Survivin. Transcriptional control of CDC20 is mediated by FOXM1, a central transcription factor in TICs. These results suggest CDC20 is a critical regulator of TIC proliferation and survival, linking two key TIC nodes – FOXM1 and p21CIP1/WAF1 — elucidating a potential point for therapeutic intervention. PMID:25938542

  3. NRAS destines tumor cells to the lungs.

    PubMed

    Giannou, Anastasios D; Marazioti, Antonia; Kanellakis, Nikolaos I; Giopanou, Ioanna; Lilis, Ioannis; Zazara, Dimitra E; Ntaliarda, Giannoula; Kati, Danai; Armenis, Vasileios; Giotopoulou, Georgia A; Krontira, Anthi C; Lianou, Marina; Agalioti, Theodora; Vreka, Malamati; Papageorgopoulou, Maria; Fouzas, Sotirios; Kardamakis, Dimitrios; Psallidas, Ioannis; Spella, Magda; Stathopoulos, Georgios T

    2017-05-01

    The lungs are frequently affected by cancer metastasis. Although NRAS mutations have been associated with metastatic potential, their exact role in lung homing is incompletely understood. We cross-examined the genotype of various tumor cells with their ability for automatic pulmonary dissemination, modulated NRAS expression using RNA interference and NRAS overexpression, identified NRAS signaling partners by microarray, and validated them using Cxcr1- and Cxcr2-deficient mice. Mouse models of spontaneous lung metastasis revealed that mutant or overexpressed NRAS promotes lung colonization by regulating interleukin-8-related chemokine expression, thereby initiating interactions between tumor cells, the pulmonary vasculature, and myeloid cells. Our results support a model where NRAS-mutant, chemokine-expressing circulating tumor cells target the CXCR1-expressing lung vasculature and recruit CXCR2-expressing myeloid cells to initiate metastasis. We further describe a clinically relevant approach to prevent NRAS-driven pulmonary metastasis by inhibiting chemokine signaling. In conclusion, NRAS promotes the colonization of the lungs by various tumor types in mouse models. IL-8-related chemokines, NRAS signaling partners in this process, may constitute an important therapeutic target against pulmonary involvement by cancers of other organs. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

  4. Imaging of giant cell tumor of bone

    PubMed Central

    Purohit, Shaligram; Pardiwala, Dinshaw N

    2007-01-01

    Giant cell tumor (GCT) of bone is a benign but locally aggressive and destructive lesion generally occurring in skeletally mature individuals. Typically involving the epiphysiometaphyseal region of long bones, the most common sites include the distal femur, proximal tibia and distal radius. On radiographs, GCT demonstrates a lytic lesion centered in the epiphysis but involving the metaphysis and extending at least in part to the adjacent articular cortex. Most are eccentric, but become symmetric and centrally located with growth. Most cases show circumscribed borders or so-called geographical destruction with no periosteal reaction unless a pathological fracture is present. There is no mineralized tumor matrix. Giant cell tumor can produce wide-ranging appearances depending on site, complications such as hemorrhage or pathological fracture and after surgical intervention. This review demonstrates a spectrum of these features and describes the imaging characteristics of GCT in conventional radiographs, computerized tomography scans, magnetic resonance imaging, bone scans, positron emission tomography scans and angiography. PMID:21139758

  5. Current detection technologies for circulating tumor cells.

    PubMed

    Shen, Zheyu; Wu, Aiguo; Chen, Xiaoyuan

    2017-04-10

    Circulating tumor cells (CTCs) are cancer cells that circulate in the blood stream after being naturally shed from original or metastatic tumors, and can lead to a new fatal metastasis. CTCs have become a hotspot research field during the last decade. Detection of CTCs, as a liquid biopsy of tumors, can be used for early diagnosis of cancers, earlier evaluation of cancer recurrence and chemotherapeutic efficacy, and choice of individual sensitive anti-cancer drugs. Therefore, CTC detection is a crucial tool to fight against cancer. Herein, we classify the currently reported CTC detection technologies, introduce some representative samples for each technology, conclude the advantages and limitations, and give a future perspective including the challenges and opportunities of CTC detection.

  6. Circulating tumor cells: utopia or reality?

    PubMed

    Conteduca, Vincenza; Zamarchi, Rita; Rossi, Elisabetta; Condelli, Valentina; Troiani, Laura; Aieta, Michele

    2013-09-01

    Circulating tumor cells (CTCs) could be considered a sign of tumor aggressiveness, but highly sensitive and specific methods of CTC detection are necessary owing to the rarity and heterogeneity of CTCs in peripheral blood. This review summarizes recent studies on tumor biology, with particular attention to the metastatic cascade, and the molecular characterization and clinical significance of CTCs. Recent technological approaches to enrich and detect these cells and challenges of CTCs for individualized cancer treatment are also discussed. This review also provides an insight into the positive and negative features of the future potential applications of CTC detection, which sometimes remains still a 'utopia', but its actual utility remains among the fastest growing research fields in oncology.

  7. Myeloid-derived cells are key targets of tumor immunotherapy

    PubMed Central

    Medina-Echeverz, José; Aranda, Fernando; Berraondo, Pedro

    2014-01-01

    Tumors are composed of heterogeneous cell populations recruited by cancer cells to promote growth and metastasis. Among cells comprising the tumor stroma, myeloid-derived cells play pleiotropic roles in supporting tumorigenesis at distinct stages of tumor development. The tumor-infiltrating myeloid cell contingent is composed of mast cells, neutrophils, dendritic cells, macrophages, and myeloid-derived suppressor cells. Such cells are capable of evading the hostile tumor environment typically prone to immune cell destruction and can even promote angiogenesis, chronic inflammation, and invasion. This paper briefly summarizes the different myeloid-derived subsets that promote tumor development and the strategies that have been used to counteract the protumorigenic activity of these cells. These strategies include myeloid cell depletion, reduction of recruitment, and inactivation or remodeling of cell phenotype. Combining drugs designed to target tumor myeloid cells with immunotherapies that effectively trigger antitumor adaptive immune responses holds great promise in the development of novel cancer treatments. PMID:25050208

  8. Escape From Tumor Cell Dormancy

    DTIC Science & Technology

    2011-10-01

    expression of E-cadherin in breast and prostate cancer cells increases chemoresistance. in revision. CM, Williams, G. Mehta, S.R. Peyton, A.S. Zeiger, K.J...SUPPLEMENTARY NOTES 14. ABSTRACT An insiduously terrifying aspect of breast cancer is its propensity to recur in metastatic sites even over a decade

  9. Combination Chemotherapy in Treating Young Patients With Recurrent or Resistant Malignant Germ Cell Tumors

    ClinicalTrials.gov

    2017-02-07

    Childhood Extracranial Germ Cell Tumor; Childhood Extragonadal Germ Cell Tumor; Childhood Malignant Ovarian Germ Cell Tumor; Childhood Malignant Testicular Germ Cell Tumor; Ovarian Choriocarcinoma; Ovarian Embryonal Carcinoma; Ovarian Yolk Sac Tumor; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Ovarian Germ Cell Tumor; Testicular Choriocarcinoma; Testicular Choriocarcinoma and Embryonal Carcinoma; Testicular Choriocarcinoma and Yolk Sac Tumor; Testicular Embryonal Carcinoma; Testicular Embryonal Carcinoma and Yolk Sac Tumor; Testicular Yolk Sac Tumor

  10. Anti-neoplastic activities of sepia officinalis ink and coelatura aegyptiaca extracts against Ehrlich ascites carcinoma in Swiss albino mice

    PubMed Central

    Soliman, Amel M; Fahmy, Sohair R; El-Abied, Salma A

    2015-01-01

    Objectives: With the development of sophisticated instruments for the isolation and elucidation of natural products structures from marine and freshwater organisms, major advances have been made in the discovery of aquatic derived therapeutics. Present investigations were carried out to evaluate cuttlefish (Sepia officinalis) ink extract (IE) and freshwater clam (Coelatura aegyptiaca) extract (CE) for their anticancer and antioxidant activities as compared to 5-flurouracil (5-Fu), in Ehrlich ascites carcinoma (EAC). Methods: Sixty female Swiss albino mice were divided into five groups (n = 12). All groups except group I received EAC cells (5 × 106 cells/mouse i.p.) and this was taken as the 0th day. Group I served as saline control (5 ml/kg 0.9% NaCl w/v p.o). Group II served as EAC control. Rats of groups III, IV and V received IE, CE (200 mg/kg body weight i.p.), and reference drug (5-Fu, 20 mg/kg body weight i.p.), respectively. Results: The reduction in tumor volume, packed cell volume, tumor cell counts and increase in median survival time and percentage increase in life span in treated animals were observed. There was a significant increase in RBC count; Hb content in treated animals and reduction in total WBC count. There was a significant decrease in AST, ALT, ALP and liver MDA levels and increase in GSH, SOD and NO levels were observed in all treated animals. Conclusion: Both IE and CE were effective in inhibiting the tumor growth in ascitic tumor models. The biochemical, antioxidants and histopathological studies were also supported their antitumor properties. PMID:26097537

  11. Recurrent Giant Cell Tumor of Skull Combined with Multiple Aneurysms

    PubMed Central

    Kim, Dae Hwan

    2016-01-01

    Giant cell tumors are benign but locally invasive and frequently recur. Giant cell tumors of the skull are extremely rare. A patient underwent a surgery to remove a tumor, but the tumor recurred. Additionally, the patient developed multiple aneurysms. The patient underwent total tumor resection and trapping for the aneurysms, followed by radiotherapy. We report this rare case and suggest some possibilities for treating tumor growth combined with aneurysm development. PMID:27195256

  12. Tumor

    MedlinePlus

    ... excessively in the body. Normally, the body controls cell growth and division. New cells are created to replace ... room for healthy replacements. If the balance of cell growth and death is disturbed, a tumor may form. ...

  13. Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment.

    PubMed

    Renner, Kathrin; Singer, Katrin; Koehl, Gudrun E; Geissler, Edward K; Peter, Katrin; Siska, Peter J; Kreutz, Marina

    2017-01-01

    Cytotoxic T lymphocytes and NK cells play an important role in eliminating malignant tumor cells and the number and activity of tumor-infiltrating T cells represent a good marker for tumor prognosis. Based on these findings, immunotherapy, e.g., checkpoint blockade, has received considerable attention during the last couple of years. However, for the majority of patients, immune control of their tumors is gray theory as malignant cells use effective mechanisms to outsmart the immune system. Increasing evidence suggests that changes in tumor metabolism not only ensure an effective energy supply and generation of building blocks for tumor growth but also contribute to inhibition of the antitumor response. Immunosuppression in the tumor microenvironment is often based on the mutual metabolic requirements of immune cells and tumor cells. Cytotoxic T and NK cell activation leads to an increased demand for glucose and amino acids, a well-known feature shown by tumor cells. These close metabolic interdependencies result in metabolic competition, limiting the proliferation, and effector functions of tumor-specific immune cells. Moreover, not only nutrient restriction but also tumor-driven shifts in metabolite abundance and accumulation of metabolic waste products (e.g., lactate) lead to local immunosuppression, thereby facilitating tumor progression and metastasis. In this review, we describe the metabolic interplay between immune cells and tumor cells and discuss tumor cell metabolism as a target structure for cancer therapy. Metabolic (re)education of tumor cells is not only an approach to kill tumor cells directly but could overcome metabolic immunosuppression in the tumor microenvironment and thereby facilitate immunotherapy.

  14. Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment

    PubMed Central

    Renner, Kathrin; Singer, Katrin; Koehl, Gudrun E.; Geissler, Edward K.; Peter, Katrin; Siska, Peter J.; Kreutz, Marina

    2017-01-01

    Cytotoxic T lymphocytes and NK cells play an important role in eliminating malignant tumor cells and the number and activity of tumor-infiltrating T cells represent a good marker for tumor prognosis. Based on these findings, immunotherapy, e.g., checkpoint blockade, has received considerable attention during the last couple of years. However, for the majority of patients, immune control of their tumors is gray theory as malignant cells use effective mechanisms to outsmart the immune system. Increasing evidence suggests that changes in tumor metabolism not only ensure an effective energy supply and generation of building blocks for tumor growth but also contribute to inhibition of the antitumor response. Immunosuppression in the tumor microenvironment is often based on the mutual metabolic requirements of immune cells and tumor cells. Cytotoxic T and NK cell activation leads to an increased demand for glucose and amino acids, a well-known feature shown by tumor cells. These close metabolic interdependencies result in metabolic competition, limiting the proliferation, and effector functions of tumor-specific immune cells. Moreover, not only nutrient restriction but also tumor-driven shifts in metabolite abundance and accumulation of metabolic waste products (e.g., lactate) lead to local immunosuppression, thereby facilitating tumor progression and metastasis. In this review, we describe the metabolic interplay between immune cells and tumor cells and discuss tumor cell metabolism as a target structure for cancer therapy. Metabolic (re)education of tumor cells is not only an approach to kill tumor cells directly but could overcome metabolic immunosuppression in the tumor microenvironment and thereby facilitate immunotherapy. PMID:28337200

  15. Synergistic efficacy of γ-radiation together with gallium trichloride and/or doxorubicin against Ehrlich carcinoma in female mice.

    PubMed

    Kandil, Eman; Aziz, Nahed Abdel

    2016-02-01

    Combining chemotherapy with radiotherapy represents a key oncology strategy for a more comprehensive attack toward cancers and improves treatment outcome for various solid tumor malignancies. The present study aims to evaluate the synergistic antitumor effect of γ-radiation together with gallium trichloride (GaCl3) and/or doxorubicin (DOX) against solid Ehrlich carcinoma (EC) in female mice. GaCl3 (300 mg/kg body weight (b.w.)) was administered by gavages daily on the seventh day after tumor inoculation, while the cytotoxic drug DOX (4 mg/kg b.w.) was administered intraperitoneally once a week. Whole-body γ-radiation was carried out at a dose 2 Gy once a week. Biochemical analysis showed that solid EC induced a significant increase in malondialdehyde (MDA) content with a significant decrease in the antioxidant state (glutathione peroxidase (GPx) and catalase (CAT) activities) and depleted serum iron concentration compared to normal control. Moreover, a significant increase was observed in calcium level and caspase-3 concentrations in both serum and tumor homogenate respectively associated with a significant alteration in heart, liver, and kidney functions, as compared to control. Treatment of EC-bearing mice with GaCl3and/or DOX combined with γ-radiation exposure significantly reduced tumor volume and displayed a significant improvement in most studied markers which may indicate a synergistic effect of this combination against organ dysfunction and cellular injury. The histopathologically investigation showed that treatment of animals bearing EC with GaCl3and/or DOX with γ-radiation exposure showed shrinkage in tumor lesions and wide zones of apoptotic cells with signs of regenerations. It was concluded that the combination of GaCl3and/or DOX with γ-radiation exposure resulted in super-additive cytotoxic effects on treatment of cancer cells.

  16. Rare Giant Cell Tumor of Olecranon Bone!!!!

    PubMed Central

    Goyal, Pawan; Gautam, Vishal; Saini, Narender; Sharma, Yogesh

    2016-01-01

    Introduction: Giant cell tumor (GCT) is a bone tumor involving epiphyseal area of bone abutting the subchondral bone. Commonly found in long bones such as proximal tibia and distal femur. We report a case of GCT of olecranon bone in a 23-year-old male. Case Report: A 23-year-old patient presented to our outpatient department with pain and mild swelling at the elbow from last 2 to 3 months. On examination, it was seen that there was a moderate swelling at the tip of the olecranon. The magnetic resonance imaging reported a lytic lesion in the olecranon but sparing the coronoid process of the ulna, the biopsy report confirmed that histologically it was a GCT of the bone. Total excision of the tumor was done after lifting the aponeurosis of the triceps muscle. The area remaining after excision of the tumor was phenol cauterized and cleaned with hydrogen peroxide solution. Triceps was reinserted on the remaining ulna. At follow-up the radiographs showed adequate excision of the tumor. The patient gained a full range of movement at the elbow and was functionally restored. There were no signs of any systemic spread of the tumor. Conclusion: GCT though a very common bone tumor could be missed if present in atypical locations. Radiographically soap bubble appearance might not be present in every case, and there could be multiple diagnoses for lytic lesion in bone. Proper investigations and histopathological examination are necessary for accurate diagnosis and further treatment planning. Early treatment helps in complete excision of tumor along with return of adequate function of the patient. PMID:28164048

  17. Curcumin reverses breast tumor exosomes mediated immune suppression of NK cell tumor cytotoxicity

    PubMed Central

    Zhang, Huang-Ge; Kim, Helen; Liu, Cunren; Yu, Shaohua; Wang, Jianhua; Grizzle, William E.; Kimberly, Robert P.; Barnes, Stephen

    2007-01-01

    An important characteristic of tumors is that they at some point in their development overcome the surveillance of the immune system. Tumors secrete exosomes, multivesicular bodies containing a distinct set of proteins that can fuse with cells of the circulating immune system. Purified exosomes from TS/A breast cancer cells, but not non-exosomal fractions, inhibit (at concentrations of nanograms per ml protein) IL-2-induced natural killer (NK) cell cytotoxicity. The dietary polyphenol, curcumin (diferuloylmethane), partially reverses tumor exosome-mediated inhibition of natural killer cell activation, which is mediated through the impairment of the ubiquitin-proteasome system. Exposure of mouse breast tumor cells to curcumin causes a dose-dependent increase in ubiquitinated exosomal proteins compared to those in untreated TS/A breast tumor cells. Furthermore, exosomes isolated from tumor cells pretreated with curcumin have a much attenuated inhibition of IL-2 stimulated NK cell activation. Jak3-mediated activation of Stat5 is required for tumor cytotoxicity of IL-2 stimulated NK cells. TS/A tumor exosomes strongly inhibit activation of Stat5, whereas the tumor exosomes isolated from curcumin-pretreated tumor cells have a lowered potency for inhibition of IL-2 stimulated NK cell cytotoxicity. These data suggest that partial reversal of tumor exosome-mediated inhibition of NK cell tumor cytotoxicity may account for the anti-cancer properties curcumin. PMID:17555831

  18. Paul Ehrlich: the Nobel Prize in physiology or medicine 1908.

    PubMed

    Piro, Anna; Tagarelli, Antonio; Tagarelli, Giuseppe; Lagonia, Paolo; Quattrone, Aldo

    2008-01-01

    We wish to commemorate Paul Ehrlich on the centennial of his being awarded the Nobel Prize in Physiology or Medicine in 1908. His studies are now considered as milestones in immunology: the morphology of leukocytes; his side-chain theory where he defined the cellular receptor for first time; and his clarification of the difference between serum therapy and chemotherapy. Ehrlich also invented the first chemotherapeutic drug: compound 606, or Salvarsan. We have used some original documents from the Royal Society of London, where Ehrlich was a fellow, and from Leipzig University, where he took a degree in medicine.

  19. Crooke's cell tumors of the pituitary.

    PubMed

    Di Ieva, Antonio; Davidson, Jennilee M; Syro, Luis V; Rotondo, Fabio; Montoya, Julian F; Horvath, Eva; Cusimano, Michael D; Kovacs, Kalman

    2015-05-01

    Crooke's cell adenomas are a rare type of pituitary neoplasm. They produce adrenocorticotropic hormone causing Cushing's disease or may be endocrinologically silent. These tumors are usually invasive, may exhibit aggressive clinical behavior, and often recur with a low success of cure after reoperation and/or radiotherapy. Due to their rarity, they present great difficulties in assessing prognosis, treatment, and clinical management. Neurosurgeons and physicians dealing with pituitary adenomas diagnosed as Crooke's cell adenomas have to be aware of their potential clinical aggressiveness to plan strict follow-up of patients and eventual multimodality treatment. We review here the published cases of Crooke's cell tumors, as well as the clinical and histopathological characteristics of these unusual neoplasms.

  20. [Circulating tumor cells and advanced prostate cancer].

    PubMed

    Murez, Thibaut; Droupy, Stéphane; Rebillard, Xavier; Alix-Panabieres, Catherine

    2012-07-01

    Despite development and widespread of PSA, current tools evaluating prostate cancer still give inconsistent or insufficiently relevant results. As encouraging data raised from circulating tumor cells detection in colon or breast cancer, they were evaluated as a surrogate prostate cancer biomarker. Tumor cells need to leave their surrounding primary environment and to survive in mesenchymal environment before they spill and metastasize. Basic research revealed several mutations required through a complex transition phenomenon, including dormancy steps. Circulating cells detection techniques are based on molecular and immunologic methods. Most of them need an enrichment step to improve sensibility and/or specificity. As of today, Veridex' CellSearch is the only FDA approved technique in the evaluation of castration resistant prostate cancer response to new drugs. Clinical research using other techniques highlighted the need for clinical endpoints, as there's no relevant tool and as techniques' target differ. Further studies are required to improve circulating tumors cells' staging and prognosis value. Cellular characterization may be the way to identify metastasis development potential more than the spillage burden. Those techniques still need improvements before they are included in daily practice decisional trees.

  1. Malignant thoracopulmonary small-cell (Askin) tumor

    SciTech Connect

    Fink, I.J.; Kurtz, D.W.; Cazenave, L.; Lieber, M.R.; Miser, J.S.; Chandra, R.; Triche, T.J.

    1985-09-01

    The clinical, radiographic, and pathologic features of 10 patients with documented malignant small-cell tumor of the thoracopulmonary region (Askin tumor) were reviewed. The tumor represents a distinct pathologic entity of neuroectodermal origin. Clinically, it presents as a chest-wall mass with or without pain. Its radiographic appearance is that of a soft-tissue mass with or without pleural or rib involvement, often with metastatic disease - to the skeletal system, bone marrow, thorax, and sympathetic chain. Two patients developed metastases to the adrenal gland and liver, one after autologous bone marrow transplantation. The radiologist should be aware of this entity and its pattern of metastatic spread since metastases are treated aggressively.

  2. Aberrant PGE₂ metabolism in bladder tumor microenvironment promotes immunosuppressive phenotype of tumor-infiltrating myeloid cells.

    PubMed

    Eruslanov, Evgeniy; Daurkin, Irina; Vieweg, Johannes; Daaka, Yehia; Kusmartsev, Sergei

    2011-07-01

    Bladder cancer is associated with enhanced inflammation and characterized by deregulated prostanoid metabolism. Here we examined prostaglandin E₂ (PGE₂) metabolism and myeloid cell subsets that infiltrate tumor tissue using two xenograft models of human bladder cancer. Human bladder tumor xenografts implanted into athymic nude mice become highly infiltrated with host CD11b myeloid cells of bone marrow origin. Fast growing SW780 bladder tumor xenografts were infiltrated with heterogeneous CD11b myeloid cell subsets including tumor-associated macrophages and myeloid-derived suppressor cells. In contrast, majority of myeloid cells in tumor tissue from slow growing bladder cancer Urothel 11 displayed more immature, homogenous phenotype and comprised mostly MHC II class-negative myeloid-derived suppressor cells. We demonstrate that human bladder tumors secrete substantial amounts of PGE₂. Normal bone marrow myeloid cell progenitors cultured in the presence of a bladder tumor-conditioned medium, which is enriched for PGE₂, failed to differentiate into mature APCs and acquired phenotype of the myeloid-derived suppressor cells or inflammatory macrophages with up-regulated chemokine receptor CXCR4. Collectively our data demonstrate that enhanced cancer-related inflammation and deregulated PGE₂ metabolism in tumor microenvironment promote immunosuppressive pro-tumoral phenotype of myeloid cells in bladder cancer. These data also suggest that not only local tumor microenvironment but other factors such as stage of cancer disease and pace of tumor growth could markedly influence the phenotype, differentiation and immune function of myeloid cells in tumor tissue.

  3. Identifying Tumor Progenitor Cells | Center for Cancer Research

    Cancer.gov

    All cells within a tumor are not identical. In fact, only a small subset appears to be capable of actually generating the tumor. These tumor-initiating cells tend to resemble normal stem cells, which have the unique ability to give rise to differentiated cells while simultaneously producing additional undifferentiated stem cells. Most chemotherapeutics affect the bulk of a tumor but spare the stem-like cells, allowing the tumor to re-grow once chemotherapy is stopped. If, however, the cancer-initiating cells could be successfully targeted, cancer recurrence could be prevented.

  4. HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.

    PubMed

    Aits, Sonja; Gustafsson, Lotta; Hallgren, Oskar; Brest, Patrick; Gustafsson, Mattias; Trulsson, Maria; Mossberg, Ann-Kristin; Simon, Hans-Uwe; Mograbi, Baharia; Svanborg, Catharina

    2009-03-01

    HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.

  5. Molecular Biomarker Analyses Using Circulating Tumor Cells

    PubMed Central

    Punnoose, Elizabeth A.; Atwal, Siminder K.; Spoerke, Jill M.; Savage, Heidi; Pandita, Ajay; Yeh, Ru-Fang; Pirzkall, Andrea; Fine, Bernard M.; Amler, Lukas C.; Chen, Daniel S.; Lackner, Mark R.

    2010-01-01

    Background Evaluation of cancer biomarkers from blood could significantly enable biomarker assessment by providing a relatively non-invasive source of representative tumor material. Circulating Tumor Cells (CTCs) isolated from blood of metastatic cancer patients hold significant promise in this regard. Methodology/Principal Findings Using spiked tumor-cells we evaluated CTC capture on different CTC technology platforms, including CellSearch® and two biochip platforms, and used the isolated CTCs to develop and optimize assays for molecular characterization of CTCs. We report similar performance for the various platforms tested in capturing CTCs, and find that capture efficiency is dependent on the level of EpCAM expression. We demonstrate that captured CTCs are amenable to biomarker analyses such as HER2 status, qRT-PCR for breast cancer subtype markers, KRAS mutation detection, and EGFR staining by immunofluorescence (IF). We quantify cell surface expression of EGFR in metastatic lung cancer patient samples. In addition, we determined HER2 status by IF and FISH in CTCs from metastatic breast cancer patients. In the majority of patients (89%) we found concordance with HER2 status from patient tumor tissue, though in a subset of patients (11%), HER2 status in CTCs differed from that observed in the primary tumor. Surprisingly, we found CTC counts to be higher in ER+ patients in comparison to HER2+ and triple negative patients, which could be explained by low EpCAM expression and a more mesenchymal phenotype of tumors belonging to the basal-like molecular subtype of breast cancer. Conclusions/Significance Our data suggests that molecular characterization from captured CTCs is possible and can potentially provide real-time information on biomarker status. In this regard, CTCs hold significant promise as a source of tumor material to facilitate clinical biomarker evaluation. However, limitations exist from a purely EpCAM based capture system and addition of antibodies

  6. Curative potential of GM-CSF-secreting tumor cell vaccines on established orthotopic liver tumors: mechanisms for the superior antitumor activity of live tumor cell vaccines.

    PubMed

    Tai, Kuo-Feng; Chen, Ding-Shinn; Hwang, Lih-Hwa

    2004-01-01

    In preclinical studies, tumor cells genetically engineered to secrete cytokines, hereafter referred to as tumor cell vaccines, can often generate systemic antitumor immunity. This study investigated the therapeutic effects of live or irradiated tumor cell vaccines that secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) on established orthotopic liver tumors. Experimental results indicated that two doses (3 x 10(7) cells per dose) of irradiated tumor cell vaccines were therapeutically ineffective, whereas one dose (3 x 10(6) cells) of live tumor cell vaccines caused complete tumor regression. In vivo depletion of CD8+ T cells, but not natural killer cells, restored tumor formation in the live vaccine-treated animals. Additionally, the treatment of cells with live vaccine induced markedly higher levels of cytotoxic T lymphocyte activity than the irradiated vaccines in the draining lymph nodes. The higher levels of cytokine and antigen loads could partly explain the superior antitumor activity of live tumor cell vaccines, but other unidentified mechanisms could also play a role in the early T cell activation in the lymph nodes. A protocol using multiple and higher dosages of irradiated tumor cell vaccines also caused significant regression of liver tumors. These results suggest that the GM-CSF-secreting tumor cell vaccines are highly promising for orthotopic liver tumors if higher levels of immune responses are elicited during early tumor development. Copyright 2004 National Science Council, ROC and S. Karger AG, Basel

  7. Childhood Central Nervous System Germ Cell Tumors Treatment

    MedlinePlus

    ... Ependymoma Treatment Research Childhood Central Nervous System Germ Cell Tumors Treatment (PDQ®)–Patient Version General Information About Childhood Central Nervous System (CNS) Germ Cell Tumors Go to Health Professional Version Key Points ...

  8. Treatment Options By Stage (Ovarian Germ Cell Tumors)

    MedlinePlus

    ... Tube, & Primary Peritoneal Cancer Screening Research Ovarian Germ Cell Tumors Treatment (PDQ®)–Patient Version General Information About Ovarian Germ Cell Tumors Go to Health Professional Version Key Points ...

  9. Efficacy of tumor cell vaccine after incorporating monophosphoryl lipid A (MPL) in tumor cell membranes containing tumor-associated ganglioside.

    PubMed

    Ravindranath, M H; Brazeau, S M; Morton, D L

    1994-07-15

    Murine B16 melanoma expresses the ganglioside GM3. GM3 shed from tumor cells is immunosuppressive and promotes tumor growth. Reduction or elimination of the shed GM3 could be therapeutic, and the anti-GM3 antibodies may reduce and clear the shed ganglioside. To test this hypothesis, mice were challenged with tumor cells, with or without inducing anti-GM3 antibody response. Since gangliosides are poor immunogens and T-cell independent antigens, an adjuvant (monophosphoryl lipid A (MPL), a non-toxic lipid A of Salmonella), directed against B-cells, was employed. MPL was incorporated onto liposomes and into the surface membrane of B16 mouse melanoma cells; both are rich in GM3. C57BL/6J mice immunized with MPL-liposomes or MPL-B16 cells responded with elevated levels of anti-GM3 IgM. Non-immunized mice or mice immunized with B16 cells alone or ganglioside GM3 alone (without MPL) elicited poor anti-GM3 IgM response, confirming the GM3's immunologic crypticity and MPL's immunopotentiating effect. MPL's immunopotentiating effect was improved by coupling it to melanoma cell membranes. C57BL/6J mice were immunized with irradiated B16 alone or MPL alone or MPL-conjugated irradiated B16. After three weekly immunizations, each mouse received a challenge dose of viable syngeneic B16. Neither MPL alone nor B16 alone had a significant effect on tumor growth or host survival; however, administration of MPL-conjugated B16 cells significantly prevented tumor growth and prolonged survival. Our results indicate that MPL-incorporated B16 cells augment the anti-GM3 IgM response, which may reverse GM3-induced immunosuppression by eliminating tumor-derived GM3, and restore immunocompetence.

  10. ME-10TUMOR MICROENVIRONMENT INFILTRATING MYELOID DERIVED SUPPRESSOR CELLS INHIBIT ANTI-TUMOR T CELL RESPONSES

    PubMed Central

    Kamran, Neha; Ayala, Mariela; Li, Youping; Assi, Hikmat; Candolfi, Marianela; Dzaman, Marta; Lowenstein, Pedro; Castro, Maria

    2014-01-01

    MDSCs represent a population of immature myeloid cells at various stages of differentiation that inhibit anti-tumor T cell-mediated responses. We demonstrate the accumulation of MDSCs in GL26 induced glioma and B16 melanoma bearing mice. Absolute numbers of Ly-6G+ (Gr-1high) MDSCs showed a 200 fold increase within the tumor microenvironment (TME) 28 days post-tumor implantation. The numbers of Ly-6C+ (Gr-1low) MDSCs also showed a similar trend within the TME. While this massive influx of MDSCs was noted within intracranial tumors, MDSC levels did not increase in the dLNs, spleen or bone marrow (BM) of intracranial tumor bearing mice. MDSCs numbers were significantly elevated in the blood of GL26 intracranial tumor bearing mice at 28 days. Mice bearing B16 tumors in the flank showed a ∼5 fold increased influx of Ly-6G+ MDSCs while the Ly6C+ MDSCs increased marginally by 1.1 fold within the tumor mass. Levels of circulating MDSCs also increased by ∼10 fold, while the levels of splenic MDSCs did not change. While both Ly-6G+ and Ly6C+ MDSCs isolated from the brain TME of GL26 intracranial tumor bearing mice inhibited antigen-specific T cell proliferation, Ly6C+ MDSC were found to be more efficient. Ly6G+ or Ly6C+ MDSCs from the bone marrow of intracranial tumor bearing mice failed to suppress antigen-specific T cell proliferation. Splenic and bone marrow MDSCs from naïve mice also did not inhibit antigen-specific T cell proliferation suggesting that TME derived factors may activate MDSCs to exert their immune-suppressive properties. Microarray analysis of glioma cell lines showed elevated levels of CXCL1 mRNA and splenic MDSCs from GL26 tumor mice showed upregulation of the CXCR2 mRNA. Preliminary experiments indicate that CXCR2 signaling mediates MDSC chemotaxis. Overall, our data suggests that strategies that inhibit MDSC recruitment to the TME and/or block their activity could enhance the T cell mediated tumor clearance.

  11. Cross-talk among myeloid-derived suppressor cells, macrophages, and tumor cells impacts the inflammatory milieu of solid tumors

    PubMed Central

    Beury, Daniel W.; Parker, Katherine H.; Nyandjo, Maeva; Sinha, Pratima; Carter, Kayla A.; Ostrand-Rosenberg, Suzanne

    2014-01-01

    MDSC and macrophages are present in most solid tumors and are important drivers of immune suppression and inflammation. It is established that cross-talk between MDSC and macrophages impacts anti-tumor immunity; however, interactions between tumor cells and MDSC or macrophages are less well studied. To examine potential interactions between these cells, we studied the impact of MDSC, macrophages, and four murine tumor cell lines on each other, both in vitro and in vivo. We focused on IL-6, IL-10, IL-12, TNF-α, and NO, as these molecules are produced by macrophages, MDSC, and many tumor cells; are present in most solid tumors; and regulate inflammation. In vitro studies demonstrated that MDSC-produced IL-10 decreased macrophage IL-6 and TNF-α and increased NO. IL-6 indirectly regulated MDSC IL-10. Tumor cells increased MDSC IL-6 and vice versa. Tumor cells also increased macrophage IL-6 and NO and decreased macrophage TNF-α. Tumor cell-driven macrophage IL-6 was reduced by MDSC, and tumor cells and MDSC enhanced macrophage NO. In vivo analysis of solid tumors identified IL-6 and IL-10 as the dominant cytokines and demonstrated that these molecules were produced predominantly by stromal cells. These results suggest that inflammation within solid tumors is regulated by the ratio of tumor cells to MDSC and macrophages and that interactions of these cells have the potential to alter significantly the inflammatory milieu within the tumor microenvironment. PMID:25170116

  12. Ectonucleotidases in Tumor Cells and Tumor-Associated Immune Cells: An Overview

    PubMed Central

    Bergamin, Letícia Scussel; Braganhol, Elizandra; Zanin, Rafael Fernandes; Edelweiss, Maria Isabel Albano; Battastini, Ana Maria Oliveira

    2012-01-01

    Increasing evidence points out that genetic alteration does not guarantee the development of a tumor and indicates that complex interactions of tumor cells with the microenvironment are fundamental to tumorigenesis. Among the pathological alterations that give tumor cells invasive potential, disruption of inflammatory response and the purinergic signaling are emerging as an important component of cancer progression. Nucleotide/nucleoside receptor-mediated cell communication is orchestrated by ectonucleotidases, which efficiently hydrolyze ATP, ADP, and AMP to adenosine. ATP can act as danger signaling whereas adenosine, acts as a negative feedback mechanism to limit inflammation. Many tumors exhibit alterations in ATP-metabolizing enzymes, which may contribute to the pathological events observed in solid cancer. In this paper, the main changes occurring in the expression and activity of ectonucleotidases in tumor cells as well as in tumor-associated immune cells are discussed. Furthermore, we focus on the understanding of the purinergic signaling primarily as exemplified by research done by the group on gliomas. PMID:23118517

  13. Targeting Quiescent Cancer Cells to Eliminate Tumor Recurrence After Therapy

    DTIC Science & Technology

    2016-12-01

    AD_________________ Award Number: W81XWH-14-1-0350 TITLE: Targeting Quiescent Cancer Cells to Eliminate Tumor Recurrence After Therapy PRINCIPAL...30 Sep 2014 - 29 Sep 2016 4. TITLE AND SUBTILE Targeting Quiescent Cancer Cells to Eliminate Tumor Recurrence After Therapy 5a. CONTRACT NUMBER...cancer. To eradicate chemoresistant tumor cells , it is important to identify the subset of tumor cells that can survive from chemotherapy and

  14. Effects of intratumoral injection of I-125 iododeoxyuridine on Ehrlich ascites carcinoma

    SciTech Connect

    Hong, S.S.; Ford, E.H.; Alfieri, A.A.; Bravo, S. )

    1989-11-01

    Intratumoral injection of I-125 iododeoxyuridine (IUdR), saline solution, and oil suspension was investigated using Ehrlich ascites tumors in the thighs of mice. The oil suspension was more effective in tumor growth delay than was the saline solution. Single injection of the oil suspension at the dose of 12.5 microCi resulted in 21.5 days growth delay, whereas 50 microCi of the saline solution resulted in 11.5 days growth delay relative to control growth delay. At 40 days after treatment, higher radioactivities were observed in the tumor and the skin of the mice treated with the oil suspension, which represented the prolongation of I-125 IUdR oil suspension within the tumor. No normal tissue toxicities were observed.

  15. NK Cells, Tumor Cell Transition, and Tumor Progression in Solid Malignancies: New Hints for NK-Based Immunotherapy?

    PubMed

    Cantoni, Claudia; Huergo-Zapico, Leticia; Parodi, Monica; Pedrazzi, Marco; Mingari, Maria Cristina; Moretta, Alessandro; Sparatore, Bianca; Gonzalez, Segundo; Olive, Daniel; Bottino, Cristina; Castriconi, Roberta; Vitale, Massimo

    2016-01-01

    Several evidences suggest that NK cells can patrol the body and eliminate tumors in their initial phases but may hardly control established solid tumors. Multiple factors, including the transition of tumor cells towards a proinvasive/prometastatic phenotype, the immunosuppressive effect of the tumor microenvironment, and the tumor structure complexity, may account for limited NK cell efficacy. Several putative mechanisms of NK cell suppression have been defined in these last years; conversely, the cross talk between NK cells and tumor cells undergoing different transitional phases remains poorly explored. Nevertheless, recent in vitro studies and immunohistochemical analyses on tumor biopsies suggest that NK cells could not only kill tumor cells but also influence their evolution. Indeed, NK cells may induce tumor cells to change the expression of HLA-I, PD-L1, or NKG2D-L and modulate their susceptibility to the immune response. Moreover, NK cells may be preferentially located in the borders of tumor masses, where, indeed, tumor cells can undergo Epithelial-to-Mesenchymal Transition (EMT) acquiring prometastatic phenotype. Finally, the recently highlighted role of HMGB1 both in EMT and in amplifying the recruitment of NK cells provides further hints on a possible effect of NK cells on tumor progression and fosters new studies on this issue.

  16. NK Cells, Tumor Cell Transition, and Tumor Progression in Solid Malignancies: New Hints for NK-Based Immunotherapy?

    PubMed Central

    Huergo-Zapico, Leticia; Parodi, Monica; Pedrazzi, Marco; Mingari, Maria Cristina; Sparatore, Bianca; Gonzalez, Segundo; Olive, Daniel; Bottino, Cristina

    2016-01-01

    Several evidences suggest that NK cells can patrol the body and eliminate tumors in their initial phases but may hardly control established solid tumors. Multiple factors, including the transition of tumor cells towards a proinvasive/prometastatic phenotype, the immunosuppressive effect of the tumor microenvironment, and the tumor structure complexity, may account for limited NK cell efficacy. Several putative mechanisms of NK cell suppression have been defined in these last years; conversely, the cross talk between NK cells and tumor cells undergoing different transitional phases remains poorly explored. Nevertheless, recent in vitro studies and immunohistochemical analyses on tumor biopsies suggest that NK cells could not only kill tumor cells but also influence their evolution. Indeed, NK cells may induce tumor cells to change the expression of HLA-I, PD-L1, or NKG2D-L and modulate their susceptibility to the immune response. Moreover, NK cells may be preferentially located in the borders of tumor masses, where, indeed, tumor cells can undergo Epithelial-to-Mesenchymal Transition (EMT) acquiring prometastatic phenotype. Finally, the recently highlighted role of HMGB1 both in EMT and in amplifying the recruitment of NK cells provides further hints on a possible effect of NK cells on tumor progression and fosters new studies on this issue. PMID:27294158

  17. The bioflavonoid galangin suppresses the growth of ehrlich ascites carcinoma in Swiss Albino mice: a molecular insight.

    PubMed

    Jaiswal, Jai V; Wadegaonkar, Prasad A; Hajare, Sunil W

    2012-07-01

    Bioflavonoids are plant compounds touted for their potential to treat or prevent several diseases including cancer caused by various stress conditions. Galangin (4H-1-Benzopyran-4-one, 3, 5, 7-trihydroxy-2-phenyl-), a flavonoid, is a polyphenolic compound found primarily in medicinal herb, Alpinia galanga. This study aims to demonstrate the galangin as a pharmacological lead compound using in vitro, in vivo, and in silico model targeting specific cancer condition and proteins. The proliferation of MCF-7 and Ehrlich ascites carcinoma (EAC) cells was significantly inhibited with an IC₅₀ of 34.11 and 22.29 μg/ml, respectively. In an animal model system, galangin has inhibited the tumor growth by 73.51% ± 4.742 in EAC-induced Swiss Albino mice with no evidences of mortality as compared to standard drug, 5-fluorouracil. The effectiveness of galangin is proven in an animal system suggesting its pharmacokinetics behavior in an animal model which is also complemented by outcome of in silico analysis with more than 88 % of human intestinal absorption and significant Caco-2 cell, MDCK cell, and skin permeability as predicted by in silico methods. Galangin was docked against 19 different proteins involved in tumorogenesis and apoptosis; the energetic analysis indicates that it exhibits higher predicted binding free energy of -12.7 kcal/mol with Bcl-xL protein.

  18. Dicer in Mammary Tumor Stem Cell Maintenance

    DTIC Science & Technology

    2008-03-01

    SUPPLEMENTARY NOTES 14. ABSTRACT To date, most cancer research has focused on alterations in the sequence, gene structure, copy number and expression of...To address the role of miR-34in cancer formation and maintenance, we generated cell lines over express miR-34. We have demonstrated that ectopic...mediators of p53 tumor suppressor network, which plays an important role in many cancer types, including breast cancer . 15. SUBJECT TERMS Dicer

  19. Induction of Postsurgical Tumor Immunity and T-Cell Memory by a Poorly Immunogenic Tumor

    PubMed Central

    Zhang, Peisheng; Côté, Anik L.; de Vries, Victor C.; Usherwood, Edward J.; Turk, Mary Jo

    2008-01-01

    The generation of protective CD8 T-cell memory against tumor-expressed self-antigens is an important but elusive goal of cancer immunotherapy. The possibility that a progressive, poorly immunogenic tumor can induce T-cell memory against self-antigens has not previously been studied. Herein, we report that growth of the poorly immunogenic B16 melanoma in the absence of regulatory T cells (Treg) generates CD8 T-cell responses that develop into functional memory after the tumor has been surgically excised. Tumor-primed memory T cells recognized melanocyte differentiation antigens TRP-2/DCT and gp100 and persisted for as long as 5 months following surgical tumor excision. Phenotypic analysis showed that these cells develop into both central and effector memory T-cell subsets, which produce IFN-γ and interleukin-2 on reencounter with antigen. Most importantly, tumor-primed memory T cells mediated the rejection of intradermal and systemically disseminated challenge tumors given 30 to 60 days following surgery. Tumor-excised mice also developed autoimmune vitiligo, showing that Treg cells prevent tissue-specific autoimmunity in tumor-bearing hosts. This study establishes that Treg depletion in tumor-bearing hosts drives the natural development of protective T-cell memory. Generating such responses may aid in the clinical management of tumor recurrence and metastasis following surgery. PMID:17616708

  20. TUMOR-SPECIFIC T CELL MEMORY: CLEARING THE Treg HURDLE

    PubMed Central

    Côté, Anik L.; Usherwood, Edward J.; Turk, Mary Jo

    2009-01-01

    Anti-tumor immune responses can be stimulated by interfering with regulatory T cell (Treg) function. However this effect is short-lived unless T cell memory to tumor antigens can be generated. Our recent studies show that Treg cells not only limit primary responses to tumor/self antigens in tumor-bearing hosts, but also prevent the natural generation of T cell memory to such antigens. Here we discuss the role of regulatory T cells in suppressing T cell memory after surgical excision of tumors, and the potential clinical benefits of overcoming this suppression. PMID:18339838

  1. How does cancer cell metabolism affect tumor migration and invasion?

    PubMed

    Han, Tianyu; Kang, De; Ji, Daokun; Wang, Xiaoyu; Zhan, Weihua; Fu, Minggui; Xin, Hong-Bo; Wang, Jian-Bin

    2013-01-01

    Cancer metastasis is the major cause of cancer-associated death. Accordingly, identification of the regulatory mechanisms that control whether or not tumor cells become "directed walkers" is a crucial issue of cancer research. The deregulation of cell migration during cancer progression determines the capacity of tumor cells to escape from the primary tumors and invade adjacent tissues to finally form metastases. The ability to switch from a predominantly oxidative metabolism to glycolysis and the production of lactate even when oxygen is plentiful is a key characteristic of cancer cells. This metabolic switch, known as the Warburg effect, was first described in 1920s, and affected not only tumor cell growth but also tumor cell migration. In this review, we will focus on the recent studies on how cancer cell metabolism affects tumor cell migration and invasion. Understanding the new aspects on molecular mechanisms and signaling pathways controlling tumor cell migration is critical for development of therapeutic strategies for cancer patients.

  2. Statins impair glucose uptake in tumor cells.

    PubMed

    Malenda, Agata; Skrobanska, Anna; Issat, Tadeusz; Winiarska, Magdalena; Bil, Jacek; Oleszczak, Bozenna; Sinski, Maciej; Firczuk, Małgorzata; Bujnicki, Janusz M; Chlebowska, Justyna; Staruch, Adam D; Glodkowska-Mrowka, Eliza; Kunikowska, Jolanta; Krolicki, Leszek; Szablewski, Leszek; Gaciong, Zbigniew; Koziak, Katarzyna; Jakobisiak, Marek; Golab, Jakub; Nowis, Dominika A

    2012-04-01

    Statins, HMG-CoA reductase inhibitors, are used in the prevention and treatment of cardiovascular diseases owing to their lipid-lowering effects. Previous studies revealed that, by modulating membrane cholesterol content, statins could induce conformational changes in cluster of differentiation 20 (CD20) tetraspanin. The aim of the presented study was to investigate the influence of statins on glucose transporter 1 (GLUT1)-mediated glucose uptake in tumor cells. We observed a significant concentration- and time-dependent decrease in glucose analogs' uptake in several tumor cell lines incubated with statins. This effect was reversible with restitution of cholesterol synthesis pathway with mevalonic acid as well as with supplementation of plasma membrane with exogenous cholesterol. Statins did not change overall GLUT1 expression at neither transcriptional nor protein levels. An exploratory clinical trial revealed that statin treatment decreased glucose uptake in peripheral blood leukocytes and lowered (18)F-fluorodeoxyglucose ((18)F-FDG) uptake by tumor masses in a mantle cell lymphoma patient. A bioinformatics analysis was used to predict the structure of human GLUT1 and to identify putative cholesterol-binding motifs in its juxtamembrane fragment. Altogether, the influence of statins on glucose uptake seems to be of clinical significance. By inhibiting (18)F-FDG uptake, statins can negatively affect the sensitivity of positron emission tomography, a diagnostic procedure frequently used in oncology.

  3. Immune response to UV-induced tumors: mediation of progressor tumor rejection by natural killer cells

    SciTech Connect

    Streeter, P.R.; Fortner, G.W.

    1986-03-01

    Skin tumors induced in mice by chronic ultraviolet (UV) irradiation are highly antigenic and can induce a state of transplantation immunity in syngeneic animals. In the present study, the authors compared the in vitro cytolytic activity of splenic lymphocytes from mice immunized with either regressor or progressor UV-tumors. The results of this comparison implicated tumor-specific cytolytic T (Tc) lymphocytes in rejection of regressor UV-tumors, and revealed that immunization with the progressor UV-tumor 2237 failed to elicit detectable levels of progressor tumor-specific Tc cells even as the tumors rejected. Following in vitro resensitization of spleen cells from either regressor or progressor tumor immune animals, the authors found NK-like lymphocytes with anti-tumor activity. As the authors had not detected cells with this activity in splenic lymphocyte preparations prior to in vitro resensitization, the authors examined lymphocytes from the local tumor environment during the course of progressor tumor rejection for this activity. This analysis revealed NK lymphocytes exhibiting significant levels of cytolytic activity against UV-tumors. These results implicate NK cells as potential effector cells in the rejection of progressor UV-tumors by immune animals, and suggests that these cells may be regulated by T lymphocytes.

  4. Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses

    PubMed Central

    Joshi, Nikhil S.; Akama-Garren, Elliot H.; Lu, Yisi; Lee, Da-Yae; Chang, Gregory P.; Li, Amy; DuPage, Michel; Tammela, Tuomas; Kerper, Natanya R.; Farago, Anna F.; Robbins, Rebecca; Crowley, Denise M.; Bronson, Roderick T.; Jacks, Tyler

    2016-01-01

    SUMMARY Infiltration of regulatory T (Treg) cells into many tumor types correlates with poor patient prognoses. However, mechanisms of intratumoral Treg cell function remain to be elucidated. We investigated Treg cell function in a genetically-engineered mouse lung adenocarcinoma model and found Treg cells suppress anti-tumor responses in tumor-associated tertiary lymphoid structures (TA-TLS). TA-TLS have been described in human lung cancers, but their function remains to be determined. TLS in this model were spatially associated with >90% of tumors and facilitated interactions between T cells and tumor-antigen presenting dendritic cells (DCs). Costimulatory ligand expression by DCs and T cell proliferation rates increased in TA-TLS upon Treg cell depletion, leading to tumor destruction. Thus, we propose Treg cells in TA-TLS can inhibit endogenous immune responses against tumors, and targeting these cells may provide therapeutic benefit for cancer patients. PMID:26341400

  5. Lymphatic endothelial cells support tumor growth in breast cancer

    PubMed Central

    Lee, Esak; Pandey, Niranjan B.; Popel, Aleksander S.

    2014-01-01

    Tumor lymphatic vessels (LV) serve as a conduit of tumor cell dissemination, due to their leaky nature and secretion of tumor-recruiting factors. Though lymphatic endothelial cells (LEC) lining the LV express distinct factors (also called lymphangiocrine factors), these factors and their roles in the tumor microenvironment are not well understood. Here we employ LEC, microvascular endothelial cells (MEC), and human umbilical vein endothelial cells (HUVEC) cultured in triple-negative MDA-MB-231 tumor-conditioned media (TCM) to determine the factors that may be secreted by various EC in the MDA-MB-231 breast tumor. These factors will serve as endothelium derived signaling molecules in the tumor microenvironment. We co-injected these EC with MDA-MB-231 breast cancer cells into animals and showed that LEC support tumor growth, HUVEC have no significant effect on tumor growth, whereas MEC suppress it. Focusing on LEC-mediated tumor growth, we discovered that TCM-treated LEC (‘tumor-educated LEC') secrete high amounts of EGF and PDGF-BB, compared to normal LEC. LEC-secreted EGF promotes tumor cell proliferation. LEC-secreted PDGF-BB induces pericyte infiltration and angiogenesis. These lymphangiocrine factors may support tumor growth in the tumor microenvironment. This study shows that LV serve a novel role in the tumor microenvironment apart from their classical role as conduits of metastasis. PMID:25068296

  6. Vaccine-induced tumor regression requires a dynamic cooperation between T cells and myeloid cells at the tumor site

    PubMed Central

    Thoreau, Maxime; Penny, HweiXian Leong; Tan, KarWai; Regnier, Fabienne; Weiss, Julia Miriam; Lee, Bernett; Johannes, Ludger; Dransart, Estelle; Le Bon, Agnès; Abastado, Jean-Pierre; Tartour, Eric

    2015-01-01

    Most cancer immunotherapies under present investigation are based on the belief that cytotoxic T cells are the most important anti-tumoral immune cells, whereas intra-tumoral macrophages would rather play a pro-tumoral role. We have challenged this antagonistic point of view and searched for collaborative contributions by tumor-infiltrating T cells and macrophages, reminiscent of those observed in anti-infectious responses. We demonstrate that, in a model of therapeutic vaccination, cooperation between myeloid cells and T cells is indeed required for tumor rejection. Vaccination elicited an early rise of CD11b+ myeloid cells that preceded and conditioned the intra-tumoral accumulation of CD8+ T cells. Conversely, CD8+ T cells and IFNγ production activated myeloid cells were required for tumor regression. A 4-fold reduction of CD8+ T cell infiltrate in CXCR3KO mice did not prevent tumor regression, whereas a reduction of tumor-infiltrating myeloid cells significantly interfered with vaccine efficiency. We show that macrophages from regressing tumors can kill tumor cells in two ways: phagocytosis and TNFα release. Altogether, our data suggest new strategies to improve the efficiency of cancer immunotherapies, by promoting intra-tumoral cooperation between macrophages and T cells. PMID:26337837

  7. Effects of alkylation and immunopotentiation against Ehrlich ascites murine carcinoma in vivo using novel tetra-O-acetate haloacetamido carbohydrate analogs.

    PubMed

    Trendowski, Matthew; Christen, Timothy D; Zoino, Joseph N; Fondy, Thomas P

    2015-06-15

    Tetra-O-acetate haloacetamido carbohydrate analogs (Tet-OAHCs) are novel alkylating agents that appear to have alkylating activity at the plasma membrane, specificity against neoplastic cells, and may potentiate host leukocyte influx. This study sought to characterize the chemical attributes and in vivo activity of Tet-OAHCs. Four Tet-OAHCs were assessed for their partition coefficient and alkylating activity to determine cellular environments where adduct formation would be favorable. In vitro, IC50 values of all four Tet-OAHCs were determined against Ehrlich ascites murine carcinoma, as well as two leukemias (U937 human monocytic leukemia and L1210 murine lymphoid leukemia) to assess their cytotoxicity in multiple neoplastic cell lines. In vivo, B6D2F1 and CD2F1 mice were challenged i.p. with Ehrlich ascites carcinoma prior to, or after being treated with a single dose of one of the analogs. Finally, a quantitative comparison of host leukocyte influx between Tet-OAHCs and other alkylating agents was performed to confirm previous in vivo observations that the tetra-O-acetate carbohydrate moiety is important for inducing a host leukocyte response in murine models. The results can be summarized as follows: 1) Tet-OAHCs appear to demonstrate high alkylating activity in amphiphilic environments. 2) All four congeners have comparable in vitro cytotoxicities against the neoplastic cell lines examined. 3) The analogs demonstrate marked in vivo activity in both B6D2F1 and CD2F1 mice challenged with a lethal dose of Ehrlich ascites carcinoma, and frequently produce long term survival at 60 days, which is not observed in simple halo derivatives or two currently approved antineoplastic agents (daunorubicin and mechlorethamine). These effects are observed when the agents are administered either before or after the tumor challenge. 4) The carbohydrate moiety appears to be important for potentiating host leukocyte influx, as Tet-OAHCs, but not other alkylating agents

  8. Phagocytosis of dying tumor cells by human peritoneal mesothelial cells.

    PubMed

    Wagner, Britta Janina; Lindau, Dennis; Ripper, Dagmar; Stierhof, York-Dieter; Glatzle, Jörg; Witte, Maria; Beck, Henning; Keppeler, Hildegard; Lauber, Kirsten; Rammensee, Hans-Georg; Königsrainer, Alfred

    2011-05-15

    Peritoneal carcinomatosis is an advanced form of metastatic disease characterized by cancer cell dissemination onto the peritoneum. It is commonly observed in ovarian and colorectal cancers and is associated with poor patient survival. Novel therapies consist of cytoreductive surgery in combination with intraperitoneal chemotherapy, aiming at tumor cell death induction. The resulting dying tumor cells are considered to be eliminated by professional as well as semi-professional phagocytes. In the present study, we have identified a hitherto unknown type of 'amateur' phagocyte in this environment: human peritoneal mesothelial cells (HMCs). We demonstrate that HMCs engulf corpses of dying ovarian and colorectal cancer cells, as well as other types of apoptotic cells. Flow cytometric, confocal and electron microscopical analyses revealed that HMCs ingest dying cell fragments in a dose- and time-dependent manner and the internalized material subsequently traffics into late phagolysosomes. Regarding the mechanisms of prey cell recognition, our results show that HMCs engulf apoptotic corpses in a serum-dependent and -independent fashion and quantitative real-time PCR (qRT-PCR) analyses revealed that diverse opsonin receptor systems orchestrating dying cell clearance are expressed in HMCs at high levels. Our data strongly suggest that HMCs contribute to dying cell removal in the peritoneum, and future studies will elucidate in what manner this influences tumor cell dissemination and the antitumor immune response.

  9. Isolated tumoral pyruvate dehydrogenase can synthesize acetoin which inhibits pyruvate oxidation as well as other aldehydes.

    PubMed

    Baggetto, L G; Lehninger, A L

    1987-05-29

    Oxidation of 1 mM pyruvate by Ehrlich and AS30-D tumor mitochondria is inhibited by acetoin, an unusual and important metabolite of pyruvate utilization by cancer cells, by acetaldehyde, methylglyoxal and excess pyruvate. The respiratory inhibition is reversed by other substrates added to pyruvate and also by 0.5 mM ATP. Kinetic properties of pyruvate dehydrogenase complex isolated from these tumor mitochondria have been studied. This complex appears to be able to synthesize acetoin from acetaldehyde plus pyruvate and is competitively inhibited by acetoin. The role of a new regulatory pattern for tumoral pyruvate dehydrogenase is presented.

  10. Generation and sequencing of pulmonary carcinoid tumor cell lines.

    PubMed

    Asiedu, Michael K; Thomas, Charles F; Tomaszek, Sandra C; Peikert, Tobias; Sanyal, Bharati; Sutor, Shari L; Aubry, Marie-Christine; Li, Peter; Wigle, Dennis A

    2014-12-01

    Pulmonary carcinoid tumors account for approximately 5% of all lung malignancies in adults, and comprise 30% of all carcinoid tumors. There are limited reagents available to study these rare tumors, and consequently no major advances have been made for patient treatment. We report the generation and characterization of human pulmonary carcinoid tumor cell lines to study underlying biology, and to provide models for testing novel chemotherapeutic agents. Tissue was harvested from three patients with primary pulmonary typical carcinoid tumors undergoing surgical resection. The tumor was dissociated and plated onto dishes in culture media. The established cell lines were characterized by immunohistochemistry, Western blotting, and cell proliferation assays. Tumorigenicity was confirmed by soft agar growth and the ability to form tumors in a mouse xenograft model. Exome and RNA sequencing of patient tumor samples and cell lines was performed using standard protocols. Three typical carcinoid tumor lines grew as adherent monolayers in vitro, expressed neuroendocrine markers consistent with the primary tumor, and formed colonies in soft agar. A single cell line produced lung tumors in nude mice after intravenous injection. Exome and RNA sequencing of this cell line showed lineage relationship with the primary tumor, and demonstrated mutations in a number of genes related to neuronal differentiation. Three human pulmonary typical carcinoid tumor cell lines have been generated and characterized as a tool for studying the biology and novel treatment approaches for these rare tumors.

  11. Giant cell tumor of the spine.

    PubMed

    Ozaki, Toshifumi; Liljenqvist, Ulf; Halm, Henry; Hillmann, Axel; Gosheger, Georg; Winkelmann, Winfried

    2002-08-01

    Six patients with giant cell tumor of the spine had surgery between 1981 and 1995. Three lesions were located in the scrum, two lesions were in the thoracic spine, and one lesion was in the lumbar spine. Preoperatively, all patients had local pain and neurologic symptoms. Two patients had cement implanted after curettage or intralesional excision of the sacral tumor; one patient had a local relapse. After the second curettage and cement implantation, the tumor was controlled. One patient with a sacral lesion had marginal excision and spondylodesis; no relapse developed. Two patients with thoracic lesions had planned marginal excision and spondylodesis; the margins finally became intralesional, but no relapse developed. One patient with a lumbar lesion had incomplete removal of the tumor and received postoperative irradiation. At the final followup (median, 69 months), five of six patients were disease-free and one patient died of disease progression. Two of the five surviving patients had pain after standing or neurologic problems. Although some contamination occurred, planning a marginal excision of the lesion seems beneficial for vertebral lesions above the sacrum. Total sacrectomy of a sacral lesion seems to be too invasive when cement implantation can control the lesion.

  12. Circulating tumor cells in breast cancer

    PubMed Central

    Pukazhendhi, Geetha; Glück, Stefan

    2014-01-01

    Circulating tumor cell (CTC) measurement in peripheral blood of patients with breast cancer offers prognostic information. In this review, we will try to identify evidence that could be used for prognosis, predictive power to draw this tool to clinical utility. We reviewed 81 manuscripts, and categorized those in discovery datasets, prognostic factors in metastatic breast cancer, identification of clinical utility in early breast cancer and in novel approaches. With each patient responding differently to chemotherapy, more efficient markers would improve clinical outcome. Current CTC diagnostic techniques use epithelial markers predominantly; however, the most appropriate method is the measurement of circulating DNA. It has been hypothesized that micrometastasis occurs early in the development of tumors. That implies the presence of CTCs in nonmetastatic setting. The origin of stimulus for malignant transformation is yet unknown. The role of microenvironment as a stimulus is also being investigated. It has been shown that CTCs vary in numbers with chemotherapy. The markers, which are followed-up in the primary tumors, are also being studied on the CTCs. There is discordance of the human epidermal growth factor receptor-2 status between the primary tumor and CTCs. This review summarizes our current knowledge about the CTCs. With genetic profiling and molecular characterization of CTCs, it is possible to overcome the diagnostic difficulties. Evidence for clinical utility of CTC as prognostic and predictive marker is increasing. Appropriate patient stratification according to CTC determination among other tests, would make personalized cancer therapy more feasible. PMID:25191136

  13. Giant cell tumors of the axial skeleton.

    PubMed

    Balke, Maurice; Henrichs, Marcel P; Gosheger, Georg; Ahrens, Helmut; Streitbuerger, Arne; Koehler, Michael; Bullmann, Viola; Hardes, Jendrik

    2012-01-01

    Background. We report on 19 cases of giant cell tumor of bone (GCT) affecting the spine or sacrum and evaluate the outcome of different treatment modalities. Methods. Nineteen patients with GCT of the spine (n = 6) or sacrum (n = 13) have been included in this study. The mean followup was 51.6 months. Ten sacral GCT were treated by intralesional procedures of which 4 also received embolization, and 3 with irradiation only. All spinal GCT were surgically treated. Results. Two (15.4%) patients with sacral and 4 (66.7%) with spinal tumors had a local recurrence, two of the letter developed pulmonary metastases. One local recurrence of the spine was successfully treated by serial arterial embolization, a procedure previously described only for sacral tumors. At last followup, 9 patients had no evidence of disease, 8 had stable disease, 1 had progressive disease, 1 died due to disease. Six patients had neurological deficits. Conclusions. GCT of the axial skeleton have a high local recurrence rate. Neurological deficits are common. En-bloc spondylectomy combined with embolization is the treatment of choice. In case of inoperability, serial arterial embolization seems to be an alternative not only for sacral but also for spinal tumors.

  14. Giant Cell Tumors of the Axial Skeleton

    PubMed Central

    Balke, Maurice; Henrichs, Marcel P.; Gosheger, Georg; Ahrens, Helmut; Streitbuerger, Arne; Koehler, Michael; Bullmann, Viola; Hardes, Jendrik

    2012-01-01

    Background. We report on 19 cases of giant cell tumor of bone (GCT) affecting the spine or sacrum and evaluate the outcome of different treatment modalities. Methods. Nineteen patients with GCT of the spine (n = 6) or sacrum (n = 13) have been included in this study. The mean followup was 51.6 months. Ten sacral GCT were treated by intralesional procedures of which 4 also received embolization, and 3 with irradiation only. All spinal GCT were surgically treated. Results. Two (15.4%) patients with sacral and 4 (66.7%) with spinal tumors had a local recurrence, two of the letter developed pulmonary metastases. One local recurrence of the spine was successfully treated by serial arterial embolization, a procedure previously described only for sacral tumors. At last followup, 9 patients had no evidence of disease, 8 had stable disease, 1 had progressive disease, 1 died due to disease. Six patients had neurological deficits. Conclusions. GCT of the axial skeleton have a high local recurrence rate. Neurological deficits are common. En-bloc spondylectomy combined with embolization is the treatment of choice. In case of inoperability, serial arterial embolization seems to be an alternative not only for sacral but also for spinal tumors. PMID:22448122

  15. Significance of Micrometastases: Circulating Tumor Cells and Disseminated Tumor Cells in Early Breast Cancer

    PubMed Central

    Oakman, Catherine; Pestrin, Marta; Bessi, Silvia; Galardi, Francesca; Di Leo, Angelo

    2010-01-01

    Adjuvant systemic therapy targets minimal residual disease. Our current clinical approach in the adjuvant setting is to presume, rather than confirm, the presence of minimal residual disease. Based on assessment of the primary tumor, we estimate an individual’s recurrence risk. Subsequent treatment decisions are based on characteristics of the primary tumor, with the presumption of consistent biology and treatment sensitivity between micrometastases and the primary lesion. An alternative approach is to identify micrometastatic disease. Detection of disseminated tumor cells (DTC) in the bone marrow and circulating tumor cells (CTC) from peripheral blood collection may offer quantification and biocharacterization of residual disease. This paper will review the prognostic and predictive potential of micrometastatic disease in early breast cancer. PMID:24281114

  16. Targeting tumor cells by enhancing radiation sensitivity.

    PubMed

    McKenna, W Gillies; Muschel, Ruth J

    2003-12-01

    The work of Al Knudson created the paradigm in which we see cancer as a result of the accumulation of multiple mutations. Our goal has been to exploit these mutations to develop strategies to enhance therapy for cancer by targeting the malignant cell while sparing the normal tissue. In studying the RAS oncogene, we observed that its expression when activated resulted in enhanced radioresistance. Conversely, inhibition of RAS made cells with activated RAS more radiosensitive. Hence, we postulated that it would be possible to sensitize tumors with RAS mutations to radiation without affecting the sensitivity of the normal tissue in patients with such tumors. This proved to be the case in animal models and has led to current clinical trials. These studies raised the question of identifying the downstream effectors of RAS that are responsible for altering the radiosensitivity of cells. We have found that phosphoinositide-3-kinase (PI3 kinase) is a critical component of this pathway. Blocking PI3 kinase enhanced the radiation response in vitro or in vivo of cells actively signaling through that pathway, but did not affect cells not actively signaling through PI3 kinase at the time of irradiation. Identification of tumors with active signaling in this pathway by immunohistochemical staining for phosphorylated AKT, the downstream target of PI3 kinase correlated with those patients for which radiation failed to achieve local control. Thus, characterization of the active signaling pathways in a given tumor might enable the selection of patients likely to respond to radiation. Pathways upstream from RAS may also be useful targets to consider for enhancing radiation therapy. Epidermal growth factor receptor (EGFR), which is upstream of PI3 kinase, may also mediate resistance through a common pathway. In addition to EGFR and RAS, PTEN can also regulate the PI3 kinase pathway. Identifying a common signal for EGFR, RAS, and PTEN that results in radiation resistance may uncover

  17. Colon tumor cells grown in NASA Bioreactor

    NASA Technical Reports Server (NTRS)

    2001-01-01

    These photos compare the results of colon carcinoma cells grown in a NASA Bioreactor flown on the STS-70 Space Shuttle in 1995 flight and ground control experiments. The cells grown in microgravity (left) have aggregated to form masses that are larger and more similar to tissue found in the body than the cells cultured on the ground (right). The principal investigator is Milburn Jessup of the University of Texas M. D. Anderson Cancer Center. The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators. Cell constructs grown in a rotating bioreactor on Earth (left) eventually become too large to stay suspended in the nutrient media. In the microgravity of orbit, the cells stay suspended. Rotation then is needed for gentle stirring to replenish the media around the cells. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). Credit: NASA and University of Texas M. D. Anderson Cancer Center.

  18. Colon tumor cells grown in NASA Bioreactor

    NASA Technical Reports Server (NTRS)

    2001-01-01

    These photos compare the results of colon carcinoma cells grown in a NASA Bioreactor flown on the STS-70 Space Shuttle in 1995 flight and ground control experiments. The cells grown in microgravity (left) have aggregated to form masses that are larger and more similar to tissue found in the body than the cells cultured on the ground (right). The principal investigator is Milburn Jessup of the University of Texas M. D. Anderson Cancer Center. The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators. Cell constructs grown in a rotating bioreactor on Earth (left) eventually become too large to stay suspended in the nutrient media. In the microgravity of orbit, the cells stay suspended. Rotation then is needed for gentle stirring to replenish the media around the cells. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). Credit: NASA and University of Texas M. D. Anderson Cancer Center.

  19. In vivo photolabeling of tumor-infiltrating cells reveals highly regulated egress of T-cell subsets from tumors

    PubMed Central

    Torcellan, Tommaso; Hampton, Henry R.; Bailey, Jacqueline; Tomura, Michio; Brink, Robert

    2017-01-01

    Immune therapy is rapidly gaining prominence in the clinic as a major weapon against cancer. Whereas much attention has been focused on the infiltration of tumors by immune cells, the subsequent fate of these infiltrates remains largely unexplored. We therefore established a photoconversion-based model that allowed us to label tumor-infiltrating immune cells and follow their migration. Using this system, we identified a population of tumor-experienced cells that emigrate from primary tumors to draining lymph nodes via afferent lymphatic vessels. Although the majority of tumor-infiltrating cells were myeloid, T cells made up the largest population of tumor-egressing leukocytes. Strikingly, the subset composition of tumor-egressing T cells was greatly skewed compared with those that had infiltrated the tumor and those resident in the draining lymph node. Some T-cell subsets such as CD8+ T cells emigrated more readily; others including CD4−CD8− T cells were preferentially retained, suggesting that specific mechanisms guide immune cell egress from tumors. Furthermore, tumor-egressing T cells were more activated and displayed enhanced effector function in comparison with their lymph node counterparts. Finally, we demonstrated that tumor-infiltrating T cells migrate to distant secondary tumors and draining lymph nodes, highlighting a mechanism whereby tumor-experienced effector T cells may mediate antitumor immunity at metastatic sites. Thus, our results provide insights into migration and function of tumor-infiltrating immune cells and the role of these cells in tumor immunity outside of primary tumor deposits. PMID:28507145

  20. Malignant granular cell tumor with unusual histological features.

    PubMed

    Behzatoğlu, Kemal; Bahadir, Burak

    2007-02-01

    Malignant granular cell tumor, although uncommon, should be differentiated from a number of granular cell-containing tumors. Reported herein is a distinctive variant of malignant granular cell tumor, clinically presenting as a rapidly enlarging scrotal mass, in which some areas morphologically displayed features indistinguishable from Kaposi sarcoma. Cells in areas simulating Kaposi sarcoma were immunohistochemically the same as typical granular cells in other portions of the tumor. The recognition of this pattern is important because it may predominate and overshadow the original nature of tumor.

  1. Tumor cell recognition by γδ T lymphocytes

    PubMed Central

    Correia, Daniel V.; Lopes, António; Silva-Santos, Bruno

    2013-01-01

    The dissection of the molecular mechanisms underlying tumor-cell recognition by γδ T-cells is crucial to improve their performance in cancer immunotherapy. Here, we discuss the controversy around the relative contributions of the γδ T-cell receptor (TCR) and natural killer receptors (NKRs) to tumor-cell targeting by γδ T cells. PMID:23483102

  2. The cultivation and identification of tumor stem cells from neuroblastoma derived tumor spheres.

    PubMed

    Liu, Qiu-Xia; Tang, Jing-Yan; Cai, Jiao-Yang; Yin, Min-Zhi; Li, Ben-Shang

    2010-12-01

    Since the proposal of the tumor stem cell hypothesis, considerable interest has been devoted to the isolation and purification of tumor stem cells. Tumor stem cell enrichment from primary tumor derived cell spheres has been demonstrated in specific, serum-free media. This goal of this study is to establish a method of cultivating floating tumor spheres from neuroblastoma cells and to confirm that neuroblastoma spheres are rich in tumor stem cells. Bone marrow aspirates were obtained from pediatric patients diagnosed with stage IV neuroblastoma. Primary tumor cells were isolated and cultivated in serum-free, stem cell-selective medium. Single sphere-forming cells were cultivated under serum-free conditions; their cloning efficiency and monoclonal tumor sphere formation rates were calculated. The expression of stem cell marker genes Oct-4 and Bmi-1 was detected by RT-PCR in sphere-forming cells and parental neurolastoma cells. Sphere-forming cells were injected into the armpit of nude mice with subsequent assessment for tumor growth. Sphere-forming cells were cultivated in differentiation medium containing 5 μmol/L 13-cis retinoic acid; changes in cell morphology were observed. Neuroblastoma cells formed non-adherent neurospheres under serum-free, stem cell-selective conditions after a period of 4 to 6 days. A single cell dissociated from a neurosphere could reform a monoclonal sphere; cloning efficiency and monoclonal sphere formation rates were 55.3% and 26.3%, respectively. RT-PCR results revealed heightened tumor sphere expression of Oct-4 and Bmi-1 as compared with parental tumor cells. Fourteen days after injection of 10(4) sphere-forming cells into nude mice, a neuroblastoma xenograft formed. Treatment of sphere-forming cells with 13-cis retinoic acid induced a gradual differentiation to neuronal cell morphology. Neuroblastoma derived tumor spheres enrich tumor stem cells and the cultivation of primary neuroblastoma cells in serum-free, stem cell

  3. A portable circulating tumor cell capture microdevice

    NASA Astrophysics Data System (ADS)

    Datar, Ram H.

    2009-03-01

    Sensitive detection of earliest metastatic spread of tumors in a minimally invasive and user-friendly manner will revolutionize the clinical management of cancer patients. The current methodologies for circulating tumor cell (CTC) capture and identification have significant limitations including time, cost, limited capture efficiency and lack of standardization. We have developed and optimized a novel parylene membrane filter-based portable microdevice for size-based isolation of CTC from human peripheral blood. Following characterization with a model system to study the recovery rate and enrichment factor, a comparison of the microdevice with the commercially available system using blood from cancer patients demonstrated superior recovery rate and the promise of clinical utility of the microdevice. The development of the microdevice and its potential clinical applicability will be discussed.

  4. [Precocious pseudopuberty secondary to granulosa cell tumor].

    PubMed

    Fernández, F; Jordán, J; Carmona, M; Oliver, A; Gracia, R; González, M; Peralta, A

    1984-12-01

    A case report of pseudoprecocity secondary to a unilateral ovarian tumor of granulosa cells is presented in a 13 month old female. Clinical manifestations appeared at two months of age as unilateral enlargement of the breast, development of pubic hair and vaginal discharge. Plasma estrogen levels were elevated, whereas there was no response of FSH and LH to LH-RH stimulation. The absence of a palpable abdominal mass and a normal ultrasound examination of the abdomen must be pointed out in our case. The suspected clinical and laboratory diagnosis was later confirmed by surgical abdominal examination and ovarian histopathology study. With the exception of a minimal breast enlargement which persists at two years of age, all other signs of pseudoprecocity have disappeared after the surgical removal of the neoplasm. The importance of surgical abdominal examination must be pointed out as a diagnostic method when clinical and laboratory findings suggest an ovarian tumor inspite of normal abdominal palpation, ultrasound and roentgenology.

  5. Isolation of Circulating Tumor Cells by Dielectrophoresis

    PubMed Central

    Gascoyne, Peter R. C.; Shim, Sangjo

    2014-01-01

    Dielectrophoresis (DEP) is an electrokinetic method that allows intrinsic dielectric properties of suspended cells to be exploited for discrimination and separation. It has emerged as a promising method for isolating circulation tumor cells (CTCs) from blood. DEP-isolation of CTCs is independent of cell surface markers. Furthermore, isolated CTCs are viable and can be maintained in culture, suggesting that DEP methods should be more generally applicable than antibody-based approaches. The aim of this article is to review and synthesize for both oncologists and biomedical engineers interested in CTC isolation the pertinent characteristics of DEP and CTCs. The aim is to promote an understanding of the factors involved in realizing DEP-based instruments having both sufficient discrimination and throughput to allow routine analysis of CTCs in clinical practice. The article brings together: (a) the principles of DEP; (b) the biological basis for the dielectric differences between CTCs and blood cells; (c) why such differences are expected to be present for all types of tumors; and (d) instrumentation requirements to process 10 mL blood specimens in less than 1 h to enable routine clinical analysis. The force equilibrium method of dielectrophoretic field-flow fractionation (DEP-FFF) is shown to offer higher discrimination and throughput than earlier DEP trapping methods and to be applicable to clinical studies. PMID:24662940

  6. Targeting Tumor Oct4 to Deplete Prostate Tumor and Metastasis Initiating Cells

    DTIC Science & Technology

    2016-10-01

    Award Number: W81XWH-13-1-0461 TITLE: Targeting Tumor Oct4 to Deplete Prostate Tumor- and Metastasis-Initiating Cells PRINCIPAL INVESTIGATOR: Daotai...29 2016 4. TITLE AND SUBTILE Targeting Tumor Oct4 to Deplete Prostate Tumor- and Metastasis-Initiating Cells 5a. CONTRACT NUMBER 5b. GRANT NUMBER...the c-MYC oncogene. POU5F1B is a pseudogene of embryonic Oct4 (POU5F1). A recent study found that tumor Oct4 found in prostate cancer cells is due

  7. Ablative Tumor Radiation Can Change the Tumor Immune Cell Microenvironment to Induce Durable Complete Remissions

    PubMed Central

    Filatenkov, Alexander; Baker, Jeanette; Mueller, Antonia M.S.; Kenkel, Justin; Ahn, G-One; Dutt, Suparna; Zhang, Nigel; Kohrt, Holbrook; Jensen, Kent; Dejbakhsh-Jones, Sussan; Shizuru, Judith A.; Negrin, Robert N.; Engleman, Edgar G.; Strober, Samuel

    2015-01-01

    Purpose The goals of the study were to elucidate the immune mechanisms that contribute to desirable complete remissions of murine colon tumors treated with single radiation dose of 30 Gy. This dose is at the upper end of the ablative range used clinically to treat advanced or metastatic colorectal, liver, and non-small cell lung tumors. Experimental design Changes in the tumor immune microenvironment of single tumor nodules exposed to radiation were studied using 21 day (>1 cm in diameter) CT26 and MC38 colon tumors. These are well-characterized weakly immunogenic tumors. Results We found that the high dose radiation transformed the immunosuppressive tumor microenvironment resulting in an intense CD8+ T cell tumor infiltrate, and a loss of myeloid derived suppressor cells (MDSCs). The change was dependent on antigen cross-presenting CD8+ dendritic cells, secretion of IFN-γ, and CD4+ T cells expressing CD40L. Anti-tumor CD8+ T cells entered tumors shortly after radiotherapy, reversed MDSC infiltration, and mediated durable remissions in an IFN-γ dependent manner. Interestingly, extended fractionated radiation regimen did not result in robust CD8+ T cell infiltration. Conclusion For immunologically sensitive tumors, these results indicate that remissions induced by a short course of high dose radiation therapy depend on the development of anti-tumor immunity that is reflected by the nature and kinetics of changes induced in the tumor cell microenvironment. These results suggest that systematic examination of the tumor immune microenvironment may help in optimizing the radiation regimen used to treat tumors by adding a robust immune response. PMID:25869387

  8. Studies of methyl 2-nitroimidazole-1-acetohydroxamate (KIN-804) 1: effect on free radical scavenging system in mice bearing Ehrlich ascites carcinoma.

    PubMed

    Abu-Zeid, M; Hori, H; Nagasawa, H; Uto, Y; Inayama, S

    2000-02-01

    Methyl 2-nitroimidazole-1-acetohydroxamate (KIN-804) is a 2-nitroimidazole derivative containing a hydroxamate side chain designed to enhance the radiosensitization response of hypoxic cells. The possible sensitization of tumor tissue by KIN-804 can be evaluated through investigation of the levels of the free radical scavengers; namely, glutathione (GSH) and its complex enzyme system including glutathione reductase (GR) and glutathione peroxidase (GSH-Px), as well as glucose-6-phosphate dehydrogenase (G-6-PD). Female albino mice were inoculated with Ehrlich carcinoma in the thigh. Administration of KIN-804 (i.p. 80 mg/kg body weight) was carried out 20 min before localized irradiation of 10 Gy. The data revealed that KIN-804 administration, followed or not by gamma irradiation, resulted in a significant decrease in GSH content in tumor tissues associated with inhibition in GR and G-6-PD activities. Blood GSH-Px was enhanced in tumor inoculated mice and the administration of KIN-804 returned it to the normal value. These changes were more noticeable in tumor bearing mice exposed to both KIN-804 and irradiation.

  9. Acoustic separation of circulating tumor cells

    PubMed Central

    Li, Peng; Mao, Zhangming; Peng, Zhangli; Zhou, Lanlan; Chen, Yuchao; Huang, Po-Hsun; Truica, Cristina I.; Drabick, Joseph J.; El-Deiry, Wafik S.; Dao, Ming; Suresh, Subra; Huang, Tony Jun

    2015-01-01

    Circulating tumor cells (CTCs) are important targets for cancer biology studies. To further elucidate the role of CTCs in cancer metastasis and prognosis, effective methods for isolating extremely rare tumor cells from peripheral blood must be developed. Acoustic-based methods, which are known to preserve the integrity, functionality, and viability of biological cells using label-free and contact-free sorting, have thus far not been successfully developed to isolate rare CTCs using clinical samples from cancer patients owing to technical constraints, insufficient throughput, and lack of long-term device stability. In this work, we demonstrate the development of an acoustic-based microfluidic device that is capable of high-throughput separation of CTCs from peripheral blood samples obtained from cancer patients. Our method uses tilted-angle standing surface acoustic waves. Parametric numerical simulations were performed to design optimum device geometry, tilt angle, and cell throughput that is more than 20 times higher than previously possible for such devices. We first validated the capability of this device by successfully separating low concentrations (∼100 cells/mL) of a variety of cancer cells from cell culture lines from WBCs with a recovery rate better than 83%. We then demonstrated the isolation of CTCs in blood samples obtained from patients with breast cancer. Our acoustic-based separation method thus offers the potential to serve as an invaluable supplemental tool in cancer research, diagnostics, drug efficacy assessment, and therapeutics owing to its excellent biocompatibility, simple design, and label-free automated operation while offering the capability to isolate rare CTCs in a viable state. PMID:25848039

  10. Acoustic separation of circulating tumor cells.

    PubMed

    Li, Peng; Mao, Zhangming; Peng, Zhangli; Zhou, Lanlan; Chen, Yuchao; Huang, Po-Hsun; Truica, Cristina I; Drabick, Joseph J; El-Deiry, Wafik S; Dao, Ming; Suresh, Subra; Huang, Tony Jun

    2015-04-21

    Circulating tumor cells (CTCs) are important targets for cancer biology studies. To further elucidate the role of CTCs in cancer metastasis and prognosis, effective methods for isolating extremely rare tumor cells from peripheral blood must be developed. Acoustic-based methods, which are known to preserve the integrity, functionality, and viability of biological cells using label-free and contact-free sorting, have thus far not been successfully developed to isolate rare CTCs using clinical samples from cancer patients owing to technical constraints, insufficient throughput, and lack of long-term device stability. In this work, we demonstrate the development of an acoustic-based microfluidic device that is capable of high-throughput separation of CTCs from peripheral blood samples obtained from cancer patients. Our method uses tilted-angle standing surface acoustic waves. Parametric numerical simulations were performed to design optimum device geometry, tilt angle, and cell throughput that is more than 20 times higher than previously possible for such devices. We first validated the capability of this device by successfully separating low concentrations (∼100 cells/mL) of a variety of cancer cells from cell culture lines from WBCs with a recovery rate better than 83%. We then demonstrated the isolation of CTCs in blood samples obtained from patients with breast cancer. Our acoustic-based separation method thus offers the potential to serve as an invaluable supplemental tool in cancer research, diagnostics, drug efficacy assessment, and therapeutics owing to its excellent biocompatibility, simple design, and label-free automated operation while offering the capability to isolate rare CTCs in a viable state.

  11. Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors

    ClinicalTrials.gov

    2017-08-15

    Germ Cell Tumor; Teratoma; Choriocarcinoma; Germinoma; Mixed Germ Cell Tumor; Yolk Sac Tumor; Childhood Teratoma; Malignant Germ Cell Neoplasm; Extragonadal Seminoma; Non-seminomatous Germ Cell Tumor; Seminoma

  12. Tumor immunogenicity determines the effect of B7 costimulation on T cell-mediated tumor immunity

    PubMed Central

    1994-01-01

    A costimulatory signal through B7 to its counter-receptor CD28 on T cells enhances T cell activation. We have generated recombinant retroviruses containing cDNA for murine B7 and transduced a panel of murine tumor lines with varying immunogenicity to study the effect of B7 costimulation on antitumor immunity. In contrast to the progressive outgrowth of all wild-type (B7-) tumors in unimmunized syngeneic mice, four immunogenic tumors, lymphoma RMA, EL4, mastocytoma P815, and melanoma E6B2, regressed completely when transduced with the B7 gene. In contrast, four nonimmunogenic tumors, sarcomas MCA101, MCA102, and Ag104, and melanoma B16, remained tumorigenic after transduction of the B7 gene. Immunization with B7-transduced immunogenic tumors enhanced protective immunity and increased specific cytotoxic T lymphocyte (CTL) activity against the respective wild-type tumors as compared to immunization with nontransduced or mock-transduced tumors. Moreover, cocultivation of CTL with B7-transduced EL4 cells augmented the specificity of tumor-reactive CTL in long-term cultures. Treatment by injection of B7-transduced tumor cells cured 60% of mice with established wild-type EL4 lymphoma. In contrast, immunization with nonimmunogenic tumors transduced with B7 did not provide protective immunity and did not increase specific CTL activity. Our results show that tumor immunogenicity is critical to the outcome of costimulation of T cell-mediated tumor immunity by B7. PMID:7507508

  13. Granular Cell Tumor of Rectum: A Very Rare Entity

    PubMed Central

    Nagaraj, Savitha V.

    2017-01-01

    Granular cell tumors are predominantly benign, occurring more commonly in women, with about 10% developing in the gastrointestinal tract. Rectal location of this tumor is very rare. We herein report one such case of a 61-year-old man with granular cell tumor in the rectum who underwent endoscopic curative resection. PMID:28255473

  14. Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature.

    PubMed

    Seaman, Steven; Zhu, Zhongyu; Saha, Saurabh; Zhang, Xiaoyan M; Yang, Mi Young; Hilton, Mary Beth; Morris, Karen; Szot, Christopher; Morris, Holly; Swing, Deborah A; Tessarollo, Lino; Smith, Sean W; Degrado, Sylvia; Borkin, Dmitry; Jain, Nareshkumar; Scheiermann, Julia; Feng, Yang; Wang, Yanping; Li, Jinyu; Welsch, Dean; DeCrescenzo, Gary; Chaudhary, Amit; Zudaire, Enrique; Klarmann, Kimberly D; Keller, Jonathan R; Dimitrov, Dimiter S; St Croix, Brad

    2017-04-10

    Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature. In contrast, pyrrolobenzodiazepine-conjugated CD276 ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival. CD276-targeted dual-compartment ablation could aid in the development of highly selective broad-acting anti-cancer therapies. Published by Elsevier Inc.

  15. Tumor cells as cellular vehicles to deliver gene therapies to metastatic tumors.

    PubMed

    García-Castro, Javier; Martínez-Palacio, Jesús; Lillo, Rosa; García-Sánchez, Félix; Alemany, Ramón; Madero, Luis; Bueren, Juan A; Ramírez, Manuel

    2005-04-01

    A long-pursued goal in cancer treatment is to deliver a therapy specifically to metastases. As a result of the disseminated nature of the metastatic disease, carrying the therapeutic agent to the sites of tumor growth represents a major step for success. We hypothesized that tumor cells injected intravenously (i.v.) into an animal with metastases would respond to many of the factors driving the metastatic process, and would target metastases. Using a model of spontaneous metastases, we report here that i.v. injected tumor cells localized on metastatic lesions. Based on this fact, we used genetically transduced tumor cells for tumor targeting of anticancer agents such as a suicide gene or an oncolytic virus, with evident antitumoral effect and negligible systemic toxicity. Therefore, autologous tumor cells may be used as cellular vehicles for systemic delivery of anticancer therapies to metastatic tumors.

  16. Risk assessment of thyroid follicular cell tumors.

    PubMed Central

    Hill, R N; Crisp, T M; Hurley, P M; Rosenthal, S L; Singh, D V

    1998-01-01

    Thyroid follicular cell tumors arise in rodents from mutations, perturbations of thyroid and pituitary hormone status with increased stimulation of thyroid cell growth by thyroid-stimulating hormone (TSH), or a combination of the two. The only known human thyroid carcinogen is ionizing radiation. It is not known for certain whether chemicals that affect thyroid cell growth lead to human thyroid cancer. The U.S. Environmental Protection Agency applies the following science policy positions: 1) chemically induced rodent thyroid tumors are presumed to be relevant to humans; 2) when interspecies information is lacking, the default is to assume comparable carcinogenic sensitivity in rodents and humans; 3) adverse rodent noncancer thyroid effects due to chemically induced thyroid-pituitary disruption are presumed to be relevant to humans; 4) linear dose-response considerations are applied to thyroid cancer induced by chemical substances that either do not disrupt thyroid functioning or lack mode of action information; 5) nonlinear thyroid cancer dose-response considerations are applied to chemicals that reduce thyroid hormone levels, increase TSH and thyroid cell division, and are judged to lack mutagenic activity; and 6) nonlinear considerations may be applied in thyroid cancer dose-response assessments on a case-by-case basis for chemicals that disrupt thyroid-pituitary functioning and demonstrate some mutagenic activity. Required data for risk assessment purposes is mode of action information on mutagenicity, increases in follicular cell growth (cell size and number) and thyroid gland weight, thyroid-pituitary hormones, site of action, correlations between doses producing thyroid effects and cancer, and reversibility of effects when dosing ceases. Images Figure 1 Figure 2 Figure 3 PMID:9681971

  17. [Circulating tumor cells and prostate cancer prognosis].

    PubMed

    Capoun, Otakar; Soukup, Viktor; Mikulová, Veronika; Jančíková, Markéta; Honová, Hana; Kološtová, Katarína; Zima, Tomáš; Hanuš, Tomáš

    2014-01-01

    Prostate cancer (PC) is the most common malignant disease in men. Prognosis of patients with metastatic PC is generally unfavourable; however there are significant differences in survival at this stage of the disease. The definition of prognosis is essential for the selection of therapy, respecting an individual risk. In recent years, the association between circulating tumor cells (CTC) detection and response to PC treatment has been widely investigated. Detection of CTC is based on a metastatic process theory and uses well-known tumor-specific antigens on the cell surface. Individual methods assess CTC with different sensitivity and are not yet efficient at the localised PC stage. Only the method of immunomagnetic separation and semi-automatic visualisation (CellSearchTM) has been validated and approved for the use in the PC management. Assessment of the CTC count directly correlates with the prognosis of patients with castration-resistant PC. Change in the CTC count during the therapy also considerably improves risk estimation and represents a marker of overall survival. New methods of CTC cultivation and gene profiling may contribute to individualisation of the treatment similarly to breast cancer. The authors present a review article about theory, methods of detection and clinical use of CTC in castration-resistant PC.

  18. T cells from the tumor microenvironment of patients with progressive myeloma can generate strong, tumor-specific cytolytic responses to autologous, tumor-loaded dendritic cells

    NASA Astrophysics Data System (ADS)

    Dhodapkar, Madhav V.; Krasovsky, Joseph; Olson, Kara

    2002-10-01

    Most untreated cancer patients develop progressive tumors. We tested the capacity of T lymphocytes from patients with clinically progressive, multiple myeloma to develop killer function against fresh autologous tumor. In this malignancy, it is feasible to reproducibly evaluate freshly isolated tumor cells and T cells from the marrow tumor environment. When we did this with seven consecutive patients, with all clinical stages of disease, we did not detect reactivity to autologous cancer cells. However, both cytolytic and IFN--producing responses to autologous myeloma were generated in six of seven patients after stimulation ex vivo with dendritic cells that had processed autologous tumor cells. The antitumor effectors recognized fresh autologous tumor but not nontumor cells in the bone marrow, myeloma cell lines, dendritic cells loaded with tumor-derived Ig, or allogeneic tumor. Importantly, these CD8+ effectors developed with similar efficiency by using T cells from both the blood and the bone marrow tumor environment. Therefore, even in the setting of clinical tumor progression, the tumor bed of myeloma patients contains T cells that can be activated readily by dendritic cells to kill primary autologous tumor.

  19. Dicer in Mammary Tumor Stem Cell Maintenance

    DTIC Science & Technology

    2007-03-01

    MicroRNAs ( miRNAs ) are a set of small RNAs produced by the RNAi machinery that play important functions in tissue organization and maintenance of cell... factor p53 is a tumor-suppressor gene that is deleted or mutated in many human cancers . To identify miRNAs that may be part of the p53 pathway, we...identity. Several miRNAs have been shown to collaborate with oncogenes in the progression of cancer , and in addition, miRNA expression profiling has

  20. Differential potency of regulatory T cell-mediated immunosuppression in kidney tumors compared to subcutaneous tumors

    PubMed Central

    Devaud, Christel; Westwood, Jennifer A; Teng, Michele WL; John, Liza B; Yong, Carmen SM; Duong, Connie PM; Smyth, Mark J; Darcy, Phillip K; Kershaw, Michael H

    2014-01-01

    In many cancers, regulatory T cells (Treg) play a crucial role in suppressing the effector immune response thereby permitting tumor development. Indeed, in mouse models, their depletion can promote the regression of tumors of various origins, including renal cell carcinoma when located subcutaneous (SC). In the present study, we aimed to assess the importance of Treg immunosuppression in the physiologic context of metastatic renal carcinoma (Renca) disease. To that purpose we inoculated renal tumors orthotopically, intra-kidney (IK), in mice. Treg depletions were performed using anti-CD4 antibody in wild type mice or diphtheria toxin (DT) in Foxp3DTR transgenic mice. Our main observation was that Treg were not the key immunosuppressive component of the IK tumoral microenvironment, compared to the same tumors located SC. We demonstrated that the CD8+ effector immune response was still suppressed in IK tumors when compared to SC tumors, following Treg depletion. Furthermore, the level of program cell death protein (PD)-1 was increased on the surface of CD4+ T cells infiltrating IK tumors compared to SC tumors. Finally, the Treg-independent immunosuppression, occurring in IK tumors, was potent enough to inhibit regression of concomitant SC tumors, normally responsive to Treg depletion. Our findings provide further insight into the immunosuppressive nature of the immune response generated in the kidney microenvironment, suggesting that it can have additional mechanisms in addition to Treg. These observations might help to identify better targets from the kidney tumor microenvironment for future cancer therapies. PMID:25941590

  1. Differential potency of regulatory T cell-mediated immunosuppression in kidney tumors compared to subcutaneous tumors.

    PubMed

    Devaud, Christel; Westwood, Jennifer A; Teng, Michele Wl; John, Liza B; Yong, Carmen Sm; Duong, Connie Pm; Smyth, Mark J; Darcy, Phillip K; Kershaw, Michael H

    2014-11-01

    In many cancers, regulatory T cells (Treg) play a crucial role in suppressing the effector immune response thereby permitting tumor development. Indeed, in mouse models, their depletion can promote the regression of tumors of various origins, including renal cell carcinoma when located subcutaneous (SC). In the present study, we aimed to assess the importance of Treg immunosuppression in the physiologic context of metastatic renal carcinoma (Renca) disease. To that purpose we inoculated renal tumors orthotopically, intra-kidney (IK), in mice. Treg depletions were performed using anti-CD4 antibody in wild type mice or diphtheria toxin (DT) in Foxp3(DTR) transgenic mice. Our main observation was that Treg were not the key immunosuppressive component of the IK tumoral microenvironment, compared to the same tumors located SC. We demonstrated that the CD8(+) effector immune response was still suppressed in IK tumors when compared to SC tumors, following Treg depletion. Furthermore, the level of program cell death protein (PD)-1 was increased on the surface of CD4(+) T cells infiltrating IK tumors compared to SC tumors. Finally, the Treg-independent immunosuppression, occurring in IK tumors, was potent enough to inhibit regression of concomitant SC tumors, normally responsive to Treg depletion. Our findings provide further insight into the immunosuppressive nature of the immune response generated in the kidney microenvironment, suggesting that it can have additional mechanisms in addition to Treg. These observations might help to identify better targets from the kidney tumor microenvironment for future cancer therapies.

  2. Establishment of a tumor sphere cell line from a metastatic brain neuroendocrine tumor.

    PubMed

    Iwata, Ryoichi; Maruyama, Masato; Ito, Tomoki; Nakano, Yosuke; Kanemura, Yonehiro; Koike, Taro; Oe, Souichi; Yoshimura, Kunikazu; Nonaka, Masahiro; Nomura, Shosaku; Sugimoto, Tetsuo; Yamada, Hisao; Asai, Akio

    2017-05-17

    Neuroendocrine tumors are rare, and little is known about the existence of cancer stem cells in this disease. Identification of the tumorigenic population will contribute to the development of effective therapies targeting neuroendocrine tumors. Surgically resected brain metastases from a primary neuroendocrine tumor of unknown origin were dissociated and cultured in serum-free neurosphere medium. Stem cell properties, including self-renewal, differentiation potential, and stem cell marker expression, were examined. Tumor formation was evaluated using intracranial xenograft models. The effect of temozolomide was measured in vitro by cell viability assays. We established the neuroendocrine tumor sphere cell line ANI-27S, which displayed stable exponential growth, virtually unlimited expansion in vitro, and expression of stem-cell markers such as CD133, nestin, Sox2, and aldehyde dehydrogenase. FBS-induced differentiation decreased Sox2 and nestin expression. On the basis of real-time PCR, ANI-27S cells expressed the neuroendocrine markers synaptophysin and chromogranin A. Intracranial xenotransplanted brain tumors recapitulated the original patient tumor and temozolomide exhibited cytotoxic effects on tumor sphere cells. For the first time, we demonstrated the presence of a sphere-forming, stem cell-like population in brain metastases from a primary neuroendocrine tumor. We also demonstrated the potential therapeutic effects of temozolomide for this disease.

  3. Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression.

    PubMed

    Miao, H Q; Lee, P; Lin, H; Soker, S; Klagsbrun, M

    2000-12-01

    Neuropilin-1 (NRP1) is a VEGF(165) and semaphorin receptor expressed by vascular endothelial cells (EC) and tumor cells. The function of NRP1 in tumor cells is unknown. NRP1 was overexpressed in Dunning rat prostate carcinoma AT2.1 cells using a tetracycline-inducible promoter. Concomitant with increased NRP1 expression in response to a tetracycline homologue, doxycycline (Dox), basal cell motility, and VEGF(165) binding were increased three- to fourfold in vitro. However, induction of NRP1 did not affect tumor cell proliferation. When rats injected with AT2.1/NRP1 tumor cells were fed Dox, NRP1 synthesis was induced in vivo and AT2.1 cell tumor size was increased 2.5- to 7-fold in a 3-4 wk period compared to controls. The larger tumors with induced NRP1 expression were characterized by markedly increased microvessel density, increased proliferating EC, dilated blood vessels, and notably less tumor cell apoptosis compared to noninduced controls. It was concluded that NRP1 expression results in enlarged tumors associated with substantially enhanced tumor angiogenesis.

  4. A Think Tank of TINK/TANKs: Tumor-Infiltrating/Tumor-Associated Natural Killer Cells in Tumor Progression and Angiogenesis

    PubMed Central

    Bruno, Antonino; Ferlazzo, Guido; Albini, Adriana; Noonan, Douglas M.

    2014-01-01

    Tumor-infiltrating leukocytes are often induced by the cancer microenvironment to display a protumor, proangiogenic phenotype. This “polarization” has been described for several myeloid cells, in particular macrophages. Natural killer (NK) cells represent another population of innate immune cells able to infiltrate tumors. The role of NK in tumor progression and angiogenesis has not yet been fully investigated. Several studies have shown that tumor-infiltrating NK (here referred to as “TINKs”) and tumor-associated NK (altered peripheral NK cells, which here we call “TANKs”) are compromised in their ability to lysew tumor cells. Recent data have suggested that they are potentially protumorigenic and can also acquire a proangiogenic phenotype. Here we review the properties of TINKs and TANKs and compare their activities to that of NK cells endowed with a physiological proangiogenic phenotype, in particular decidual NK cells. We speculate on the potential origins of TINKs and TANKs and on the immune signals involved in their differentiation and polarization. The TINK and TANK phenotype has broad implications in the immune response to tumors, ranging from a deficient control of cancer and cancer stem cells to an altered crosstalk with other relevant players of the immune response, such as dendritic cells, to induction of cancer angiogenesis. With this recently acquired knowledge that has not yet been put into perspective, we point out new potential avenues for therapeutic intervention involving NK cells as a target or an ally in oncology. PMID:25178695

  5. A think tank of TINK/TANKs: tumor-infiltrating/tumor-associated natural killer cells in tumor progression and angiogenesis.

    PubMed

    Bruno, Antonino; Ferlazzo, Guido; Albini, Adriana; Noonan, Douglas M

    2014-08-01

    Tumor-infiltrating leukocytes are often induced by the cancer microenvironment to display a protumor, proangiogenic phenotype. This "polarization" has been described for several myeloid cells, in particular macrophages. Natural killer (NK) cells represent another population of innate immune cells able to infiltrate tumors. The role of NK in tumor progression and angiogenesis has not yet been fully investigated. Several studies have shown that tumor-infiltrating NK (here referred to as "TINKs") and tumor-associated NK (altered peripheral NK cells, which here we call "TANKs") are compromised in their ability to lysew tumor cells. Recent data have suggested that they are potentially protumorigenic and can also acquire a proangiogenic phenotype. Here we review the properties of TINKs and TANKs and compare their activities to that of NK cells endowed with a physiological proangiogenic phenotype, in particular decidual NK cells. We speculate on the potential origins of TINKs and TANKs and on the immune signals involved in their differentiation and polarization. The TINK and TANK phenotype has broad implications in the immune response to tumors, ranging from a deficient control of cancer and cancer stem cells to an altered crosstalk with other relevant players of the immune response, such as dendritic cells, to induction of cancer angiogenesis. With this recently acquired knowledge that has not yet been put into perspective, we point out new potential avenues for therapeutic intervention involving NK cells as a target or an ally in oncology.

  6. Collision tumors: pancreatic adenocarcinoma and mantle cell lymphoma.

    PubMed

    Dasanu, Constantin A; Shimanovsky, Alexei; Rotundo, Edyta K; Posteraro, Anthony F; Cooper, Dennis L; Atienza, Jonessa A

    2013-07-10

    Collision tumors are very rare entities composed of two or more distinct tumor components, each separated by normal tissue. Perhaps due to technical advances in the last decade, the incidence of collision tumors has been on the rise. To the best of our knowledge, collision tumors featuring mantle cell lymphoma and pancreatic adenocarcinoma have not been previously described in the scientific literature. For the first time, we describe herein the clinical course of a collision tumor between pancreatic adenocarcinoma and mantle cell lymphoma. We hypothesize several aspects in the pathogenesis of a such event and review the existing literature on collision tumors.

  7. Single Unpurified Breast Tumor-Initiating Cells from Multiple Mouse Models Efficiently Elicit Tumors in Immune-Competent Hosts

    PubMed Central

    Kurpios, Natasza A.; Girgis-Gabardo, Adele; Hallett, Robin M.; Rogers, Stephen; Gludish, David W.; Kockeritz, Lisa; Woodgett, James; Cardiff, Robert; Hassell, John A.

    2013-01-01

    The tumor-initiating cell (TIC) frequency of bulk tumor cell populations is one of the criteria used to distinguish malignancies that follow the cancer stem cell model from those that do not. However, tumor-initiating cell frequencies may be influenced by experimental conditions and the extent to which tumors have progressed, parameters that are not always addressed in studies of these cells. We employed limiting dilution cell transplantation of minimally manipulated tumor cells from mammary tumors of several transgenic mouse models to determine their tumor-initiating cell frequency. We determined whether the tumors that formed following tumor cell transplantation phenocopied the primary tumors from which they were isolated and whether they could be serially transplanted. Finally we investigated whether propagating primary tumor cells in different tissue culture conditions affected their resident tumor-initiating cell frequency. We found that tumor-initiating cells comprised between 15% and 50% of the bulk tumor cell population in multiple independent mammary tumors from three different transgenic mouse models of breast cancer. Culture of primary mammary tumor cells in chemically-defined, serum-free medium as non-adherent tumorspheres preserved TIC frequency to levels similar to that of the primary tumors from which they were established. By contrast, propagating the primary tumor cells in serum-containing medium as adherent populations resulted in a several thousand-fold reduction in their tumor-initiating cell fraction. Our findings suggest that experimental conditions, including the sensitivity of the transplantation assay, can dramatically affect estimates of tumor initiating cell frequency. Moreover, conditional on cell culture conditions, the tumor-initiating cell fraction of bulk mouse mammary tumor cell preparations can either be maintained at high or low frequency in vitro thus permitting comparative studies of tumorigenic and non-tumorigenic cancer cells

  8. Single unpurified breast tumor-initiating cells from multiple mouse models efficiently elicit tumors in immune-competent hosts.

    PubMed

    Kurpios, Natasza A; Girgis-Gabardo, Adele; Hallett, Robin M; Rogers, Stephen; Gludish, David W; Kockeritz, Lisa; Woodgett, James; Cardiff, Robert; Hassell, John A

    2013-01-01

    The tumor-initiating cell (TIC) frequency of bulk tumor cell populations is one of the criteria used to distinguish malignancies that follow the cancer stem cell model from those that do not. However, tumor-initiating cell frequencies may be influenced by experimental conditions and the extent to which tumors have progressed, parameters that are not always addressed in studies of these cells. We employed limiting dilution cell transplantation of minimally manipulated tumor cells from mammary tumors of several transgenic mouse models to determine their tumor-initiating cell frequency. We determined whether the tumors that formed following tumor cell transplantation phenocopied the primary tumors from which they were isolated and whether they could be serially transplanted. Finally we investigated whether propagating primary tumor cells in different tissue culture conditions affected their resident tumor-initiating cell frequency. We found that tumor-initiating cells comprised between 15% and 50% of the bulk tumor cell population in multiple independent mammary tumors from three different transgenic mouse models of breast cancer. Culture of primary mammary tumor cells in chemically-defined, serum-free medium as non-adherent tumorspheres preserved TIC frequency to levels similar to that of the primary tumors from which they were established. By contrast, propagating the primary tumor cells in serum-containing medium as adherent populations resulted in a several thousand-fold reduction in their tumor-initiating cell fraction. Our findings suggest that experimental conditions, including the sensitivity of the transplantation assay, can dramatically affect estimates of tumor initiating cell frequency. Moreover, conditional on cell culture conditions, the tumor-initiating cell fraction of bulk mouse mammary tumor cell preparations can either be maintained at high or low frequency in vitro thus permitting comparative studies of tumorigenic and non-tumorigenic cancer cells.

  9. Cancer cell differentiation heterogeneity and aggressive behavior in solid tumors.

    PubMed

    Jögi, Annika; Vaapil, Marica; Johansson, Martin; Påhlman, Sven

    2012-05-01

    The differentiation stage of tumors is a central aspect in the histopathological classification of solid malignancies. The differentiation stage is strongly associated with tumor behavior, and generally an immature tumor is more aggressive than the more differentiated counterpart. While this is common knowledge in surgical pathology, the contribution of differentiation-related gene expression and functions to tumor behavior is often overlooked in the experimental, tumor biological setting. The mechanisms by which tumor cell differentiation stages are perturbed or affected are poorly explored but have recently come into focus with the introduction.of the tumor stem cell concept. While developmental biologists view the differentiation as a unidirectional event, pathologists and tumor biologists have introduced the concept of dedifferentiation to explain phenotypic changes occurring in solid tumors. In this review we discuss the impact of the tumor cell differentiation stage as used in surgical pathology. We further discuss knowledge gained from exploring the molecular basis of the differentiation and dedifferentiation processes in neuroblastoma and breast cancer, two tumor forms where the tumor cell differentiation concept is used in the clinical diagnostic work and where the tumor stem cell theory has been applied.

  10. Tumor cell "dead or alive": caspase and survivin regulate cell death, cell cycle and cell survival.

    PubMed

    Suzuki, A; Shiraki, K

    2001-04-01

    Cell death and cell cycle progression are two sides of the same coin, and these two different phenomenons are regulated moderately to maintain the cellular homeostasis. Tumor is one of the disease states produced as a result of the disintegrated regulation and is characterized as cells showing an irreversible progression of cell cycle and a resistance to cell death signaling. Several investigations have been performed for the understanding of cell death or cell cycle, and cell death research has remarkably progressed in these 10 years. Caspase is a nomenclature referring to ICE/CED-3 cysteine proteinase family and plays a central role during cell death. Recently, several investigations raised some possible hypotheses that caspase is also involved in cell cycle regulation. In this issue, therefore, we review the molecular basis of cell death and cell cycle regulated by caspase in tumor, especially hepatocellular carcinoma cells.

  11. Vaccination with tumor cells pulsed with foreign peptide induces immunity to the tumor itself

    PubMed Central

    Schlingmann, Tobias R.; Rininsland, Frauke H.; Bartholomae, Wolf C.; Kuekrek, Haydar; Lehmann, Paul V.; Tary-Lehmann, Magdalena

    2009-01-01

    EMT-6 mammary carcinoma and B16 melanoma (B16M) cells are lethal and barely immunogenic in syngeneic BALB/c and C57BL/6 mice, respectively. We show that mice vaccinated with tumor cells pulsed with a MHC class I-restricted peptide develop a T cell response, not only to the peptide, but also to the unpulsed tumor. These mice display protective immunity against the unpulsed tumor, and their T cells adoptively transfer tumor-specific protection to immunodeficient SCID mice. Our data have implications for cancer vaccine strategies. Grafting a single well-defined foreign peptide on tumor cells might suffice to trigger anti-tumor immunity. PMID:19589730

  12. Enrichment and single-cell analysis of circulating tumor cells

    PubMed Central

    Song, Yanling; Tian, Tian; Shi, Yuanzhi; Liu, Wenli; Zou, Yuan; Khajvand, Tahereh; Wang, Sili; Zhu, Zhi

    2017-01-01

    Up to 90% of cancer-related deaths are caused by metastatic cancer. Circulating tumor cells (CTCs), a type of cancer cell that spreads through the blood after detaching from a solid tumor, are essential for the establishment of distant metastasis for a given cancer. As a new type of liquid biopsy, analysis of CTCs offers the possibility to avoid invasive tissue biopsy procedures with practical implications for diagnostics. The fundamental challenges of analyzing and profiling CTCs are the extremely low abundances of CTCs in the blood and the intrinsic heterogeneity of CTCs. Various technologies have been proposed for the enrichment and single-cell analysis of CTCs. This review aims to provide in-depth insights into CTC analysis, including various techniques for isolation of CTCs with capture methods based on physical and biochemical principles, and single-cell analysis of CTCs at the genomic, proteomic and phenotypic level, as well as current developmental trends and promising research directions. PMID:28451298

  13. A tumor cell growth inhibitor from Saposhnikovae divaricata.

    PubMed

    Kuo, Yuh-Chi; Lin, Yun-Lian; Huang, Cheng-Po; Shu, Jia-Wei; Tsai, Wei-Jern

    2002-01-01

    In the present study, we tested ethanolic extracts from 10 Chinese herbs for their effects on K562, Raji, Wish, HeLa, Calu-1, and Vero tumor cells proliferation. On a percentage basis, panaxynol purified from Saposhnikovae divaricata had the highest inhibitory activity on various tumor cells proliferation. Cell-cycle analysis indicated that panaxynol arrested the cell cycle progression of tumor cells from the G1 transition to the S phase. In an attempt to further localize the point in the cell cycle where arrest occurred, gene expression of cyclin E, a key regulatory event leading to the G1/S boundary was examined. Results indicated that the levels of cyclin E mRNA in various tumor cells were decreased by panaxynol. Thus, the suppressant effects of panaxynol on proliferation of various tumor cells appeared to be mediated, at least in part, through impairments of cyclin E mRNA levels and arresting cell cycle progression in the cells.

  14. Expression of Hyaluronidase by Tumor Cells Induces Angiogenesis in vivo

    NASA Astrophysics Data System (ADS)

    Liu, Dacai; Pearlman, Eric; Diaconu, Eugenia; Guo, Kun; Mori, Hiroshi; Haqqi, Tariq; Markowitz, Sanford; Willson, James; Sy, Man-Sun

    1996-07-01

    Hyaluronic acid is a proteoglycan present in the extracellular matrix and is important for the maintenance of tissue architecture. Depolymerization of hyaluronic acid may facilitate tumor invasion. In addition, oligosaccharides of hyaluronic acid have been reported to induce angiogenesis. We report here that a hyaluronidase similar to the one on human sperm is expressed by metastatic human melanoma, colon carcinoma, and glioblastoma cell lines and by tumor biopsies from patients with colorectal carcinomas, but not by tissues from normal colon. Moreover, angiogenesis is induced by hyaluronidase+ tumor cells but not hyaluronidase- tumor cells and can be blocked by an inhibitor of hyaluronidase. Tumor cells thus use hyaluronidase as one of the ``molecular saboteurs'' to depolymerize hyaluronic acid to facilitate invasion. As a consequence, breakdown products of hyaluronic acid can further promote tumor establishment by inducing angiogenesis. Hyaluronidase on tumor cells may provide a target for anti-neoplastic drugs.

  15. Expression of hyaluronidase by tumor cells induces angiogenesis in vivo.

    PubMed Central

    Liu, D; Pearlman, E; Diaconu, E; Guo, K; Mori, H; Haqqi, T; Markowitz, S; Willson, J; Sy, M S

    1996-01-01

    Hyaluronic acid is a proteoglycan present in the extracellular matrix and is important for the maintenance of tissue architecture. Depolymerization of hyaluronic acid may facilitate tumor invasion. In addition, oligosaccharides of hyaluronic acid have been reported to induce angiogenesis. We report here that a hyaluronidase similar to the one on human sperm is expressed by metastatic human melanoma, colon carcinoma, and glioblastoma cell lines and by tumor biopsies from patients with colorectal carcinomas, but not by tissues from normal colon. Moreover, angiogenesis is induced by hyaluronidase+ tumor cells but not hyaluronidase- tumor cells and can be blocked by an inhibitor of hyaluronidase. Tumor cells thus use hyaluronidase as one of the "molecular saboteurs" to depolymerize hyaluronic acid to facilitate invasion. As a consequence, breakdown products of hyaluronic acid can further promote tumor establishment by inducing angiogenesis. Hyaluronidase on tumor cells may provide a target for anti-neoplastic drugs. Images Fig. 1 Fig. 2 Fig. 3 PMID:8755562

  16. Antitumour activity of Prosopis cineraria (L.) Druce against Ehrlich ascites carcinoma-induced mice.

    PubMed

    Robertson, Stellaa; Narayanan, N; Raj Kapoor, B

    2011-04-01

    The antitumour activity of the hydroalcoholic extract of the leaf (PCL) and stem bark (PCB) of Prosopis cineraria (L.) in Swiss albino mice was evaluated against an Ehrlich ascites carcinoma (EAC) tumour model. The activity was assessed using survival time, peritoneal cells, haematological studies, lipid peroxidation, antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase, solid tumour mass and in vitro cytotoxicity. PCL and PCB were found to be potent and possessed significant cytotoxicity towards EAC tumour cells.

  17. Tumor-associated B-cells induce tumor heterogeneity and therapy resistance.

    PubMed

    Somasundaram, Rajasekharan; Zhang, Gao; Fukunaga-Kalabis, Mizuho; Perego, Michela; Krepler, Clemens; Xu, Xiaowei; Wagner, Christine; Hristova, Denitsa; Zhang, Jie; Tian, Tian; Wei, Zhi; Liu, Qin; Garg, Kanika; Griss, Johannes; Hards, Rufus; Maurer, Margarita; Hafner, Christine; Mayerhöfer, Marius; Karanikas, Georgios; Jalili, Ahmad; Bauer-Pohl, Verena; Weihsengruber, Felix; Rappersberger, Klemens; Koller, Josef; Lang, Roland; Hudgens, Courtney; Chen, Guo; Tetzlaff, Michael; Wu, Lawrence; Frederick, Dennie Tompers; Scolyer, Richard A; Long, Georgina V; Damle, Manashree; Ellingsworth, Courtney; Grinman, Leon; Choi, Harry; Gavin, Brian J; Dunagin, Margaret; Raj, Arjun; Scholler, Nathalie; Gross, Laura; Beqiri, Marilda; Bennett, Keiryn; Watson, Ian; Schaider, Helmut; Davies, Michael A; Wargo, Jennifer; Czerniecki, Brian J; Schuchter, Lynn; Herlyn, Dorothee; Flaherty, Keith; Herlyn, Meenhard; Wagner, Stephan N

    2017-09-19

    In melanoma, therapies with inhibitors to oncogenic BRAF(V600E) are highly effective but responses are often short-lived due to the emergence of drug-resistant tumor subpopulations. We describe here a mechanism of acquired drug resistance through the tumor microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce the growth factor FGF-2, which activates tumor-infiltrating B cells to produce the growth factor IGF-1. B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3. Consistently, resistance of melanomas to BRAF and/or MEK inhibitors is associated with increased CD20 and IGF-1 transcript levels in tumors and IGF-1 expression in tumor-associated B cells. Furthermore, first clinical data from a pilot trial in therapy-resistant metastatic melanoma patients show anti-tumor activity through B-cell depletion by anti-CD20 antibody. Our findings establish a mechanism of acquired therapy resistance through tumor-associated B cells with important clinical implications.Resistance to BRAFV600E inhibitors often occurs in melanoma patients. Here, the authors describe a potential mechanism of acquired drug resistance mediated by tumor-associated B cells-derived IGF-1.

  18. Circulating Tumor Cell and Cell-free Circulating Tumor DNA in Lung Cancer.

    PubMed

    Nurwidya, Fariz; Zaini, Jamal; Putra, Andika Chandra; Andarini, Sita; Hudoyo, Achmad; Syahruddin, Elisna; Yunus, Faisal

    2016-09-01

    Circulating tumor cells (CTCs) are tumor cells that are separated from the primary site or metastatic lesion and disseminate in blood circulation. CTCs are considered to be part of the long process of cancer metastasis. As a 'liquid biopsy', CTC molecular examination and investigation of single cancer cells create an important opportunity for providing an understanding of cancer biology and the process of metastasis. In the last decade, we have seen dramatic development in defining the role of CTCs in lung cancer in terms of diagnosis, genomic alteration determination, treatment response and, finally, prognosis prediction. The aims of this review are to understand the basic biology and to review methods of detection of CTCs that apply to the various types of solid tumor. Furthermore, we explored clinical applications, including treatment monitoring to anticipate therapy resistance as well as biomarker analysis, in the context of lung cancer. We also explored the potential use of cell-free circulating tumor DNA (ctDNA) in the genomic alteration analysis of lung cancer.

  19. Circulating Tumor Cell and Cell-free Circulating Tumor DNA in Lung Cancer

    PubMed Central

    Zaini, Jamal; Putra, Andika Chandra; Andarini, Sita; Hudoyo, Achmad; Syahruddin, Elisna; Yunus, Faisal

    2016-01-01

    Circulating tumor cells (CTCs) are tumor cells that are separated from the primary site or metastatic lesion and disseminate in blood circulation. CTCs are considered to be part of the long process of cancer metastasis. As a 'liquid biopsy', CTC molecular examination and investigation of single cancer cells create an important opportunity for providing an understanding of cancer biology and the process of metastasis. In the last decade, we have seen dramatic development in defining the role of CTCs in lung cancer in terms of diagnosis, genomic alteration determination, treatment response and, finally, prognosis prediction. The aims of this review are to understand the basic biology and to review methods of detection of CTCs that apply to the various types of solid tumor. Furthermore, we explored clinical applications, including treatment monitoring to anticipate therapy resistance as well as biomarker analysis, in the context of lung cancer. We also explored the potential use of cell-free circulating tumor DNA (ctDNA) in the genomic alteration analysis of lung cancer. PMID:27689025

  20. Tumor-Induced Myeloid-Derived Suppressor Cells.

    PubMed

    De Sanctis, Francesco; Bronte, Vincenzo; Ugel, Stefano

    2016-06-01

    Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous, immune-suppressive leukocyte population that develops systemically and infiltrates tumors. MDSCs can restrain the immune response through different mechanisms including essential metabolite consumption, reactive oxygen and nitrogen species production, as well as display of inhibitory surface molecules that alter T-cell trafficking and viability. Moreover, MDSCs play a role in tumor progression, acting directly on tumor cells and promoting cancer stemness, angiogenesis, stroma deposition, epithelial-to-mesenchymal transition, and metastasis formation. Many biological and pharmaceutical drugs affect MDSC expansion and functions in preclinical tumor models and patients, often reversing host immune dysfunctions and allowing a more effective tumor immunotherapy.

  1. Residual tumor cells are unique cellular targets in glioblastoma.

    PubMed

    Glas, Martin; Rath, Barbara H; Simon, Matthias; Reinartz, Roman; Schramme, Anja; Trageser, Daniel; Eisenreich, Ramona; Leinhaas, Anke; Keller, Mihaela; Schildhaus, Hans-Ulrich; Garbe, Stephan; Steinfarz, Barbara; Pietsch, Torsten; Steindler, Dennis A; Schramm, Johannes; Herrlinger, Ulrich; Brüstle, Oliver; Scheffler, Björn

    2010-08-01

    Residual tumor cells remain beyond the margins of every glioblastoma (GBM) resection. Their resistance to postsurgical therapy is considered a major driving force of mortality, but their biology remains largely uncharacterized. In this study, residual tumor cells were derived via experimental biopsy of the resection margin after standard neurosurgery for direct comparison with samples from the routinely resected tumor tissue. In vitro analysis of proliferation, invasion, stem cell qualities, GBM-typical antigens, genotypes, and in vitro drug and irradiation challenge studies revealed these cells as unique entities. Our findings suggest a need for characterization of residual tumor cells to optimize diagnosis and treatment of GBM.

  2. Astrocytes Directly Influence Tumor Cell Invasion and Metastasis In Vivo

    PubMed Central

    Wang, Ling; Cossette, Stephanie M.; Rarick, Kevin R.; Gershan, Jill; Dwinell, Michael B.; Harder, David R.; Ramchandran, Ramani

    2013-01-01

    Brain metastasis is a defining component of tumor pathophysiology, and the underlying mechanisms responsible for this phenomenon are not well understood. Current dogma is that tumor cells stimulate and activate astrocytes, and this mutual relationship is critical for tumor cell sustenance in the brain. Here, we provide evidence that primary rat neonatal and adult astrocytes secrete factors that proactively induced human lung and breast tumor cell invasion and metastasis capabilities. Among which, tumor invasion factors namely matrix metalloprotease-2 (MMP-2) and MMP-9 were partly responsible for the astrocyte media-induced tumor cell invasion. Inhibiting MMPs reduced the ability of tumor cell to migrate and invade in vitro. Further, injection of astrocyte media-conditioned breast cancer cells in mice showed increased invasive activity to the brain and other distant sites. More importantly, blocking the preconditioned tumor cells with broad spectrum MMP inhibitor decreased the invasion and metastasis of the tumor cells, in particular to the brain in vivo. Collectively, our data implicate astrocyte-derived MMP-2 and MMP-9 as critical players that facilitate tumor cell migration and invasion leading to brain metastasis. PMID:24324647

  3. Pharmacogenomics of Scopoletin in Tumor Cells.

    PubMed

    Seo, Ean-Jeong; Saeed, Mohamed; Law, Betty Yuen Kwan; Wu, An Guo; Kadioglu, Onat; Greten, Henry Johannes; Efferth, Thomas

    2016-04-15

    Drug resistance and the severe side effects of chemotherapy necessitate the development of novel anticancer drugs. Natural products are a valuable source for drug development. Scopoletin is a coumarin compound, which can be found in several Artemisia species and other plant genera. Microarray-based RNA expression profiling of the NCI cell line panel showed that cellular response of scopoletin did not correlate to the expression of ATP-binding cassette (ABC) transporters as classical drug resistance mechanisms (ABCB1, ABCB5, ABCC1, ABCG2). This was also true for the expression of the oncogene EGFR and the mutational status of the tumor suppressor gene, TP53. However, mutations in the RAS oncogenes and the slow proliferative activity in terms of cell doubling times significantly correlated with scopoletin resistance. COMPARE and hierarchical cluster analyses of transcriptome-wide mRNA expression resulted in a set of 40 genes, which all harbored binding motifs in their promoter sequences for the transcription factor, NF-κB, which is known to be associated with drug resistance. RAS mutations, slow proliferative activity, and NF-κB may hamper its effectiveness. By in silico molecular docking studies, we found that scopoletin bound to NF-κB and its regulator IκB. Scopoletin activated NF-κB in a SEAP-driven NF-κB reporter cell line, indicating that NF-κB might be a resistance factor for scopoletin. In conclusion, scopoletin might serve as lead compound for drug development because of its favorable activity against tumor cells with ABC-transporter expression, although NF-κB activation may be considered as resistance factor for this compound. Further investigations are warranted to explore the full therapeutic potential of this natural product.

  4. Sodium orthovanadate associated with pharmacological doses of ascorbate causes an increased generation of ROS in tumor cells that inhibits proliferation and triggers apoptosis.

    PubMed

    Günther, Tânia Mara Fischer; Kviecinski, Maicon Roberto; Baron, Carla Cristine; Felipe, Karina Bettega; Farias, Mirelle Sifroni; da Silva, Fabiana Ourique; Bücker, Nádia Cristina Falcão; Pich, Claus Tröger; Ferreira, Eduardo Antonio; Wilhelm Filho, Danilo; Verrax, Julien; Calderon, Pedro Buc; Pedrosa, Rozangela Curi

    2013-01-18

    Pharmacological doses of ascorbate were evaluated for its ability to potentiate the toxicity of sodium orthovanadate (Na(3)VO(4)) in tumor cells. Cytotoxicity, inhibition of cell proliferation, generation of ROS and DNA fragmentation were assessed in T24 cells. Na(3)VO(4) was cytotoxic against T24 cells (EC(50)=5.8 μM at 24 h), but in the presence of ascorbate (100 μM) the EC(50) fell to 3.3 μM. Na(3)VO(4) plus ascorbate caused a strong inhibition of cell proliferation (up to 20%) and increased the generation of ROS (4-fold). Na(3)VO(4) did not directly cleave plasmid DNA, at this aspect no synergism was found occurring between Na(3)VO(4) and ascorbate once the resulting action of the combination was no greater than that of both substances administered separately. Cells from Ehrlich ascites carcinoma-bearing mice were used to determine the activity of antioxidant enzymes, the extent of the oxidative damage and the type of cell death. Na(3)VO(4) alone, or combined with ascorbate, increased catalase activity, but only Na(3)VO(4) plus ascorbate increased superoxide dismutase activity (up to 4-fold). Oxidative damage on proteins and lipids was higher due to the treatment done with Na(3)VO(4) plus ascorbate (2-3-fold). Ascorbate potentiated apoptosis in tumor cells from mice treated with Na(3)VO(4). The results indicate that pharmacological doses of ascorbate enhance the generation of ROS induced by Na(3)VO(4) in tumor cells causing inhibition of proliferation and apoptosis. Apoptosis induced by orthovanadate and ascorbate is closer related to inhibition on Bcl-xL and activation of Bax. Our data apparently rule out a mechanism of cell demise p53-dependent or related to Cdk2 impairment. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Testicular germ cell tumors: pathogenesis, diagnosis and treatment.

    PubMed

    Winter, Christian; Albers, Peter

    2011-01-01

    Testicular germ cell tumors represent the most common solid malignancy of young men aged 15-40 years. Histopathologically, testicular germ cell tumors are divided into two major groups: pure seminoma and nonseminoma. The pathogenesis of testicular germ cell tumors remains unknown; however, cryptorchidism is the main risk factor, and molecular studies have shown strong evidence of an association between genetic alterations and testicular germ cell tumors. In cases of suspicion for testicular germ cell tumor, a surgical exploration with orchiectomy is obligatory. After completion of diagnostic procedures, levels of serum tumor markers and the clinical stage based on the International Union Against Cancer tumor-node-metastasis classification should be defined. Patients with early-stage testicular germ cell tumors are treated by individualized risk stratification within a multidisciplinary approach. The individual management (surveillance, chemotherapy or radiotherapy) has to be balanced according to clinical features and the risk of short-term and long-term toxic effects. Treatment for metastatic tumors is based on risk stratification according to International Germ Cell Cancer Collaborative Group classification and is performed with cisplatin-based chemotherapy and residual tumor resection in cases of residual tumor lesion. High-dose chemotherapy represents a curative option for patients with second or subsequent relapses.

  6. Biochemical and pathological studies on the effects of levamisole and chlorambucil on Ehrlich ascites carcinoma-bearing mice.

    PubMed

    Salem, Fakhry S; Badr, Mohamed O T; Neamat-Allah, Ahmed N F

    2011-01-01

    Clinicopathological studies on the effects of combining immunostimulant drugs (levamisole) with anti-cancer drugs (chlorambucil) revealed the enhancement of the latter against Ehrlich ascites carcinoma-bearing mice and resulted in a reduction in the size of tumour. An evaluation of liver and kidney functions showed a significant increase of alanine transaminase (ALT), aspartate transaminase (AST) and creatinine in all groups. Histopathological studies of one group that received an intraperitoneal injection of Ehrlich ascites carcinoma cells (2.5 × 10⁶) showed that hepatic parenchyma revealed degenerative changes. The portal area was oedematous and showed rounded cell aggregations. Cell death within hypertrophied Kupper cells was observed in some hepatic cells. The neoplastic emboli could be seen either inside blood vessels or hepatic sinusoids, while another group which had been treated orally with a combination of Leukeran(™) (0.2 mg/kg body weight) and levamisole (5 mg/kg body weight) revealed that hepatic parenchyma revealed massive necrosis with proliferative bile duct epithelium. No neoplastic cells were observed without the hepatic parenchyma, while the renal cortex presented a large number of lymphocytes and plasma cells forming bands or aggregates, mainly around the blood vessels. It was concluded that the addition of levamisole to chlorambucil improved the anti-cancer effect of chlorambucil against Ehrlich ascites carcinoma. However, it had adverse effects on the liver and kidneys as shown by liver and kidney function tests and confirmed by histopathology.

  7. Engineering Active IKKβ in T Cells Drives Tumor Rejection1

    PubMed Central

    Evaristo, César; Spranger, Stefani; Barnes, Sarah E.; Miller, Michelle L.; Molinero, Luciana L.; Locke, Frederick; Gajewski, Thomas F.; Alegre, Maria-Luisa

    2016-01-01

    Acquired dysfunction of tumor-reactive T cells is one mechanism by which tumors can evade the immune system. Identifying and correcting pathways that contribute to such dysfunction should enable novel anti-cancer therapy design. During cancer growth, T cells show reduced NF-κB activity, which is required for tumor rejection. Impaired T cell-NF-κB may create a vicious cycle conducive to tumor progression and further T cell dysfunction. We hypothesized that forcing T cell-NF-κB activation might break this cycle and induce tumor elimination. NF-κB was activated in T cells by inducing the expression of a constitutively active form of the upstream activator IKKβ. T cell-restricted caIKKβ augmented the frequency of functional tumor-specific CD8+ T cells and improved tumor control. Transfer of caIKKβ-transduced T cells also boosted endogenous T cell responses that controlled pre-established tumors. Our results demonstrate that driving T cell-NF-κB can result in tumor control, thus identifying a pathway with potential clinical applicability. PMID:26903482

  8. Regulatory B cells preferentially accumulate in tumor-draining lymph nodes and promote tumor growth.

    PubMed

    Ganti, Sheila N; Albershardt, Tina C; Iritani, Brian M; Ruddell, Alanna

    2015-07-20

    Our previous studies found that B16-F10 melanoma growth in the rear footpad of immunocompetent mice induces marked B cell accumulation within tumor-draining popliteal lymph nodes (TDLN). This B cell accumulation drives TDLN remodeling that precedes and promotes metastasis, indicating a tumor-promoting role for TDLN B cells. Here we show that phenotypic characterization of lymphocytes in mice bearing B16-F10 melanomas identifies preferential accumulation of T2-MZP B cells in the TDLN. Comparison of non-draining LNs and spleens of tumor-bearing mice with LNs and spleens from naïve mice determined that this pattern of B cell accumulation was restricted to the TDLN. B cell-deficient and immunocompetent mice reconstituted with T2-MZP B cells but not with other B cell subsets displayed accelerated tumor growth, demonstrating that T2-MZP B cells possess regulatory activity in tumor-bearing mice. Unlike splenic regulatory B cells, however, these TDLN B cells did not exhibit increased IL-10 production, nor did they promote Treg generation in the TDLN. These findings demonstrate that tumors initially signal via the lymphatic drainage to stimulate the preferential accumulation of T2-MZP regulatory B cells. This local response may be an early and critical step in generating an immunosuppressive environment to permit tumor growth and metastasis.

  9. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages.

    PubMed

    Ugel, Stefano; De Sanctis, Francesco; Mandruzzato, Susanna; Bronte, Vincenzo

    2015-09-01

    The generation of an inflammatory environment is favorable and often decisive for the growth of both primary tumors and metastases. Tumor cells either express membrane molecules or release tumor-derived soluble factors able to alter myelopoiesis. Tumor-reprogrammed myeloid cells not only create a tolerogenic environment by blocking T cell functions and proliferation, but also directly drive tumor growth by promoting cancer stemness, angiogenesis, stroma deposition, epithelial-to-mesenchymal transition, and metastasis formation. In this Review, we discuss the interplay between immunosuppressive and protumoral myeloid cells and detail their immune-regulatory mechanisms, the molecular pathways involved in their differentiation, as well as their potential role as prognostic and diagnostic biomarkers and prospective targets for innovative approaches to treat tumor-bearing hosts.

  10. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages

    PubMed Central

    Ugel, Stefano; De Sanctis, Francesco; Mandruzzato, Susanna; Bronte, Vincenzo

    2015-01-01

    The generation of an inflammatory environment is favorable and often decisive for the growth of both primary tumors and metastases. Tumor cells either express membrane molecules or release tumor-derived soluble factors able to alter myelopoiesis. Tumor-reprogrammed myeloid cells not only create a tolerogenic environment by blocking T cell functions and proliferation, but also directly drive tumor growth by promoting cancer stemness, angiogenesis, stroma deposition, epithelial-to-mesenchymal transition, and metastasis formation. In this Review, we discuss the interplay between immunosuppressive and protumoral myeloid cells and detail their immune-regulatory mechanisms, the molecular pathways involved in their differentiation, as well as their potential role as prognostic and diagnostic biomarkers and prospective targets for innovative approaches to treat tumor-bearing hosts. PMID:26325033

  11. Sclareol modulates the Treg intra-tumoral infiltrated cell and inhibits tumor growth in vivo.

    PubMed

    Noori, Shokoofe; Hassan, Zuhair M; Mohammadi, Mehdi; Habibi, Zohre; Sohrabi, Nooshin; Bayanolhagh, Saeed

    2010-01-01

    A regulatory or suppressor T cell is functionally defined as a T cell that inhibits an immune response by influencing the activity of another cell type. On the other hand, Th1 cells express IFN-gamma and mediate cellular immunity. Sclareol exhibits growth inhibition and cytotoxic activity against a variety of human cancer cell lines. In the first set of experiments, Sclareol was isolated from the plant Salvia sclarea and our study assessed the immuno-therapeutic effectiveness of Sclareol by direct intra-tumoral injection. Secondly, several immunological parameters such as splenocytes proliferation, intra-tumor CD4+CD25+Foxp3+ Treg cells, IFN-gamma and IL-4 secretion and tumor size were assessed to evaluate the anti-tumoral immune response. By all means, the findings confirmed that the activity of Sclareol could reduce the tumor growth in vivo against breast cancer. Copyright (c) 2010. Published by Elsevier Inc.

  12. Migratory neighbors and distant invaders: tumor-associated niche cells.

    PubMed

    Wels, Jared; Kaplan, Rosandra N; Rafii, Shahin; Lyden, David

    2008-03-01

    The cancer environment is comprised of tumor cells as well as a wide network of stromal and vascular cells participating in the cellular and molecular events necessary for invasion and metastasis. Tumor secretory factors can activate the migration of host cells, both near to and far from the primary tumor site, as well as promote the exodus of cells to distant tissues. Thus, the migration of stromal cells and tumor cells among specialized microenvironments takes place throughout tumor and metastatic progression, providing evidence for the systemic nature of a malignancy. Investigations of the tumor-stromal and stromal-stromal cross-talk involved in cellular migration in cancer may lead to the design of novel therapeutic strategies.

  13. Tumor Heterogeneity, Single-Cell Sequencing, and Drug Resistance

    PubMed Central

    Schmidt, Felix; Efferth, Thomas

    2016-01-01

    Tumor heterogeneity has been compared with Darwinian evolution and survival of the fittest. The evolutionary ecosystem of tumors consisting of heterogeneous tumor cell populations represents a considerable challenge to tumor therapy, since all genetically and phenotypically different subpopulations have to be efficiently killed by therapy. Otherwise, even small surviving subpopulations may cause repopulation and refractory tumors. Single-cell sequencing allows for a better understanding of the genomic principles of tumor heterogeneity and represents the basis for more successful tumor treatments. The isolation and sequencing of single tumor cells still represents a considerable technical challenge and consists of three major steps: (1) single cell isolation (e.g., by laser-capture microdissection), fluorescence-activated cell sorting, micromanipulation, whole genome amplification (e.g., with the help of Phi29 DNA polymerase), and transcriptome-wide next generation sequencing technologies (e.g., 454 pyrosequencing, Illumina sequencing, and other systems). Data demonstrating the feasibility of single-cell sequencing for monitoring the emergence of drug-resistant cell clones in patient samples are discussed herein. It is envisioned that single-cell sequencing will be a valuable asset to assist the design of regimens for personalized tumor therapies based on tumor subpopulation-specific genetic alterations in individual patients. PMID:27322289

  14. [Prevalence and clinicopathological characteristics of giant cell tumors].

    PubMed

    Estrada-Villaseñor, E G; Linares-González, L M; Delgado-Cedillo, E A; González-Guzmán, R; Rico-Martínez, G

    2015-01-01

    The frequency of giant cell tumors reported in the literature is very variable. Considering that our population has its own features, which distinguish it from the Anglo-Saxon and Asian populations, we think that both the frequency and the clinical characteristics of giant cell tumors in our population are different. The major aim of this paper was to determine the frequency and clinicopathological characteristics of giant cell tumors of the bone. A cross-sectional descriptive study was conducted of the cases diagnosed at our service as giant cell tumors of the bone from January to December 2013. The electronic clinical records, radiologic records and histologic slides from each case were reviewed. Giant cell tumors represented 17% of total bone tumors and 28% of benign tumors. Patients included 13 females and 18 males. The most frequent locations of giant cell tumors were: the proximal tibia, 9 cases (29%), and the distal femur, 6 cases (19%). Forty-five percent of giant cell tumors were associated with aneurysmal bone cyst (ABC) (14 cases) and one case (3%) was malignant. The frequency of giant cell tumors in this case series was intermediate, that is, higher than the one reported in Anglo-Saxon countries (usually low), but without reaching the frequency rates reported in Asian countries (high).

  15. Tumor Heterogeneity, Single-Cell Sequencing, and Drug Resistance.

    PubMed

    Schmidt, Felix; Efferth, Thomas

    2016-06-16

    Tumor heterogeneity has been compared with Darwinian evolution and survival of the fittest. The evolutionary ecosystem of tumors consisting of heterogeneous tumor cell populations represents a considerable challenge to tumor therapy, since all genetically and phenotypically different subpopulations have to be efficiently killed by therapy. Otherwise, even small surviving subpopulations may cause repopulation and refractory tumors. Single-cell sequencing allows for a better understanding of the genomic principles of tumor heterogeneity and represents the basis for more successful tumor treatments. The isolation and sequencing of single tumor cells still represents a considerable technical challenge and consists of three major steps: (1) single cell isolation (e.g., by laser-capture microdissection), fluorescence-activated cell sorting, micromanipulation, whole genome amplification (e.g., with the help of Phi29 DNA polymerase), and transcriptome-wide next generation sequencing technologies (e.g., 454 pyrosequencing, Illumina sequencing, and other systems). Data demonstrating the feasibility of single-cell sequencing for monitoring the emergence of drug-resistant cell clones in patient samples are discussed herein. It is envisioned that single-cell sequencing will be a valuable asset to assist the design of regimens for personalized tumor therapies based on tumor subpopulation-specific genetic alterations in individual patients.

  16. Antineoplastic activity of N-(2-hydroxybenzylidene)2'-hydroxyphenylimine aqua nickel(II) complex [NI(H₂O)HHP] on ehrlich ascites carcinoma (EAC) in Swiss albino mice.

    PubMed

    Hossain, Israt Ara; Khanam, Jahan Ara; Jesmin, Mele; Ali, Mohammud Mohshin

    2016-01-01

    The present study is aimed at evaluating the antineoplastic activity of N[(2-hydroxybenzylidene)2'-hydroxyphenylimine] aqua nickel(II) complex abbreviated as [Ni(H2O)HHP] complex against Ehrlich ascites carcinoma (EAC) cells in Swiss albino mice. The effectiveness of the drug at doses of 0.5, 1.0 and 2.0 mg/kg body weight was assessed for five consecutive days in previously inoculated tumor (137×10(4) EAC) cells containing mice. After administration of the last dose followed by 16 h fasting, the effect of the [Ni(H2O)HHP] complex on tumor was assessed by EAC cell growth inhibition, solid tumor mass, survival time, peritoneal cell count, hematological profiles like red blood cells (RBC), white blood cells (WBC), haemoglobin (Hb)% and differential counts (i.e., lymphocytes, neutrophils, monocytes) and biochemical parameters like serum glucose, total cholesterol, total protein, serum urea and liver enzymes, respectively. The results have been compared with the data obtained by using a standard and highly effective clinically used anticancer drug bleomycin. [Ni(H2O)HHP] complex at dose 2.0 mg/kg i.p. (intra peritoneal) showed a significant (P=0.001) decrease in tumor volume of each mice and increased the life span as well as mean survival time of EAC bearing mice. Hematological and biochemical parameters of EAC bearing mice get back normal values after 15 days of the initial treatment. From the above outcomes indicate the possible potential use of the compound as antitumor agent in advanced researches. Copyright © 2015 Elsevier GmbH. All rights reserved.

  17. Prospective Identification of Glioblastoma Cells Generating Dormant Tumors

    PubMed Central

    Segal, Ehud; Ma, Lili; Dixit, Niharika; Ijaz, Ambreen; Hlatky, Lynn; Abdollahi, Amir; Almog, Nava

    2012-01-01

    Although dormant tumors are highly prevalent within the human population, the underlying mechanisms are still mostly unknown. We have previously identified the consensus gene expression pattern of dormant tumors. Here, we show that this gene expression signature could be used for the isolation and identification of clones which generate dormant tumors. We established single cell-derived clones from the aggressive tumor-generating U-87 MG human glioblastoma cell line. Based only on the expression pattern of genes which were previously shown to be associated with tumor dormancy, we identified clones which generate dormant tumors. We show that very high expression levels of thrombospondin and high expression levels of angiomotin and insulin-like growth factor binding protein 5 (IGFBP5), together with low levels of endothelial specific marker (ESM) 1 and epithelial growth factor receptor (EGFR) characterize the clone which generates dormant U-87 MG derived glioblastomas. These tumors remained indolent both in subcutaneous and orthotopic intracranial sites, in spite of a high prevalence of proliferating cells. We further show that tumor cells which form U-87 MG derived dormant tumors have an impaired angiogenesis potential both in vitro and in vivo and have a slower invasion capacity. This work demonstrates that fast-growing tumors contain tumor cells that when isolated will form dormant tumors and serves as a proof-of-concept for the use of transcriptome profiles in the identification of such cells. Isolating the tumor cells that form dormant tumors will facilitate understanding of the underlying mechanisms of dormant micro-metastases, late recurrence, and changes in rate of tumor progression. PMID:22970208

  18. Tumor-Related Methylated Cell-Free DNA and Circulating Tumor Cells in Melanoma

    PubMed Central

    Salvianti, Francesca; Orlando, Claudio; Massi, Daniela; De Giorgi, Vincenzo; Grazzini, Marta; Pazzagli, Mario; Pinzani, Pamela

    2016-01-01

    Solid tumor release into the circulation cell-free DNA (cfDNA) and circulating tumor cells (CTCs) which represent promising biomarkers for cancer diagnosis. Circulating tumor DNA may be studied in plasma from cancer patients by detecting tumor specific alterations, such as genetic or epigenetic modifications. Ras association domain family 1 isoform A (RASSF1A) is a tumor suppressor gene silenced by promoter hypermethylation in a variety of human cancers including melanoma. The aim of the present study was to assess the diagnostic performance of a tumor-related methylated cfDNA marker in melanoma patients and to compare this parameter with the presence of CTCs. RASSF1A promoter methylation was quantified in cfDNA by qPCR in a consecutive series of 84 melanoma patients and 68 healthy controls. In a subset of 68 cases, the presence of CTCs was assessed by a filtration method (Isolation by Size of Epithelial Tumor Cells, ISET) as well as by an indirect method based on the detection of tyrosinase mRNA by RT-qPCR. The distribution of RASSF1A methylated cfDNA was investigated in cases and controls and the predictive capability of this parameter was assessed by means of the area under the ROC curve (AUC). The percentage of cases with methylated RASSF1A promoter in cfDNA was significantly higher in each class of melanoma patients (in situ, invasive and metastatic) than in healthy subjects (Pearson chi-squared test, p < 0.001). The concentration of RASSF1A methylated cfDNA in the subjects with a detectable quantity of methylated alleles was significantly higher in melanoma patients than in controls. The biomarker showed a good predictive capability (in terms of AUC) in discriminating between melanoma patients and healthy controls. This epigenetic marker associated to cfDNA did not show a significant correlation with the presence of CTCs, but, when the two parameters are jointly considered, we obtain a higher sensitivity of the detection of positive cases in invasive and

  19. Detection and Characterization of Circulating Tumor Cells

    NASA Astrophysics Data System (ADS)

    Bruce, Richard

    2009-03-01

    Circulating tumor cells (CTCs) occur in blood below the concentration of 1 cell in a hundred thousand white blood cells and can provide prognostic and diagnostic information about the underlying disease. While numeration of CTCs has provided useful information on progression-free and overall survival, it does not provide guidance of treatment choice. Since CTCs are presumed contain features of the metastatic tissue, characterization of cancer markers on these cells could help selection of treatment. At such low concentrations, reliable location and identification of these cells represents a significant technical challenge. Automated digital microscopy (ADM) provides high levels of sensitivity, but the analysis time is prohibitively long for a clinical assay. Enrichment methods have been developed to reduce sample size but can result in cell loss. A major barrier in reliable enrichment stems from the biological heterogeneity of CTCs, exhibited in a wide range of genetic, biochemical, immunological and biological characteristics. We have developed an approach that uses fiber-optic array scanning technology (FAST) to detect CTCs. Here, laser-printing optics are used to excite 300,000 cells/sec, and fluorescence from immuno-labels is collected in an array of optical fibers that forms a wide collection aperture. The FAST cytometer can locate CTCs at a rate that is 500 times faster than an ADM with comparable sensitivity and improved specificity. With this high scan rate, no enrichment of CTCs is required. The target can be a cytoplasm protein with a very high expression level, which reduces sensitivity to CTC heterogeneity. We use this method to measure expression levels of multiple markers on CTCs to help predict effective cancer treatment.

  20. Experimental Adaptation of Rotaviruses to Tumor Cell Lines

    PubMed Central

    Guerrero, Carlos A.; Guerrero, Rafael A.; Silva, Elver; Acosta, Orlando; Barreto, Emiliano

    2016-01-01

    A number of viruses show a naturally extended tropism for tumor cells whereas other viruses have been genetically modified or adapted to infect tumor cells. Oncolytic viruses have become a promising tool for treating some cancers by inducing cell lysis or immune response to tumor cells. In the present work, rotavirus strains TRF-41 (G5) (porcine), RRV (G3) (simian), UK (G6-P5) (bovine), Ym (G11-P9) (porcine), ECwt (murine), Wa (G1-P8), Wi61 (G9) and M69 (G8) (human), and five wild-type human rotavirus isolates were passaged multiple times in different human tumor cell lines and then combined in five different ways before additional multiple passages in tumor cell lines. Cell death caused by the tumor cell-adapted isolates was characterized using Hoechst, propidium iodide, 7-AAD, Annexin V, TUNEL, and anti-poly-(ADP ribose) polymerase (PARP) and -phospho-histone H2A.X antibodies. Multiple passages of the combined rotaviruses in tumor cell lines led to a successful infection of these cells, suggesting a gain-of-function by the acquisition of greater infectious capacity as compared with that of the parental rotaviruses. The electropherotype profiles suggest that unique tumor cell-adapted isolates were derived from reassortment of parental rotaviruses. Infection produced by such rotavirus isolates induced chromatin modifications compatible with apoptotic cell death. PMID:26828934

  1. Role of myoepithelial cells in breast tumor progression.

    PubMed

    Pandey, Puspa Raj; Saidou, Jamila; Watabe, Kounosuke

    2010-01-01

    Myoepithelial cells form a semi-continuous protective sheet separating the human breast epithelium and the surrounding stroma. They suppress stromal invasion of tumor cells by the secretion of various anti-angiogenic and anti-invasive factors. The disruption of this cell layer results in the release of the growth factors, angiogenic factors, and reactive oxygen species causing an alteration in the microenvironment. This helps in the proliferation of surrounding cells and increases the invasiveness of tumor cells. Two theories are proposed for the mechanism of tumor epithelial cells progression from in situ to invasive stage. According to the first theory, tumor cell invasion is triggered by the overproduction of proteolytic enzymes by myoepithelial cells and surrounding tumor cells. The second theory states that tumor invasion is a multistep process, the interactions between damaged myoepithelial cells and the immunoreactive cells trigger the release of basement membrane degrading enzymes causing tumor progression. Further studies in understanding of molecular mechanism of myoepithelial cell functions in tumor suppression may lead to the identification of novel therapeutic targets for breast cancer.

  2. Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells

    PubMed Central

    Wu, Annie A; Drake, Virginia; Huang, Huai-Shiuan; Chiu, ShihChi; Zheng, Lei

    2015-01-01

    It has become evident that tumor-induced immuno-suppressive factors in the tumor microenvironment play a major role in suppressing normal functions of effector T cells. These factors serve as hurdles that limit the therapeutic potential of cancer immunotherapies. This review focuses on illustrating the molecular mechanisms of immunosuppression in the tumor microenvironment, including evasion of T-cell recognition, interference with T-cell trafficking, metabolism, and functions, induction of resistance to T-cell killing, and apoptosis of T cells. A better understanding of these mechanisms may help in the development of strategies to enhance the effectiveness of cancer immunotherapies. PMID:26140242

  3. Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells.

    PubMed

    Wu, Annie A; Drake, Virginia; Huang, Huai-Shiuan; Chiu, ShihChi; Zheng, Lei

    2015-07-01

    It has become evident that tumor-induced immuno-suppressive factors in the tumor microenvironment play a major role in suppressing normal functions of effector T cells. These factors serve as hurdles that limit the therapeutic potential of cancer immunotherapies. This review focuses on illustrating the molecular mechanisms of immunosuppression in the tumor microenvironment, including evasion of T-cell recognition, interference with T-cell trafficking, metabolism, and functions, induction of resistance to T-cell killing, and apoptosis of T cells. A better understanding of these mechanisms may help in the development of strategies to enhance the effectiveness of cancer immunotherapies.

  4. Principles of treatment for mast cell tumors.

    PubMed

    Govier, Susanne M

    2003-05-01

    Mast cell tumors (MCT) are the most common malignant cutaneous tumors that occur in dogs. They are most commonly found on the trunk, accounting for approximately 50% to 60% of all sites. MCTs associated with the limbs account for approximately 25% of all sites. Cutaneous MCTs have a wide variety of clinical appearances. Histologic grade is the most consistent prognostic factor available for dogs. MCTs located at 'nail bed' (subungual), inguinal/preputial area, and any mucocutaneous area like perineum or oral cavity carry a guarded prognosis and tend to metastasize. MCTs usually exfoliate well and are cytologically distinct. The extent of staging procedures following fine-needle aspirate cytologic diagnosis is based on the presence or absence of negative prognostic indicators. Surgery is the treatment of choice for solitary MCTs with no evidence of metastasis. Reponses rates to chemotherapy, (partial response) as high as 78% have been reported, and preliminary evidence suggests that multiagent (prednisone and vinblastine) protocols may confer a higher response rate than single-agent therapy. MCTs are the second most common cutaneous tumor in the cat. There are two distinct forms of cutaneous MCTs in the cat. The more common form is the mastocytic form, and the less common is the histiocytic form. Unlike in the dog, the head and neck are the most common sites for MCTs in the cat followed by the trunk and limbs. Cats with disseminated forms of MCT often present with systemic signs of illness, which include depression, anorexia, weight loss, and vomiting. The diagnosis and staging of MCTs in cats is similar to that in the dog. As with dogs with cutaneous MCTs, surgery is the treatment of choice. Little is known about the effectiveness of adjunctive chemotherapy options for cutaneous MCTs. Adjunctive chemotherapy does not appear to increase survival times.

  5. DAPK loss in colon cancer tumor buds: implications for migration capacity of disseminating tumor cells

    PubMed Central

    Karamitopoulou, Eva; Dawson, Heather; Koelzer, Viktor Hendrik; Agaimy, Abbas; Garreis, Fabian; Söder, Stephan; Laqua, William; Lugli, Alessandro; Hartmann, Arndt; Rau, Tilman T.; Schneider-Stock, Regine

    2015-01-01

    Defining new therapeutic strategies to overcome therapy resistance due to tumor heterogeneity in colon cancer is challenging. One option is to explore the molecular profile of aggressive disseminating tumor cells. The cytoskeleton-associated Death-associated protein kinase (DAPK) is involved in the cross talk between tumor and immune cells at the invasion front of colorectal cancer. Here dedifferentiated tumor cells histologically defined as tumor budding are associated with a high risk of metastasis and poor prognosis. Analyzing samples from 144 colorectal cancer patients we investigated immunhistochemical DAPK expression in different tumor regions such as center, invasion front, and buds. Functional consequences for tumor aggressiveness were studied in a panel of colon tumor cell lines using different migration, wound healing, and invasion assays. DAPK levels were experimentally modified by siRNA transfection and overexpression as well as inhibitor treatments. We found that DAPK expression was reduced towards the invasion front and was nearly absent in tumor buds. Applying the ECIS system with HCT116 and HCT116 stable lentiviral DAPK knock down cells (HCTshDAPK) we identified an important role for DAPK in decreasing the migratory capacity whereas proliferation was not affected. Furthermore, the migration pattern differed with HCTshDAPK cells showing a cluster-like migration of tumor cell groups. DAPK inhibitor treatment revealed that the migration rate was independent of DAPK's catalytic activity. Modulation of DAPK expression level in SW480 and DLD1 colorectal cancer cells significantly influenced wound closure rate. DAPK seems to be a major player that influences the migratory capability of disseminating tumor cells and possibly affects the dynamic interface between pro- and anti-survival factors at the invasion front of colorectal cancer. This interesting and new finding requires further evaluation. PMID:26405175

  6. Innate Immune Cells Induce Hemorrhage in Tumors during Thrombocytopenia

    PubMed Central

    Ho-Tin-Noé, Benoit; Carbo, Carla; Demers, Mélanie; Cifuni, Stephen M.; Goerge, Tobias; Wagner, Denisa D.

    2009-01-01

    Platelets are crucial regulators of tumor vascular homeostasis and continuously prevent tumor hemorrhage through secretion of their granules. However, the reason for tumor bleeding in the absence of platelets remains unknown. Tumors are associated with inflammation, a cause of hemorrhage in thrombocytopenia. Here, we investigated the role of the inflamed tumor microenvironment in the induction of tumor vessel injury in thrombocytopenic mice. Using s.c. injections of vascular endothelial growth factor or tumor necrosis factor-α combined with depletion of neutrophils, we demonstrate that enhancing the opening of endothelial cell junctions was not sufficient to cause bleeding in the absence of platelets; instead, induction of tissue hemorrhage in thrombocytopenia required recruitment of leukocytes. Immunohistology revealed that thrombocytopenia-induced tumor hemorrhage occurs at sites of macrophage and neutrophil accumulation. Mice deficient in β2 or β3 integrins, which have decreased neutrophil and/or macrophage infiltration in their tumor stroma, were protected from thrombocytopenia-induced tumor hemorrhage, indicating that, in the absence of platelets, stroma-infiltrating leukocytes induced tumor vessel injury. This injury was independent of reactive oxygen species generation and of complement activation, as suggested by the persistence of tumor hemorrhage in C3- and nicotinamide adenine dinucleotide phosphate oxidase-deficient thrombocytopenic mice. Our results show that platelets counteract tumor-associated inflammation and that the absence of this platelet function elicits vascular injuries by tumor-infiltrating innate immune cells. PMID:19729481

  7. Clinical relevance and biology of circulating tumor cells

    PubMed Central

    2011-01-01

    Most breast cancer patients die due to metastases, and the early onset of this multistep process is usually missed by current tumor staging modalities. Therefore, ultrasensitive techniques have been developed to enable the enrichment, detection, isolation and characterization of disseminated tumor cells in bone marrow and circulating tumor cells in the peripheral blood of cancer patients. There is increasing evidence that the presence of these cells is associated with an unfavorable prognosis related to metastatic progression in the bone and other organs. This review focuses on investigations regarding the biology and clinical relevance of circulating tumor cells in breast cancer. PMID:22114869

  8. Host cell infiltration into PDT-treated tumor

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Krosl, Gorazd; Dougherty, Graeme J.; Chaplin, David J.

    1992-06-01

    C3H mice bearing SCCVII squamous cell carcinoma were treated with photodynamic therapy (PDT) 24 hours after receiving Photofrin (25 mg/kg, i.v.). Single cell suspensions obtained by the enzymatic digestion of tumors excised either 30 minutes or 4 hours after PDT were analyzed for the content of host immune cells and colony forming ability of malignant cells. The results were compared to the data obtained with non-treated tumors. It is shown that there is a marked increase in the content of cells expressing Mac-1 (monocytes/macrophages or granulocytes) in the tumor 30 minutes post PDT, while a high level of other leucocytes are found within the tumors by 4 hours after PDT. As elaborated in Discussion, the infiltration rate of host immune cells, dying of malignant tumor cells, and yet unknown death rate of host cells originally present in PDT treated tumor occurring concomitantly during this time period complicates this analysis. The results of this study suggest a massive infiltration of macrophages and other leucocytes in PDT treated SCCVII tumor, supporting the suggestion that a potent immune reaction is one of the main characteristics of PDT action in solid tumors. It remains to be determined to what extent is the activity of tumor infiltrating immune cells responsible for its eradication by PDT.

  9. Fibroblast cell interactions with human melanoma cells affect tumor cell growth as a function of tumor progression.

    PubMed Central

    Cornil, I; Theodorescu, D; Man, S; Herlyn, M; Jambrosic, J; Kerbel, R S

    1991-01-01

    It is known from a variety of experimental systems that the ability of tumor cells to grow locally and metastasize can be affected by the presence of adjacent normal tissues and cells, particularly mesenchymally derived stromal cells such as fibroblasts. However, the comparative influence of such normal cell-tumor cell interactions on tumor behavior has not been thoroughly investigated from the perspective of different stages of tumor progression. To address this question we assessed the influence of normal dermal fibroblasts on the growth of human melanoma cells obtained from different stages of tumor progression. We found that the in vitro growth of most (4 out of 5) melanoma cell lines derived from early-stage radial growth phase or vertical growth phase metastatically incompetent primary lesions is repressed by coculture with normal dermal fibroblasts, suggesting that negative homeostatic growth controls are still operative on melanoma cells from early stages of disease. On the other hand, 9 out of 11 melanoma cell lines derived from advanced metastatically competent vertical growth phase primary lesions, or from distant metastases, were found to be consistently stimulated to grow in the presence of dermal fibroblasts. Evidence was obtained to show that this discriminatory fibroblastic influence is mediated by soluble inhibitory and stimulatory growth factor(s). Taken together, these results indicate that fibroblast-derived signals can have antithetical growth effects on metastatic versus metastatically incompetent tumor subpopulations. This resultant conversion in responsiveness to host tissue environmental factors may confer upon small numbers of metastatically competent cells a growth advantage, allowing them to escape local growth constraints both in the primary tumor site and at distant ectopic tissue sites. PMID:2068080

  10. Identification and Quantitation of Circulating Tumor Cells.

    PubMed

    Rawal, Siddarth; Yang, Yu-Ping; Cote, Richard; Agarwal, Ashutosh

    2017-03-06

    Circulating tumor cells (CTCs) are shed from the primary tumor into the circulatory system and act as seeds that initiate cancer metastasis to distant sites. CTC enumeration has been shown to have a significant prognostic value as a surrogate marker in various cancers. The widespread clinical utility of CTC tests, however, is still limited due to the inherent rarity and heterogeneity of CTCs, which necessitate robust techniques for their efficient enrichment and detection. Significant recent advances have resulted in technologies with the ability to improve yield and purity of CTC enrichment as well as detection sensitivity. Current efforts are largely focused on the translation and standardization of assays to fully realize the clinical utility of CTCs. In this review, we aim to provide a comprehensive overview of CTC enrichment and detection techniques with an emphasis on novel approaches for rapid quantification of CTCs. Expected final online publication date for the Annual Review of Analytical Chemistry Volume 10 is June 12, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  11. Newcastle disease virus selectively kills human tumor cells.

    PubMed

    Reichard, K W; Lorence, R M; Cascino, C J; Peeples, M E; Walter, R J; Fernando, M B; Reyes, H M; Greager, J A

    1992-05-01

    Newcastle disease virus (NDV), strain 73-T, has previously been shown to be cytolytic to mouse tumor cells. In this study, we have evaluated the ability of NDV to replicate in and kill human tumor cells in culture and in athymic mice. Plaque assays were used to determine the cytolytic activity of NDV on six human tumor cell lines, fibrosarcoma (HT1080), osteosarcoma (KHOS), cervical carcinoma (KB8-5-11), bladder carcinoma (HCV29T), neuroblastoma (IMR32), and Wilm's tumor (G104), and on nine different normal human fibroblast lines. NDV formed plaques on all tumor cells tested as well as on chick embryo cells (CEC), the native host for NDV. Plaques did not form on any of the normal fibroblast lines. To detect NDV replication, virus yield assays were performed which measured virus particles in infected cell culture supernatants. Virus yield increased 10,000-fold within 24 hr in tumor and CEC supernatants. Titers remained near zero in normal fibroblast supernatants. In vivo tumoricidal activity was evaluated in athymic nude Balb-c mice by subcutaneous injection of 9 x 10(6) tumor cells followed by intralesional injection of either live or heat-killed NDV (1.0 x 10(6) plaque forming units [PFU]), or medium. After live NDV treatment, tumor regression occurred in 10 out of 11 mice bearing KB8-5-11 tumors, 8 out of 8 with HT-1080 tumors, and 6 out of 7 with IMR-32 tumors. After treatment with heat-killed NDV no regression occurred (P less than 0.01, Fisher's exact test). Nontumor-bearing mice injected with 1.0 x 10(8) PFU of NDV remained healthy. These results indicate that NDV efficiently and selectively replicates in and kills tumor cells, but not normal cells, and that intralesional NDV causes complete tumor regression in athymic mice with a high therapeutic index.

  12. Mathematical Modeling of Tumor Cell Growth and Immune System Interactions

    NASA Astrophysics Data System (ADS)

    Rihan, Fathalla A.; Safan, Muntaser; Abdeen, Mohamed A.; Abdel-Rahman, Duaa H.

    In this paper, we provide a family of ordinary and delay differential equations to describe the dynamics of tumor-growth and immunotherapy interactions. We explore the effects of adoptive cellular immunotherapy on the model and describe under what circumstances the tumor can be eliminated. The possibility of clearing the tumor, with a strategy, is based on two parameters in the model: the rate of influx of the effector cells, and the rate of influx of IL2. The critical tumor-growth rate, below which endemic tumor does not exist, has been found. One can use the model to make predictions about tumor-dormancy.

  13. Culture and isolation of brain tumor initiating cells.

    PubMed

    Lenkiewicz, Monika; Li, Na; Singh, Sheila K

    2009-10-01

    This unit describes protocols for the culture and isolation of brain tumor initiating cells (BTIC). The cancer stem cell (CSC) hypothesis suggests that tumors are maintained exclusively by a rare fraction of cells that have stem cell properties. We applied culture conditions and assays originally used for normal neural stem cells (NSCs) in vitro to a variety of brain tumors. The BTIC were isolated by fluorescence activated cell sorting for the neural precursor cell surface marker CD133. Only the CD133(+) brain tumor fraction contains cells capable of sphere formation and sustained self-renewal in vitro, and tumor initiation in NOD-SCID mouse brains. Therefore, CD133(+) BTICs satisfy the definition of cancer stem cells in that they are able to generate a replica of the patient's tumor and they exhibit self-renewal ability through serial retransplantation. This established that only a rare subset of brain tumor cells with stem cell properties are tumor-initiating, and, in this unit, we describe their culture and isolation.

  14. Dendritic-tumor fusion cells in cancer immunotherapy.

    PubMed

    Takakura, Kazuki; Kajihara, Mikio; Ito, Zensho; Ohkusa, Toshifumi; Gong, Jianlin; Koido, Shigeo

    2015-03-01

    A promising area of clinical investigation is the use of cancer immunotherapy to treat cancer patients. Dendritic cells (DCs) operate as professional antigen-presenting cells (APCs) and play a critical role in the induction of antitumor immune responses. Thus, DC-based cancer immunotherapy represents a powerful strategy. One DC-based cancer immunotherapy strategy that has been investigated is the administration of fusion cells generated with DCs and whole tumor cells (DC-tumor fusion cells). The DC-tumor fusion cells can process a broad array of tumor-associated antigens (TAAs), including unidentified molecules, and present them through major histocompatibility complex (MHC) class I and II pathways in the context of co-stimulatory signals. Improving the therapeutic efficacy of DC-tumor fusion cell-based cancer immunotherapy requires increased immunogenicity of DCs and whole tumor cells. We discuss the potential ability of DC-tumor fusion cells to activate antigen-specific T cells and strategies to improve the immunogenicity of DC-tumor fusion cells as anticancer vaccines.

  15. Transcriptional targeting of tumor endothelial cells for gene therapy

    PubMed Central

    Dong, Zhihong; Nör, Jacques E.

    2009-01-01

    It is well known that angiogenesis plays a critical role in the pathobiology of tumors. Recent clinical trials have shown that inhibition of angiogenesis can be an effective therapeutic strategy for patients with cancer. However, one of the outstanding issues in anti-angiogenic treatment for cancer is the development of toxicities related to off-target effects of drugs. Transcriptional targeting of tumor endothelial cells involves the use of specific promoters for selective expression of therapeutic genes in the endothelial cells lining the blood vessels of tumors. Recently, several genes that are expressed specifically in tumor-associated endothelial cells have been identified and characterized. These discoveries have enhanced the prospectus of transcriptionaly targeting tumor endothelial cells for cancer gene therapy. In this manuscript, we review the promoters, vectors, and therapeutic genes that have been used for transcriptional targeting of tumor endothelial cells, and discuss the prospects of such approaches for cancer gene therapy. PMID:19393703

  16. Schwann cells: a new player in the tumor microenvironment.

    PubMed

    Bunimovich, Yuri L; Keskinov, Anton A; Shurin, Galina V; Shurin, Michael R

    2017-08-01

    Cancerous cells must cooperate with the surrounding stroma and non-malignant cells within the microenvironment to support the growth and invasion of the tumor. The nervous system is a component of every organ system of the body, and therefore, is invariably at the front line of the tumor invasion. Due to the complexity of the nervous system physiology, this review separately discusses the contributions of the central and peripheral nervous systems to the tumorigenesis and tumor progression. We further focus the discussion on the evidence that Schwann cells aid in tumor growth and invasion. Schwann cells, a largely unexplored element of the tumor microenvironment, may participate in the creation of tumor-favorable conditions through both bi-directional interaction with cancer cells and the facilitation of the immune-suppressive microenvironment through the mechanism of neural repair and immunomodulation.

  17. Stem and progenitor cell-mediated tumor selective gene therapy.

    PubMed

    Aboody, K S; Najbauer, J; Danks, M K

    2008-05-01

    The poor prognosis for patients with aggressive or metastatic tumors and the toxic side effects of currently available treatments necessitate the development of more effective tumor-selective therapies. Stem/progenitor cells display inherent tumor-tropic properties that can be exploited for targeted delivery of anticancer genes to invasive and metastatic tumors. Therapeutic genes that have been inserted into stem cells and delivered to tumors with high selectivity include prodrug-activating enzymes (cytosine deaminase, carboxylesterase, thymidine kinase), interleukins (IL-2, IL-4, IL-12, IL-23), interferon-beta, apoptosis-promoting genes (tumor necrosis factor-related apoptosis-inducing ligand) and metalloproteinases (PEX). We and others have demonstrated that neural and mesenchymal stem cells can deliver therapeutic genes to elicit a significant antitumor response in animal models of intracranial glioma, medulloblastoma, melanoma brain metastasis, disseminated neuroblastoma and breast cancer lung metastasis. Most studies reported reduction in tumor volume (up to 90%) and increased survival of tumor-bearing animals. Complete cures have also been achieved (90% disease-free survival for >1 year of mice bearing disseminated neuroblastoma tumors). As we learn more about the biology of stem cells and the molecular mechanisms that mediate their tumor-tropism and we identify efficacious gene products for specific tumor types, the clinical utility of cell-based delivery strategies becomes increasingly evident.

  18. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal.

    PubMed Central

    Kindblom, L. G.; Remotti, H. E.; Aldenborg, F.; Meis-Kindblom, J. M.

    1998-01-01

    The interstitial cells of Cajal (ICC) form a complex cell network within the gastrointestinal tract wall where they function as a pacemaker system. Expression of the kit proto-oncogene is essential for the development of this system. The aim of our study was to examine the hypothesis that gastrointestinal stromal tumors differentiate toward cells with an ICC phenotype. Ultrastructurally, 58 stromal tumors were characterized and found to share many features with ICC. Seventy-eight stromal tumors were immunophenotyped, particularly with regard to the kit receptor. All 78 tumors revealed strong, homogeneous immunoreactivity for the kit receptor as did ICC of adjacent and control gastrointestinal walls. Focal hyperplasia and hypertrophy of kit receptor positive cells were also observed in the gastrointestinal wall adjacent to the tumors. CD34 immunoreactivity observed in interstitial cells surrounding Auerbach's ganglia suggests that a subpopulation of ICC is CD34 positive and may explain why 56 of 78 stromal tumors were CD34 positive. Thirty control tumors, including gastrointestinal leiomyomas and leiomyosarcomas, were all negative for the kit receptor. We conclude that gastrointestinal stromal tumors show striking morphological and immunophenotypic similarities with ICC and that they may originate from stem cells that differentiate toward a pacemaker cell phenotype. We propose that the noncommittal name "gastrointestinal stromal tumor" be replaced by gastrointestinal pacemaker cell tumor. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 PMID:9588894

  19. Classification of subpopulations of cells within human primary brain tumors by single cell gene expression profiling.

    PubMed

    Möllerström, Elin; Rydenhag, Bertil; Andersson, Daniel; Lebkuechner, Isabell; Puschmann, Till B; Chen, Meng; Wilhelmsson, Ulrika; Ståhlberg, Anders; Malmgren, Kristina; Pekny, Milos

    2015-02-01

    Brain tumors are heterogeneous with respect to genetic and histological properties of cells within the tumor tissue. To study subpopulations of cells, we developed a protocol for obtaining viable single cells from freshly isolated human brain tissue for single cell gene expression profiling. We evaluated this technique for characterization of cell populations within brain tumor and tumor penumbra. Fresh tumor tissue was obtained from one astrocytoma grade IV and one oligodendroglioma grade III tumor as well as the tumor penumbra of the latter tumor. The tissue was dissociated into individual cells and the expression of 36 genes was assessed by reverse transcription quantitative PCR followed by data analysis. We show that tumor cells from both the astrocytoma grade IV and oligodendroglioma grade III tumor constituted cell subpopulations defined by their gene expression profiles. Some cells from the oligodendroglioma grade III tumor proper shared molecular characteristics with the cells from the penumbra of the same tumor suggesting that a subpopulation of cells within the oligodendroglioma grade III tumor consisted of normal brain cells. We conclude that subpopulations of tumor cells can be identified by using single cell gene expression profiling.

  20. Vibrational Profiling of Brain Tumors and Cells.

    PubMed

    Nelson, Sultan L; Proctor, Dustin T; Ghasemloonia, Ahmad; Lama, Sanju; Zareinia, Kourosh; Ahn, Younghee; Al-Saiedy, Mustafa R; Green, Francis Hy; Amrein, Matthias W; Sutherland, Garnette R

    2017-01-01

    This study reports vibration profiles of neuronal cells and tissues as well as brain tumor and neocortical specimens. A contact-free method and analysis protocol was designed to convert an atomic force microscope into an ultra-sensitive microphone with capacity to record and listen to live biological samples. A frequency of 3.4 Hz was observed for both cultured rat hippocampal neurons and tissues and vibration could be modulated pharmacologically. Malignant astrocytoma tissue samples obtained from operating room, transported in artificial cerebrospinal fluid, and tested within an hour, vibrated with a much different frequency profile and amplitude, compared to meningioma or lateral temporal cortex providing a quantifiable measurement to accurately distinguish the three tissues in real-time. Vibration signals were converted to audible sound waves by frequency modulation, thus demonstrating, acoustic patterns unique to meningioma, malignant astrocytoma and neocortex.

  1. Immunohistochemical characterization of feline mast cell tumors.

    PubMed

    Mallett, C L; Northrup, N C; Saba, C F; Rodriguez, C O; Rassnick, K M; Gieger, T L; Childress, M O; Howerth, E W

    2013-01-01

    Expression of histamine, serotonin, and KIT was evaluated in 61 archived feline mast cell tumors (MCTs) from the skin (n = 29), spleen (n = 17), and gastrointestinal (GI) tract (n = 15) using immunohistochemistry. Twenty-eight percent of cutaneous MCTs, 18% of splenic MCTs, and 53% of GI MCTs displayed histamine immunoreactivity. Serotonin immunoreactivity was detected in 3 GI and 1 cutaneous MCT. Sixty-nine percent of cutaneous MCTs, 35% of splenic MCTs, and 33% of GI MCTs were positive for KIT. Expression of these biogenic amines and KIT was less common than expected. Results of this study suggest heterogeneity in feline MCTs based on anatomic location. Further studies are needed to explain the significance of these differences.

  2. Vibrational Profiling of Brain Tumors and Cells

    PubMed Central

    Nelson, Sultan L; Proctor, Dustin T; Ghasemloonia, Ahmad; Lama, Sanju; Zareinia, Kourosh; Ahn, Younghee; Al-Saiedy, Mustafa R; Green, Francis HY; Amrein, Matthias W; Sutherland, Garnette R

    2017-01-01

    This study reports vibration profiles of neuronal cells and tissues as well as brain tumor and neocortical specimens. A contact-free method and analysis protocol was designed to convert an atomic force microscope into an ultra-sensitive microphone with capacity to record and listen to live biological samples. A frequency of 3.4 Hz was observed for both cultured rat hippocampal neurons and tissues and vibration could be modulated pharmacologically. Malignant astrocytoma tissue samples obtained from operating room, transported in artificial cerebrospinal fluid, and tested within an hour, vibrated with a much different frequency profile and amplitude, compared to meningioma or lateral temporal cortex providing a quantifiable measurement to accurately distinguish the three tissues in real-time. Vibration signals were converted to audible sound waves by frequency modulation, thus demonstrating, acoustic patterns unique to meningioma, malignant astrocytoma and neocortex. PMID:28744324

  3. Failure of anti tumor-derived endothelial cell immunotherapy depends on augmentation of tumor hypoxia

    PubMed Central

    Pezzolo, Annalisa; Marimpietri, Danilo; Raffaghello, Lizzia; Cocco, Claudia; Pistorio, Angela; Gambini, Claudio; Cilli, Michele; Horenstein, Alberto; Malavasi, Fabio; Pistoia, Vito

    2014-01-01

    We have previously demonstrated that Tenascin-C (TNC)+ human neuroblastoma (NB) cells transdifferentiate into tumor-derived endothelial cells (TDEC), which have been detected both in primary tumors and in tumors formed by human NB cell lines in immunodeficient mice. TDEC are genetically unstable and may favor tumor progression, suggesting that their elimination could reduce tumor growth and dissemination. So far, TDEC have never been targeted by antibody-mediated immunotherapy in any of the tumor models investigated. To address this issue, immunodeficient mice carrying orthotopic NB formed by the HTLA-230 human cell line were treated with TDEC-targeting cytotoxic human (h)CD31, that spares host-derived endothelial cells, or isotype-matched mAbs. hCD31 mAb treatment did not affect survival of NB-bearing mice, but increased significantly hypoxia in tumor microenvironment, where apoptotic and proliferating TDEC coexisted, indicating the occurrence of vascular remodeling. Tumor cells from hCD31 mAb treated mice showed i) up-regulation of epithelial-mesenchymal transition (EMT)-related and vascular mimicry (VM)-related gene expression, ii) expression of endothelial (i.e. CD31 and VE-cadherin) and EMT-associated (i.e. Twist-1, N-cadherin and TNC) immunophenotypic markers, and iii) up-regulation of high mobility group box-1 (HMGB-1) expression. In vitro experiments with two NB cell lines showed that hypoxia was the common driver of all the above phenomena and that human recombinant HMGB-1 amplified EMT and TDEC trans-differentiation. In conclusion, TDEC targeting with hCD31 mAb increases tumor hypoxia, setting the stage for the occurrence of EMT and of new waves of TDEC trans-differentiation. These adaptive responses to the changes induced by immunotherapy in the tumor microenvironment allow tumor cells to escape from the effects of hCD31 mAb. PMID:25362644

  4. Failure of anti tumor-derived endothelial cell immunotherapy depends on augmentation of tumor hypoxia.

    PubMed

    Pezzolo, Annalisa; Marimpietri, Danilo; Raffaghello, Lizzia; Cocco, Claudia; Pistorio, Angela; Gambini, Claudio; Cilli, Michele; Horenstein, Alberto; Malavasi, Fabio; Pistoia, Vito

    2014-11-15

    We have previously demonstrated that Tenascin-C (TNC)(+) human neuroblastoma (NB) cells transdifferentiate into tumor-derived endothelial cells (TDEC), which have been detected both in primary tumors and in tumors formed by human NB cell lines in immunodeficient mice. TDEC are genetically unstable and may favor tumor progression, suggesting that their elimination could reduce tumor growth and dissemination. So far, TDEC have never been targeted by antibody-mediated immunotherapy in any of the tumor models investigated. To address this issue, immunodeficient mice carrying orthotopic NB formed by the HTLA-230 human cell line were treated with TDEC-targeting cytotoxic human (h)CD31, that spares host-derived endothelial cells, or isotype-matched mAbs. hCD31 mAb treatment did not affect survival of NB-bearing mice, but increased significantly hypoxia in tumor microenvironment, where apoptotic and proliferating TDEC coexisted, indicating the occurrence of vascular remodeling. Tumor cells from hCD31 mAb treated mice showed i) up-regulation of epithelial-mesenchymal transition (EMT)-related and vascular mimicry (VM)-related gene expression, ii) expression of endothelial (i.e. CD31 and VE-cadherin) and EMT-associated (i.e. Twist-1, N-cadherin and TNC) immunophenotypic markers, and iii) up-regulation of high mobility group box-1 (HMGB-1) expression. In vitro experiments with two NB cell lines showed that hypoxia was the common driver of all the above phenomena and that human recombinant HMGB-1 amplified EMT and TDEC trans-differentiation. In conclusion, TDEC targeting with hCD31 mAb increases tumor hypoxia, setting the stage for the occurrence of EMT and of new waves of TDEC trans-differentiation. These adaptive responses to the changes induced by immunotherapy in the tumor microenvironment allow tumor cells to escape from the effects of hCD31 mAb.

  5. Myeloid Cells as Targets for Therapy in Solid Tumors

    PubMed Central

    Cotechini, Tiziana; Medler, Terry R.; Coussens, Lisa M.

    2016-01-01

    It is well established that cancer development ensues based on reciprocal interactions between genomically altered neoplastic cells and diverse populations of recruited “host” cells co-opted to support malignant progression. Among the host cells recruited into tumor microenvironments, several subtypes of myeloid cells, including macrophages, monocytes, dendritic cells, and granulocytes contribute to tumor development by providing tumor-promoting factors as well as a spectrum of molecules that suppress cytotoxic activities of T lymphocytes. Based on compelling preclinical data revealing that inhibition of critical myeloid-based programs leads to tumor suppression, novel immune-based therapies and approaches are now entering the clinic for evaluation. This review discusses mechanisms underlying protumorigenic programming of myeloid cells and discusses how targeting of these has potential to attenuate solid tumor progression via the induction and of mobilization CD8+ cytotoxic T cell immunity. PMID:26222088

  6. Myosin 1e promotes breast cancer malignancy by enhancing tumor cell proliferation and stimulating tumor cell de-differentiation

    PubMed Central

    Ouderkirk-Pecone, Jessica L.; Goreczny, Gregory J.; Chase, Sharon E.; Tatum, Arthur H.; Turner, Christopher E.; Krendel, Mira

    2016-01-01

    Despite advancing therapies, thousands of women die every year of breast cancer. Myosins, actin-dependent molecular motors, are likely to contribute to tumor formation and metastasis via their effects on cell adhesion and migration and may provide promising new targets for cancer therapies. Using the MMTV-PyMT murine model of breast cancer, we identified Myosin 1e (MYO1E) as a novel tumor promoter. Tumor latency in mice lacking MYO1E was significantly increased, and tumors formed in the absence of MYO1E displayed unusual papillary morphology, with well-differentiated layers of epithelial cells covering fibrovascular cores, rather than solid sheets of tumor cells typically observed in this cancer model. These tumors were reminiscent of papillary breast cancer in humans that is typically non-invasive and often cured by tumor excision. MYO1E-null tumors exhibited decreased expression of the markers of cell proliferation, which was recapitulated in primary tumor cells derived from MYO1E-null mice. In agreement with our findings, meta-analysis of patient survival data indicated that MYO1E expression level was associated with reduced recurrence-free survival in basal-like breast cancer. Overall, our data suggests that MYO1E contributes to breast tumor malignancy and regulates the differentiation and proliferation state of breast tumor cells. PMID:27329840

  7. Tumor endothelial cells express high pentraxin 3 levels.

    PubMed

    Hida, Kyoko; Maishi, Nako; Kawamoto, Taisuke; Akiyama, Kosuke; Ohga, Noritaka; Hida, Yasuhiro; Yamada, Kenji; Hojo, Takayuki; Kikuchi, Hiroshi; Sato, Masumi; Torii, Chisaho; Shinohara, Nobuo; Shindoh, Masanobu

    2016-12-01

    It has been described that tumor progression has many similarities to inflammation and wound healing in terms of the signaling processes involved. Among biological responses, angiogenesis, which is necessary for tumor progression and metastasis, is a common hallmark; therefore, tumor blood vessels have been considered as important therapeutic targets in anticancer therapy. We focused on pentraxin 3 (PTX3), which is a marker of cancer-related inflammation, but we found no reports on its expression and function in tumor blood vessels. Here we showed that PTX3 is expressed in mouse and human tumor blood vessels based on immunohistochemical analysis. We found that PTX3 is upregulated in primary mouse and human tumor endothelial cells compared to normal endothelial cells. We also showed that PTX3 plays an important role in the proliferation of the tumor endothelial cells. These results suggest that PTX3 is an important target for antiangiogenic therapy.

  8. Intravital characterization of tumor cell migration in pancreatic cancer

    PubMed Central

    Beerling, Evelyne; Oosterom, Ilse; Voest, Emile; Lolkema, Martijn; van Rheenen, Jacco

    2016-01-01

    ABSTRACT Curing pancreatic cancer is difficult as metastases often determine the poor clinical outcome. To gain more insight into the metastatic behavior of pancreatic cancer cells, we characterized migratory cells in primary pancreatic tumors using intravital microscopy. We visualized the migratory behavior of primary tumor cells of a genetically engineered pancreatic cancer mouse model and found that pancreatic tumor cells migrate with a mesenchymal morphology as single individual cells or collectively as a stream of non-cohesive single motile cells. These findings may improve our ability to conceive treatments that block metastatic behavior. PMID:28243522

  9. Human Tumor-Infiltrating Myeloid Cells: Phenotypic and Functional Diversity

    PubMed Central

    Elliott, Louise A.; Doherty, Glen A.; Sheahan, Kieran; Ryan, Elizabeth J.

    2017-01-01

    Our current understanding of human tumor-resident myeloid cells is, for the most part, based on a large body of work in murine models or studies enumerating myeloid cells in patient tumor samples using immunohistochemistry (IHC). This has led to the establishment of the theory that, by and large, tumor-resident myeloid cells are either “protumor” M2 macrophages or myeloid-derived suppressor cells (MDSC). This concept has accelerated our understanding of myeloid cells in tumor progression and enabled the elucidation of many key regulatory mechanisms involved in cell recruitment, polarization, and activation. On the other hand, this paradigm does not embrace the complexity of the tumor-resident myeloid cell phenotype (IHC can only measure 1 or 2 markers per sample) and their possible divergent function in the hostile tumor microenvironment. Here, we examine the criteria that define human tumor-infiltrating myeloid cell subsets and provide a comprehensive and critical review of human myeloid cell nomenclature in cancer. We also highlight new evidence characterizing their contribution to cancer pathogenesis based on evidence derived from clinical studies drawing comparisons with murine studies where necessary. We then review the mechanisms in which myeloid cells are regulated by tumors in humans and how these are being targeted therapeutically. PMID:28220123

  10. [The problems of yolk sac tumor morphogenesis in a light of the tumor stem cell theory].

    PubMed

    Karseladze, A I

    2011-01-01

    The analysis of possible morphogenesis of the different structures in human yolk sac tumor has been considered. The author has supposed that features of blood vessel microarchitecture formation and perpetual differentiation of tumor cells or theirs functional modification play a crucial role in the morphogenesis of YST. The immunohistochemical investigation of some stem cells markers has showed the necessity of accounting of their distribution pattern in various cellular structures for the differential diagnosis of morphogenetical steps of YST. The growth of tumor<