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Sample records for cardiotrophin-1 induces tumor

  1. Cardiotrophin-1 in Patients with Acute Myocardial Infarction

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    Abdolreza S. Jahromi; Mohammad Shojaie; Abdoulhossain Madani

    2010-01-01

    Problem statement: Myocardial infarction is the combined result of environmental and personal factors. Prothrombotic factors might play an important role in this phenomenon. Inflammation plays a pivotal role in atherosclerosis and coronary heart disease. Cardiotrophin-1 (CT-1), a member of the IL-6 family of cytokines, was identified as a growth factor for cardiac myocytes that induces cardiomyocyte hypertrophy and stimulates cardiac fibroblasts, protects myocytes from cell death. This study ...

  2. Cardiotrophin-1 in Patients with Acute Myocardial Infarction

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    Abdolreza S. Jahromi

    2010-01-01

    Full Text Available Problem statement: Myocardial infarction is the combined result of environmental and personal factors. Prothrombotic factors might play an important role in this phenomenon. Inflammation plays a pivotal role in atherosclerosis and coronary heart disease. Cardiotrophin-1 (CT-1, a member of the IL-6 family of cytokines, was identified as a growth factor for cardiac myocytes that induces cardiomyocyte hypertrophy and stimulates cardiac fibroblasts, protects myocytes from cell death. This study was designed to investigate whether plasma concentration of Cardiotrophin-1 (CT-1, in patients who had the first acute myocardial infarction and to analyze their relationship with traditional cardiovascular risk factors. Approach: This study was carried out on 45 patients with Acute Myocardial Infarction (AMI in their first 24 h of admission as case group and 36 healthy matched individuals were studied as the control. Plasma level of cardiotrophin-1 was determined by enzyme-linked immunosorbent assay and the results were compared. Results: Plasma CT-1 levels in the patients with AMI on admission 615.279±5.109 pmol L-1 were significantly higher than those in the control group 534.767±6.750 pmol L-1 (p = 0.001. Plasma CT-1 level was not correlated with diabetes mellitus, hyperlipidemia, sex, age and smoking. Conclusion: Our findings suggested that high plasma CT-1 level in patients with AMI is indicative of hypercoagulable state that is not related to the traditional cardiovascular risk factors.

  3. Common genetic variation in the human CTF1 locus, encoding cardiotrophin-1, determines insulin sensitivity.

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    Stefan Z Lutz

    Full Text Available AIMS/HYPOTHESIS: Recently, cardiotrophin-1, a member of the interleukin-6 family of cytokines was described to protect beta-cells from apoptosis, to improve glucose-stimulated insulin secretion and insulin resistance, and to prevent streptozotocin-induced diabetes in mice. Here, we studied whether common single nucleotide polymorphisms (SNPs in the CTF1 locus, encoding cardiotrophin-1, influence insulin secretion and insulin sensitivity in humans. METHODS: We genotyped 1,771 German subjects for three CTF1 tagging SNPs (rs1046276, rs1458201, and rs8046707. The subjects were metabolically characterized by an oral glucose tolerance test. Subgroups underwent magnetic resonance (MR imaging/spectroscopy and hyperinsulinaemic-euglycaemic clamps. RESULTS: After appropriate adjustment, the minor allele of CTF1 SNP rs8046707 was significantly associated with decreased in vivo measures of insulin sensitivity. The other tested SNPs were not associated with OGTT-derived sensitivity parameters, nor did the three tested SNPs show any association with OGTT-derived parameters of insulin release. In the MR subgroup, SNP rs8046707 was nominally associated with lower visceral adipose tissue. Furthermore, the SNP rs1458201 showed a nominal association with increased VLDL levels. CONCLUSIONS: In conclusion, this study, even though preliminary and awaiting further confirmation by independent replication, provides first evidence that common genetic variation in CTF1 could contribute to insulin sensitivity in humans. Our SNP data indicate an insulin-desensitizing effect of cardiotrophin-1 and underline that cardiotrophin-1 represents an interesting target to influence insulin sensitivity.

  4. Update on the Pathophysiological Activities of the Cardiac Molecule Cardiotrophin-1 in Obesity

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    Mohamed Asrih

    2013-01-01

    Full Text Available Cardiotrophin-1 (CT-1 is a heart-targeting cytokine that has been reported to exert a variety of activities also in other organs such as the liver, adipose tissue, and atherosclerotic arteries. CT-1 has been shown to induce these effects via binding to a transmembrane receptor, comprising the leukaemia inhibitory factor receptor (LIFRβ subunit and the glycoprotein 130 (gp130, a common signal transducer. Both local and systemic concentrations of CT-1 have been shown to potentially play a critical role in obesity. For instance, CT-1 plasma concentrations have been shown to be increased in metabolic syndrome (a cluster disease including obesity probably due to adipose tissue overexpression. Interestingly, treatment with exogenous CT-1 has been shown to improve lipid and glucose metabolism in animal models of obesity. These benefits might suggest a potential therapeutic role for CT-1. However, beyond its beneficial properties, CT-1 has been also shown to induce some adverse effects, such as cardiac hypertrophy and adipose tissue inflammation. Although scientific evidence is still needed, CT-1 might be considered as a potential example of damage/danger-associated molecular pattern (DAMP in obesity-related cardiovascular diseases. In this narrative review, we aimed at discussing and updating evidence from basic research on the pathophysiological and potential therapeutic roles of CT-1 in obesity.

  5. Cardiotrophin-1, a muscle-derived cytokine, is required for the survival of subpopulations of developing motoneurons.

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    Oppenheim, R W; Wiese, S; Prevette, D; Armanini, M; Wang, S; Houenou, L J; Holtmann, B; Gotz, R; Pennica, D; Sendtner, M

    2001-02-15

    Developing motoneurons require trophic support from their target, the skeletal muscle. Despite a large number of neurotrophic molecules with survival-promoting activity for isolated embryonic motoneurons, those factors that are required for motoneuron survival during development are still not known. Cytokines of the ciliary neurotrophic factor (CNTF)-leukemia inhibitory factor (LIF) family have been shown to play a role in motoneuron (MN) survival. Importantly, in mice lacking the LIFRbeta or the CNTFRalpha there is a significant loss of MNs during embryonic development. Because genetic deletion of either (or both) CNTF or LIF fails, by contrast, to perturb MN survival before birth, it was concluded that another ligand exists that is functionally inactivated in the receptor deleted mice, resulting in MN loss during development. One possible candidate for this ligand is the CNTF-LIF family member cardiotrophin-1 (CT-1). CT-1 is highly expressed in embryonic skeletal muscle, secreted by myotubes, and promotes the survival of cultured embryonic mouse and rat MNs. Here we show that ct-1 deficiency causes increased motoneuron cell death in spinal cord and brainstem nuclei of mice during a period between embryonic day 14 and the first postnatal week. Interestingly, no further loss was detectable during the subsequent postnatal period, and nerve lesion in young adult ct-1-deficient mice did not result in significant additional loss of motoneurons, as had been previously observed in mice lacking both CNTF and LIF. CT-1 is the first bona fide muscle-derived neurotrophic factor to be identified that is required for the survival of subgroups of developing motoneurons. PMID:11160399

  6. Tumor-Induced Hyperlipidemia Contributes to Tumor Growth

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    Jianfeng Huang

    2016-04-01

    Full Text Available The known link between obesity and cancer suggests an important interaction between the host lipid metabolism and tumorigenesis. Here, we used a syngeneic tumor graft model to demonstrate that tumor development influences the host lipid metabolism. BCR-Abl-transformed precursor B cell tumors induced hyperlipidemia by stimulating very low-density lipoprotein (VLDL production and blunting VLDL and low-density lipoprotein (LDL turnover. To assess whether tumor progression was dependent on tumor-induced hyperlipidemia, we utilized the VLDL production-deficient mouse model, carboxylesterase3/triacylglycerol hydrolase (Ces3/TGH knockout mice. In Ces3/Tgh−/− tumor-bearing mice, plasma triglyceride and cholesterol levels were attenuated. Importantly tumor weight was reduced in Ces3/Tgh−/− mice. Mechanistically, reduced tumor growth in Ces3/Tgh−/− mice was attributed to reversal of tumor-induced PCSK9-mediated degradation of hepatic LDLR and decrease of LDL turnover. Our data demonstrate that tumor-induced hyperlipidemia encompasses a feed-forward loop that reprograms hepatic lipoprotein homeostasis in part by providing LDL cholesterol to support tumor growth.

  7. Chemotherapy induces tumor clearance independent of apoptosis

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    Guerriero, Jennifer L.; Ditsworth, Dara; Fan, Yongjun; Zhao, Fangping; Crawford, Howard C.; Zong, Wei-Xing

    2008-01-01

    Dysregulation of apoptosis is associated with the development of human cancer and resistance to anti-cancer therapy. The ultimate goal of cancer treatment is to selectively induce cancer cell death and overcome drug resistance. A deeper understanding of how a given chemotherapy affects tumor cell death is needed to develop strategically designed anti-cancer agents. Here we utilize a xenograft mouse tumor system generated from genetically defined cells deficient in apoptosis to examine the inv...

  8. Radiation-induced nitric oxide mitigates tumor hypoxia and radioresistance in a murine SCCVII tumor model

    International Nuclear Information System (INIS)

    Highlights: •IR-induced NO increased tissue perfusion and pO2. •IR increased NO production in tumors without changes in the mRNA and protein levels of NOS isoforms. •NOS activity assay showed that IR upregulated eNOS activity in tumors. •IR-induced NO decreased tumor hypoxia and altered tumor radiosensitivity. -- Abstract: Tumor hypoxia, which occurs mainly as a result of inadequate tissue perfusion in solid tumors, is a well-known challenge for successful radiotherapy. Recent evidence suggests that ionizing radiation (IR) upregulates nitric oxide (NO) production and that IR-induced NO has the potential to increase intratumoral circulation. However, the kinetics of NO production and the responsible isoforms for NO synthase in tumors exposed to IR remain unclear. In this study, we aimed to elucidate the mechanism by which IR stimulates NO production in tumors and the effect of IR-induced NO on tumor radiosensitivity. Hoechst33342 perfusion assay and electron spin resonance oxymetry showed that IR increased tissue perfusion and pO2 in tumor tissue. Immunohistochemical analysis using two different hypoxic probes showed that IR decreased hypoxic regions in tumors; treatment with a nitric oxide synthase (NOS) inhibitor, L-NAME, abrogated the effects of IR. Moreover, IR increased endothelial NOS (eNOS) activity without affecting its mRNA or protein expression levels in SCCVII-transplanted tumors. Tumor growth delay assay showed that L-NAME decreased the anti-tumor effect of fractionated radiation (10 Gy × 2). These results suggested that IR increased eNOS activity and subsequent tissue perfusion in tumors. Increases in intratumoral circulation simultaneously decreased tumor hypoxia. As a result, IR-induced NO increased tumor radiosensitivity. Our study provides a new insight into the NO-dependent mechanism for efficient fractionated radiotherapy

  9. Brain tumors induced by radiation in rhesus monkeys

    International Nuclear Information System (INIS)

    Two out of four pubescent rhesus monkeys, which received 1,500 rads of supervoltage X-irradiation, showed malignant brain tumors afer the survival of 52 and 102 weeks each. Since the incidence of spontaneous developing brain tumors in monkeys cited in the literatures was quite low, the tumors in the present series may have been radiation induced. (author)

  10. Expression of Hyaluronidase by Tumor Cells Induces Angiogenesis in vivo

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    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.

  11. The Role of Hedgehog Signaling in Tumor Induced Bone Disease

    International Nuclear Information System (INIS)

    Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung), directly invade into bone (head and neck) or originate from the bone (melanoma, chondrosarcoma) where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein) that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors

  12. The Role of Hedgehog Signaling in Tumor Induced Bone Disease

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    Cannonier, Shellese A.; Sterling, Julie A., E-mail: Julie.sterling@vanderbilt.edu [Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37235 (United States); Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology Vanderbilt University, Nashville, TN 372335 (United States); Department of Cancer Biology, Vanderbilt University, Nashville, TN 37235 (United States)

    2015-08-26

    Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung), directly invade into bone (head and neck) or originate from the bone (melanoma, chondrosarcoma) where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein) that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors.

  13. Radiation-induced malignant and atypical peripheral nerve sheath tumors

    International Nuclear Information System (INIS)

    The reported peripheral nerve complications of therapeutic irradiation in humans include brachial and lumbar plexus fibrosis and cranial and peripheral nerve atrophy. We have encountered 9 patients with malignant (7) and atypical (2) peripheral nerve tumors occurring in an irradiated site suggesting that such tumors represent another delayed effect of radiation treatment on peripheral nerve. In all instances the radio-theray was within an acceptable radiation dosage, yet 3 patients developed local radiation-induced skin and bony abnormalities. The malignant peripheral nerve sheath tumors developed only in the radiation port. Animal studies support the clinical observation that malignant peripheral nerve sheath tumors can occur as a delayed effect of irradiation

  14. Molecular analysis of radiation-induced experimental tumors in mice

    International Nuclear Information System (INIS)

    Molecular analysis was made on mouse tumors induced by radiation and chemicals. Expression of oncogenes was studied in 12 types of 178 mouse tumors. Southern blotting was done on tumors in which overexpression of oncogenes was noted. Amplification of the myc oncogene was found in chemically induced sarcomas, but not those induced by radiations. Radiogenic thymomas were studied in detail. These thymomas were induced in two different ways. The first was thymomas induced by direct irradiation of F1 mice between C57BL/6NxC3H/He. Southern analysis of DNA revealed deletion of specific minisatellite bands in these tumors. DNA from directly induced thymomas induced focus formation when transfected into normal Golden hamster cells. The mouse K-ras oncogene was detected in these transformants. The second type of thymomas was induced by X-irradiation of thymectomized B10.thy1.2 mice in which normal thymus from congenic B10,thy1.1. mice was grafted. Thymomas of the donor origin was analysed by transfection and the transformants by DNA from those indirectly induced thymomas did not contain activated ras oncogenes. (author)

  15. The role of autophagy induced by tumor microenvironment in different cells and stages of cancer

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    Yang, Xue; Yu, Dan-Dan; Yan, Fei; Jing, Ying-Ying; Han, Zhi-Peng; Sun, Kai; Liang, Lei; Hou, Jing; Li-xin WEI

    2015-01-01

    Development of a tumor is a very complex process, and invasion and metastasis of malignant tumors are hallmarks and are difficult problems to overcome. The tumor microenvironment plays an important role in controlling tumor fate and autophagy induced by the tumor microenvironment is attracting more and more attention. Autophagy can be induced by several stressors in the tumor microenvironment and autophagy modifies the tumor microenvironment, too. Autophagy has dual roles in tumor growth. In ...

  16. Molecular characterization of radon-induced rat lung tumors

    International Nuclear Information System (INIS)

    The radon gas is a well known lung carcinogenic factor in human at high doses but the cancer risk at low doses is not established. Indeed, epidemiological studies at low doses are difficult to conduct because of the human exposure to other lung carcinogenic factors. These data underlined the necessity to conduct experiments on lung tumors developed on animal model. The aim of this work was to characterize rat lung tumors by working on a series of radon-induced tumors that included adenocarcinomas (A.C.), squamous cell carcinomas (S.C.C.) and adeno-squamous carcinomas (A.S.C.), that are mixed tumors with both A.C. and S.C.C. cellular components. A C.G.H. analysis of the three types of tumors allowed us to define chromosomal recurrent unbalances and to target candidate genes potentially implicated in lung carcinogenesis, as p16Ink4a, p19Arf, Rb1, K-Ras or c-Myc. A more precise analysis of the p16Ink4a/Cdk4/Rb1 and p19Arf/Mdm2/Tp53 pathways was performed and indicated that the Rb1 pathway was frequently inactivated through an absence of p16Ink4a protein expression, indicating that it has a major role in rat lung carcinogenesis. Finally, a comparative transcriptomic analysis of the three types of tumors allowed us to show for the first time that the complex tumors A.S.C. have a transcriptomic profile in accordance with their mixed nature but that they also display their own expression profiles specificities. This work allowed us to find molecular characteristics common to murine and human lung tumors, indicating that the model of lung tumors in rat is pertinent to search for radiation-induced lung tumors specificities and to help for a better molecular identification of this type of tumors in human. (author)

  17. Expression of hyaluronidase by tumor cells induces angiogenesis in vivo.

    OpenAIRE

    D. Liu; 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 colorect...

  18. NNK-Induced Lung Tumors: A Review of Animal Model

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    Hua-Chuan Zheng; Yasuo Takano

    2011-01-01

    The incidence of lung adenocarcinoma has been remarkably increasing in recent years due to the introduction of filter cigarettes and secondary-hand smoking because the people are more exposed to higher amounts of nitrogen oxides, especially 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK), which is widely applied in animal model of lung tumors. In NNK-induced lung tumors, genetic mutation, chromosome instability, gene methylation, and activation of oncogenes have been found so as to disrup...

  19. Osteomalacia inducida por tumor: hemangiopericitoma rinosinusal Tumor-induced osteomalacia: rhinosinusal hemangiopericytoma

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    Enriqueta M. Serafini

    2013-02-01

    Full Text Available La osteomalacia inducida por tumor es una rara enfermedad del metabolismo óseo caracterizada por el aumento en la excreción de fosfato a nivel renal seguido de hipofosfatemia. Es causada por agentes fosfatúricos producidos por determinados tumores. La resección total del tumor resulta en la completa reversión de las anormalidades bioquímicas, la desaparición de las manifestaciones clínicas y los hallazgos en los estudios por imágenes. Presentamos el caso de un varón de 61 años con cuadro clínico y laboratorio compatibles con osteomalacia oncogénica inducida por tumor mesenquimático de localización rinosinusal. En nuestro caso el diagnóstico histológico correspondió a una neoplasia de tipo vascular: hemangiopericitoma.Tumor-induced osteomalacia is a rare disease of bone metabolism. The characteristic of this disease is an increase in phosphate excretion followed by hypophosphatemia, due to phosphaturic agents produced by different types of tumors. Tumor resection results in complete resolution of clinical, biochemical and radiological abnormalities. We present the case of a 61 year old man with signs, symptoms and laboratory findings consistent with oncogenic osteomalacia due to a rhino-sinusal mesenchymal tumor. The histological diagnosis showed a vascular neoplasm: hemangiopericytoma.

  20. Hybrid modeling of tumor-induced angiogenesis

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    Bonilla, L. L.; Capasso, V.; Alvaro, M.; Carretero, M.

    2014-12-01

    When modeling of tumor-driven angiogenesis, a major source of analytical and computational complexity is the strong coupling between the kinetic parameters of the relevant stochastic branching-and-growth of the capillary network, and the family of interacting underlying fields. To reduce this complexity, we take advantage of the system intrinsic multiscale structure: we describe the stochastic dynamics of the cells at the vessel tip at their natural mesoscale, whereas we describe the deterministic dynamics of the underlying fields at a larger macroscale. Here, we set up a conceptual stochastic model including branching, elongation, and anastomosis of vessels and derive a mean field approximation for their densities. This leads to a deterministic integropartial differential system that describes the formation of the stochastic vessel network. We discuss the proper capillary injecting boundary conditions and include the results of relevant numerical simulations.

  1. Dichloroacetate induces tumor-specific radiosensitivity in vitro but attenuates radiation-induced tumor growth delay in vivo

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    Zwicker, F.; Roeder, F.; Debus, J.; Huber, P.E. [University Hospital Center Heidelberg, Heidelberg (Germany). Dept. of Radiation Oncology; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg (Germany). Clinical Cooperation Unit Molecular Radiation Oncology; Kirsner, A.; Weber, K.J. [University Hospital Center Heidelberg, Heidelberg (Germany). Dept. of Radiation Oncology; Peschke, P. [Deutsches Krebsforschungszentrum (DKFZ), Heidelberg (Germany). Clinical Cooperation Unit Molecular Radiation Oncology

    2013-08-15

    Background: Inhibition of pyruvate dehydrogenase kinase (PDK) by dichloroacetate (DCA) can shift tumor cell metabolism from anaerobic glycolysis to glucose oxidation, with activation of mitochondrial activity and chemotherapy-dependent apoptosis. In radiotherapy, DCA could thus potentially enhance the frequently moderate apoptotic response of cancer cells that results from their mitochondrial dysfunction. The aim of this study was to investigate tumor-specific radiosensitization by DCA in vitro and in a human tumor xenograft mouse model in vivo. Materials and methods: The interaction of DCA with photon beam radiation was investigated in the human tumor cell lines WIDR (colorectal) and LN18 (glioma), as well as in the human normal tissue cell lines HUVEC (endothelial), MRC5 (lung fibroblasts) and TK6 (lymphoblastoid). Apoptosis induction in vitro was assessed by DAPI staining and sub-G1 flow cytometry; cell survival was quantified by clonogenic assay. The effect of DCA in vivo was investigated in WIDR xenograft tumors growing subcutaneously on BALB/c-nu/nu mice, with and without fractionated irradiation. Histological examination included TUNEL and Ki67 staining for apoptosis and proliferation, respectively, as well as pinomidazole labeling for hypoxia. Results: DCA treatment led to decreased clonogenic survival and increased specific apoptosis rates in tumor cell lines (LN18, WIDR) but not in normal tissue cells (HUVEC, MRC5, TK6). However, this significant tumor-specific radiosensitization by DCA in vitro was not reflected by the situation in vivo: The growth suppression of WIDR xenograft tumors after irradiation was reduced upon additional DCA treatment (reflected by Ki67 expression levels), although early tumor cell apoptosis rates were significantly increased by DCA. This apparently paradoxical effect was accompanied by a marked DCA-dependent induction of hypoxia in tumor-tissue. Conclusion: DCA induced tumor-specific radiosensitization in vitro but not in vivo

  2. Brain tumors induced in rats by human adenovirus type 12

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    Murao,Tsuyoshi

    1974-02-01

    Full Text Available Oncogenesis of human adenovirus type 12 in the brain of rats was examined. Newborn rats of Sprague-Dawley and Donryu strains were injected intracranially with human adenovirus type 12. The incidence of intracranial tumors was 91% (30/33 in SpragueDawley and 56% (14/25 in Donryu rats. Except for one tumor nodule located in the parietal cortex of a Sprague.Dawley rat, all tumors developed in the paraventricular areas or in the meninges. Tumors were quite similar histologically to those induced in hamsters and mice resembling the undifferentiated human brain tumors such as medulloblastoma, ependymoblastoma and embryonic gliomas. From the histological features and primary sites of tumor development, it is suggested that the tumors in the brain of rats induced by adenovirus type 12 originate from the embryonic cells in the paraventricular area and also from the undifferentiated supporting cells of the peripheral nerves in the leptomeninges.

  3. Bone scintigraphic patterns in patients of tumor induced osteomalacia

    International Nuclear Information System (INIS)

    Tumor induced osteomalacia (TIO) or oncogenic osteomalacia is a rare condition associated with small tumor that secretes one of the phosphaturic hormones, i.e., fibroblast growth factor 23, resulting in abnormal phosphate metabolism. Patients may present with non-specific symptoms leading to delay in the diagnosis. Extensive skeletal involvement is frequently seen due to delay in the diagnosis and treatment. The small sized tumor and unexpected location make the identification of tumor difficult even after diagnosis of osteogenic osteomalacia. The bone scan done for the skeletal involvement may show the presence of metabolic features and the scan findings are a sensitive indicator of metabolic bone disorders. We present the bone scan findings in three patients diagnosed to have TIO

  4. Computed tomography of virally induced monkey brain tumors

    International Nuclear Information System (INIS)

    Thirty-five (35) Japanese monkeys (Macaca fuscata) were inoculated intracerebrally with chickembryo fibroblasts which were producing the Schmidt-Ruppin strain of the Rous sarcoma virus. These were then studied by means of computed tomography (CT) to detect brain tumors. Tumors were induced in 54.3% (19/35), with an average latency of 32.6 (15 - 43) days before a CT image appeared. The brains were sectioned into 5-mm slices, coplanar with the CT images. Various CT features, such as necrosis, hemorrhage, and peritumoral edema, correlated with the pathological findings. Contrast-enhanced CT detected tumors greater than 4-6 mm in diameter, and it was accurate within 2 mm in determining. Following brain tumors by CT in 6 monkeys revealed changes in the tumor size. One monkey was treated by differential hypothermia following craniectomy; the therapeutic effect and the tumor size, as subsequently evaluated for six months, revealed tumor regression during the initial 5 weeks, followed by stabilization and late (6 months) progression. The large brain size, 90-110 grams in adults, and the availability of these monkeys make them an excellent model system for neurological, neurosurgical, CT, and multimodality therapeutic experimentation. (author)

  5. Investigation of HIFU-induced anti-tumor immunity in a murine tumor model

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    Lyerly H Kim

    2007-07-01

    Full Text Available Abstract Background High intensity focused ultrasound (HIFU is an emerging non-invasive treatment modality for localized treatment of cancers. While current clinical strategies employ HIFU exclusively for thermal ablation of the target sites, biological responses associated with both thermal and mechanical damage from focused ultrasound have not been thoroughly investigated. In particular, endogenous danger signals from HIFU-damaged tumor cells may trigger the activation of dendritic cells. This response may play a critical role in a HIFU-elicited anti-tumor immune response which can be harnessed for more effective treatment. Methods Mice bearing MC-38 colon adenocarcinoma tumors were treated with thermal and mechanical HIFU exposure settings in order to independently observe HIFU-induced effects on the host's immunological response. In vivo dendritic cell activity was assessed along with the host's response to challenge tumor growth. Results Thermal and mechanical HIFU were found to increase CD11c+ cells 3.1-fold and 4-fold, respectively, as compared to 1.5-fold observed for DC injection alone. In addition, thermal and mechanical HIFU increased CFSE+ DC accumulation in draining lymph nodes 5-fold and 10-fold, respectively. Moreover, focused ultrasound treatments not only caused a reduction in the growth of primary tumors, with tumor volume decreasing by 85% for thermal HIFU and 43% for mechanical HIFU, but they also provided protection against subcutaneous tumor re-challenge. Further immunological assays confirmed an enhanced CTL activity and increased tumor-specific IFN-γ-secreting cells in the mice treated by focused ultrasound, with cytotoxicity induced by mechanical HIFU reaching as high as 27% at a 10:1 effector:target ratio. Conclusion These studies present initial encouraging results confirming that focused ultrasound treatment can elicit a systemic anti-tumor immune response, and they suggest that this immunity is closely related to

  6. Local hyperthermia treatment of tumors induces CD8+ T cell-mediated resistance against distal and secondary tumors

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    Zhang, Peisheng; Chen, Lei; Baird, Jason R.; Demidenko, Eugene; Turk, Mary Jo; Hoopes, P. Jack; Conejo-Garcia, Jose R.; Fiering, Steven

    2014-01-01

    Combinatorial use of iron oxide nanoparticles (IONPs) and an alternating magnetic filed (AMF) can induce local hyperthermia in tumors in a controlled and uniform manner. Heating B16 primary tumors at 43°C for 30 minutes activated dendritic cells (DCs) and subsequently CD8+ T cells in the draining lymph node (dLN) and conferred resistance against rechallenge with B16 (but not unrelated Lewis Lung carcinoma) given 7 days post hyperthermia on both the primary tumor side and the contralateral side in a CD8+ T cell-dependent manner. Mice with heated primary tumors also resisted rechallenge given 30 days post hyperthermia. Mice with larger heated primary tumors had greater resistance to secondary tumors. No rechallenge resistance occurred when tumors were heated at 45°C. Our results demonstrate the promising potential of local hyperthermia treatment applied to identified tumors in inducing anti-tumor immune responses that reduce the risk of recurrence and metastasis. PMID:24566274

  7. Changes in liver mitochondrial plasticity induced by brain tumor

    International Nuclear Information System (INIS)

    Accumulating data suggest that liver is a major target organ of systemic effects observed in the presence of a cancer. In this study, we investigated the consequences of the presence of chemically induced brain tumors in rats on biophysical parameters accounting for the dynamics of water in liver mitochondria. Tumors of the central nervous system were induced by intraveinous administration of ethylnitrosourea (ENU) to pregnant females on the 19th day of gestation. The mitochondrial crude fraction was isolated from the liver of each animal and the dynamic parameters of total water and its macromolecule-associated fraction (structured water, H2Ost) were calculated from Nuclear Magnetic Resonance (NMR) measurements. The presence of a malignant brain tumor induced a loss of water structural order that implicated changes in the physical properties of the hydration shells of liver mitochondria macromolecules. This feature was linked to an increase in the membrane cholesterol content, a way to limit water penetration into the bilayer and then to reduce membrane permeability. As expected, these alterations in mitochondrial plasticity affected ionic exchanges and led to abnormal features of mitochondrial biogenesis and caspase activation. This study enlightens the sensitivity of the structured water phase in the liver mitochondria machinery to external conditions such as tumor development at a distant site. The profound metabolic and functional changes led to abnormal features of ion transport, mitochondrial biogenesis and caspase activation

  8. Changes in liver mitochondrial plasticity induced by brain tumor

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    Debien Emilie

    2006-10-01

    Full Text Available Abstract Background Accumulating data suggest that liver is a major target organ of systemic effects observed in the presence of a cancer. In this study, we investigated the consequences of the presence of chemically induced brain tumors in rats on biophysical parameters accounting for the dynamics of water in liver mitochondria. Methods Tumors of the central nervous system were induced by intraveinous administration of ethylnitrosourea (ENU to pregnant females on the 19th day of gestation. The mitochondrial crude fraction was isolated from the liver of each animal and the dynamic parameters of total water and its macromolecule-associated fraction (structured water, H2Ost were calculated from Nuclear Magnetic Resonance (NMR measurements. Results The presence of a malignant brain tumor induced a loss of water structural order that implicated changes in the physical properties of the hydration shells of liver mitochondria macromolecules. This feature was linked to an increase in the membrane cholesterol content, a way to limit water penetration into the bilayer and then to reduce membrane permeability. As expected, these alterations in mitochondrial plasticity affected ionic exchanges and led to abnormal features of mitochondrial biogenesis and caspase activation. Conclusion This study enlightens the sensitivity of the structured water phase in the liver mitochondria machinery to external conditions such as tumor development at a distant site. The profound metabolic and functional changes led to abnormal features of ion transport, mitochondrial biogenesis and caspase activation.

  9. Tumor environmental factors glucose deprivation and lactic acidosis induce mitotic chromosomal instability--an implication in aneuploid human tumors.

    Directory of Open Access Journals (Sweden)

    Chunyan Dai

    Full Text Available Mitotic chromosomal instability (CIN plays important roles in tumor progression, but what causes CIN is incompletely understood. In general, tumor CIN arises from abnormal mitosis, which is caused by either intrinsic or extrinsic factors. While intrinsic factors such as mitotic checkpoint genes have been intensively studied, the impact of tumor microenvironmental factors on tumor CIN is largely unknown. We investigate if glucose deprivation and lactic acidosis--two tumor microenvironmental factors--could induce cancer cell CIN. We show that glucose deprivation with lactic acidosis significantly increases CIN in 4T1, MCF-7 and HCT116 scored by micronuclei, or aneuploidy, or abnormal mitosis, potentially via damaging DNA, up-regulating mitotic checkpoint genes, and/or amplifying centrosome. Of note, the feature of CIN induced by glucose deprivation with lactic acidosis is similar to that of aneuploid human tumors. We conclude that tumor environmental factors glucose deprivation and lactic acidosis can induce tumor CIN and propose that they are potentially responsible for human tumor aneuploidy.

  10. Mitochondrial mutagenesis induced by tumor-specific radiation bystander effects.

    LENUS (Irish Health Repository)

    Gorman, Sheeona

    2012-02-01

    The radiation bystander effect is a cellular process whereby cells not directly exposed to radiation display cellular alterations similar to directly irradiated cells. Cellular targets including mitochondria have been postulated to play a significant role in this process. In this study, we utilized the Random Mutation Capture assay to quantify the levels of random mutations and deletions in the mitochondrial genome of bystander cells. A significant increase in the frequency of random mitochondrial mutations was found at 24 h in bystander cells exposed to conditioned media from irradiated tumor explants (p = 0.018). CG:TA mutations were the most abundant lesion induced. A transient increase in the frequency of random mitochondrial deletions was also detected in bystander cells exposed to conditioned media from tumor but not normal tissue at 24 h (p = 0.028). The increase in both point mutations and deletions was transient and not detected at 72 h. To further investigate mitochondrial dysfunction, mitochondrial membrane potential and reactive oxygen species were assessed in these bystander cells. There was a significant reduction in mitochondrial membrane potential and this was positively associated with the frequency of random point mutation and deletions in bystander cells treated with conditioned media from tumor tissue (r = 0.71, p = 0.02). This study has shown that mitochondrial genome alterations are an acute consequence of the radiation bystander effect secondary to mitochondrial dysfunction and suggests that this cannot be solely attributable to changes in ROS levels alone.

  11. Paclitaxel-induced macrophage activities in the tumor-bearing host: immunologic implications and therapeutic applications

    OpenAIRE

    Mullins, David Warren

    1998-01-01

    Tumors induce immune dysfunction through the production of soluble factors that subvert macrophage (Mf) function to favor tumor growth. Previous studies suggested that tumor-induced immune cell dysfunction may be reversible through regimens that disrupt tumor cell suppressor mechanisms and concurrently promote tumoricidal activities. Because the antineoplastic agent paclitaxel (TAXOL) activates Mf function, we studied mechanisms of paclitaxel-mediated cytotoxic and immunostimulatory respons...

  12. The Liver is a Site for Tumor Induced Myeloid-Derived Suppressor Cell Accumulation and Immunosuppression

    OpenAIRE

    Ilkovitch, Dan; Lopez, Diana M.

    2009-01-01

    Tumor-induced immunosuppression plays a key role in tumor evasion of the immune system. A key cell population recognized as myeloid-derived suppressor cells (MDSC) contributes and helps orchestrate this immunosuppression. MDSC can interact with T cells, macrophages, and NK cells, to create an environment favorable for tumor progression. In various tumor models their presence at high levels has been reported in the bone marrow, blood, spleen, and tumor. We report for the first time that MDSC a...

  13. Experimentally induced tumors used for angiographic estimation of embolisation and cytostatic treatment

    International Nuclear Information System (INIS)

    In 12 rats tumors have been induced chemically by intraperitoneal application of dimethylnitrosamine. This method is simple and reliable and the effect of tumor embolisation can be followed easyly. Thymus aplastic nude mice with transplanted human tumors deserve strict care. Tumor microangiograms of 48 animals demonstrate a close similarity with angiograms of corresponding human tumors. The vascular pattern does not alterate after several transplantations, after cytostatic therapy a slight hypervascularisation developes. (orig.)

  14. Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization

    International Nuclear Information System (INIS)

    Patients with pancreatic ductal adenocarcinoma (PDAC) are frequently complicated with metastatic disease or locally advanced tumors, and consequently need chemotherapy. Gemcitabine is commonly used for PDAC treatment, but with limited efficacy. The capacity of gemcitabine to generate reactive oxygen species (ROS) in human pancreatic cancer cells, prompted us to examine its effects on the expression of pro-inflammatory cytokines and chemokines. We observed that gemcitabine enhanced selectively the expression of CXCL8 in human pancreatic cancer cells through ROS generation and NF-κB activation. In vitro blocking of CXCL8 failed to modulate gemcitabine-mediated inhibition of cell proliferation in human pancreatic cancer cells. Gemcitabine also enhanced CXCL8 expression in pancreatic cancer cells in xenografted tumor tissues. Moreover, anti-CXCL8 antibody treatment in vivo attenuated tumor formation as well as intra-tumoral vascularity in nude mice, which were transplanted with Miapaca-2 cells and treated with gemcitabine. Thus, gemcitabine-induced CXCL8 may counteract the drug through inducing neovascularization. - Highlights: • Gemcitabine induced CXCL8 expression in human pancreatic cancer cells. • CXCL8 expression required ROS generation and NF-κB activation. • CXCL8 did not affect in vitro proliferation of human pancreatic cancer cells. • CXCL8 in vivo counteracted gemcitabine by inducing neovascularization

  15. Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization

    Energy Technology Data Exchange (ETDEWEB)

    Song, Yao; Baba, Tomohisa [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192 (Japan); Li, Ying-Yi [Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Furukawa, Kaoru; Tanabe, Yamato [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192 (Japan); School of Natural System Bioengineering Course, College of Science and Engineering, Kanazawa University, Kanazawa, Ishikawa (Japan); Matsugo, Seiichi [School of Natural System Bioengineering Course, College of Science and Engineering, Kanazawa University, Kanazawa, Ishikawa (Japan); Sasaki, Soichiro [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192 (Japan); Mukaida, Naofumi, E-mail: mukaida@staff.kanazawa-u.ac.jp [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192 (Japan)

    2015-03-06

    Patients with pancreatic ductal adenocarcinoma (PDAC) are frequently complicated with metastatic disease or locally advanced tumors, and consequently need chemotherapy. Gemcitabine is commonly used for PDAC treatment, but with limited efficacy. The capacity of gemcitabine to generate reactive oxygen species (ROS) in human pancreatic cancer cells, prompted us to examine its effects on the expression of pro-inflammatory cytokines and chemokines. We observed that gemcitabine enhanced selectively the expression of CXCL8 in human pancreatic cancer cells through ROS generation and NF-κB activation. In vitro blocking of CXCL8 failed to modulate gemcitabine-mediated inhibition of cell proliferation in human pancreatic cancer cells. Gemcitabine also enhanced CXCL8 expression in pancreatic cancer cells in xenografted tumor tissues. Moreover, anti-CXCL8 antibody treatment in vivo attenuated tumor formation as well as intra-tumoral vascularity in nude mice, which were transplanted with Miapaca-2 cells and treated with gemcitabine. Thus, gemcitabine-induced CXCL8 may counteract the drug through inducing neovascularization. - Highlights: • Gemcitabine induced CXCL8 expression in human pancreatic cancer cells. • CXCL8 expression required ROS generation and NF-κB activation. • CXCL8 did not affect in vitro proliferation of human pancreatic cancer cells. • CXCL8 in vivo counteracted gemcitabine by inducing neovascularization.

  16. Tumor-infiltrating lymphocyte activity is enhanced in tumors with low IL-10 production in HBV-induced hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Yang, E-mail: yangshi_xz@126.com; Song, Qingwei; Hu, Dianhe; Zhuang, Xiaohu; Yu, Shengcai

    2015-05-22

    Hepatocellular carcinoma (HCC) is one of the most common cancers and can be induced by chronic HBV infection. The role of HBV-specific immune responses in mediating tumorigenesis and HCC prognosis is debated. The effect of intratumoral microenvironment on tumor-infiltrating lymphocytes (TILs) is also unclear. Here, we examined resected tumor tissue from 36 patients with HBV-induced HCC. We categorized study cohort based on ex vivo IL-10 secretion by tumor cells into high IL-10-secreting (Hi10) and low IL-10-secreting (Lo10) groups, and found that the Lo10 group was less sensitive to TLR ligand stimulation. TILs from the Lo10 group contained higher frequencies of HBV-specific IFN-g-producing cells and total IFN-g-producing cells, and possessed higher proliferative capacity. Moreover, the proliferative capacity of TILs from the Hi10 group was negatively correlated with IL-10 secretion from tumor cells. Together, our data demonstrated that low IL-10-producing capacity in HBV-induced HCC tumors is associated with enhanced TIL activity. - Highlights: • We examined intratumoral IL-10 production in HBV-induced HCC. • We grouped HCC tumors into Hi10 and Lo10 groups based on their IL-10 production. • Lo10 groups had better IFN-g response by TILs. • Lo10 groups had better TIL proliferative capacity. • Lo10 group tumor cells were refractory to TLR ligand stimulation.

  17. Numerical simulation of blood flow and interstitial fluid pressure in solid tumor microcirculation based on tumor-induced angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Gaiping Zhao; Jie Wu; Shixiong Xu; M. W. Collins; Quan Long; Carola S. K(o)nig; Yuping Jiang; Jian Wang; A. R. Padhani

    2007-01-01

    A coupled intravascular-transvascular-interstitial fluid flow model is developed to study the distributions of blood flow and interstitial fluid pressure in solid tumor microcirculation based on a tumor-induced microvascular network.This is generated from a 2D nine-point discrete mathematical model of tumor angiogenesis and contains two parent vessels.Blood flow through the microvascular network and interstitial fluid flow in tumor tissues are performed by the extended Poiseuille's law and Darcy's law, respectively, transvascular flow is described by Starling's law; effects of the vascular permeability and the interstitial hydraulic conductivity are also considered. The simulation results predict the heterogeneous blood supply, interstitial hypertension and low convectionon the inside of the tumor, which are consistent with physiological observed facts. These results may provide beneficial information for anti-angiogenesis treatment of tumor and further clinical research.

  18. Radiation as an inducer of in-situ autologous vaccine in the treatment of solid tumors

    International Nuclear Information System (INIS)

    Radiation therapy (RT) is conventionally used for local tumor control. Although local control of the primary tumor can prevent the development of subsequent systemic metastases, tumor irradiation is not effective in controlling pre-existing systemic disease. The concept of radiation-enhanced antigen presentation and immunomodulation allows the harnessing of tumor cell death induced by radiation as a potential source of tumor antigens for immunotherapy. Immunomodulation using RT is a novel strategy of in situ tumor vaccination where primary tumor irradiation can contribute to the control of pre-existing systemic metastatic disease. The absence of systemic immunosuppression (often associated with chemotherapy) and the generally lower toxicity makes radiation a desirable adjuvant regimen for immunotherapy and tumor vaccination strategies. Increased understanding of tumor immunology and the biology of radiation-mediated immune modulation should enhance the efficacy of combining these therapeutic modalities. Here we aim to provide an overview of the biology of radiation-induced immune modulation. (author)

  19. Tumor necrosis factor induced stimulation of granulopoiesis and radioprotection

    International Nuclear Information System (INIS)

    Human recombinant tumor necrosis factor, TNF, was used to assess its ability to stimulate granulopoiesis and to protect mice against lethal irradiation, effects known to be inducable with TNF-rich postendotoxin serum from BCG infected mice (BCG/ET serum). Although the endotoxin contamination of this TNF preparation is extremely low its effects were compared in endotoxin low responder C3H/HeJ mice and susceptible NMRI mice. TNF is a potent inducer of serum colony stimulating activity, CSA, in both mouse strains. In peripheral blood a marked granulocytosis with a concomitant decrease in lymphocytes and monocytopenia occurs at 2 hours after injection of TNF. Moreover, TNF induces an increase in the number of splenic myelopoietic committed stem cells (GM-CFC, granulocyte-macrophage colony forming cells) determined five days after injection. The lethality rate, registered over 30 days after exposure to 660 cGy whole body X-irradiation is reduced to 40% in C3H/HeJ mice as compared to 75% in control animals. The reduction in lethality is observed both, when TNF was injected 24 hours before or after irradiation. In vitro, TNF significantly increases the number of colonies in the presence of CSA in bone marrow cultures. TNF per se does not effect colony growth. The studies reported here demonstrate that TNF is a myelopoiesis stimulating factor in mice which may be related to the reduction in lethality following whole body irradiation

  20. MG132, a proteasome inhibitor, induces apoptosis in tumor cells.

    Science.gov (United States)

    Guo, Na; Peng, Zhilan

    2013-03-01

    The balance between cell proliferation and apoptosis is critical for normal development and for the maintenance of homeostasis in adult organisms. Disruption of this balance has been implicated in a large number of disease processes, ranging from autoimmunity and neurodegenerative disorders to cancer. The ubiquitin-proteasome pathway, responsible for mediating the majority of intracellular proteolysis, plays a crucial role in the regulation of many normal cellular processes, including the cell cycle, differentiation and apoptosis. Apoptosis in cancer cells is closely connected with the activity of ubiquitin-proteasome pathway. The peptide-aldehyde proteasome inhibitor MG132 (carbobenzoxyl-L-leucyl-L-leucyl-L-leucine) induces the apoptosis of cells by a different intermediary pathway. Although the pathway of induction of apoptosis is different, it plays a crucial role in anti-tumor treatment. There are many cancer-related molecules in which the protein levels present in cells are regulated by a proteasomal pathway; for example, tumor inhibitors (P53, E2A, c-Myc, c-Jun, c-Fos), transcription factors (transcription factor nuclear factor-kappa B, IκBα, HIFI, YYI, ICER), cell cycle proteins (cyclin A and B, P27, P21, IAP1/3), MG132 induces cell apoptosis through formation of reactive oxygen species or the upregulation and downregulation of these factors, which is ultimately dependent upon the activation of the caspase family of cysteine proteases. In this article we review the mechanism of the induction of apoptosis in order to provide information required for research. PMID:22897979

  1. Targeting tumor antigens to secreted membrane vesicles in vivo induces efficient antitumor immune responses.

    NARCIS (Netherlands)

    Zeelenberg, I.S.; Ostrowski, M.; Krumeich, S.; Bobrie, A.; Jancic, C.; Boissonnas, A.; Delcayre, A.; Pecq, JB Le; Combadiere, B.; Amigorena, S.; Thery, C.

    2008-01-01

    Expression of non-self antigens by tumors can induce activation of T cells in vivo, although this activation can lead to either immunity or tolerance. CD8+ T-cell activation can be direct (if the tumor expresses MHC class I molecules) or indirect (after the capture and cross-presentation of tumor an

  2. Photodynamic therapy with aluminum-chloro-phthalocyanine induces necrosis and vascular damage in mice tongue tumors.

    Science.gov (United States)

    Longo, João Paulo Figueiró; Lozzi, Silene Paulino; Simioni, Andreza Ribeiro; Morais, Paulo César; Tedesco, Antônio Cláudio; Azevedo, Ricardo Bentes

    2009-02-01

    In this paper we describe the efficacy of the liposomal-AlClPc (aluminum-chloro-phthalocyanine) formulation in PDT study against Ehrlich tumor cells proliferation in immunocompetent swiss mice tongue. Experiments were conduced in sixteen tumor induced mice that were divided in three control groups: (1) tumor without treatment; (2) tumor with 100J/cm(2) laser (670nm) irradiation; and (3) tumor with AlClPc peritumoral injection; and a PDT experimental group when tumors received AlClPc injection followed by tumor irradiation. Control groups present similar macroscopically and histological patterns after treatments, while PDT treatment induced 90% of Ehrlich tumor necrosis after 24h of one single application, showing the efficacy of liposome-AlClPc (aluminum-chloro-phthalocyanine) mediated PDT on the treatment of oral cancer. PMID:19097802

  3. Overcoming Hypoxic-Resistance of Tumor Cells to TRAIL-Induced Apoptosis through Melatonin

    Directory of Open Access Journals (Sweden)

    You-Jin Lee

    2014-07-01

    Full Text Available A solid tumor is often exposed to hypoxic or anoxic conditions; thus, tumor cell responses to hypoxia are important for tumor progression as well as tumor therapy. Our previous studies indicated that tumor cells are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL-induced cell apoptosis under hypoxic conditions. Melatonin inhibits cell proliferation in many cancer types and induces apoptosis in some particular cancer types. Here, we examined the effects of melatonin on hypoxic resistant cells against TRAIL-induced apoptosis and the possible mechanisms of melatonin in the hypoxic response. Melatonin treatment increased TRAIL-induced A549 cell death under hypoxic conditions, although hypoxia inhibited TRAIL-mediated cell apoptosis. In a mechanistic study, hypoxia inducible factor-1α and prolyl-hydroxylase 2 proteins, which increase following exposure to hypoxia, were dose-dependently down-regulated by melatonin treatment. Melatonin also blocked the hypoxic responses that reduced pro-apoptotic proteins and increased anti-apoptotic proteins including Bcl-2 and Bcl-xL. Furthermore, melatonin treatment reduced TRAIL resistance by regulating the mitochondrial transmembrane potential and Bax translocation. Our results first demonstrated that melatonin treatment induces apoptosis in TRAIL-resistant hypoxic tumor cells by diminishing the anti-apoptotic signals mediated by hypoxia and also suggest that melatonin could be a tumor therapeutic tool by combining with other apoptotic ligands including TRAIL, particularly in solid tumor cells exposed to hypoxia.

  4. Cisplatin-induced Casepase-3 activation in different tumor cells

    Science.gov (United States)

    Shi, Hua; Li, Xiao; Su, Ting; Zhang, Yu-Hai

    2008-12-01

    Apoptosis plays an essential role in normal organism development which is one of the main types of programmed cell death to help tissues maintain homeostasis. Defective apoptosis can result in cell accumulation and therefore effects on tumor pathogenesis, progression and therapy resistance. A family of proteins, known as caspases, is typically activated in the early stages of apoptosis. Therefore, studying the kinetics of activation of caspases induced by antitumor drugs can contribute to antitumor drug discovery and explanation of the molecular mechanisms. This paper detected the Caspase-3 activity induced by cisplatin in human adenoid cystic carcinoma cell line (ACC-M), human hepatocellular liver carcinoma cell line (HepG2) and human epithelial carcinoma cell line (Hela) with stably expressing ECFP-DEVDDsRed (CD3) probe, a fluorescent probe consisting of Enhanced Cyan Fluorescent Protein (ECFP), red fluorescent protein (DsRed) and a linker with a recognition site of Caspase-3, by using the capillary electrophoresis (CE) and fluorescence resonance energy transfer (FRET) imaging system. Under the same concentration of cisplatin, ACC-M cells responded the most rapidly, and then HepG2 cells and Hela cells, respectively, in the early 30 hours. Later, HepG2 cells represented acceleration in the Caspase-3 activation speed and reached full activation the earliest comparing to other two cell types. The results demonstrated that ACC-M cell is more sensitive than the other two cell types under the treatment of cisplatin.

  5. Interferon-inducible protein-10 identified as a mediator of tumor necrosis in vivo

    OpenAIRE

    Sgadari, Cecilia; Angiolillo, Anne L.; Cherney, Barry W.; Pike, Sandra E.; Farber, Joshua M.; Koniaris, Leonidas G.; Vanguri, Padmavathy; Burd, Parris R.; Sheikh, Nasreen; Gupta, Ghanshyam; Teruya-Feldstein, Julie; Tosato, Giovanna

    1996-01-01

    Human Burkitt lymphoma cell lines give rise to progressively growing subcutaneous tumors in athymic mice. These tumors are induced to regress by inoculation of Epstein–Barr virus-immortalized normal human lymphocytes. In the present study, analysis of profiles of murine cytokine/chemokine gene expression in Burkitt tumor tissues excised from the nude mice showed that expression of the murine α-chemokine interferon-inducible protein-10 (IP-10) was higher in the regressi...

  6. Hormonal relations of radiation-induced tumors of Arabidopsis thaliana

    International Nuclear Information System (INIS)

    When gamma-irradiated Arabidopsis seed was germinated, tumors appeared on hypocotyls and apical meristems of the resulting plants. Several tumors have been cultured on hormone free medium for over two years since excision from the plants. The tumor lines display a range of phenotypes suggestive of abnormal hormone balance. To determine whether hormone overproduction or hypersensitivity is involved in tumorigenesis, we are measuring hormone levels in the tumor lines and characterizing their response to exogenously supplied growth regulators. Growth of two tumor lines is stimulated by either NAA or BAP, one is stimulated by NAA only, two by BAP only, and one is stimulated by neither. Growth of all lines tested thus far is inhibited by gibberellic acid, ethephon and ACC. The tumor lines appear more sensitive to ACC than normal callus tissue. Most tumors studied to date appear unlikely to have arisen due to increased hormone sensitivity. Experiments are in progress to determine auxin and cytokinin levels in the tumor lines

  7. Transgenic CHD1L expression in mouse induces spontaneous tumors.

    Directory of Open Access Journals (Sweden)

    Muhan Chen

    Full Text Available BACKGROUND: Amplification of 1q21 is the most frequent genetic alteration in hepatocellular carcinoma (HCC, which was detected in 58-78% of primary HCC cases by comparative genomic hybridization (CGH. Using chromosome microdissection/hybrid selection approach we recently isolated a candidate oncogene CHD1L from 1q21 region. Our previous study has demonstrated that CHD1L had strong oncogenic ability, which could be effectively suppressed by siRNA against CHD1L. The molecular mechanism of CHD1L in tumorigenesis has been associated with its role in promoting cell proliferation. METHODOLOGY/PRINCIPAL FINDINGS: To further investigate the in vivo oncogenic role of CHD1L, CHD1L ubiquitous-expression transgenic mouse model was generated. Spontaneous tumor formations were found in 10/41 (24.4% transgenic mice, including 4 HCCs, but not in their 39 wild-type littermates. In addition, alcohol intoxication was used to induce hepatocyte pathological lesions and results found that overexpression of CHD1L in hepatocytes could promote tumor susceptibility in CHD1L-transgenic mice. To address the mechanism of CHD1L in promoting cell proliferation, DNA content between CHD1L-transgenic and wildtype mouse embryo fibroblasts (MEFs was compared by flow cytometry. Flow cytometry results found that CHD1L could facilitate DNA synthesis and G1/S transition through the up-regulation of Cyclin A, Cyclin D1, Cyclin E, CDK2, and CDK4, and down-regulation of Rb, p27(Kip1, and p53. CONCLUSION/SIGNIFICANCE: Taken together, our data strongly support that CHD1L is a novel oncogene and plays an important role in HCC pathogenesis.

  8. Interferon-inducible protein-10 identified as a mediator of tumor necrosis in vivo

    Science.gov (United States)

    Sgadari, Cecilia; Angiolillo, Anne L.; Cherney, Barry W.; Pike, Sandra E.; Farber, Joshua M.; Koniaris, Leonidas G.; Vanguri, Padmavathy; Burd, Parris R.; Sheikh, Nasreen; Gupta, Ghanshyam; Teruya-Feldstein, Julie; Tosato, Giovanna

    1996-01-01

    Human Burkitt lymphoma cell lines give rise to progressively growing subcutaneous tumors in athymic mice. These tumors are induced to regress by inoculation of Epstein–Barr virus-immortalized normal human lymphocytes. In the present study, analysis of profiles of murine cytokine/chemokine gene expression in Burkitt tumor tissues excised from the nude mice showed that expression of the murine α-chemokine interferon-inducible protein-10 (IP-10) was higher in the regressing than in the progressive Burkitt tumors. We tested the effects of IP-10 on Burkitt tumor growth in nude mice. Inoculation of established Burkitt tumors either with crude preparations of murine IP-10 or with purified human IP-10 caused visible tumor necrosis in a proportion of the animals, although no complete tumor regressions were observed. Constitutive expression of murine IP-10 in Burkitt cells reduced their ability to grow as subcutaneous tumors, and caused visible tumor necrosis in a proportion of the animals. Histologically, IP-10-treated and IP-10-expressing Burkitt tumors had widespread evidence of tumor tissue necrosis and of capillary damage, including intimal thickening and vascular thrombosis. Thus, IP-10 is an antitumor agent that promotes damage in established tumor vasculature and causes tissue necrosis in human Burkitt lymphomas established subcutaneously in athymic mice. PMID:8943014

  9. 10B compound distribution in rat tissue of transplanted and ethylnitrosourea-induced brain tumors

    International Nuclear Information System (INIS)

    The distribution of 10B compound, sodium mercaptoundecahydrododecaborate Na210B12H11SH, which is now in practical use for boron neutron capture therapy for brain tumors, was studied qualitatively and quantitatively using neutron-induced alpha autoradiography. Transplanted intracerebral tumors and brain tumors induced by ethylnitrosourea (ENU) in SD rats were used. 10B accumulated in the brain tumors in close relation to the actual tumor cells. The concentration of 10B in transplanted brain tumors was usually less in the central viable tumor tissue. The concentration and the distribution of 10B in ENU-induced gliomas varied with the size and histological type of the tumor and correlated to the permeability of vessels to horse-radish peroxidase and Evans blue. The tumor/blood concentration ratio of 10B increased with time after injection and reached 1, 12 and 7 hours after injection in the transplanted tumor and ENU-induced tumor, respectively. The tumor concentrations calculated at that time were 18 μg 10B/cm3 and 30 μg 10B/cm3, respectively. As for other tissues, a large amount of 10B was found in the pituitary gland, trigeminal ganglion, cornea, sclera and choroidea of the eyes and skin. This study clearly shows that the distribution of this 10B compound in brain tumors is roughly proportionate to the vascularity and to the vascular permeability of tumors and suggests that irradiation of thermal neutrons into the cranium in 7 to 12 hours after 10B injection should destroy the tumor tissue but yet inflict very little damage on normal tissue, and few untoward effects on pituitary gland and ganglia of nerves in rats. (J.P.N.)

  10. Mifepristone inhibits MPA-and FGF2-induced mammary tumor growth but not FGF2-induced mammary hyperplasia

    Directory of Open Access Journals (Sweden)

    Juan P. Cerliani

    2010-12-01

    Full Text Available We have previously demonstrated a crosstalk between fibroblast growth factor 2 (FGF2 and progestins inducing experimental breast cancer growth. The aim of the present study was to compare the effects of FGF2 and of medroxyprogesterone acetate (MPA on the mouse mammary glands and to investigate whether the antiprogestin RU486 was able to reverse the MPA- or FGF2-induced effects on both, mammary gland and tumor growth. We demonstrate that FGF2 administered locally induced an intraductal hyperplasia that was not reverted by RU486, suggesting that FGF2-induced effects are progesterone receptor (PR-independent. However, MPA-induced paraductal hyperplasia was reverted by RU486 and a partial agonistic effect was observed in RU486-treated glands. Using C4-HD tumors which only grow in the presence of MPA, we showed that FGF2 administered intratumorally was able to stimulate tumor growth as MPA. The histology of FGF2-treated tumors showed different degrees of gland differentiation. RU486 inhibited both, MPA or FGF2 induced tumor growth. However, only complete regression was observed in MPA-treated tumors. Our results support the hypothesis that stromal FGF2 activates PR inducing hormone independent tumor growth.

  11. Growing tumors induce a local STING dependent Type I IFN response in dendritic cells.

    Science.gov (United States)

    Andzinski, Lisa; Spanier, Julia; Kasnitz, Nadine; Kröger, Andrea; Jin, Lei; Brinkmann, Melanie M; Kalinke, Ulrich; Weiss, Siegfried; Jablonska, Jadwiga; Lienenklaus, Stefan

    2016-09-15

    The importance of endogenous Type I IFNs in cancer immune surveillance is well established by now. Their role in polarization of tumor-associated neutrophilic granulocytes into anti-tumor effector cells has been recently demonstrated. Yet, the cellular source of Type I IFNs as well as the mode of induction is not clearly defined. Here, we demonstrate that IFN-β is induced by growing murine tumors. Induction is mainly mediated via STING-dependent signaling pathways, suggesting tumor derived DNA as trigger. Transcription factors IRF3 and IRF5 were activated under these conditions which is consistent with tumor infiltrating dendritic cells (DCs) being the major cellular source of IFN-β at the tumor site. Besides DCs, tumor cells themselves are induced to contribute to the production of IFN-β. Taken together, our data provide further information on immune surveillance by Type I IFNs and suggest novel potent cellular targets for future cancer therapy. PMID:27116225

  12. Heat-shocked tumor cell lysate-pulsed dendritic cells induce effective anti-tumor immune response in vivo

    Institute of Scientific and Technical Information of China (English)

    Jian Qiu; Guo-Wei Li; Yan-Fang Sui; Hong-Ping Song; Shao-Yan Si; Wei Ge

    2006-01-01

    AIM: To study whether heat-shocked tumor cells could enhance the effect of tumor cell lysate-pulsed dendritic cells (DCs) in evoking anti-tumor immune response in vivo.METHODS: Mouse undifferentiated colon cancer cells(CT-26) were heated at 42℃ for 1 h and then frozenthawed. The bone marrow-derived DCs pulsed with heatshocked CT-26 cell lysate (HSCT-26 DCs) were recruited to immunize syngeneic naive BALB/c mice. The cytotoxic activity of tumor specific cytotoxic T lymphocytes (CTLs)in mouse spleen was evaluated by IFN-enzyme-linked immunospot (ELISpot) and LDH release assay. The immunoprophylactic effects induced by HSCT-26 DCs in mouse colon cancer model were compared to those induced by single CT-26 cell lysate-pulsed DCs (CT-26DCs) on tumor volume, peritoneal metastasis and survival time of the mice.RESULTS: Heat-treated CT-26 cells showed a higher hsp70 protein expression. Heat-shocked CT-26 cell lysate pulsing elevated the co-stimulatory and MHC-Ⅱ molecule expression of bone marrow-derived DCs as well as interleukin-12 p70 secretion. The IFN-γ secreting CTLs induced by HSCT-26 DCs were significantly more than those induced by CT-26 DCs (P= 0.002). The former CTLs' specific cytotoxic activity was higher than the latter CTLs' at a serial E/T ratio of 10:1, 20:1, and 40:1. Mouse colon cancer model showed that the tumor volume of HSCT-26 DC vaccination group was smaller than that of CT-26 DC vaccination group on tumor volume though there was no statistical difference between them(24 mm3 vs 8 mm3, P= 0.480). The median survival time of mice immunized with HSCT-26 DCs was longer than that of those immunized with CT-26 DCs (57 d vs 43 d,P= 0.0384).CONCLUSION: Heat-shocked tumor cell lysate-pulsed DCs can evoke anti-tumor immune response in vivo effectively and serve as a novel DC-based tumor vaccine.

  13. Nitric Oxide Synthase Inhibition by NG-Nitro-l-Arginine Methyl Ester Inhibits Tumor-Induced Angiogenesis in Mammary Tumors

    Science.gov (United States)

    Jadeski, Lorraine C.; Lala, Peeyush K.

    1999-01-01

    Using a murine breast cancer model, we earlier found a positive correlation between the expression of nitric oxide synthase (NOS) and tumor progression; treatment with inhibitors of NOS, NG-methyl-l-arginine (NMMA) and NG-nitro-l-arginine methyl ester (L-NAME), had antitumor and antimetastatic effects that were partly attributed to reduced tumor cell invasiveness. In the present study, we used a novel in vivo model of tumor angiogenesis using subcutaneous implants of tumor cells suspended in growth factor-reduced Matrigel to examine the angiogenic role of NO in a highly metastatic murine mammary adenocarcinoma cell line. This cell line, C3L5, expresses endothelial (e) NOS in vitro and in vivo, and inducible (i) NOS in vitro on stimulation with lipopolysaccharide and interferon-γ. Female C3H/HeJ mice received subcutaneous implants of growth factor-reduced Matrigel inclusive of C3L5 cells on one side, and on the contralateral side, Matrigel alone; L-NAME and D-NAME (inactive enantiomer) were subsequently administered for 14 days using osmotic minipumps. Immediately after sacrifice, implants were removed and processed for immunolocalization of eNOS and iNOS proteins, and measurement of angiogenesis. Neovascularization was quantified in sections stained with Masson’s trichrome or immunostained for the endothelial cell specific CD31 antigen. While most tumor cells and endothelial cells expressed immunoreactive eNOS protein, iNOS was localized in endothelial cells and some macrophages within the tumor-inclusive implants. Measurable angiogenesis occurred only in implants containing tumor cells. Irrespective of the method of quantification used, tumor-induced neovascularization was significantly reduced in L-NAME-treated mice relative to those treated with D-NAME. The quantity of stromal tissue was lower, but the quantity of necrotic tissue higher in L-NAME relative to D-NAME-treated animals. The total mass of viable tissue (ie, stroma and tumor cells) was lower in L

  14. Androgen via p21 Inhibits Tumor Necrosis Factor α-induced JNK Activation and Apoptosis*

    OpenAIRE

    Tang, Fangming; Kokontis, John; Lin, Yuting; Liao, Shutsung; Lin, Anning; Xiang, Jialing

    2009-01-01

    The male hormone androgen is a growth/survival factor for its target tissues or organs. Yet, the underlying mechanism is incompletely understood. Here, we report that androgen via p21 inhibits tumor necrosis factor α-induced JNK activation and apoptosis. Inhibition by androgen requires the transcription activity of androgen receptor (AR) and de novo protein synthesis. Androgen·AR induces expression of p21 that in turn inhibits tumor necrosis factor α-induced JNK and apoptosis. Furthermore, ge...

  15. E2F1 Induces Pituitary Tumor Transforming Gene (PTTG1) Expression in Human Pituitary Tumors

    OpenAIRE

    Zhou, Cuiqi; Wawrowsky, Kolja; Bannykh, Serguei; Gutman, Shiri; Melmed, Shlomo

    2009-01-01

    Rb/E2F is dysregulated in murine and human pituitary tumors. Pituitary tumor transforming gene (PTTG1), a securin protein, is required for pituitary tumorigenesis, and PTTG1 deletion attenuates pituitary tumor development in Rb+/− mice. E2F1 and PTTG1 were concordantly overexpressed in 29 of 46 Rb+/− murine pituitary tissues and also in 45 of 80 human pituitary tumors (P < 0.05). E2F1 specifically bound the hPTTG1 promoter as assessed by chromatin immunoprecipitation and biotin-streptavidin p...

  16. Antioxidant intervention of smoking-induced lung tumor in mice by vitamin E and quercetin

    International Nuclear Information System (INIS)

    Epidemiological and in vitro studies suggest that antioxidants such as quercetin and vitamin E (VE) can prevent lung tumor caused by smoking; however, there is limited evidence from animal studies. In the present study, Swiss mouse was used to examine the potential of quercetin and VE for prevention lung tumor induced by smoking. Our results suggest that the incidence of lung tumor and tumor multiplicity were 43.5% and 1.00 ± 0.29 in smoking group; Quercetin has limited effects on lung tumor prevention in this in vivo model, as measured by assays for free radical scavenging, reduction of smoke-induced DNA damage and inhibition of apoptosis. On the other hand, vitamin E drastically decreased the incidence of lung tumor and tumor multiplicity which were 17.0% and 0.32 ± 0.16, respectively (p < 0.05); and demonstrated prominent antioxidant effects, reduction of DNA damage and decreased cell apoptosis (p < 0.05). Combined treatment with quercetin and VE in this animal model did not demonstrate any effect greater than that due to vitamin E alone. In addition, gender differences in the occurrence of smoke induced-lung tumor and antioxidant intervention were also observed. We conclude that VE might prevent lung tumor induced by smoking in Swiss mice

  17. Cyclin D expression in plutonium-induced lung tumors in F344 rats

    International Nuclear Information System (INIS)

    The genetic mechanisms responsible for α-radiation-induced lung cancer in rats following inhalation of 239Pu is an ongoing area of research in our laboratory. Previous studies have examined the status of the p53 gene by immunohistochemistry. Only two tumors (2/26 squamous cell carcinomas) exhibited detectable levels of p53 products. Both were the result of mutations in codons 280 and 283. More recent studies of X-ray-induced lung tumors in rats showed a similar lack of involvement of p53. In conclusion, we found that α-radiation-induced rat lung tumors have a high incidence (31 of 39) of cyclin D1 overexpression

  18. Metastatic Tumor Dormancy in Cutaneous Melanoma: Does Surgery Induce Escape?

    International Nuclear Information System (INIS)

    According to the concept of tumor dormancy, tumor cells may exist as single cells or microscopic clusters of cells that are clinically undetectable, but remain viable and have the potential for malignant outgrowth. At metastatic sites, escape from tumor dormancy under more favorable local microenvironmental conditions or through other, yet undefined stimuli, may account for distant recurrence after supposed “cure” following surgical treatment of the primary tumor. The vast majority of evidence to date in support of the concept of tumor dormancy originates from animal studies; however, extensive epidemiologic data from breast cancer strongly suggests that this process does occur in human disease. In this review, we aim to demonstrate that metastatic tumor dormancy does exist in cutaneous melanoma based on evidence from mouse models and clinical observations of late recurrence and occult transmission by organ transplantation. Experimental data underscores the critical role of impaired angiogenesis and immune regulation as major mechanisms for maintenance of tumor dormancy. Finally, we examine evidence for the role of surgery in promoting escape from tumor dormancy at metastatic sites in cutaneous melanoma

  19. Metastatic Tumor Dormancy in Cutaneous Melanoma: Does Surgery Induce Escape?

    Energy Technology Data Exchange (ETDEWEB)

    Tseng, William W. [Department of Surgery, University of California at San Francisco, 513 Parnassus Avenue, Room S-321, San Francisco, CA 94143 (United States); Fadaki, Niloofar; Leong, Stanley P., E-mail: leongsx@cpmcri.org [Department of Surgery and Center for Melanoma Research and Treatment, California Pacific Medical Center and Research Institute, 2340 Clay Street, 2nd floor, San Francisco, CA 94115 (United States)

    2011-02-21

    According to the concept of tumor dormancy, tumor cells may exist as single cells or microscopic clusters of cells that are clinically undetectable, but remain viable and have the potential for malignant outgrowth. At metastatic sites, escape from tumor dormancy under more favorable local microenvironmental conditions or through other, yet undefined stimuli, may account for distant recurrence after supposed “cure” following surgical treatment of the primary tumor. The vast majority of evidence to date in support of the concept of tumor dormancy originates from animal studies; however, extensive epidemiologic data from breast cancer strongly suggests that this process does occur in human disease. In this review, we aim to demonstrate that metastatic tumor dormancy does exist in cutaneous melanoma based on evidence from mouse models and clinical observations of late recurrence and occult transmission by organ transplantation. Experimental data underscores the critical role of impaired angiogenesis and immune regulation as major mechanisms for maintenance of tumor dormancy. Finally, we examine evidence for the role of surgery in promoting escape from tumor dormancy at metastatic sites in cutaneous melanoma.

  20. Metastatic Tumor Dormancy in Cutaneous Melanoma: Does Surgery Induce Escape?

    Directory of Open Access Journals (Sweden)

    William W. Tseng

    2011-02-01

    Full Text Available According to the concept of tumor dormancy, tumor cells may exist as single cells or microscopic clusters of cells that are clinically undetectable, but remain viable and have the potential for malignant outgrowth. At metastatic sites, escape from tumor dormancy under more favorable local microenvironmental conditions or through other, yet undefined stimuli, may account for distant recurrence after supposed “cure” following surgical treatment of the primary tumor. The vast majority of evidence to date in support of the concept of tumor dormancy originates from animal studies; however, extensive epidemiologic data from breast cancer strongly suggests that this process does occur in human disease. In this review, we aim to demonstrate that metastatic tumor dormancy does exist in cutaneous melanoma based on evidence from mouse models and clinical observations of late recurrence and occult transmission by organ transplantation. Experimental data underscores the critical role of impaired angiogenesis and immune regulation as major mechanisms for maintenance of tumor dormancy. Finally, we examine evidence for the role of surgery in promoting escape from tumor dormancy at metastatic sites in cutaneous melanoma.

  1. Differential inhibition of lipopolysaccharide-induced phenomena by anti-tumor necrosis factor alpha antibody.

    OpenAIRE

    Vogel, S N; Havell, E A

    1990-01-01

    Tumor necrosis factor alpha (TNF alpha) has been implicated as a major mediator of lipopolysaccharide (LPS)-induced phenomena. Administration to mice of a polyclonal, monospecific antibody prepared against recombinant murine TNF alpha abolished detection of LPS-induced TNF alpha activity and significantly reduced levels of LPS-induced colony-stimulating factor but failed to reduce the production of LPS-induced interferon, corticosterone, or LPS-induced hypoglycemia.

  2. Tumor Induced Hepatic Myeloid Derived Suppressor Cells Can Cause Moderate Liver Damage

    OpenAIRE

    Eggert, Tobias; Medina-Echeverz, José; Kapanadze, Tamar; Kruhlak, Michael J.; Korangy, Firouzeh; Greten, Tim F.

    2014-01-01

    Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC) not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and B...

  3. Rethinking the Stalk Effect: A New Hypothesis Explaining Suprasellar Tumor-Induced Hyperprolactinemia

    OpenAIRE

    Skinner, Donal C.

    2008-01-01

    The pars tuberalis is a distinct subdivision of the pituitary gland but its function remains poorly understood. Suprasellar tumors in this pars tuberalis region are frequently accompanied by hyperprolactinemia. As these tumors do not immunoreact for any of the established pituitary hormones, they are classified as non-secretory. It has been postulated that these suprasellar tumors induce hyperprolactinemia by compressing the pituitary stalk, resulting in impaired dopamine delivery to the pitu...

  4. Somatic mutations in stilbene estrogen-induced Syrian hamster kidney tumors identified by DNA fingerprinting

    Directory of Open Access Journals (Sweden)

    Roy Deodutta

    2004-01-01

    Full Text Available Abstract Kidney tumors from stilbene estrogen (diethylstilbestrol-treated Syrian hamsters were screened for somatic genetic alterations by Random Amplified Polymorphic DNA-polymerase chain-reaction (RAPD-PCR fingerprinting. Fingerprints from tumor tissue were generated by single arbitrary primers and compared with fingerprints for normal tissue from the same animal, as well as normal and tumor tissues from different animals. Sixty one of the arbitrary primers amplified 365 loci that contain approximately 476 kbp of the hamster genome. Among these amplified DNA fragments, 44 loci exhibited either qualitative or quantitative differences between the tumor tissues and normal kidney tissues. RAPD-PCR loci showing decreased and increased intensities in tumor tissue DNA relative to control DNA indicate that loci have undergone allelic losses and gains, respectively, in the stilbene estrogen-induced tumor cell genome. The presence or absence of the amplified DNA fragments indicate homozygous insertions or deletions in the kidney tumor DNA compared to the age-matched normal kidney tissue DNA. Seven of 44 mutated loci also were present in the kidney tissues adjacent to tumors (free of macroscopic tumors. The presence of mutated loci in uninvolved (non-tumor surrounding tissue adjacent to tumors from stilbene estrogen-treated hamsters suggests that these mutations occurred in the early stages of carcinogenesis. The cloning and sequencing of RAPD amplified loci revealed that one mutated locus had significant sequence similarity with the hamster Cyp1A1 gene. The results show the ability of RAPD-PCR to detect and isolate, in a single step, DNA sequences representing genetic alterations in stilbene estrogen-induced cancer cells, including losses of heterozygosity, and homozygous deletion and insertion mutations. RAPD-PCR provides an alternative molecular approach for studying cancer cytogenetics in stilbene estrogen-induced tumors in humans and experimental

  5. Chemically-induced mouse lung tumors: applications to human health assessments [Poster 2014

    Science.gov (United States)

    A state-of-the-science workshop on chemically-induced mouse lung tumors was conducted by U.S. Environmental Protection Agency to discuss issues related to the use of mouse lung tumor data in human health assessments. Naphthalene, styrene, and ethylbenzene were chosen for the anal...

  6. Chemically-induced Mouse Lung Tumors: Applications to Human Health Assessments

    Science.gov (United States)

    A state-of-the-science workshop on chemically-induced mouse lung tumors was conducted by U.S. Environmental Protection Agency to better understand the mouse lung tumor data’s role in human health assessments. Three environmental chemicals - naphthalene, styrene, and ethylbe...

  7. Squaraine PDT induces oxidative stress in skin tumor of swiss albino mice

    Science.gov (United States)

    Cibin, T. R.; Gayathri, Devi D.; Ramaiah, D.; Abraham, Annie

    2010-02-01

    Photodynamic Therapy (PDT) using a sensitizing drug is recognized as a promising medical technique for cancer treatment. It is a two step process that requires the administration of a photosensitizer followed by light exposure to treat a disease. Following light exposure the photosensitizer is excited to a higher energy state which generates free radicals and singlet oxygen. The present study was carried out to assess the oxidative damage induced by bis (3, 5-diiodo-2, 4, 6- trihydroxyphenyl) squaraine in skin tumor tissues of mice with/ without light treatment. Skin tumor was induced using 7, 12-Dimethyl Benz(a)anthracene and croton oil. The tumor bearing mice were given an intraperitoneal injection with the squaraine dye. After 24h, the tumor area of a few animals injected with the dye, were exposed to visible light from a 1000 W halogen lamp and others kept away from light. All the mice were sacrificed one week after the PDT treatment and the oxidative profile was analyzed (TBARS, SOD, catalase, GSH, GPx and GR) in tumor/ skin tissues. The dye induces oxidative stress in the tumor site only on illumination and the oxidative status of the tumor tissue was found to be unaltered in the absence of light. The results of the study clearly shows that the tumor destruction mediated by PDT using bis (3, 5-diiodo-2, 4, 6-trihydroxyphenyl) squaraine as a photosensitizer is due to the generation of reactive oxygen species, produced by the light induced changes in the dye.

  8. Sensitivity of fibroblast growth factor 23 measurements in tumor-induced osteomalacia

    DEFF Research Database (Denmark)

    Imel, Erik A; Peacock, Munro; Pitukcheewanont, Pisit;

    2006-01-01

    Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome of hypophosphatemia, decreased renal phosphate reabsorption, normal or low serum 1,25-dihydryxyvitamin-D concentration, myopathy, and osteomalacia. Fibroblast growth factor 23 (FGF23) is a phosphaturic protein overexpressed in tumors...

  9. Noise-induced first-order transition in anti-tumor immunotherapy

    OpenAIRE

    Zhong, Wei-Rong; Shao, Yuan-Zhi; He, Zhen-Hui

    2005-01-01

    We studied the single-variable dynamics model of the tumor growth. A first-order phase transition induced by an additive noise is shown to reproduce the main features of tumor growth under immune surveillance. The critical average cells population has a power-law function relationship with the immune coefficient.

  10. Increased bioprotein production in rats with tumors induced by radon inhalation and benzonaphtoflavone administration

    International Nuclear Information System (INIS)

    Serial determinations of urinary biopterin were performed in rats during the development of lung tumors induced by radon inhalation and 5,6-benzonaphtoflavone administration. A striking increase in biopterin levels was observed in animals which developed single or multiple epidermoid carcinoma of the lung and this increase occurred several weeks before tumors could be detected radiographically. (author)

  11. Radiation-induced thyroid tumors in infant rats

    International Nuclear Information System (INIS)

    Three hundred rad of x rays given to the neck region of 10-day-old rats led to the development of more thyroid tumors with a shorter latent period than the same dose of x rays given to the thyroid gland of adult animals. A subsequent treatment of irradiated animals with methylthiouracil significantly increased the number of thyroid adenomas and carcinomas and shortened the latent period. The thyroid tumors examined were predominantly of a follicular type. Papillary and medullary tumor variants were observed in a few animals only

  12. Physiology of Hormone Autonomous Tissue Lines Derived From Radiation-Induced Tumors of Arabidopsis thaliana.

    Science.gov (United States)

    Campell, B R; Town, C D

    1991-11-01

    gamma-Radiation-induced tumors of Arabidopsis thaliana L. have been produced as a novel approach to isolation of genes that regulate plant development. Tumors excised from irradiated plants are hormone autonomous in culture and have been maintained on hormone-free medium for up to 4 years. Five tumor tissue lines having different morphologies and growth rates were analyzed for auxin, cytokinin, and 1-aminocyclopropane-1-carboxylic acid (ACC) content, ethylene production, and response to exogenous growth regulators. Normal tissues and two crown gall tissue lines were analyzed for comparison. Rosettes and whole seedlings each contained approximately 30 nanograms. (gram fresh weight)(-1) free indoleacetic acid (IAA), 150 nanograms. (gram fresh weight)(-1) ester-conjugated IAA, and 10 to 20 micrograms. (gram fresh weight)(-1) amide-conjugated IAA. The crown gall lines contained similar amounts of free and ester-conjugated IAA but less amide conjugates. Whereas three of the radiation-induced tumor lines had IAA profiles similar to normal tissues, one line had 10- to 100-fold more free IAA and three- to 10-fold less amide-conjugated IAA. The fifth line had normal free IAA levels but more conjugated IAA than control tissues. Whole seedlings contained approximately 2 nanograms. (gram fresh weight)(-1) of both zeatin riboside and isopentenyladenosine. The crown gall lines had 100- to 1000-fold higher levels of each cytokinin. In contrast, the three radiation-induced tumor lines analyzed contained cytokinin levels similar to the control tissue. The radiation-induced tumor tissues produced very little ethylene, although each contained relatively high levels of ACC. Normal callus contained similar amounts of ACC but produced several times more ethylene than the radiation-induced tumor lines. Each of the radiation-induced tumor tissues displayed a unique set of responses to exogenously supplied growth regulators. Only one tumor line showed the same response as normal callus to

  13. Physiology of Hormone Autonomous Tissue Lines Derived From Radiation-Induced Tumors of Arabidopsis thaliana 1

    Science.gov (United States)

    Campell, Bruce R.; Town, Christopher D.

    1991-01-01

    γ-Radiation-induced tumors of Arabidopsis thaliana L. have been produced as a novel approach to isolation of genes that regulate plant development. Tumors excised from irradiated plants are hormone autonomous in culture and have been maintained on hormone-free medium for up to 4 years. Five tumor tissue lines having different morphologies and growth rates were analyzed for auxin, cytokinin, and 1-aminocyclopropane-1-carboxylic acid (ACC) content, ethylene production, and response to exogenous growth regulators. Normal tissues and two crown gall tissue lines were analyzed for comparison. Rosettes and whole seedlings each contained approximately 30 nanograms· (gram fresh weight)−1 free indoleacetic acid (IAA), 150 nanograms· (gram fresh weight)−1 ester-conjugated IAA, and 10 to 20 micrograms· (gram fresh weight)−1 amide-conjugated IAA. The crown gall lines contained similar amounts of free and ester-conjugated IAA but less amide conjugates. Whereas three of the radiation-induced tumor lines had IAA profiles similar to normal tissues, one line had 10- to 100-fold more free IAA and three- to 10-fold less amide-conjugated IAA. The fifth line had normal free IAA levels but more conjugated IAA than control tissues. Whole seedlings contained approximately 2 nanograms· (gram fresh weight)−1 of both zeatin riboside and isopentenyladenosine. The crown gall lines had 100- to 1000-fold higher levels of each cytokinin. In contrast, the three radiation-induced tumor lines analyzed contained cytokinin levels similar to the control tissue. The radiation-induced tumor tissues produced very little ethylene, although each contained relatively high levels of ACC. Normal callus contained similar amounts of ACC but produced several times more ethylene than the radiation-induced tumor lines. Each of the radiation-induced tumor tissues displayed a unique set of responses to exogenously supplied growth regulators. Only one tumor line showed the same response as normal callus to

  14. Glutamate Release by Primary Brain Tumors Induces Epileptic Activity

    OpenAIRE

    Buckingham, Susan C.; Campbell, Susan L.; Haas, Brian R.; Montana, Vedrana; Robel, Stefanie; Ogunrinu, Toyin; Sontheimer, Harald

    2011-01-01

    Epileptic seizures are a common and poorly understood co-morbidity for individuals with primary brain tumors. To investigate peritumoral seizure etiology, we implanted patient-derived glioma cells into scid mice. Within 14–18 days, glioma-bearing animals developed spontaneous, recurring abnormal EEG events consistent with epileptic activity that progressed over time. Acute brain slices from these animals showed significant glutamate release from the tumor mediated by the system xc − cystine/g...

  15. Non-invasive quantification of brain tumor-induced astrogliosis

    Directory of Open Access Journals (Sweden)

    Baird Andrew

    2011-01-01

    Full Text Available Abstract Background CNS injury including stroke, infection, and tumor growth lead to astrogliosis, a process that involves upregulation of glial fibrillary acidic protein (GFAP in astrocytes. However, the kinetics of astrogliosis that is related to these insults (i.e. tumor is largely unknown. Results Using transgenic mice expressing firefly luciferase under the regulation of the GFAP promoter (GFAP-luc, we developed a model system to monitor astrogliosis upon tumor growth in a rapid, non-invasive manner. A biphasic induction of astrogliosis was observed in our xenograft model in which an early phase of activation of GFAP was associated with inflammatory response followed by a secondary, long-term upregulation of GFAP. These animals reveal GFAP activation with kinetics that is in parallel with tumor growth. Furthermore, a strong correlation between astrogliosis and tumor size was observed. Conclusions Our results suggest that non-invasive, quantitative bioluminescent imaging using GFAP-luc reporter animal is a useful tool to monitor temporal-spatial kinetics of host-mediated astrogliosis that is associated with glioma and metastatic brain tumor growth.

  16. Retrovirus particles in spontaneously occurring and radiation-induced tumors in ddy mice

    International Nuclear Information System (INIS)

    Among spontaneously occurring tumors, pulmonary tumor, malignant lymphoma, mammary tumor, and ovarian tumor were the major ones in 232 ddY female mice. The former three tumors appeared significantly earlier and the latter one increased in incidence in 229 mice given 600 R whole or 800 R partial body (tunk) x-irradiation at the age of 10 weeks. Five tumors were examined electronmicroscopically from each tumor type of both the spontaneously occurring and radiation-induced tumors. C type virus particles were present only in the malignant lymphoma and B particles in the mammary, ovarian and pulmonary tumors, which are all of epithelial character. Thus, as far as we were concerned in this mouse strain, B particles were produced preferentially in epithelial cells and C particles in non-epithelial cells. The retrovirus particles were found in the same frequency, namely, 10 of 20 tumors examined in both the tumor groups. From our results, the intervention of virus in radiation carcinogenesis still remains in question. (author)

  17. Immunological response induced by alternated cooling and heating of breast tumor.

    Science.gov (United States)

    Dong, Jiaxiang; Liu, Ping; Zhang, Aili; Xu, Lisa X

    2007-01-01

    A new in-situ thermal physical method combining both cryosurgery and local hyperthermia was used to treat mice bearing 4T1 murine mammary carcinoma. The induced anti-tumor immune response was investigated. The cryo/heat treatment resulted in stimulation of CTL response and attraction of immunocytes into the tumor debris, which correlated well to the tumor rejection in re-implantation. The results suggested that alternated cooling and heating had synergistic effect and might be developed into an alternative modality for tumor therapy. PMID:18002249

  18. Intra-tumor distribution of metallofullerene using micro-particle induced X-ray emission (PIXE).

    Science.gov (United States)

    Yamamoto, Yohei; Yamamoto, Tetsuya; Horiguchi, Yukichi; Shirakawa, Makoto; Satoh, Takahiro; Koka, Masashi; Nagasaki, Yukio; Nakai, Kei; Matsumura, Akira

    2014-06-01

    To clarify the intra tumor distribution of gadlinium containing fullerene (Gd@C82), micro particle induced X-ray emission (Micro-PIXE) analysis were performed. The tumor bearing BALB/c mice were injected Gd@C82 and subcutaneous tumors were taken from 48h after the intravenous injection. Using the Micro-PIXE method, we could visualize Gd intra tumor distribution. Therefore our results indicate the possibility that Micro-PIXE is useful technique for imaging the bioditribution of Gd, and Gd@C82 is potentially useful Gd carrier for NCT. PMID:24491681

  19. Intra-tumor distribution of metallofullerene using micro-particle induced X-ray emission (PIXE)

    International Nuclear Information System (INIS)

    To clarify the intra tumor distribution of gadlinium containing fullerene (Gd@C82), micro particle induced X-ray emission (Micro-PIXE) analysis were performed. The tumor bearing BALB/c mice were injected Gd@C82 and subcutaneous tumors were taken from 48 h after the intravenous injection. Using the Micro-PIXE method, we could visualize Gd intra tumor distribution. Therefore our results indicate the possibility that Micro-PIXE is useful technique for imaging the bioditribution of Gd, and Gd@C82 is potentially useful Gd carrier for NCT

  20. Hypoxia-Inducible Factor Pathway Inhibition Resolves Tumor Hypoxia and Improves Local Tumor Control After Single-Dose Irradiation

    International Nuclear Information System (INIS)

    Purpose: To study the effects of BAY-84-7296, a novel orally bioavailable inhibitor of mitochondrial complex I and hypoxia-inducible factor 1 (HIF-1) activity, on hypoxia, microenvironment, and radiation response of tumors. Methods and Materials: UT-SCC-5 and UT-SCC-14 human squamous cell carcinomas were transplanted subcutaneously in nude mice. When tumors reached 4 mm in diameter BAY-84-7296 (Bayer Pharma AG) or carrier was daily administered to the animals. At 7 mm tumors were either excised for Western blot and immunohistologic investigations or were irradiated with single doses. After irradiation animals were randomized to receive BAY-84-7296 maintenance or carrier. Local tumor control was evaluated 150 days after irradiation, and the dose to control 50% of tumors (TCD50) was calculated. Results: BAY-84-7296 decreased nuclear HIF-1α expression. Daily administration of inhibitor for approximately 2 weeks resulted in a marked decrease of pimonidazole hypoxic fraction in UT-SCC-5 (0.5% vs 21%, P50, with an enhancement ratio of 1.37 (95% confidence interval [CI] 1.13-1.72) in UT-SCC-5 and of 1.55 (95% CI 1.26-1.94) in UT-SCC-14. BAY-84-7296 maintenance after irradiation did not further decrease TCD50. Conclusions: BAY-84-7296 resulted in a marked decrease in tumor hypoxia and substantially reduced radioresistance of tumor cells with the capacity to cause a local recurrence after irradiation. The data suggest that reduction of cellular hypoxia tolerance by BAY-84-7296 may represent the primary biological mechanism underlying the observed enhancement of radiation response. Whether this mechanism contributes to the improved outcome of fractionated chemoradiation therapy warrants further investigation

  1. Hypoxia-Inducible Regulation of a Prodrug-Activating Enzyme for Tumor-Specific Gene Therapy

    Directory of Open Access Journals (Sweden)

    Toru Shibata

    2002-01-01

    Full Text Available Previous studies have suggested that tumor hypoxia could be exploited for cancer gene therapy. Using hypoxia-responsive elements derived from the human vascular endothelial growth factor gene, we have generated vectors expressing a bacterial nitroreductase. (20NTR gene that can activate the anticancer prodrug CB1954. Stable transfectants of human HT1080 tumor cells with hypoxia-inducible vectors were established with G418 selection. Hypoxic induction of NTR protein correlated with increased sensitivity to in vitro exposure of HT 1080 cells to the prodrug. Growth delay assays were performed with established tumor xenografts derived from the same cells to detect the in vivo efficacy of CB1954 conversion to its cytotoxic form. Significant antitumor effects were achieved with intraperitoneal injections of CB1954 both in tumors that express NTR constitutively or with a hypoxia-inducible promoter. In addition, respiration of 10% O2 increased tumor hypoxia in vivo and enhanced the antitumor effects. Taken together, these results demonstrate that hypoxia-inducible vectors may be useful for tumor-selective gene therapy, although the problem of delivery of the vector to the tumors, particularly to the hypoxic cells in the tumors, is not addressed by these studies.

  2. Stochastic fluctuation induced the competition between extinction and recurrence in a model of tumor growth

    Energy Technology Data Exchange (ETDEWEB)

    Li, Dongxi, E-mail: lidongxi@yahoo.cn [Department of Applied Mathematics, Northwestern Polytechnical University, Xi' an, 710072 (China); Xu, Wei; Sun, Chunyan; Wang, Liang [Department of Applied Mathematics, Northwestern Polytechnical University, Xi' an, 710072 (China)

    2012-04-30

    We investigate the phenomenon that stochastic fluctuation induced the competition between tumor extinction and recurrence in the model of tumor growth derived from the catalytic Michaelis–Menten reaction. We analyze the probability transitions between the extinction state and the state of the stable tumor by the Mean First Extinction Time (MFET) and Mean First Return Time (MFRT). It is found that the positional fluctuations hinder the transition, but the environmental fluctuations, to a certain level, facilitate the tumor extinction. The observed behavior could be used as prior information for the treatment of cancer. -- Highlights: ► Stochastic fluctuation induced the competition between extinction and recurrence. ► The probability transitions are investigated. ► The positional fluctuations hinder the transition. ► The environmental fluctuations, to a certain level, facilitate the tumor extinction. ► The observed behavior can be used as prior information for the treatment of cancer.

  3. Stochastic fluctuation induced the competition between extinction and recurrence in a model of tumor growth

    International Nuclear Information System (INIS)

    We investigate the phenomenon that stochastic fluctuation induced the competition between tumor extinction and recurrence in the model of tumor growth derived from the catalytic Michaelis–Menten reaction. We analyze the probability transitions between the extinction state and the state of the stable tumor by the Mean First Extinction Time (MFET) and Mean First Return Time (MFRT). It is found that the positional fluctuations hinder the transition, but the environmental fluctuations, to a certain level, facilitate the tumor extinction. The observed behavior could be used as prior information for the treatment of cancer. -- Highlights: ► Stochastic fluctuation induced the competition between extinction and recurrence. ► The probability transitions are investigated. ► The positional fluctuations hinder the transition. ► The environmental fluctuations, to a certain level, facilitate the tumor extinction. ► The observed behavior can be used as prior information for the treatment of cancer.

  4. Hypoxia-inducible factor 1α promotes primary tumor growth and tumor-initiating cell activity in breast cancer

    OpenAIRE

    Schwab, Luciana P; Peacock, Danielle L.; Majumdar, Debeshi; Ingels, Jesse F; Jensen, Laura C; Smith, Keisha D; Cushing, Richard C; Seagroves, Tiffany N

    2012-01-01

    Introduction Overexpression of the oxygen-responsive transcription factor hypoxia-inducible factor 1α (HIF-1α) correlates with poor prognosis in breast cancer patients. The mouse mammary tumor virus polyoma virus middle T (MMTV-PyMT) mouse is a widely utilized preclinical mouse model that resembles human luminal breast cancer and is highly metastatic. Prior studies in which the PyMT model was used demonstrated that HIF-1α is essential to promoting carcinoma onset and lung metastasis, although...

  5. The influence of septal lesions on sodium and water retention induced by Walker 256 tumor

    Directory of Open Access Journals (Sweden)

    F. Guimarães

    1999-03-01

    Full Text Available In the course of studies on the effects of septal area lesions on neuroimmunomodulation and Walker 256 tumor development, it was observed that tumor-induced sodium and water retention was less marked in lesioned than in non-lesioned rats. In the present study possible mechanisms involved in this phenomenon were investigated. The experiments were performed in septal-lesioned (LW; N = 15 and sham-operated (SW; N = 7 8-week-old male Wistar rats, which received multifocal simultaneous subcutaneous (sc inoculations of Walker 256 tumor cells about 30 days after the stereotaxic surgery. Control groups (no tumor, sham-operated food-restricted (SFR, N = 7 and lesioned food-restricted (LFR, N = 10 were subjected to a feeding pattern similar to that observed in tumor-bearing animals. Multifocal inoculation of Walker 256 tumor rapidly induces anorexia, which is paradoxically accompanied by an increase in body weight, as a result of renal Na+ and fluid retention. These effects of the tumor were also seen in LW rats, although the rise in fractional sodium balance during the early clinical period was significantly smaller than in SW rats (day 4: SW = 47.6 ± 6.4% and LW = 13.8 ± 5.2%; day 5: SW = 57.5 ± 3.5% and LW = 25.7 ± 4.8%; day 6: SW = 54.4 ± 3.8% and LW = 32.1 ± 4.4%; P<0.05, suggesting a temporary reduction in tumor-induced sodium retention. In contrast, urine output was significantly reduced in SW rats and increased in LW rats (LW up to -0.85 and SW up to 4.5 ml/100 g body weight, with no change in osmolar excretion. These temporary changes in the tumor's effects on LW rats may reflect a "reversal" of the secondary central antidiuretic response induced by the tumor (from antidiuretic to diuretic.

  6. Studies on apoptosis in bone tumor cells induced by 153Sm

    Institute of Scientific and Technical Information of China (English)

    ZHU Shou-Peng; XIAO Dong; HAN Xiao-Feng

    2004-01-01

    The apoptosis in human bone tumor cells induced by internal irradiation with 153Sm was studied. The morphological changes in bone tumor cells were observed by electronic and fluorescent microscopy, as well as DNA agarose gel eletrophoresis. DNA chain fragmentation, microautoradiographic tracing and the inhibition rate of proliferation in bone tumor cells exposed to 153Sm with different duration time were examined. It was demonstrated that the bone tumor cells exposed to 153Sm displayed nuclear fragmentation, pyknosis, margination of condensed chromatin, and formation of membrane bounded apoptotic bodies, whereas the percentage of DNA chain fragmentation of bone tumor cells increases in direct proportion to the duration of irradiation with 153Sm, as well as DNA ladder formation in apoptotic cells. Also a marked inhibition effect of proliferation in bone tumor cells after exposure with 153Sm was observed.

  7. Studies on apoptosis in bone tumor cells induced by 153Sm

    International Nuclear Information System (INIS)

    The apoptosis in human bone tumor cells induced by internal irradiation with 153Sm was studied. The morphological changes in bone tumor cells were observed by electronic and fluorescent microscopy, as well as DNA agarose gel electrophoresis. DNA chain fragmentation, microautoradiographic tracing and the inhibition rate of proliferation in bone tumor cells exposed to 153Sm with different duration time were examined. It was demonstrated that the bone tumor cells exposed to 153Sm displayed nuclear fragmentation, pyknosis, margination of condensed chromatin, and formation of membrane bounded apoptotic bodies, whereas the percentage of DNA chain fragmentation of bone tumor cells increases in direct proportion to the duration of irradiation with 153Sm, as well as DNA ladder formation in apoptotic cells. Also a marked inhibition effect of proliferation in bone tumor cells after exposure with 153Sm was observed. (authors)

  8. Production of Nitric Oxide and Expression of Inducible Nitric Oxide Synthase in Ovarian Cystic Tumors

    Directory of Open Access Journals (Sweden)

    Rosekeila Simões Nomelini

    2008-01-01

    Full Text Available Tumor sections from nonneoplastic (n=15, benign (n=28, and malignant ovarian tumors (n=20 were obtained from 63 women. Immunohistochemistry of the tumor sections demonstrated that inducible nitric oxide synthase (iNOS expression was increased in ovarian cancer samples compared to nonneoplastic or benign tumor samples. Using the Griess method, nitric oxide (NO metabolite levels were also found to be elevated in malignant tumor samples compared to benign tumor samples (P80 μM were more frequent than NO levels <80 μM, and iNOS expression in well-differentiated carcinomas was greater than in moderately/poorly differentiated carcinomas (P<.05. These data suggest an important role for NO in ovarian carcinogenesis.

  9. Galectin-3 disruption impaired tumoral angiogenesis by reducing VEGF secretion from TGFβ1-induced macrophages

    International Nuclear Information System (INIS)

    In order to study the role of galectin-3 in tumor angiogenesis associated with tumor-associated macrophages (TAM) and tumor parenchyma, the galectin-3 expression was reconstituted in Tm1 melanoma cell line that lacks this protein. Galectin-3-expressing cells (Tm1G3) and mock-vector transfected cells (Tm1N3) were injected into wild-type (WT) and galectin-3 knockout (KO) C57Bl/6 mice. Tumors originated from Tm1G3 were larger in tumor volume with enlarged functional vessels, decreased necrotic areas, and increased vascular endothelial growth factor (VEGF) protein levels. Galectin-3-nonexpressing-cells injected into WT and KO showed increased levels of transforming growth factor beta 1 (TGFβ1) and, in WT animals this feature was also accompanied by increased VEGFR2 expression and its phosphorylation. In KO animals, tumors derived from galectin-3-expressing cells were infiltrated by CD68+-cells, whereas in tumors derived from galectin-3-nonexpressing-cells, CD68+ cells failed to infiltrate tumors and accumulated in the periphery of the tumor mass. In vitro studies showed that Tm1G3 secreted more VEGF than Tm1N3 cells. In the latter case, TGFβ1 induced VEGF production. Basal secretion of VEGF was higher in WT-bone marrow-derived macrophages (BMDM) than in KO-BMDM. TGFβ1 induced secretion of VEGF only in WT-BMDM. Tm1G3-induced tumors had the Arginase I mRNA increased, which upregulated alternative macrophage (M2)/TAM induction. M2 stimuli, such as interleukin-4 (IL4) and TGFβ1, increased Arginase I protein levels and galectin-3 expression in WT- BMDM, but not in cells from KO mice. Hence, we report that galectin-3 disruption in tumor stroma and parenchyma decreases angiogenesis through interfering with the responses of macrophages to the interdependent VEGF and TGFβ1 signaling pathways

  10. Failure of the cultivated mushroom (Agaricus bisporus) to induce tumors in the A/J mouse lung tumor model

    DEFF Research Database (Denmark)

    Pilegaard, Kirsten; Kristiansen, E.; Meyer, Otto A.;

    1997-01-01

    We studied whether the cultivated mushroom (Agaricus bisporus) or 4-(carboxy)phenylhydrazine (CP) induce lung adenomas in the A/J mouse lung tumor model. For 26 weeks female mice were fed a semisynthetic diet where 11 or 22% of the diet was replaced by freeze-dried mushrooms. The intake...... of the mushroom diets was equivalent to an intake of agaritine, the major phenylhydrazine derivative occurring in the mushroom, of 92 or 166 mg/kg body weight per day. The intake of CP was 106 mg/kg body weight per day. Neither the;freeze-dried mushroom nor CP induced statistically significant increased numbers...

  11. Apoptosis induced by norcantharidin in human tumor cells

    Institute of Scientific and Technical Information of China (English)

    Zhen Xiao Sun; Qing Wen Ma; Tian De Zhao; Yu Lin Wei; Guang Sheng Wang; Jia Shi Li

    2000-01-01

    @@INTRODUCTION The antitumor activity of norcantharidin (NCTD),the demethylated analogue of cantharidin, was studied in the early 1980s in China. NCTD has no side effects on urinary organs which cantharidin has shown and is easier to synthesize, and it can inhibit the proliferation of several tumor cell lines as well as transplanted tumors. Clinical trials with NCTD as a monotherapeutic agent indicated that NCTD had beneficial effects in patients with different kinds of digestive tract cancers, such as primary hepatoma,carcinomas of esophagus and gastric cancer, but no depressive effect on bone marrow cells. NCTD can increase the white blood cell count by stimulating the bone marrow and has some antagonistic effect against leukopenia caused by other agents. The exact cellular and molecular mechanisms of NCTD on tumor cells have not yet been elucidated to date[1-3].

  12. Histological type of Thorotrast-induced liver tumors associated with the translocation of deposited radionuclides

    International Nuclear Information System (INIS)

    Exposure to internally deposited radionuclides is known to induce malignant tumors of various histological types. Thorotrast, a colloidal suspension of radioactive Thorium dioxide (232ThO2) that emits alpha-particles, was used as a radiographic contrast during World War II. Thorotrast is known to induce liver tumors, particularly intrahepatic cholangiocarcinoma (ICC) and angiosarcoma (AS), decades after injection. Therefore, patients injected with Thorotrast comprise a suitable study group to understand biological effects of internal ionizing radiation injury. Autoradiography and X-ray fluorescence spectrometry (XRF) were carried out on non-tumorous liver sections from Thorotrast-induced ICC (T-ICC) and Thorotrast-induced AS (T-AS). Autoradiography revealed that the slope of the regression line of the number of alpha tracks for the amount of deposited Thorium (232Th) was higher in non-tumorous parts of the liver with T-ICC than those with T-AS. XRF showed that the intensity ratio of Radium (Ra) to Thorium (Th) in non-tumorous liver tissue with T-ICC was significantly higher than that with T-AS. Furthermore, the mean 228Ra/232Th radioactivity ratio at the time of death calculated was also significantly higher in T-ICC cases than in T-AS cases. These suggest that the metabolic behavior of radionuclides such as relocation and excretion, as well as the content of deposited radionuclides, is a major factor in determining the histological type of Thorotrast-induced liver tumors. (author)

  13. Metastasis-inducing S100A4 and RANTES cooperate in promoting tumor progression in mice.

    Directory of Open Access Journals (Sweden)

    Birgitte Forst

    Full Text Available BACKGROUND: The tumor microenvironment has been described as a critical milieu determining tumor growth and metastases. A pivotal role of metastasis-inducing S100A4 in the development of tumor stroma has been proven in animal models and verified in human breast cancer biopsies. Expression and release of S100A4 has been shown in various types of stroma composing cells, including fibroblasts and immune cells. However, the events implicated in upstream and downstream pathways regulating the activity of the extracellular S100A4 protein in the tumor milieu remain unsolved. METHODOLOGY/PRINCIPAL FINDINGS: We studied the interplay between the tumor cell-derived cytokine regulated-upon-activation, normal T-cell expressed and secreted (RANTES; CCL5 and S100A4 which were shown to be critical factors in tumor progression. We found that RANTES stimulates the externalization of S100A4 via microparticle shedding from the plasma membrane of tumor and stroma cells. Conversely, the released S100A4 protein induces the upregulation of fibronectin (FN in fibroblasts and a number of cytokines, including RANTES in tumor cells as well as stimulates cell motility in a wound healing assay. Importantly, using wild type and S100A4-deficient mouse models, we demonstrated a substantial influence of tumor cell-derived RANTES on S100A4 release into blood circulation which ultimately increases the metastatic burden in mice. CONCLUSIONS/SIGNIFICANCE: Altogether, the data presented strongly validate the pro-metastatic function of S100A4 in the tumor microenvironment and define how the tumor cell-derived cytokine RANTES acts as a critical regulator of S100A4-dependent tumor cell dissemination. Additionally, for the first time we demonstrated the mechanism of S100A4 release associated with plasma membrane microparticle shedding from various cells types.

  14. Immunotherapy-induced CD8+ T Cells Instigate Immune Suppression in the Tumor

    Science.gov (United States)

    McGray, A J Robert; Hallett, Robin; Bernard, Dannie; Swift, Stephanie L; Zhu, Ziqiang; Teoderascu, Florentina; VanSeggelen, Heather; Hassell, John A; Hurwitz, Arthur A; Wan, Yonghong; Bramson, Jonathan L

    2014-01-01

    Despite clear evidence of immunogenicity, cancer vaccines only provide a modest clinical benefit. To evaluate the mechanisms that limit tumor regression following vaccination, we have investigated the weak efficacy of a highly immunogenic experimental vaccine using a murine melanoma model. We discovered that the tumor adapts rapidly to the immune attack instigated by tumor-specific CD8+ T cells in the first few days following vaccination, resulting in the upregulation of a complex set of biological networks, including multiple immunosuppressive processes. This rapid adaptation acts to prevent sustained local immune attack, despite continued infiltration by increasing numbers of tumor-specific T cells. Combining vaccination with adoptive transfer of tumor-specific T cells produced complete regression of the treated tumors but did not prevent the adaptive immunosuppression. In fact, the adaptive immunosuppressive pathways were more highly induced in regressing tumors, commensurate with the enhanced level of immune attack. Examination of tumor infiltrating T-cell functionality revealed that the adaptive immunosuppression leads to a progressive loss in T-cell function, even in tumors that are regressing. These novel observations that T cells produced by therapeutic intervention can instigate a rapid adaptive immunosuppressive response within the tumor have important implications for clinical implementation of immunotherapies. PMID:24196579

  15. Tumor necrosis factor-alpha induced enhancement of cryosurgery

    Science.gov (United States)

    Goel, Raghav; Paciotti, Guilio F.; Bischof, John C.

    2008-02-01

    Local recurrence of cancer after cryosurgery is related to the inability to monitor and predict destruction of cancer (temperatures > -40°C) within an iceball. We previously reported that a cytokine adjuvant TNF-α could be used to achieve complete cancer destruction at the periphery of an iceball (0 to -40°C). This study is a further development of that work in which cryosurgery was performed using cryoprobes operating at temperatures > -40°C. LNCaP Pro 5 tumor grown in a dorsal skin fold chamber (DSFC) was frozen at -6°C after TNF-α incubation for 4 or 24 hours. Tumors grown in the hind limb were frozen with a probe tip temperature of -40°C, 4 or 24 hours after systemic injection with TNF-α. Both cryosurgery alone or TNF-α treatment alone caused only a minimal damage to the tumor tissue at the conditions used in the study. The combination of TNF-α and cryosurgery produced a significant damage to the tumor tissue in both the DSFC and the hind limb model system. This augmentation in cryoinjury was found to be time-dependent with 4-hour time period between the two treatments being more effective than 24-hour. These results suggests the possibility of cryotreatment at temperatures > -40°C with the administration of TNF-α.

  16. HPMA Copolymer-Bound Doxorubicin Induces Immunogenic Tumor Cell Death

    Czech Academy of Sciences Publication Activity Database

    Šírová, Milada; Kabešová, Martina; Kovář, Lubomír; Etrych, Tomáš; Strohalm, Jiří; Ulbrich, Karel; Říhová, Blanka

    2013-01-01

    Roč. 20, č. 38 (2013), s. 4815-4826. ISSN 0929-8673 R&D Projects: GA ČR GAP301/12/1254 Institutional support: RVO:61388971 ; RVO:61389013 Keywords : Anti-tumor immune response * calreticulin * heat shock proteins Subject RIV: CE - Biochemistry Impact factor: 3.715, year: 2013

  17. Hypoxia Induced Tumor Metabolic Switch Contributes to Pancreatic Cancer Aggressiveness

    International Nuclear Information System (INIS)

    Pancreatic ductal adenocarcinoma remains one of the most lethal of all solid tumors with an overall five-year survival rate of only 3–5%. Its aggressive biology and resistance to conventional and targeted therapeutic agents lead to a typical clinical presentation of incurable disease once diagnosed. The disease is characterized by the presence of a dense stroma of fibroblasts and inflammatory cells, termed desmoplasia, which limits the oxygen diffusion in the organ, creating a strong hypoxic environment within the tumor. In this review, we argue that hypoxia is responsible for the highly aggressive and metastatic characteristics of this tumor and drives pancreatic cancer cells to oncogenic and metabolic changes facilitating their proliferation. However, the molecular changes leading to metabolic adaptations of pancreatic cancer cells remain unclear. Cachexia is a hallmark of this disease and illustrates that this cancer is a real metabolic disease. Hence, this tumor must harbor metabolic pathways which are probably tied in a complex inter-organ dialog during the development of this cancer. Such a hypothesis would better explain how under fuel source limitation, pancreatic cancer cells are maintained, show a growth advantage, and develop metastasis

  18. Roles of interleukin-1 and tumor necrosis factor in lipopolysaccharide-induced hypoglycemia.

    OpenAIRE

    Vogel, S N; Henricson, B E; Neta, R

    1991-01-01

    In this study, hypoglycemia induced by injection of lipopolysaccharide (LPS) or the recombinant cytokine interleukin-1 alpha or tumor necrosis factor alpha (administered alone or in combination) was compared. LPS-induced hypoglycemia was reversed significantly by recombinant interleukin-1 receptor antagonist.

  19. Elevated epidermal growth factor receptor binding in plutonium-induced lung tumors from dogs

    International Nuclear Information System (INIS)

    The objective of this study is to examine and characterize epidermal growth factor receptor (EGF-R) binding in inhaled plutonium-induced canine lung-tumor tissue and to compare it with that in normal canine lung tissue. Crude membrane preparations from normal and lung-tumor tissue from beagle dogs were examined in a radioreceptor assay, using 125I-labeled epidermal growth factor (EGF) as a ligand. Specific EGF receptor binding was determined in the presence of excess unlabeled EGF. We have examined EGF receptor binding in eight lung-tumor samples obtained from six dogs. Epidermal growth factor receptor binding was significantly greater in lung-tumor samples (31.38%) compared with that in normal lung tissue (3.76%). Scatchard plot analysis from the displacement assay revealed that there was no statistical difference in the binding affinity but significantly higher concentration of EGF-R sites in the lung-tumor tissue (619 fmol/mg) than in normal lung tissue (53 fmol/mg). The increase in EGF-R number in plutonium-induced dog lung tumors does not seem to correlate with increase in the initial lung burden exposure to plutonium. Our results demonstrate that there is a significant increase in EGF-R binding in inhaled plutonium-induced dog lung tumors

  20. TGF-β in jaw tumor fluids induces RANKL expression in stromal fibroblasts

    Science.gov (United States)

    Yamada, Chiaki; Aikawa, Tomonao; Okuno, Emi; Miyagawa, Kazuaki; Amano, Katsuhiko; Takahata, Sosuke; Kimata, Masaaki; Okura, Masaya; Iida, Seiji; Kogo, Mikihiko

    2016-01-01

    Odontogenic tumors and cysts, arising in the jawbones, grow by resorption and destruction of the jawbones. However, mechanisms underlying bone resorption by odontogenic tumors/cysts remain unclear. Odontogenic tumors/cysts comprise odontogenic epithelial cells and stromal fibroblasts, which originate from the developing tooth germ. It has been demonstrated that odontogenic epithelial cells of the developing tooth germ induce osteoclastogenesis to prevent the tooth germ from invading the developing bone to maintain its structure in developing bones. Thus, we hypothesized that odontogenic epithelial cells of odontogenic tumors/cysts induce osteoclast formation, which plays potential roles in tumor/cyst outgrowth into the jawbone. The purpose of this study was to examine osteoclastogenesis by cytokines, focusing on transforming growth factor-β (TGF-β), produced by odontogenic epithelial cells. We observed two pathways for receptor activator of NF-κB ligand (RANKL) induction by keratocystic odontogenic tumor fluid: the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway through interleukin-1α (IL-1α) signaling and non-COX-2/PGE2 pathway through TGF-β receptor signaling. TGF-β1 and IL-1α produced by odontogenic tumors/cysts induced osteoclastogenesis directly in the osteoclast precursor cells and indirectly via increased RANKL induction in the stroma. PMID:27279422

  1. Study of radiation-induced tumors in the Ohita Prefectural Hospital

    International Nuclear Information System (INIS)

    An epidemiological study on radiation induced tumor was carried out in the Ohita Prefectural Hospital in 1989. Radiation induced tumors were chosen among 62,831 surgical or biopsy specimens examined since 1968 to 1988. These tumors were defined as following conditions such as having a history of radiation therapy, occurring in the same field of irradiation, and having a latent period over five years. Total of eleven malignant tumors were selected with the average age of 64.2 years old, and the average latency of 16.4 years. All of them were female and seven cases belonged to A-1 group according to the reliability classification. The first tumor was all malignant and consisted of 9 uterus cancers and one rectal cancer. The second tumor included three rectal cancers, three vaginal cancers, two ureto-bladder cancers, one uterine body cancer, and one lymphangiosarcoma. Histological study showed poorly differentiated adenocarcinoma in two rectal cancers in which this type was unusual as rectal cancer. Others were common histological types identical to the location. Delayed effects of irradiation was confirmed in a background of some tumors. For instance, marked fibrosis, atypical fibroblast, and thickening of blood vessel were nominated. Total amount of irradiation ranged form 24 to 92 grey, and the year of irradiation concentrated in 1969 to 1973 (75%) and the year of discovery concentrated in 1983 to 1988 (75%). This study suggested the necessity of further investigation in other medical institutions and accumulation of the tumors. (author)

  2. Nanovectorized radiotherapy, a new strategy to induce anti-tumor immunity

    Directory of Open Access Journals (Sweden)

    ClaireVanpouille-Box

    2012-10-01

    Full Text Available Recent experimental findings show that activation of the host immune system is required for the success of chemo- and radio-therapy. However, clinically-apparent tumors have already developed multiple mechanisms to escape anti-tumor immunity. The fact that tumors are able to induce a state of tolerance and immunosuppression is a major obstacle in immunotherapy. Hence, there is an overwhelming need to develop new strategies that overcome this state of immune tolerance and induce an anti-tumor immune response both at primary and metastatic sites. Nanovectorized radiotherapy that combines ionizing radiation and nano-devices, is one strategy that could boost the quality and magnitude of an immune response in a predictable and designable fashion. The potential benefits of this emerging treatment may be based on the unique combination of immuno-stimulatory properties of nanoparticles with the ability of ionizing radiation to induce immunogenic tumor cell death. In this review, we will discuss available data and propose that the nanovectorized radiotherapy could be a powerful new strategy to induce anti-tumor immunity required for positive patient outcome.

  3. Potent inhibition of tumoral hypoxia-inducible factor 1α by albendazole

    Directory of Open Access Journals (Sweden)

    Poruchynsky Marianne S

    2010-04-01

    Full Text Available Abstract Background Emerging reports suggest resistance, increased tumor invasiveness and metastasis arising from treatment with drugs targeting vascular endothelial growth factor (VEGF. It is believed that increased tumoral hypoxia plays a prominent role in the development of these phenomena. Inhibition of tumoral hypoxia inducible factor (HIF-1α is thus becoming an increasingly attractive therapeutic target in the treatment of cancer. We hypothesized that the anti-VEGF effect of albendazole (ABZ could be mediated through inhibition of tumoral HIF-1α. Method In vitro, the effects of ABZ on HIF-1α levels in human ovarian cancer cells (OVCAR-3 were investigated using hypoxic chamber or desferrioxamine (DFO induced-hypoxia. In vivo, the effects of ABZ (150 mg/kg, i.p., single dose on the tumor levels of HIF-1α and VEGF protein and mRNA were investigated by western blotting, RT-PCR and real time-PCR. Results In vitro, ABZ inhibited cellular HIF-1α protein accumulation resulting from placement of cells under hypoxic chamber or exposure to DFO. In vivo, tumors excised from vehicle treated mice showed high levels of both HIF-1α and VEGF. Whereas, tumoral HIF-1α and VEGF protein levels were highly suppressed in ABZ treated mice. Tumoral VEGFmRNA (but not HIF-1αmRNA was also found to be highly suppressed by ABZ. Conclusion These results demonstrate for the first time the effects of an acute dose of ABZ in profoundly suppressing both HIF-1α and VEGF within the tumor. This dual inhibition may provide additional value in inhibiting angiogenesis and be at least partially effective in inhibiting tumoral HIF-1α surge, tumor invasiveness and metastasis.

  4. Equine estrogen-induced mammary tumors in rats

    OpenAIRE

    Okamoto, Yoshinori; Liu, Xiaoping; Suzuki, Naomi; OKAMOTO, KANAKO; Kim, Hyo Jeong; Santosh Laxmi, Y. R.; Sayama, Kazutoshi; Shibutani, Shinya

    2010-01-01

    Long-term hormone replacement therapy is associated with an increased risk of breast, ovarian and endometrial cancers in women. Equine estrogens are a principal component of hormone replacement therapy; however, their tumorigenic potential toward mammary tissue and reproductive organs has not been extensively explored. A pellet containing equilin was inserted under the skin of female ACI rats and the development of mammary tumors was monitored. Histological examination revealed premalignant l...

  5. Guanine nucleotide regulation of dopamine receptor agonist affinity states in rat estradiol-induced pituitary tumors

    Energy Technology Data Exchange (ETDEWEB)

    Di Paolo, T.; Falardeau, P.

    1987-08-31

    The authors have investigated dopamine (DA) receptor agonist high- and low-affinity states in female rate estradiol-induced prolactin (PRL)-secreting pituitary tumors and intact pituitary tissue. Estradiol treatment increased the anterior pituitary weight 9-fold and plasma prolactin levels 74-fold and these measures are correlated (R = 0.745, n = 73, p < 0.001). Competition for (/sup 3/H)-spiperone binding to the DA receptor by apomorphine was compared in normal and adenomatous pituitary tissue. The inhibition constants (Ki) and the proportions of the two apomorphine sites are unchanged in tumors compared to intact pituitary tissue. Guanosine 5'-(..beta..-..gamma..-imino)triphosphate (Gpp(NH)p) causes complete conversion of the high into low affinity dopaminergic agonist site in normal pituitary and in tumors. These results suggest that rats with primary estradiol-induced pituitary tumors have normal and functional DA receptors. 9 references, 2 tables.

  6. Guanine nucleotide regulation of dopamine receptor agonist affinity states in rat estradiol-induced pituitary tumors

    International Nuclear Information System (INIS)

    The authors have investigated dopamine (DA) receptor agonist high- and low-affinity states in female rate estradiol-induced prolactin (PRL)-secreting pituitary tumors and intact pituitary tissue. Estradiol treatment increased the anterior pituitary weight 9-fold and plasma prolactin levels 74-fold and these measures are correlated (R = 0.745, n = 73, p 3H]-spiperone binding to the DA receptor by apomorphine was compared in normal and adenomatous pituitary tissue. The inhibition constants (Ki) and the proportions of the two apomorphine sites are unchanged in tumors compared to intact pituitary tissue. Guanosine 5'-[β-γ-imino]triphosphate (Gpp(NH)p) causes complete conversion of the high into low affinity dopaminergic agonist site in normal pituitary and in tumors. These results suggest that rats with primary estradiol-induced pituitary tumors have normal and functional DA receptors. 9 references, 2 tables

  7. Dysfunction of Murine Dendritic Cells Induced by Incubation with Tumor Cells

    Institute of Scientific and Technical Information of China (English)

    Fengguang Gao; Xin Hui; Xianghuo He; Dafang Wan; Jianren Gu

    2008-01-01

    In vivo studies showed that dendritic cell (DC) dysfunction occurred in tumor microcnvironment. As tumors were composed of many kinds of cells, the direct effects of tumor cells on immature DCs (imDCs) are needed for further studies in vitro. In the present study, bone marrow-derived imDCs were incubated with lymphoma, hepatoma and menaloma cells in vitro and surface molecules in imDCs were determined by flow cytometry. Then, imDCs incubated with tumor cells or control imDCs were further pulsed with tumor lysates and then incubated with splenocytes to perform mixed lymphocyte reaction. The DC-dependent tumor antigen-specific T cell proliferation,and IL-12 secretion were determined by flow cytometry, and enzyme-linked immunosorbent assay respectively.Finally, the DC-dependent tumor-associated antigen-specific CTL was determined by enzyme-linked immunospot assay. The results showed that tumor cell-DC incubation down-regulated the surface molecules in imDCs, such as CD80, CD54, CDllb, CD11a and MHC class Ⅱ molecules. The abilities of DC-dependent antigen-specific T cell proliferation and IL-12 secretion were also decreased by tumor cell incubation in vitro. Most importantly, the ability for antigenic-specific CTL priming of DCs was also decreased by incubation with tumor cells. In the present in vitro study demonstrated that the defective abilities of DCs induced by tumor cell co-incubation and the co-incubation system might be useful for future study of tumor-immune cells direct interaction and for drug screen of immune-modulation.

  8. Intratumoral administration of dendritic cells combined with hyperthermia induces both local and systemic antitumor effect in murine tumor models

    International Nuclear Information System (INIS)

    We examined whether intratumoral (i.t.) administration of dendritic cells (DCs) into a treated tumor could induce local and systemic antitumor effects in a mouse tumor model. C57BL/6 mice were inoculated s.c in the right and left thighs with MCA-102 fibrosarcoma cells on day 0 and on day 7, respectively. On day 7, the tumors (usually 6 mm in diameter) on the right thigh were heated by immersing the tumor-bearing leg in a circulating water bath at 43 .deg. C for 30 min; thereafter, the immature DCs were i.t. administered to the right thigh tumors. This immunization procedure was repeated on days 7, 14 and 21. The tumors in both the right and left thighs were measured every 7 days and the average sizes were determined by applying the following formula, tumor size = 0.5 x (length + width). Cytotoxicity assay was done to determine tumor-specific cytotoxic T-lymphocyte activity. Hyperthermia induced apoptosis and heat shock proteins (HSPs) in tumor occurred maximally after 6 hr. For the local treated tumor, Hyperthermia (HT) alone inhibited tumor growth compared with the untreated tumors (ρ < 0.05), and furthermore, the i.t. administered DCs combined with hyperthermia (HT + DCs) additively inhibited tumor growth compared with HT alone (ρ < 0.05). On the distant untreated tumor, HT alone significantly inhibited tumor growth (ρ < 0.05), and also HT + DCs potently inhibited tumor growth (ρ < 0.001); however, compared with HT alone, the difference was not statistically significant. In addition, HT + DCs induced strong cytotoxicity of the splenocytes against tumor cells compared to DCs or HT alone. HT + DCs induced apoptosis and increased the expression of HSPs, and so this induced a potent local and systemic antitumor response in tumor-bearing mice. This regimen may be beneficial for the treatment of human cancers

  9. Vaccination with Necroptotic Cancer Cells Induces Efficient Anti-tumor Immunity

    OpenAIRE

    Aaes, Tania Løve; Kaczmarek, Agnieszka; Delvaeye, Tinneke; De Craene, Bram; De Koker, Stefaan; Heyndrickx, Liesbeth; Delrue, Iris; Taminau, Joachim; Wiernicki, Bartosz; De Groote, Philippe; Garg, Abhishek; Leybaert, Luc; Grooten, Johan; Bertrand, Mathieu J. M.; Agostinis, Patrizia

    2016-01-01

    Successful immunogenic apoptosis in experimental cancer therapy depends on the induction of strong host anti-tumor responses. Given that tumors are often resistant to apoptosis, it is important to identify alternative molecular mechanisms that elicit immunogenic cell death. We have developed a genetic model in which direct dimerization of FADD combined with inducible expression of RIPK3 promotes necroptosis. We report that necroptotic cancer cells release damage-associated molecular patterns ...

  10. [Role of HIF-induced EMT in invasion and
metastasis of tumor].

    Science.gov (United States)

    Chen, Yang; Shi, Yan; Dai, Guanghai

    2016-08-01

    Hypoxia plays a vital role in tumor metabolism, proliferation, apoptosis, invasion and metastasis via hypoxia-inducible factor (HIF). Epithelial to mesenchymal transition (EMT) is a crucial process to metastasis, which could be triggered by hypoxia. EMT could be regulated by HIF via multiple pathways including TGF-β, Notch, and Wnt/β-catenin. It has been shown that anti-HIF drugs combined with anti-EMT therapies could be a promising strategy for tumor therapy. PMID:27600018

  11. Pulmonary tumor thrombotic microangiopathy induced by gastric carcinoma: Morphometric and immunohistochemical analysis of six autopsy cases

    OpenAIRE

    Shinozaki Minoru; Sasai Daisuke; Hiruta Nobuyuki; Abe Fumihito; Yokose Tomoyuki; Nemoto Tetsuo; Kitahara Kanako; Wakayama Megumi; Okubo Yoichiro; Nakayama Haruo; Ishiwatari Takao; Shibuya Kazutoshi

    2011-01-01

    Abstract Background Pulmonary tumor thrombotic microangiopathy (PTTM) has been known as a rare and serious cancer-related pulmonary complication. However, the pathogenesis and pathophysiology of this debilitating condition still remains obscure and no effective management was recommended. The present study aims to elucidate the pathophysiology of PTTM. Methods Autopsy records were searched to extract cases of pulmonary tumor embolism induced by metastasis of gastric carcinoma in the Toho Univ...

  12. TRAIL-induced programmed necrosis as a novel approach to eliminate tumor cells

    International Nuclear Information System (INIS)

    The cytokine TRAIL represents one of the most promising candidates for the apoptotic elimination of tumor cells, either alone or in combination therapies. However, its efficacy is often limited by intrinsic or acquired resistance of tumor cells to apoptosis. Programmed necrosis is an alternative, molecularly distinct mode of programmed cell death that is elicited by TRAIL under conditions when the classical apoptosis machinery fails or is actively inhibited. The potential of TRAIL-induced programmed necrosis in tumor therapy is, however, almost completely uncharacterized. We therefore investigated its impact on a panel of tumor cell lines of wide-ranging origin. Cell death/viability was measured by flow cytometry/determination of intracellular ATP levels/crystal violet staining. Cell surface expression of TRAIL receptors was detected by flow cytometry, expression of proteins by Western blot. Ceramide levels were quantified by high-performance thin layer chromatography and densitometric analysis, clonogenic survival of cells was determined by crystal violet staining or by soft agarose cloning. TRAIL-induced programmed necrosis killed eight out of 14 tumor cell lines. Clonogenic survival was reduced in all sensitive and even one resistant cell lines tested. TRAIL synergized with chemotherapeutics in killing tumor cell lines by programmed necrosis, enhancing their effect in eight out of 10 tested tumor cell lines and in 41 out of 80 chemotherapeutic/TRAIL combinations. Susceptibility/resistance of the investigated tumor cell lines to programmed necrosis seems to primarily depend on expression of the pro-necrotic kinase RIPK3 rather than the related kinase RIPK1 or cell surface expression of TRAIL receptors. Furthermore, interference with production of the lipid ceramide protected all tested tumor cell lines. Our study provides evidence that TRAIL-induced programmed necrosis represents a feasible approach for the elimination of tumor cells, and that this treatment may

  13. Atm-haploinsufficiency enhances susceptibility to carcinogen-induced mammary tumors.

    OpenAIRE

    Lu, Shu; Shen, Kate; Wang, Yaolin; Santner, Steven J.; Chen, Jie; Brooks, S. C.; Wang, Y. Alan

    2006-01-01

    Biomarkers of exposure & effect:: validationBiomarker: A-T carriersExposure/effect represented: DMBAStudy type (in vitro, animals, humans): Atm male miceMode of exposure (if in vivo) (acute, chronic, root of exposure): administration by oral gavageMethod of analysis: PCRDose-response: Nearly twice as many Atm heterozygotes developed mammary tumors (64.7%) as the wild-type mice (37.5%). RR for DMBA-induced mammary tumors is 1.7 for Atm heterozygotesAtm heterozygotes developed mammary tumors wi...

  14. CCL11-induced eosinophils inhibit the formation of blood vessels and cause tumor necrosis.

    Science.gov (United States)

    Xing, Yanjiang; Tian, Yijun; Kurosawa, Takamasa; Matsui, Sayaka; Touma, Maki; Yanai, Takanori; Wu, Qiong; Sugimoto, Kenkichi

    2016-06-01

    We previously demonstrated that IL-18 and CCL11 were highly expressed in an NFSA tumor cell line that showed limited angiogenesis and severe necrosis. However, IL-18 was not responsible for the immune cell accumulation and necrosis. Here, we attempted to clarify the relevance of CCL11 in angiogenesis and tumor formation. We established CCL11-overexpressing MS-K cell clones (MS-K-CCL11) to assess the role of CCL11 in immune cell accumulation and angiogenesis. The MS-K-CCL11 cells did not form tumors in mice. MS-K-CCL11-conditioned medium (CM) and recombinant CCL11 induced macrophage and eosinophil differentiation from bone marrow cells. The MS-K-CCL11-CM effectively recruited the differentiated eosinophils. Furthermore, the eosinophils damaged the MS-K, NFSA and endothelial cells in a dose-dependent manner. Administration of an antagonist of CCR3, a CCL11 receptor, to NFSA tumor-bearing mice restored the blood vessel formation and blocked the eosinophil infiltration into the NFSA tumors. Furthermore, other CCL11-overexpressing LM8 clones were established, and their tumor formation ability was reduced compared to the parental LM8 cells, accompanied by increased eosinophil infiltration, blockade of angiogenesis and necrosis. These results indicate that CCL11 was responsible for the limited angiogenesis and necrosis by inducing and attracting eosinophils in the tumors. PMID:27169545

  15. Macrophage inflammatory protein-2 contributes to liver resection-induced acceleration of hepatic metastatic tumor growth

    Institute of Scientific and Technical Information of China (English)

    Otto Kollmar; Michael D Menger; Martin K Schilling

    2006-01-01

    AIM: To study the role of macrophage inflammatory protein (MIP)-2 in liver resection-induced acceleration of tumor growth in a mouse model of hepatic metastasis.METHODS: After a 50% hepatectomy, 1×105 CT26.WT cells were implanted into the left liver lobe of syngeneic balb/c mice (PHx). Additional animals were treated with a monoclonal antibody (MAB452) neutralizing MIP-2(PHx+mAB). Non-resected and non-mAB-treated mice (Con) served as controls. After 7 d, tumor angiogenesis and microcirculation as well as cell proliferation, tumor growth, and CXCR-2 expression were analyzed using intravital fluorescence microscopy, histology, immunohistochemistry, and flow cytometry.RESULTS: Partial hepatectomy increased (P<0.05) the expression of the MIP-2 receptor CXCR-2 on tumor cells when compared with non-resected controls, and markedly accelerated (P<0.05) angiogenesis and metastatic tumor growth. Neutralization of MIP-2 by MAB452 treatment significantly (P<0.05) depressed CXCR-2 expression. Further, the blockade of MIP-2 reduced the angiogenic response (P<0.05) and inhibited tumor growth (P< 0.05). Of interest, liver resection-induced hepatocyte proliferation was not effected by anti-MIP-2 treatment.CONCLUSION: MIP-2 significantly contributes to liver resection-induced acceleration of colorectal CT26.WT hepatic metastasis growth.

  16. Attenuated recombinant vaccinia virus expressing oncofetal antigen (tumor-associated antigen) 5T4 induces active therapy of established tumors.

    Science.gov (United States)

    Mulryan, Kate; Ryan, Matthew G; Myers, Kevin A; Shaw, David; Wang, Who; Kingsman, Susan M; Stern, Peter L; Carroll, Miles W

    2002-10-01

    The human oncofetal antigen 5T4 (h5T4) is a transmembrane glycoprotein overexpressed by a wide spectrum of cancers, including colorectal, ovarian, and gastric, but with a limited normal tissue expression. Such properties make 5T4 an excellent putative target for cancer immunotherapy. The murine homologue of 5T4 (m5T4) has been cloned and characterized, which allows for the evaluation of immune intervention strategies in "self-antigen" in vivo tumor models. We have constructed recombinant vaccinia viruses based on the highly attenuated and modified vaccinia virus ankara (MVA strain), expressing h5T4 (MVA-h5T4), m5T4 (MVA-m5T4), and Escherichia coli LacZ (MVA-LacZ). Immunization of BALB/c and C57BL/6 mice with MVA-h5T4 and MVA-m5T4 constructs induced antibody responses to human and mouse 5T4, respectively. C57BL/6 and BALB/c mice vaccinated with MVA-h5T4 were challenged with syngeneic tumor line transfectants, B16 melanoma, and CT26 colorectal cells that express h5T4. MVA-h5T4-vaccinated mice showed significant tumor retardation compared with mice vaccinated with MVA-LacZ or PBS. In active treatment studies, inoculation with MVA-h5T4 was able to treat established CT26-h5T4 lung tumor and to a lesser extent B16.h5T4 s.c. tumors. Additionally, when C57BL/6 mice vaccinated with MVA-m5T4 were challenged with B16 cells expressing m5T4, resulting growth of the tumors was significantly retarded compared with control animals. Furthermore, mice vaccinated with MVA-m5T4 showed no signs of autoimmune toxicity. These data support the use of MVA-5T4 for tumor immunotherapy. PMID:12481437

  17. Hypoxia-Inducible Factor Pathway Inhibition Resolves Tumor Hypoxia and Improves Local Tumor Control After Single-Dose Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Helbig, Linda [OncoRay–National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Koi, Lydia [OncoRay–National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Deutsches Konsortium für Translationale Krebsforschung, Site Dresden, Dresden (Germany); Brüchner, Kerstin [Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Institute of Radiooncology Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany); Gurtner, Kristin [Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Hess-Stumpp, Holger; Unterschemmann, Kerstin [Global Drug Discovery, Bayer Pharma, Berlin (Germany); Pruschy, Martin [Radiation Oncology, University of Zurich, Zurich (Switzerland); and others

    2014-01-01

    Purpose: To study the effects of BAY-84-7296, a novel orally bioavailable inhibitor of mitochondrial complex I and hypoxia-inducible factor 1 (HIF-1) activity, on hypoxia, microenvironment, and radiation response of tumors. Methods and Materials: UT-SCC-5 and UT-SCC-14 human squamous cell carcinomas were transplanted subcutaneously in nude mice. When tumors reached 4 mm in diameter BAY-84-7296 (Bayer Pharma AG) or carrier was daily administered to the animals. At 7 mm tumors were either excised for Western blot and immunohistologic investigations or were irradiated with single doses. After irradiation animals were randomized to receive BAY-84-7296 maintenance or carrier. Local tumor control was evaluated 150 days after irradiation, and the dose to control 50% of tumors (TCD{sub 50}) was calculated. Results: BAY-84-7296 decreased nuclear HIF-1α expression. Daily administration of inhibitor for approximately 2 weeks resulted in a marked decrease of pimonidazole hypoxic fraction in UT-SCC-5 (0.5% vs 21%, P<.0001) and in UT-SCC-14 (0.3% vs 19%, P<.0001). This decrease was accompanied by a significant increase in fraction of perfused vessels in UT-SCC-14 but not in UT-SCC-5. Bromodeoxyuridine and Ki67 labeling indices were significantly reduced only in UT-SCC-5. No significant changes were observed in vascular area or necrosis. BAY-84-7296 before single-dose irradiation significantly decreased TCD{sub 50}, with an enhancement ratio of 1.37 (95% confidence interval [CI] 1.13-1.72) in UT-SCC-5 and of 1.55 (95% CI 1.26-1.94) in UT-SCC-14. BAY-84-7296 maintenance after irradiation did not further decrease TCD{sub 50}. Conclusions: BAY-84-7296 resulted in a marked decrease in tumor hypoxia and substantially reduced radioresistance of tumor cells with the capacity to cause a local recurrence after irradiation. The data suggest that reduction of cellular hypoxia tolerance by BAY-84-7296 may represent the primary biological mechanism underlying the observed enhancement of

  18. Cyclin D expression in plutonium-induced lung tumors in F344 rats

    Energy Technology Data Exchange (ETDEWEB)

    Hahn, F.F.; Kelly, G. [SouthWest Scientific Resources, Inc., Albuquerque, NM (United States)

    1995-12-01

    The genetic mechanisms responsible for {alpha}-radiation-induced lung cancer in rats following inhalation of {sup 239}Pu is an ongoing area of research in our laboratory. Previous studies have examined the status of the p53 gene by immunohistochemistry. Only two tumors (2/26 squamous cell carcinomas) exhibited detectable levels of p53 products. Both were the result of mutations in codons 280 and 283. More recent studies of X-ray-induced lung tumors in rats showed a similar lack of involvement of p53. In conclusion, we found that {alpha}-radiation-induced rat lung tumors have a high incidence (31 of 39) of cyclin D{sub 1} overexpression.

  19. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells

    Science.gov (United States)

    Gallina, Giovanna; Dolcetti, Luigi; Serafini, Paolo; Santo, Carmela De; Marigo, Ilaria; Colombo, Mario P.; Basso, Giuseppe; Brombacher, Frank; Borrello, Ivan; Zanovello, Paola; Bicciato, Silvio; Bronte, Vincenzo

    2006-01-01

    Active suppression of tumor-specific T lymphocytes can limit the efficacy of immune surveillance and immunotherapy. While tumor-recruited CD11b+ myeloid cells are known mediators of tumor-associated immune dysfunction, the true nature of these suppressive cells and the fine biochemical pathways governing their immunosuppressive activity remain elusive. Here we describe a population of circulating CD11b+IL-4 receptor α+ (CD11b+IL-4Rα+), inflammatory-type monocytes that is elicited by growing tumors and activated by IFN-γ released from T lymphocytes. CD11b+IL-4Rα+ cells produced IL-13 and IFN-γ and integrated the downstream signals of these cytokines to trigger the molecular pathways suppressing antigen-activated CD8+ T lymphocytes. Analogous immunosuppressive circuits were active in CD11b+ cells present within the tumor microenvironment. These suppressor cells challenge the current idea that tumor-conditioned immunosuppressive monocytes/macrophages are alternatively activated. Moreover, our data show how the inflammatory response elicited by tumors had detrimental effects on the adaptive immune system and suggest novel approaches for the treatment of tumor-induced immune dysfunctions. PMID:17016559

  20. Immunohistochemical Study Effects of Spirulina Algae on the Induced Mammary Tumor in Rats

    International Nuclear Information System (INIS)

    This work aimed at investigating the protective effects of Spirulina platensis on the induced mammary tumor in rats by dimethylbenz(a)anthracene (DMBA) and the proliferation of the tumor cells by using immunohistochemical staining for proliferating cell nuclear antigen (PCNA). At 50 days of age, group 1 remained untreated, group 2 treated with 2% Spirulina platenesis in food, group 3 received 50 mg/kg DMBA i.p. groupe 4 received 50 mg/kg DMBA i.p and fed on 2% spirulina. Rats were killed when the largest mammary tumor reached 1-2 cm in diameter or after 6 months of animal>s age. All the tumors produced by DMBA were ductal carcinoma in 100% of group 3, but in group 4 two rats had mammary tumor. The groups 1 and 2 had no tumor and have the same histological and immunostaining features, but in group 4, 13/15 rats had no tumor except formation of some cysts and hyperplasia in epithelial cells. The conclusion of this work suggests that Spirulina platnesis could be considered as a chemotherapeutic agent that causes apoptosis to tumor cells by reducing the number of malignant cells and resists cancer formation. (author)

  1. Depletion of tumor associated macrophages slows the growth of chemically-induced mouse lung adenocarcinomas

    Directory of Open Access Journals (Sweden)

    Jason M. Fritz

    2014-11-01

    Full Text Available Chronic inflammation is a risk factor for lung cancer, and low dose aspirin intake reduces lung cancer risk. However, the roles that specific inflammatory cells and their products play in lung carcinogenesis have yet to be fully elucidated. In mice, alveolar macrophage numbers increase as lung tumors progress, and pulmonary macrophage programming changes within 2 weeks of carcinogen exposure. To examine how macrophages specifically affect lung tumor progression, they were depleted in mice bearing urethane-induced lung tumors using clodronate-encapsulated liposomes. Alveolar macrophage populations decreased to ≤ 50% of control levels after 4-6 weeks of liposomal clodronate treatment. Tumor burden decreased by 50% compared to vehicle treated mice, and tumor cell proliferation, as measured by Ki67 staining, was also attenuated. Pulmonary fluid levels of IGF-I, CXCL1, IL-6 and CCL2 diminished with clodronate liposome treatment. Tumor associated macrophages expressed markers of both M1 and M2 programming in vehicle and clodronate liposome treated mice. Mice lacking CCR2 (the receptor for macrophage chemotactic factor CCL2 had comparable numbers of alveolar macrophages and showed no difference in tumor growth rates when compared to similarly treated wild-type mice suggesting that while CCL2 may recruit macrophages to lung tumor microenvironments, redundant pathways can compensate when CCL2/CCR2 signaling is inactivated. Depletion of pulmonary macrophages rather than inhibition of their recruitment may be an advantageous strategy for attenuating lung cancer progression.

  2. Chemoprevention with Acetylsalicylic Acid, Vitamin D and Calcium Reduces Risk of Carcinogen-induced Lung Tumors

    DEFF Research Database (Denmark)

    Pommergaard, Hans-Christian; Burcharth, Jakob; Rosenberg, J; Raskov, Hans

    2013-01-01

    Background/Aim: Research has shown that chemoprevention may be effective against the development of lung cancer. The purpose of the present study was to evaluate the effect of oral chemoprevention in a mouse model of tobacco carcinogen-induced lung tumor.......Background/Aim: Research has shown that chemoprevention may be effective against the development of lung cancer. The purpose of the present study was to evaluate the effect of oral chemoprevention in a mouse model of tobacco carcinogen-induced lung tumor....

  3. Tumors induce coordinate growth of artery, vein, and lymphatic vessel triads

    International Nuclear Information System (INIS)

    Tumors drive blood vessel growth to obtain oxygen and nutrients to support tumor expansion, and they also can induce lymphatic vessel growth to facilitate fluid drainage and metastasis. These processes have generally been studied separately, so that it is not known how peritumoral blood and lymphatic vessels grow relative to each other. The murine B16-F10 melanoma and chemically-induced squamous cell carcinoma models were employed to analyze large red-colored vessels growing between flank tumors and draining lymph nodes. Immunostaining and microscopy in combination with dye injection studies were used to characterize these vessels. Each peritumoral red-colored vessel was found to consist of a triad of collecting lymphatic vessel, vein, and artery, that were all enlarged. Peritumoral veins and arteries were both functional, as detected by intravenous dye injection. The enlarged lymphatic vessels were functional in most mice by subcutaneous dye injection assay, however tumor growth sometimes blocked lymph drainage to regional lymph nodes. Large red-colored vessels also grew between benign papillomas or invasive squamous cell carcinomas and regional lymph nodes in chemical carcinogen-treated mice. Immunostaining of the red-colored vessels again identified the clustered growth of enlarged collecting lymphatics, veins, and arteries in the vicinity of these spontaneously arising tumors. Implanted and spontaneously arising tumors induce coordinate growth of blood and lymphatic vessel triads. Many of these vessel triads are enlarged over several cm distance between the tumor and regional lymph nodes. Lymphatic drainage was sometimes blocked in mice before lymph node metastasis was detected, suggesting that an unknown mechanism alters lymph drainage patterns before tumors reach draining lymph nodes

  4. Ionizing radiation induces tumor cell lysyl oxidase secretion

    DEFF Research Database (Denmark)

    Shen, Colette J; Sharma, Ashish; Vuong, Dinh-Van;

    2014-01-01

    BACKGROUND: Ionizing radiation (IR) is a mainstay of cancer therapy, but irradiation can at times also lead to stress responses, which counteract IR-induced cytotoxicity. IR also triggers cellular secretion of vascular endothelial growth factor, transforming growth factor beta and matrix metallop......BACKGROUND: Ionizing radiation (IR) is a mainstay of cancer therapy, but irradiation can at times also lead to stress responses, which counteract IR-induced cytotoxicity. IR also triggers cellular secretion of vascular endothelial growth factor, transforming growth factor beta and matrix...

  5. TRIADIMEFON INDUCES RAT THYROID TUMORS THROUGH A NON-TSH MEDIATED MODE OF ACTION

    Science.gov (United States)

    Conazoles are a class of fungicides used as agricultural and pharmaceutical products which inhibit ergosterol biosynthesis. Members of this class are hepatotoxic and cause mouse hepatocellular tumors and/or rat thyroid follicular cell tumors. Triadimefon-induced rat thyroid tumor...

  6. H-2 restriction of the T cell response to chemically induced tumors: evidence from F1 → parent chimeras

    International Nuclear Information System (INIS)

    It has been well established that T cells that react to tumor antigen on virus-induced tumors must share H-2D or H-2K specificities with the tumor. It has been impossible to perform similar studies with chemically induced tumors because each chemically induced tumor expresses a unique tumor antigen that cannot be studied in association with other H-2 types. This study provies evidence that H-2 recognition is also necessary for recognition of chemically induced tumors. We have found that F1 → parent chimeras preferentially recognize chemically induced tumors of parental H-2 type. C3H/HeJ and C57BL/6 mice were lethally irradiated and restored with (C3H x C57BL/6) F1 hybrid bone marrow. The F1 → C3H chimera but not the F1 → C57BL/6 chimera was able to respond to a C3H fibrosarcoma in mixed lymphocyte-tumor cell culture and also to neutralize the tumor in an in vivo tumor neutralization assay. On the other hand, the F1 → C57BL/6 chimera but not the F1 → C3H chimera was able to kill the C57BL/6 lymphoma EL4 in an in vitro cytotoxicity assay. Both chimeras were tolerant to C3H and C57BL/6 alloantigens but could respond normally to Con A and to BALB/c spleen cells in mixed lymphocyte cultures and cytotoxicity assay

  7. Identification and localization of transformed cells in agrobacterium tumefaciens-induced plant tumors

    Science.gov (United States)

    Rezmer; Schlichting; Wachter; Ullrich

    1999-10-01

    Agrobacterium tumefaciens-induced tumors of dicotyledonous plants consist of well-defined vascular bundle-like structures originating from transformed cells. The current view that 25% of the tumor cells are transformed has been re-investigated by using beta-glucuronidase (gus)-gene-containing wild-type bacteria (A281 p35S gus-int). Regularly growing stem and leaf tumors showed irregular GUS-staining patterns in the different plant species, Ricinus communis L., Cucurbita maxima L., Vicia faba L. and Kalanchoe daigremontiana Hamet et Perrier. Variable staining and inconsistency between staining and tumor growth suggested an inhibition of gus expression. By polymerase chain reaction (PCR) and reverse transcriptase-PCR analyses it became evident that gus is also integrated into the DNA of unstainable tumor parts but not expressed. These results and area calculations of tissues unable to contain the bacterial transferred-DNA with gus provide strong evidence that in A. tumefaciens-induced tumors most cells, or even all, are transformed, i.e. ca. 100%. PMID:10550620

  8. Pyruvate induces transient tumor hypoxia by enhancing mitochondrial oxygen consumption and potentiates the anti-tumor effect of a hypoxia-activated prodrug TH-302.

    Directory of Open Access Journals (Sweden)

    Yoichi Takakusagi

    Full Text Available BACKGROUND: TH-302 is a hypoxia-activated prodrug (HAP of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302. METHODOLOGY/RESULTS: The hypoxia-dependent cytotoxicity of TH-302 was evaluated by a viability assay in murine SCCVII and human HT29 cells. Modulation in cellular oxygen consumption and in vivo tumor oxygenation by the pyruvate treatment was monitored by extracellular flux analysis and electron paramagnetic resonance (EPR oxygen imaging, respectively. The enhancement of the anti-tumor effect of TH-302 by pyruvate treatment was evaluated by monitoring the growth suppression of the tumor xenografts inoculated subcutaneously in mice. TH-302 preferentially inhibited the growth of both SCCVII and HT29 cells under hypoxic conditions (0.1% O2, with minimal effect under aerobic conditions (21% O2. Basal oxygen consumption rates increased after the pyruvate treatment in SCCVII cells in a concentration-dependent manner, suggesting that pyruvate enhances the mitochondrial respiration to consume excess cellular oxygen. In vivo EPR oxygen imaging showed that the intravenous administration of pyruvate globally induced the transient hypoxia 30 min after the injection in SCCVII and HT29 tumors at the size of 500-1500 mm(3. Pretreatment of SCCVII tumor bearing mice with pyruvate 30 min prior to TH-302 administration, initiated with small tumors (∼ 550 mm(3, significantly delayed tumor growth. CONCLUSIONS/SIGNIFICANCE: Our in vitro and in vivo studies showed that pyruvate induces transient hypoxia by enhancing mitochondrial oxygen consumption in tumor cells. TH-302 therapy can be potentiated by pyruvate pretreatment if started at the

  9. Second primary tumor and radiation induced neoplasma in the uterine cancer

    Energy Technology Data Exchange (ETDEWEB)

    Sakurai, Tomoyasu; Nishio, Masamichi; Kagami, Yoshikazu; Murakami, Yoshitaka; Narimatsu, Naoto; Kanemoto, Toshitaka (National Hospital of Sapporo (Japan))

    1984-09-01

    This report is concerned with multiple primary cancers developing in invasive uterine cancer. Second primary tumors were recorded 27 women with a total of 30 non-uterine cancer (exception of radiation-induced cancer). 17 patients of radiation-induced neoplasm were observed (Rectal cancer 4, soft part sarcoma 4, cancer of urinary bladder 3, bone tumor 3, uterin cancer 2 and cancer of Vulva 1). One case is 4 legions (corpus, sigma, thymoma and stomach), 2 cases are 3 lesions (uterine cervix, stomach and maxillay siuis: uterine cervix, thyroidal gland and radiation-induced soft part sarcoma). Only 5 of these 17 patients were known irradiated dose (50 Gy--55 Gy), however others unknown. The mean latent periods of 17 cases of radiation induced neoplasms are 19.4 years. 16 patients of late second cancers of the cervix appearing from 11 to 36 years (average 19.5 years) after initial radiotherapy were recorded.

  10. Role of Acid Sphingomyelinase-Induced Signaling in Melanoma Cells for Hematogenous Tumor Metastasis

    Directory of Open Access Journals (Sweden)

    Alexander Carpinteiro

    2016-01-01

    Full Text Available Background: Hematogenous metastasis of malignant tumor cells is a multistep process that requires release of tumor cells from the local tumor mass, interaction of the tumor cells with platelets in the blood, and adhesion of either the activated tumor cells or the complexes of platelets and tumor cells to the endothelial cells of the target organ. We have previously shown that the interaction of melanoma cells with platelets results in the release of acid sphingomyelinase (Asm from activated platelets. Secreted platelet-derived Asm acts on malignant tumor cells to cluster and activate integrins; such clustering and activation are necessary for tumor cell adhesion to endothelial cells and for metastasis. Methods: We examined the response of tumor cells to treatment with extracellular sphingomyelinase or co-incubation with wild-type and Asm-deficient platelets. We determined the phosphorylation and activation of several intracellular signaling molecules, in particular p38 kinase (p38K, phospholipase Cγ (PLCγ, ezrin, and extracellular signal-regulated kinases. Results: Incubation of B16F10 melanoma cells with Asm activates p38 MAP kinase (p38K, phospholipase Cγ (PLCγ, ezrin, and extracellular signal-regulated kinases. Co-incubation of B16F10 melanoma cells with wild-type or Asm-deficient platelets showed that the phosphorylation/activation of p38K is dependent on Asm. Pharmacological blockade of p38K prevents activation of β1 integrin and adhesion in vitro. Most importantly, inhibition of p38K activity in B16F10 melanoma cells prevents tumor cell adhesion and metastasis to the lung in vivo, a finding indicating the importance of p38K for metastasis. Conclusions: Asm, secreted from activated platelets after tumor cell-platelet contact, induces p38K phosphorylation in tumor cells. This in turn stimulates β1 integrin activation that is necessary for adhesion and subsequent metastasis of tumor cells. Thus, inhibition of p38K might be a novel

  11. Inhibition of autophagy stimulate molecular iodine-induced apoptosis in hormone independent breast tumors

    International Nuclear Information System (INIS)

    Highlights: ► Molecular iodine (I2) causes non-apoptotic cell death in MDA-MB231 breast tumor cells. ► Autophagy is activated as a survival mechanism in response to I2 in MDA-MB231. ► Autophagy inhibition sensitizes tumor cells to I2-induced apoptotic cell death. ► Autophagy inhibitor potentiates apoptosis and tumor regressive effects of I2 in mice. -- Abstract: Estrogen receptor negative (ER−ve) and p53 mutant breast tumors are highly aggressive and have fewer treatment options. Previously, we showed that molecular Iodine (I2) induces apoptosis in hormone responsive MCF-7 breast cancer cells, and non-apoptotic cell death in ER−ve–p53 mutant MDA-MB231 cells (Shrivastava, 2006). Here we show that I2 (3 μM) treatment enhanced the features of autophagy in MDA-MB231 cells. Since autophagy is a cell survival response to most anti-cancer therapies, we used both in vitro and in vivo systems to determine whether ER−ve mammary tumors could be sensitized to I2-induced apoptosis by inhibiting autophagy. Autophagy inhibition with chloroquine (CQ) and inhibitors for PI3K (3MA, LY294002) and H+/ATPase (baflomycin) resulted in enhanced cell death in I2 treated MDA-MB231 cells. Further, CQ (20 μM) in combination with I2, showed apoptotic features such as increased sub-G1 fraction (∼5-fold), expression of cleaved caspase-9 and -3 compared to I2 treatment alone. Flowcytometry of I2 and CQ co-treated cells revealed increase in mitochondrial membrane permeability (p 2 treatment. For in vivo studies ICRC mice were transplanted subcutaneously with MMTV-induced mammary tumors. A significant reduction in tumor volumes, as measured by MRI, was found in I2 and CQ co-treated mice relative to I2 or vehicle treated mice. These data indicate that inhibition of autophagy renders ER−ve breast tumor cells more sensitive to I2 induced apoptosis. Thus, I2 together with autophagy inhibitor could have a potential tumorostatic role in ER−ve aggressive breast tumors that may be

  12. Fluctuations induced extinction and stochastic resonance effect in a model of tumor growth with periodic treatment

    International Nuclear Information System (INIS)

    We investigate a stochastic model of tumor growth derived from the catalytic Michaelis-Menten reaction with positional and environmental fluctuations under subthreshold periodic treatment. Firstly, the influences of environmental fluctuations on the treatable stage are analyzed numerically. Applying the standard theory of stochastic resonance derived from the two-state approach, we derive the signal-to-noise ratio (SNR) analytically, which is used to measure the stochastic resonance phenomenon. It is found that the weak environmental fluctuations could induce the extinction of tumor cells in the subthreshold periodic treatment. The positional stability is better in favor of the treatment of the tumor cells. Besides, the appropriate and feasible treatment intensity and the treatment cycle should be highlighted considered in the treatment of tumor cells.

  13. Fluctuations induced extinction and stochastic resonance effect in a model of tumor growth with periodic treatment

    Energy Technology Data Exchange (ETDEWEB)

    Li Dongxi, E-mail: lidongxi@mail.nwpu.edu.c [Department of Applied Mathematics, Northwestern Polytechnical University, Xi' an 710072 (China); Xu Wei; Guo, Yongfeng; Xu Yong [Department of Applied Mathematics, Northwestern Polytechnical University, Xi' an 710072 (China)

    2011-01-31

    We investigate a stochastic model of tumor growth derived from the catalytic Michaelis-Menten reaction with positional and environmental fluctuations under subthreshold periodic treatment. Firstly, the influences of environmental fluctuations on the treatable stage are analyzed numerically. Applying the standard theory of stochastic resonance derived from the two-state approach, we derive the signal-to-noise ratio (SNR) analytically, which is used to measure the stochastic resonance phenomenon. It is found that the weak environmental fluctuations could induce the extinction of tumor cells in the subthreshold periodic treatment. The positional stability is better in favor of the treatment of the tumor cells. Besides, the appropriate and feasible treatment intensity and the treatment cycle should be highlighted considered in the treatment of tumor cells.

  14. Pulmonary Tumor Thrombotic Microangiopathy Induced by Ureteral Carcinoma: A Necropsy Case Report

    OpenAIRE

    Marumo, Satoshi; Sakaguchi, Masahiro; TERANISHI, TAKASHI; HIGAMI, YUICHI; Koshimo, Yoshiyuki; Kato, Motokazu

    2014-01-01

    Background Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal cancer-related pulmonary complication with rapidly progressing dyspnea and pulmonary hypertension that occasionally induces sudden death. We report the first case of PTTM induced by ureter carcinoma. Case Presentation The patient was an 80-year-old Japanese female with chief complaints of dry cough and dyspnea. An echocardiogram revealed severe pulmonary hypertension. A chest radiograph showed ground glass opacity of bila...

  15. Severe hypoxia induces chemo-resistance in clinical cervical tumors through MVP over-expression

    International Nuclear Information System (INIS)

    Oxygen molecule modulates tumour response to radiotherapy. Higher radiation doses are required under hypoxic conditions to induce cell death. Hypoxia may inhibit the non-homologous end-joining DNA repair through down regulating Ku70/80 expression. Hypoxia induces drug resistance in clinical tumours, although the mechanism is not clearly elucidated. Vaults are ribonucleoprotein particles with a hollow barrel-like structure composed of three proteins: major vault protein (MVP), vault poly(ADP-ribose) polymerase, and telomerase associated protein-1 and small untranslated RNA. Over-expression of MVP has been associated with chemotherapy resistance. Also, it has been related to poor outcome in patients treated with radiotherapy alone. The aim of the present study was to assess the relation of Major Vault Protein expression and tumor hypoxia in clinical cervical tumors. MVP, p53 and angiogenesis, together with tumor oxygenation, were determined in forty-three consecutive patients suffering from localized cervix carcinoma. High MVP expression was related to severe hypoxia compared to low MVP expressing tumors (p = 0.022). Tumors over-expressing MVP also showed increased angiogenesis (p = 0.003). Besides it, in this study we show for the first time that severe tumor hypoxia is associated with high MVP expression in clinical cervical tumors. Up-regulation of MVP by hypoxia is of critical relevance as chemotherapy is currently a standard treatment for those patients. From our results it could be suggested that hypoxia not only induces increased genetic instability, oncogenic properties and metastatization, but through the correlation observed with MVP expression, another pathway of chemo and radiation resistance could be developed

  16. Severe hypoxia induces chemo-resistance in clinical cervical tumors through MVP over-expression.

    Science.gov (United States)

    Lara, Pedro C; Lloret, Marta; Clavo, Bernardino; Apolinario, Rosa M; Henríquez-Hernández, Luis Alberto; Bordón, Elisa; Fontes, Fausto; Rey, Agustín

    2009-01-01

    Oxygen molecule modulates tumour response to radiotherapy. Higher radiation doses are required under hypoxic conditions to induce cell death. Hypoxia may inhibit the non-homologous end-joining DNA repair through down regulating Ku70/80 expression. Hypoxia induces drug resistance in clinical tumours, although the mechanism is not clearly elucidated. Vaults are ribonucleoprotein particles with a hollow barrel-like structure composed of three proteins: major vault protein (MVP), vault poly(ADP-ribose) polymerase, and telomerase associated protein-1 and small untranslated RNA. Over-expression of MVP has been associated with chemotherapy resistance. Also, it has been related to poor outcome in patients treated with radiotherapy alone. The aim of the present study was to assess the relation of Major Vault Protein expression and tumor hypoxia in clinical cervical tumors. MVP, p53 and angiogenesis, together with tumor oxygenation, were determined in forty-three consecutive patients suffering from localized cervix carcinoma. High MVP expression was related to severe hypoxia compared to low MVP expressing tumors (p = 0.022). Tumors over-expressing MVP also showed increased angiogenesis (p = 0.003). Besides it, in this study we show for the first time that severe tumor hypoxia is associated with high MVP expression in clinical cervical tumors. Up-regulation of MVP by hypoxia is of critical relevance as chemotherapy is currently a standard treatment for those patients. From our results it could be suggested that hypoxia not only induces increased genetic instability, oncogenic properties and metastatization, but through the correlation observed with MVP expression, another pathway of chemo and radiation resistance could be developed. PMID:19660100

  17. Severe hypoxia induces chemo-resistance in clinical cervical tumors through MVP over-expression

    Directory of Open Access Journals (Sweden)

    Apolinario Rosa M

    2009-08-01

    Full Text Available Abstract Oxygen molecule modulates tumour response to radiotherapy. Higher radiation doses are required under hypoxic conditions to induce cell death. Hypoxia may inhibit the non-homologous end-joining DNA repair through down regulating Ku70/80 expression. Hypoxia induces drug resistance in clinical tumours, although the mechanism is not clearly elucidated. Vaults are ribonucleoprotein particles with a hollow barrel-like structure composed of three proteins: major vault protein (MVP, vault poly(ADP-ribose polymerase, and telomerase associated protein-1 and small untranslated RNA. Over-expression of MVP has been associated with chemotherapy resistance. Also, it has been related to poor outcome in patients treated with radiotherapy alone. The aim of the present study was to assess the relation of Major Vault Protein expression and tumor hypoxia in clinical cervical tumors. MVP, p53 and angiogenesis, together with tumor oxygenation, were determined in forty-three consecutive patients suffering from localized cervix carcinoma. High MVP expression was related to severe hypoxia compared to low MVP expressing tumors (p = 0.022. Tumors over-expressing MVP also showed increased angiogenesis (p = 0.003. Besides it, in this study we show for the first time that severe tumor hypoxia is associated with high MVP expression in clinical cervical tumors. Up-regulation of MVP by hypoxia is of critical relevance as chemotherapy is currently a standard treatment for those patients. From our results it could be suggested that hypoxia not only induces increased genetic instability, oncogenic properties and metastatization, but through the correlation observed with MVP expression, another pathway of chemo and radiation resistance could be developed.

  18. The phytoestrogenic Cyclopia extract, SM6Met, increases median tumor free survival and reduces tumor mass and volume in chemically induced rat mammary gland carcinogenesis.

    Science.gov (United States)

    Visser, Koch; Zierau, Oliver; Macejová, Dana; Goerl, Florian; Muders, Michael; Baretton, Gustavo B; Vollmer, Günter; Louw, Ann

    2016-10-01

    SM6Met, a phytoestrogenic extract of Cyclopia subternata indigenous to the Western Cape province of South Africa, displays estrogenic attributes with potential for breast cancer chemoprevention. In this study, we report that SM6Met, in the presence of estradiol, induces a significant cell cycle G0/G1 phase arrest similar to the selective estrogen receptor modulator, tamoxifen. Furthermore, as a proof of concept, in the N-Methyl-N-nitrosourea induced rat mammary gland carcinogenesis model, SM6Met increases tumor latency by 7days and median tumor free survival by 42 days, while decreasing palpable tumor frequency by 32%, tumor mass by 40%, and tumor volume by 53%. Therefore, the current study provides proof of concept that SM6Met has definite potential as a chemopreventative agent against the development and progression of breast cancer. PMID:27142456

  19. Correlation of drug-induced sister chromatid exchanges in vitro with in vivo tumor response

    International Nuclear Information System (INIS)

    A spontaneous hepatocarcinoma (HCa) grown in C/sub 3/Hf/Kam mice was used to investigate the ability of the in vitro sister chromatid exchange (SCE) assay to predict in vivo tumor sensitivity to 3 chemotherapeutic agents: melphalan, cis-Platinum, and BCNU. For HCa cells grown in monolayer culture, melphalan was the most efficient at inducing SCEs, followed by cis-Platinum, with BCNU inducing the least. According to in vitro cell survival curves, HCa was most sensitive to melphalan, less sensitive to cis-Platinum, and essentially resistant to BCNU. The relative antineoplastic effects of melphalan, cis-Platinum, and BCNU in vivo were compared by the response of artificial and spontaneous pulmonary metastases and solid tumors to these agents. BCNU had no effect on the number of artificial metastases, while there was a dose-dependent decrease in the number of lung nodules in mice treated with melphalan or cis-Platinum, with melphalan being the more effective. Spontaneous pulmonary metastases generated from HCa leg tumors were reduced in those mice treated with melphalan, unaffected by cis-Platinum, and increased by BCNU. In HCa leg tumors (5 to 6 mm in diameter), melphalan induced the longest growth delay, with cis-Platinum inducing less, and BCNU the least. Thus, the relative effects produced by these 3 drugs in vivo were the same as predicted by SCE assay in vitro

  20. Bromocriptine induces parapoptosis as the main type of cell death responsible for experimental pituitary tumor shrinkage

    International Nuclear Information System (INIS)

    Bromocriptine (Bc) produces pituitary tumoral mass regression which induces the cellular death that was classically described as apoptosis. However, recent works have related that other mechanisms of cell death could also be involved in the maintenance of physiological and pathological pituitary homeostasis. The aim of this study was to evaluate and characterize the different types of cell death in the involution induced by Bc in experimental rat pituitary tumors. The current study demonstrated that Bc induced an effective regression of estrogen induced pituitary tumors by a mechanism identified as parapoptosis. This alternative cell death was ultrastructurally recognized by extensive cytoplasmic vacuolization and an increased cell electron density, represented around 25% of the total pituitary cells counted. Furthermore, the results obtained from biochemical assays did not correspond to the criteria of apoptosis or necrosis. We also investigated the participation of p38, ERK1/2 and PKCδ in the parapoptotic pathway. An important observation was the significant increase in phosphorylated forms of these MAPKs, the holoenzyme and catalytic fragments of PKCδ in nuclear fractions after Bc administration compared to control and estrogen treated rats. Furthermore, the immunolocalization at ultrastructural level of these kinases showed a similar distribution pattern, with a prevalent localization at nuclear level in lactotrophs from Bc treated rats. In summary, we determined that parapoptosis is the predominant cell death type involved in the regression of pituitary tumors in response to Bc treatment, and may cause the activation of PKCδ, ERK1/2 and p38.

  1. Obesity decreases serum selenium levels in DMBA-induced mammary tumor using Obese Zucker Rat Model

    Science.gov (United States)

    Recently, we reported that obese Zucker rats had increased susceptibility to DMBA-induced mammary tumors compared to lean Zucker rats. Several studies suggest that lower serum selenium may play an important role in increasing the risk of several types of cancers (e.g, colon, breast and prostate canc...

  2. Tumor associated macrophages protect colon cancer cells from TRAIL-induced apoptosis through IL-1beta-dependent stabilization of Snail in tumor cells.

    Directory of Open Access Journals (Sweden)

    Pawan Kaler

    Full Text Available BACKGROUND: We recently reported that colon tumor cells stimulate macrophages to release IL-1beta, which in turn inactivates GSK3beta and enhances Wnt signaling in colon cancer cells, generating a self-amplifying loop that promotes the growth of tumor cells. PRINCIPAL FINDINGS: Here we describe that macrophages protect HCT116 and Hke-3 colon cancer cells from TRAIL-induced apoptosis. Inactivation of IL-1beta by neutralizing IL-1beta antibody, or silencing of IL-1beta in macrophages inhibited their ability to counter TRAIL-induced apoptosis. Accordingly, IL-1beta was sufficient to inhibit TRAIL-induced apoptosis. TRAIL-induced collapse of the mitochondrial membrane potential (Delta psi and activation of caspases were prevented by macrophages or by recombinant IL-1beta. Pharmacological inhibition of IL-1beta release from macrophages by vitamin D(3, a potent chemopreventive agent for colorectal cancer, restored the ability of TRAIL to induce apoptosis of tumor cells cultured with macrophages. Macrophages and IL-1beta failed to inhibit TRAIL-induced apoptosis in HCT116 cells expressing dnIkappaB, dnAKT or dnTCF4, confirming that they oppose TRAIL-induced cell death through induction of Wnt signaling in tumor cells. We showed that macrophages and IL-1beta stabilized Snail in tumor cells in an NF-kappaB/Wnt dependent manner and that Snail deficient tumor cells were not protected from TRAIL-induced apoptosis by macrophages or by IL-1beta, demonstrating a crucial role of Snail in the resistance of tumor cells to TRAIL. SIGNIFICANCE: We have identified a positive feedback loop between tumor cells and macrophages that propagates the growth and promotes the survival of colon cancer cells: tumor cells stimulate macrophages to secrete IL-1beta, which in turn, promotes Wnt signaling and stabilizes Snail in tumor cells, conferring resistance to TRAIL. Vitamin D(3 halts this amplifying loop by interfering with the release of IL-1beta from macrophages

  3. Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling

    OpenAIRE

    Vincent, Loïc; Kermani, Pouneh; Young, Lauren M.; Cheng, Joseph; Zhang, Fan; Shido, Koji; Lam, George; Bompais-Vincent, Heidi; Zhu, Zhenping; Hicklin, Daniel J.; Bohlen, Peter; Chaplin, David J.; May, Chad; Rafii, Shahin

    2005-01-01

    The molecular and cellular pathways that support the maintenance and stability of tumor neovessels are not well defined. The efficacy of microtubule-disrupting agents, such as combretastatin A4 phosphate (CA4P), in inducing rapid regression of specific subsets of tumor neovessels has opened up new avenues of research to identify factors that support tumor neoangiogenesis. Herein, we show that CA4P selectively targeted endothelial cells, but not smooth muscle cells, and induced regression of u...

  4. Treatment of injuries induced by radiotherapy of malignant tumors

    International Nuclear Information System (INIS)

    The problems of treatment of delayed and early radiation injuries induced by ionizing radiations therapy of oncologic patients are considered. It is shown that in planning radio therapy its delayed effects sometimes are under-estimated. Changes in blood and lymphatic vessels exposed to irradiation lead to clinical manifestation of the delayed radiation injury. These pathologic processes can aggravate in patients with accompanying changes in endocrine background and different somatic diseases. Timely and intensive treatment of local radiation injuries of different organs and tissues permits to fight successfully with the radiotherapy complications

  5. Cinnamon extract induces tumor cell death through inhibition of NFκB and AP1

    Directory of Open Access Journals (Sweden)

    Lee Sung

    2010-07-01

    Full Text Available Abstract Background Cinnamomum cassia bark is the outer skin of an evergreen tall tree belonging to the family Lauraceae containing several active components such as essential oils (cinnamic aldehyde and cinnamyl aldehyde, tannin, mucus and carbohydrate. They have various biological functions including anti-oxidant, anti-microbial, anti-inflammation, anti-diabetic and anti-tumor activity. Previously, we have reported that anti-cancer effect of cinnamon extracts is associated with modulation of angiogenesis and effector function of CD8+ T cells. In this study, we further identified that anti-tumor effect of cinnamon extracts is also link with enhanced pro-apoptotic activity by inhibiting the activities NFκB and AP1 in mouse melanoma model. Methods Water soluble cinnamon extract was obtained and quality of cinnamon extract was evaluated by HPLC (High Performance Liquid Chromatography analysis. In this study, we tested anti-tumor activity and elucidated action mechanism of cinnamon extract using various types of tumor cell lines including lymphoma, melanoma, cervix cancer and colorectal cancer in vitro and in vivo mouse melanoma model. Results Cinnamon extract strongly inhibited tumor cell proliferation in vitro and induced active cell death of tumor cells by up-regulating pro-apoptotic molecules while inhibiting NFκB and AP1 activity and their target genes such as Bcl-2, BcL-xL and survivin. Oral administration of cinnamon extract in melanoma transplantation model significantly inhibited tumor growth with the same mechanism of action observed in vitro. Conclusion Our study suggests that anti-tumor effect of cinnamon extracts is directly linked with enhanced pro-apoptotic activity and inhibition of NFκB and AP1 activities and their target genes in vitro and in vivo mouse melanoma model. Hence, further elucidation of active components of cinnamon extract could lead to development of potent anti-tumor agent or complementary and alternative

  6. Cinnamon extract induces tumor cell death through inhibition of NFκB and AP1

    International Nuclear Information System (INIS)

    Cinnamomum cassia bark is the outer skin of an evergreen tall tree belonging to the family Lauraceae containing several active components such as essential oils (cinnamic aldehyde and cinnamyl aldehyde), tannin, mucus and carbohydrate. They have various biological functions including anti-oxidant, anti-microbial, anti-inflammation, anti-diabetic and anti-tumor activity. Previously, we have reported that anti-cancer effect of cinnamon extracts is associated with modulation of angiogenesis and effector function of CD8+ T cells. In this study, we further identified that anti-tumor effect of cinnamon extracts is also link with enhanced pro-apoptotic activity by inhibiting the activities NFκB and AP1 in mouse melanoma model. Water soluble cinnamon extract was obtained and quality of cinnamon extract was evaluated by HPLC (High Performance Liquid Chromatography) analysis. In this study, we tested anti-tumor activity and elucidated action mechanism of cinnamon extract using various types of tumor cell lines including lymphoma, melanoma, cervix cancer and colorectal cancer in vitro and in vivo mouse melanoma model. Cinnamon extract strongly inhibited tumor cell proliferation in vitro and induced active cell death of tumor cells by up-regulating pro-apoptotic molecules while inhibiting NFκB and AP1 activity and their target genes such as Bcl-2, BcL-xL and survivin. Oral administration of cinnamon extract in melanoma transplantation model significantly inhibited tumor growth with the same mechanism of action observed in vitro. Our study suggests that anti-tumor effect of cinnamon extracts is directly linked with enhanced pro-apoptotic activity and inhibition of NFκB and AP1 activities and their target genes in vitro and in vivo mouse melanoma model. Hence, further elucidation of active components of cinnamon extract could lead to development of potent anti-tumor agent or complementary and alternative medicine for the treatment of diverse cancers

  7. The microtubule stabilizer patupilone counteracts ionizing radiation-induced matrix metalloproteinase activity and tumor cell invasion

    International Nuclear Information System (INIS)

    Ionizing radiation (IR) in combination with microtubule stabilizing agents (MSA) is a promising combined treatment modality. Supra-additive treatment responses might result from direct tumor cell killing and cooperative indirect, tumor cell-mediated effects on the tumor microenvironment. Here we investigated deregulation of matrix metalloproteinase (MMP) activity, as an important component of the tumor microenvironment, by the combined treatment modality of IR with the clinically relevant MSA patupilone. Expression, secretion and activity of MMPs and related tissue inhibitors of metalloproteinases (TIMPs) were determined in cell extracts and conditioned media derived from human fibrosarcoma HT1080 and human glioblastoma U251 tumor cells in response to treatment with IR and the MSA patupilone. Treatment-dependent changes of the invasive capacities of these tumor cell lines were analysed using a Transwell invasion assay. Control experiments were performed using TIMP-directed siRNA and TIMP-directed inhibitory antibodies. Enzymatic activity of secreted MMPs was determined after treatment with patupilone and irradiation in the human fibrosarcoma HT1080 and the human glioblastoma U251 tumor cell line. IR enhanced the activity of secreted MMPs up to 2-fold and cellular pretreatment with low dose patupilone (0.05-0.2 nM) counteracted specifically the IR-induced MMP activity. The cell invasive capacity of HT1080 and U251 cells was increased after irradiation with 2 Gy by 30% and 50%, respectively, and patupilone treatment completely abrogated IR-induced cell invasion. Patupilone did not alter the level of MMP expression, but interestingly, the protein level of secreted TIMP-1 and TIMP-2 was lower after combined treatment than after irradiation treatment alone. Furthermore, siRNA depletion of TIMP-1 or TIMP-2 prevented IR-mediated induction of MMP activity and cell invasion. These results indicate that patupilone counteracts an IR-induced MMP activation process by the

  8. Involvement of Mouse Constitutive Androstane Receptor in Acifluorfen-Induced Liver Injury and Subsequent Tumor Development.

    Science.gov (United States)

    Kuwata, Kazunori; Inoue, Kaoru; Ichimura, Ryohei; Takahashi, Miwa; Kodama, Yukio; Shibutani, Makoto; Yoshida, Midori

    2016-06-01

    Acifluorfen (ACI), a protoporphyrinogen oxidase (PROTOX) inhibitor herbicide, promotes the accumulation of protoporphyrin IX (PPIX), and induces tumors in the rodent liver. Porphyria is a risk factor for liver tumors in humans; however, the specific mechanisms through which ACI induces hepatocarcinogenesis in rodents are unclear. Here, we investigated the mode of action of ACI-induced hepatocarcinogenesis, focusing on constitutive androstane receptor (CAR, NR1I3), which is essential for the development of rodent liver tumors in response to certain cytochrome P450 (CYP) 2B inducers. Dietary treatment with 2500 ppm ACI for up to 13 weeks increased Cyp2b10 expression in the livers of wild-type (WT) mice, but not in CAR-knockout (CARKO) mice. Microscopically, ACI treatment-induced cytotoxic changes, including hepatocellular necrosis and inflammation, and caused regenerative changes accompanied by prolonged increases in the numbers of proliferating cell nuclear antigen-positive hepatocytes in WT mice. In contrast, these cytotoxic and regenerative changes in hepatocytes were significantly attenuated, but still observed, in CARKO mice. ACI treatment also increased liver PPIX levels similarly in both genotypes; however, no morphological evidence of porphyrin deposition was found in hepatocytes from either genotype. Treatment with 2500 ppm ACI for 26 weeks after initiation with diethylnitrosamine increased the incidence and multiplicities of altered foci and adenomas in hepatocytes from WT mice; these effects were significantly reduced in CARKO mice. These results indicated that prolonged cytotoxicity in the liver was a key factor for ACI-induced hepatocarcinogenesis, and that CAR played an important role in ACI-induced liver injury and tumor development in mice. PMID:26928356

  9. Boswellia sacra essential oil induces tumor cell-specific apoptosis and suppresses tumor aggressiveness in cultured human breast cancer cells

    Directory of Open Access Journals (Sweden)

    Suhail Mahmoud M

    2011-12-01

    Full Text Available Abstract Background Gum resins obtained from trees of the Burseraceae family (Boswellia sp. are important ingredients in incense and perfumes. Extracts prepared from Boswellia sp. gum resins have been shown to possess anti-inflammatory and anti-neoplastic effects. Essential oil prepared by distillation of the gum resin traditionally used for aromatic therapy has also been shown to have tumor cell-specific anti-proliferative and pro-apoptotic activities. The objective of this study was to optimize conditions for preparing Boswellea sacra essential oil with the highest biological activity in inducing tumor cell-specific cytotoxicity and suppressing aggressive tumor phenotypes in human breast cancer cells. Methods Boswellia sacra essential oil was prepared from Omani Hougari grade resins through hydrodistillation at 78 or 100 oC for 12 hours. Chemical compositions were identified by gas chromatography-mass spectrometry; and total boswellic acids contents were quantified by high-performance liquid chromatography. Boswellia sacra essential oil-mediated cell viability and death were studied in established human breast cancer cell lines (T47D, MCF7, MDA-MB-231 and an immortalized normal human breast cell line (MCF10-2A. Apoptosis was assayed by genomic DNA fragmentation. Anti-invasive and anti-multicellular tumor properties were evaluated by cellular network and spheroid formation models, respectively. Western blot analysis was performed to study Boswellia sacra essential oil-regulated proteins involved in apoptosis, signaling pathways, and cell cycle regulation. Results More abundant high molecular weight compounds, including boswellic acids, were present in Boswellia sacra essential oil prepared at 100 oC hydrodistillation. All three human breast cancer cell lines were sensitive to essential oil treatment with reduced cell viability and elevated cell death, whereas the immortalized normal human breast cell line was more resistant to essential oil

  10. Dietary quercetin exacerbates the development of estrogen-induced breast tumors in female ACI rats

    International Nuclear Information System (INIS)

    Phytoestrogens are plant compounds that structurally mimic the endogenous estrogen 17β-estradiol (E2). Despite intense investigation, the net effect of phytoestrogen exposure on the breast remains unclear. The objective of the current study was to examine the effects of quercetin on E2-induced breast cancer in vivo. Female ACI rats were given quercetin (2.5 g/kg food) for 8 months. Animals were monitored weekly for palpable tumors, and at the end of the experiment, rats were euthanized, breast tumor and different tissues excised so that they could be examined for histopathologic changes, estrogen metabolic activity and oxidant stress. Quercetin alone did not induce mammary tumors in female ACI rats. However, in rats implanted with E2 pellets, co-exposure to quercetin did not protect rats from E2-induced breast tumor development with 100% of the animals developing breast tumors within 8 months of treatment. No changes in serum quercetin levels were observed in quercetin and quercetin + E2-treated groups at the end of the experiment. Tumor latency was significantly decreased among rats from the quercetin + E2 group relative to those in the E2 group. Catechol-O-methyltransferase (COMT) activity was significantly downregulated in quercetin-exposed mammary tissue. Analysis of 8-isoprostane F2α (8-iso-PGF2α) levels as a marker of oxidant stress showed that quercetin did not decrease E2-induced oxidant stress. These results indicate that quercetin (2.5 g/kg food) does not confer protection against breast cancer, does not inhibit E2-induced oxidant stress and may exacerbate breast carcinogenesis in E2-treated ACI rats. Inhibition of COMT activity by quercetin may expose breast cells chronically to E2 and catechol estrogens. This would permit longer exposure times to the carcinogenic metabolites of E2 and chronic exposure to oxidant stress as a result of metabolic redox cycling to estrogen metabolites, and thus quercetin may exacerbate E2-induced breast tumors in female

  11. Allelic losses in mouse skin tumors induced by {gamma}-irradiation of p53 heterozygotes

    Energy Technology Data Exchange (ETDEWEB)

    Miyazawa, Tomonori; Sato, Hiroki; Hatakeyama, Katsuyoshi; Kominami, Ryo [Niigata Univ. (Japan). Graduate School of Medical and Dental Sciences; Kitagawa, Tomoyuki [Cancer Inst., Tokyo (Japan)

    2002-09-01

    Skin tumors were induced by {gamma}-irradiation in F{sub 1} mice between C3H/He or BALB/c and MSM carrying a p53-deficient allele. The incidence was 39.1% (34/87) in p53(KO/+) mice of the C3H/MSM genetic background and 14.3% (19/133) in those of the BALB/MSM background. Interestingly, most of the tumors (82%) lost the wild-type p53 allele and no skin tumor was found in p53(+/+) F{sub 1} mice. This suggests a requirement of p53 loss for the skin cancer development. Genome scan localized a chromosomal locus showing frequent allelic losses near D12Mit2, which may harbor a tumor suppressor gene. In addition, 23 loci distributed on 13 chromosomes exhibited allelic losses at frequencies of more than 20%. The genome-wide occurrence of allelic losses suggests that genomic instability of the skin tumors may be implicated in radiation-induced carcinogenesis. The present study is the first to report a mouse model system useful for the analysis of radiation induction of skin cancer in man. (author)

  12. MR-guided laser-induced thermotherapy in recurrent extrahepatic abdominal tumors

    Energy Technology Data Exchange (ETDEWEB)

    Mack, M.G.; Straub, R.; Eichler, K.; Boettger, M.; Woitaschek, D.; Vogl, T.J. [Dept. of Diagnostic and Interventional Radiology, University of Frankfurt (Germany); Roggan, A. [LMTB GmbH, Berlin (Germany)

    2001-10-01

    The aim of this study was to evaluate the feasibility of MR-guided laser-induced thermotherapy (LITT) for treatment of recurrent extrahepatic abdominal tumors. In 11 patients (6 women and 5 men; mean age 53 years, age range 29-67 years) with 14 lesions the following tumors were treated in this study: paravertebral recurrence of hypernephroma (n=1); recurrence of uterus carcinoma (n=1); recurrence of chondrosarcoma of the pubic bone (n=1); presacral recurrence of rectal carcinoma (n=1); recurrent anal cancer (n=1); metastases in the abdominal wall (n=1); and lymph node metastases from colorectal cancer (n=8). A total of 27 laser applications were performed. A fast low-angle shot 2D sequence (TR/TE/flip angle=102 ms/8 ms/70 ) was used for nearly real-time monitoring during treatment. All patients had no other treatment option. Seventeen LITT sessions were performed using a conventional laser system with a mean laser power of 5.2 W (range 4.5-5.7 W), and 10 LITT session were performed using a power laser system with a mean laser power of 28.0 W. In 10 lesions total destruction could be achieved. In the remaining recurrent tumors, significant reduction of tumor volume by 60-80% was obtained. All patients tolerated the procedure well under local anesthesia. No complications occurred during treatment. Laser-induced thermotherapy is a practicable, minimally invasive, well-tolerated technique that can produce large areas of necrosis within recurrent tumors, substantially reducing active tumor volume if not resulting in outright destruction of tumor. (orig.)

  13. Tumor-induced rickets in a child with a central giant cell granuloma: a case report.

    Science.gov (United States)

    Fernández-Cooke, Elisa; Cruz-Rojo, Jaime; Gallego, Carmen; Romance, Ana Isabel; Mosqueda-Peña, Rocio; Almaden, Yolanda; Sánchez del Pozo, Jaime

    2015-06-01

    Tumor-induced osteomalacia/rickets is a rare paraneoplastic disorder associated with a tumor-producing fibroblast growth factor 23 (FGF23). We present a child with symptoms of rickets as the first clinical sign of a central giant cell granuloma (CGCG) with high serum levels of FGF23, a hormone associated with decreased phosphate resorption. A 3-year-old boy presented with a limp and 6 months later with painless growth of the jaw. On examination gingival hypertrophy and genu varum were observed. Investigations revealed hypophosphatemia, normal 1,25 and 25 (OH) vitamin D, and high alkaline phosphatase. An MRI showed an osteolytic lesion of the maxilla. Radiographs revealed typical rachitic findings. Incisional biopsy of the tumor revealed a CGCG with mesenchymal matrix. The CGCG was initially treated with calcitonin, but the lesions continued to grow, making it necessary to perform tracheostomy and gastrostomy. One year after onset the hyperphosphaturia worsened, necessitating increasing oral phosphate supplements up to 100 mg/kg per day of elemental phosphorus. FGF23 levels were extremely high. Total removal of the tumor was impossible, and partial reduction was achieved after percutaneous computed tomography-guided radiofrequency, local instillation of triamcinolone, and oral propranolol. Compassionate use of cinacalcet was unsuccessful in preventing phosphaturia. The tumor slowly regressed after the third year of disease; phosphaturia improved, allowing the tapering of phosphate supplements, and FGF23 levels normalized. Tumor-induced osteomalacia/rickets is uncommon in children and is challenging for physicians to diagnose. It should be suspected in patients with intractable osteomalacia or rickets. A tumor should be ruled out if FGF23 levels are high. PMID:26009620

  14. The p75NTR tumor suppressor induces cell cycle arrest facilitating caspase mediated apoptosis in prostate tumor cells

    International Nuclear Information System (INIS)

    The p75 neurotrophin receptor (p75NTR) is a death receptor which belongs to the tumor necrosis factor receptor super-family of membrane proteins. This study shows that p75NTR retarded cell cycle progression by induced accumulation of cells in G0/G1 and a reduction in the S phase of the cell cycle. The rescue of tumor cells from cell cycle progression by a death domain deleted (ΔDD) dominant-negative antagonist of p75NTR showed that the death domain transduced anti-proliferative activity in a ligand-independent manner. Conversely, addition of NGF ligand rescued retardation of cell cycle progression with commensurate changes in components of the cyclin/cdk holoenzyme complex. In the absence of ligand, p75NTR-dependent cell cycle arrest facilitated an increase in apoptotic nuclear fragmentation of the prostate cancer cells. Apoptosis of p75NTR expressing cells occurred via the intrinsic mitochondrial pathway leading to a sequential caspase-9 and -7 cascade. Since the death domain deleted dominant-negative antagonist of p75NTR rescued intrinsic caspase associated apoptosis in PC-3 cells, this shows p75NTR was integral to ligand independent induction of apoptosis. Moreover, the ability of ligand to ameliorate the p75NTR-dependent intrinsic apoptotic cascade indicates that NGF functioned as a survival factor for p75NTR expressing prostate cancer cells

  15. Poly I:C enhances cycloheximide-induced apoptosis of tumor cells through TLR3 pathway

    International Nuclear Information System (INIS)

    Toll-like receptor 3 (TLR3) is a critical component of the innate immune response to dsRNA viruses, which was considered to be mainly expressed in immune cells and some endothelial cells. In this study, we investigated the expression and proapoptotic activity of TLR3 in human and murine tumor cell lines. RT-PCR and FACS analysis were used to detect expression of TLR3 in various human and murine tumor cell lines. All tumor cell lines were cultured with poly I:C, CHX, or both for 12 h, 24 h, 72 h, and then the cell viability was analyzed with CellTiter 96® AQueous One Solution, the apoptosis was measured by FACS with Annexin V and PI staining. Production of Type I IFN in poly I:C/CHX mediated apoptosis were detected through western blotting. TLR3 antibodies and IFN-β antibodies were used in Blockade and Neutralization Assay. We show that TLR3 are widely expressed on human and murine tumor cell lines, and activation of TLR3 signaling in cancerous cells by poly I:C made Hela cells (human cervical cancer) and MCA38 cells (murine colon cancer) become dose-dependently sensitive to protein synthesis inhibitor cycloheximide (CHX)-induced apoptosis. Blockade of TLR3 recognition with anti-TLR3 antibody greatly attenuated the proapoptotic effects of poly I:C on tumor cells cultured with CHX. IFN-β production was induced after poly I:C/CHX treatment and neutralization of IFN-β slightly reduced poly I:C/CHX -induced apoptosis. Our study demonstrated the proapoptotic activity of TLR3 expressed by various tumor cells, which may open a new range of clinical applications for TLR3 agonists as an adjuvant of certain cancer chemotherapy

  16. Radiation induced oxidative stress: I. Studies in Ehrlich solid tumor in mice.

    Science.gov (United States)

    Agrawal, A; Choudhary, D; Upreti, M; Rath, P C; Kale, R K

    2001-07-01

    Understanding the response of tumors to ionizing radiation might potentially lead to improvement in tumor control and patient morbidity. Since the antioxidant status is likely to be linked to radioresponse, its modulation needs to be examined. Therefore, Swiss albino male mice (7-8 weeks old) with Ehrlich solid tumors were irradiated with different doses of gamma rays (0-9 Gy) at a dose rate of 0.0153 Gy/s; and enzymes involved in antioxidant functions were determined in the tumors. Radiation effects in terms of oxidative damage, LDH, nitric oxide and DNA fragmentation were also examined. In tumors, the specific activity of SOD was increased with dose but declined 6 Gy onwards. GST, DTD and GSH showed an almost progressive increase. These enhanced activities might have resulted from the increased protein expression. This possibility was supported by the Western Blot analysis for GST protein. These changes might be closely linked to the radiation-induced oxidative stress as reflected by the enhanced levels of peroxidative damage, DNA fragmentation, LDH activity and nitric oxide levels. These findings may have relevance to radiation therapy of cancer as the elevated antioxidant status of irradiated tumors is likely to limit the effectiveness of radiation dose and adversely affect the therapeutic gain. PMID:11681724

  17. Withaferin-A suppress AKT induced tumor growth in colorectal cancer cells.

    Science.gov (United States)

    Suman, Suman; Das, Trinath P; Sirimulla, Suman; Alatassi, Houda; Ankem, Murali K; Damodaran, Chendil

    2016-03-22

    The oncogenic activation of AKT gene has emerged as a key determinant of the aggressiveness of colorectal cancer (CRC); hence, research has focused on targeting AKT signaling for the treatment of advanced stages of CRC. In this study, we explored the anti-tumorigenic effects of withaferin A (WA) on CRC cells overexpressing AKT in preclinical (in vitro and in vivo) models. Our results indicated that WA, a natural compound, resulted in significant inhibition of AKT activity and led to the inhibition of cell proliferation, migration and invasion by downregulating the epithelial to mesenchymal transition (EMT) markers in CRC cells overexpressing AKT. The oral administration of WA significantly suppressed AKT-induced aggressive tumor growth in a xenograft model. Molecular analysis revealed that the decreased expression of AKT and its downstream pro-survival signaling molecules may be responsible for tumor inhibition. Further, significant inhibition of some important EMT markers, i.e., Snail, Slug, β-catenin and vimentin, was observed in WA-treated human CRC cells overexpressing AKT. Significant inhibition of micro-vessel formation and the length of vessels were evident in WA-treated tumors, which correlated with a low expression of the angiogenic marker RETIC. In conclusion, the present study emphasizes the crucial role of AKT activation in inducing cell proliferation, angiogenesis and EMT in CRC cells and suggests that WA may overcome AKT-induced cell proliferation and tumor growth in CRC. PMID:26883103

  18. miR-137 Modulates a Tumor Suppressor Network-Inducing Senescence in Pancreatic Cancer Cells

    Directory of Open Access Journals (Sweden)

    Mathieu Neault

    2016-03-01

    Full Text Available Activating K-Ras mutations occurs frequently in pancreatic cancers and is implicated in their development. Cancer-initiating events, such as oncogenic Ras activation, lead to the induction of cellular senescence, a tumor suppressor response. During senescence, the decreased levels of KDM4A lysine demethylase contribute to p53 activation, however, the mechanism by which KDM4A is downregulated is unknown. We show that miR-137 targets KDM4A mRNA during Ras-induced senescence and activates both p53 and retinoblastoma (pRb tumor suppressor pathways. Restoring the KDM4A expression contributed to bypass of miR-137-induced senescence and inhibition of endogenous miR-137 with an miRNA sponge-compromised Ras-induced senescence. miR-137 levels are significantly reduced in human pancreatic tumors, consistent with previous studies revealing a defective senescence response in this cancer type. Restoration of miR-137 expression inhibited proliferation and promoted senescence of pancreatic cancer cells. These results suggest that modulating levels of miR-137 may be important for triggering tumor suppressor networks in pancreatic cancer.

  19. Platycodin D exerts anti-tumor efficacy in H22 tumor-bearing mice via improving immune function and inducing apoptosis.

    Science.gov (United States)

    Li, Wei; Tian, Yu-Hong; Liu, Ying; Wang, Zi; Tang, Shan; Zhang, Jing; Wang, Ying-Ping

    2016-01-01

    Platycodin D (PD), a major saponin derived and isolated from the roots of Platycodon grandiflorum, exerts potent growth inhibition and strong cytotoxicity against various cancer cell lines. However, the anti-tumor efficacy of PD on H22 hepatocellular carcinoma remains unknown. In the present study, we aimed to explore the anti-hepatoma activity in vivo and the underlying mechanism of PD in H22 tumor-bearing mice. The results revealed that PD could considerably suppress tumor growth with no significant side effects on immune organs and body weight. Further investigations showed that the levels of serum cytokines, including interferon gamma (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-2 (IL-2), were enhanced by PD administration. On the other hand, PD inhibited the production of vascular endothelial growth factor (VEGF) in serum of H22 tumor mice. Additionally, the observations from H&E and Hoechst 33258 staining results demonstrated that PD noticeably induced apoptosis in H22 hepatocellular carcinoma cells. Importantly, immunohistochemical analysis showed that PD treatment increased Bax expression and decreased Bcl-2 and VEGF expression of H22 tumor tissues in a dose-dependent manner. Taken together, the findings in the present investigation clearly demonstrated that the PD markedly suppressed the tumor growth of H22 transplanted tumor in vivo at least partly via improving the immune functions, inducing apoptosis, and inhibiting angiogenesis. PMID:27193733

  20. Cks1 Is Required for Tumor Cell Proliferation but Not Sufficient to Induce Hematopoietic Malignancies

    OpenAIRE

    Kratzat, Susanne; Nikolova, Viktoriya; Miething, Cornelius; Hoellein, Alexander; Schoeffmann, Stephanie; Gorka, Oliver; Pietschmann, Elke; Illert, Anna-Lena; Ruland, Jürgen; Peschel, Christian; Nilsson, Jonas; Duyster, Justus; Keller, Ulrich

    2012-01-01

    The Cks1 component of the SCFSkp2 complex is necessary for p27Kip1 ubiquitylation and degradation. Cks1 expression is elevated in various B cell malignancies including Burkitt lymphoma and multiple myeloma. We have previously shown that loss of Cks1 results in elevated p27Kip1 levels and delayed tumor development in a mouse model of Myc-induced B cell lymphoma. Surprisingly, loss of Skp2 in the same mouse model also resulted in elevated p27Kip1 levels but exhibited no impact on tumor onset. T...

  1. Intra-operative visualization of brain tumors with 5-aminolevulinic acid-induced fluorescence.

    Science.gov (United States)

    Widhalm, Georg

    2014-01-01

    Precise histopathological diagnosis of brain tumors is essential for the correct patient management. Furthermore, complete resection of brain tumors is associated with an improved patient prognosis. However, histopathological undergrading and incomplete tumor removal are not uncommon, especially due to insufficient intra-operative visualization of brain tumor tissue. The fluorescent dye 5-aminolevulinic acid (5-ALA) is currently applied for fluorescence-guided resections of high-grade gliomas. The value of 5-ALA-induced protoporphyrin (PpIX) fluorescence for intra-operative visualization of other tumors than high-grade gliomas remains unclear. Within the frame of this thesis, we found a significantly higher rate of complete resections of our high-grade gliomas as compared to control cases by using the newly established 5-ALA fluorescence technology at our department. Additionally, we showed that MRI spectroscopy-based chemical shift imaging (CSI) is capable to identify intratumoral high-grade glioma areas (= anaplastic foci) during navigation guided resections to avoid histopathological undergrading. However, the accuracy of navigation systems with integrated pre-operative imaging data such as CSI declines during resections due to intra-operative brainshift. In two further studies, we found that 5-ALA induced PpIX fluorescence is capable as a novel intra-operative marker to detect anaplastic foci within initially suspected low-grade gliomas independent of brainshift. Finally, we showed that the application of 5-ALA is also of relevance in needle biopsies for intra-operative identification of representative brain tumor tissue. These data indicate that 5-ALA is not only of major importance for resection of high-grade gliomas, but also for intra-operative visualization of anaplastic foci as well as representative brain tumor tissue in needle biopsies unaffected by brainshift. Consequently, this new technique might become a novel standard in brain tumor surgery that

  2. Tumor vaccine composed of C-class CpG oligodeoxynucleotides and irradiated tumor cells induces long-term antitumor immunity

    Directory of Open Access Journals (Sweden)

    Cerkovnik Petra

    2010-09-01

    Full Text Available Abstract Background An ideal tumor vaccine should activate both effector and memory immune response against tumor-specific antigens. Beside the CD8+ T cells that play a central role in the generation of a protective immune response and of long-term memory, dendritic cells (DCs are important for the induction, coordination and regulation of the adaptive immune response. The DCs can conduct all of the elements of the immune orchestra and are therefore a fundamental target and tool for vaccination. The present study was aimed at assessing the ability of tumor vaccine composed of C-class CpG ODNs and irradiated melanoma tumor cells B16F1 followed by two additional injections of CpG ODNs to induce the generation of a functional long-term memory response in experimental tumor model in mice (i.p. B16F1. Results It has been shown that the functional memory response in vaccinated mice persists for at least 60 days after the last vaccination. Repeated vaccination also improves the survival of experimental animals compared to single vaccination, whereas the proportion of animals totally protected from the development of aggressive i.p. B16F1 tumors after vaccination repeated three times varies between 88.9%-100.0%. Additionally, the long-term immune memory and tumor protection is maintained over a prolonged period of time of at least 8 months. Finally, it has been demonstrated that following the vaccination the tumor-specific memory cells predominantly reside in bone marrow and peritoneal tissue and are in a more active state than their splenic counterparts. Conclusions In this study we demonstrated that tumor vaccine composed of C-class CpG ODNs and irradiated tumor cells followed by two additional injections of CpG ODNs induces a long-term immunity against aggressive B16F1 tumors.

  3. Selenium Induces an Anti-tumor Effect Via Inhibiting Intratumoral Angiogenesis in a Mouse Model of Transplanted Canine Mammary Tumor Cells.

    Science.gov (United States)

    Li, Wenyu; Guo, Mengyao; Liu, Yuzhu; Mu, Weiwei; Deng, Ganzhen; Li, Chengye; Qiu, Changwei

    2016-06-01

    Selenium (Se) has been widely reported to possess anti-tumor effects. Angiogenesis is the formation of new blood vessels and is required to supply oxygen, nutrients, and growth factors for tumor growth, progression, and metastasis. To explore whether the anti-tumor effect of Se was associated with angiogenesis in vivo, we studied the effects of sodium selenite (Sel) and methylseleninic acid (MSA) on tumors induced by canine mammary tumor cells (CMT1211) in mice; cyclophosphamide (CTX) served as a positive control. The results showed that the Se content was significantly increased in the Sel and MSA groups. Se significantly inhibited the tumor weights and volumes. Large necrotic areas and scattered and abnormal small necrotic areas were observed in the Se treatment group. Immunofluorescence double staining showed a reduction in the microvessel density (MVD) and increment in the vessel maturation index (VMI) compared with the untreated control group. As expected, the protein and mRNA levels of the angiogenesis factors angiopoietin-2 (Ang-2), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) were decreased in the Se-treated tumors by IHC, as shown by western blotting and RT-QPCR. We also found that organic Se MSA provided stronger inhibition of tumor growth compared with inorganic sodium selenite (Sel). Altogether, our results indicated that Se exerted anti-tumor effects in vivo at least partially by inhibiting angiogenic factors. PMID:26507439

  4. Tumor-associated antigens identified by mRNA expression profiling induce protective anti-tumor immunity

    DEFF Research Database (Denmark)

    Mathiassen, S; Lauemøller, S L; Ruhwald, M;

    2001-01-01

    clinical signs of autoimmune reactions were observed. Thus, it appears possible to evaluate the entire metabolism of any given tumor and use this information rationally to identify multiple epitopes of value in the generation of tumor-specific immunotherapy. We expect that human tumors express similar......Defined tumor-associated antigens (TAA) are attractive targets for anti-tumor immunotherapy. Here, we describe a novel genome-wide approach to identify multiple TAA from any given tumor. A panel of transplantable thymomas was established from an inbred p53-/- mouse strain. The resulting tumors were...... examined for gene expression by mRNA microarray scanning. This analysis revealed heterogeneity of the tumors in agreement with the assumption that they represent different tumorigenic events. Several genes were overexpressed in one or more of the tumors. To examine whether overexpressed genes might be used...

  5. Sapodilla plum (Achras sapota) induces apoptosis in cancer cell lines and inhibits tumor progression in mice.

    Science.gov (United States)

    Srivastava, Mrinal; Hegde, Mahesh; Chiruvella, Kishore K; Koroth, Jinsha; Bhattacharya, Souvari; Choudhary, Bibha; Raghavan, Sathees C

    2014-01-01

    Intake of fruits rich in antioxidants in daily diet is suggested to be cancer preventive. Sapota is a tropical fruit grown and consumed extensively in several countries including India and Mexico. Here we show that methanolic extracts of Sapota fruit (MESF) induces cytotoxicity in a dose-dependent manner in cancer cell lines. Cell cycle analysis suggested activation of apoptosis, without arresting cell cycle progression. Annexin V-propidium iodide double-staining demonstrated that Sapota fruit extracts potentiate apoptosis rather than necrosis in cancer cells. Loss of mitochondrial membrane potential, upregulation of proapoptotic proteins, activation of MCL-1, PARP-1, and Caspase 9 suggest that MESF treatment leads to activation of mitochondrial pathway of apoptosis. More importantly, we show that MESF treatment leads to significant inhibition of tumor growth and a 3-fold increase in the life span of tumor bearing animals compared to untreated tumor mice. PMID:25142835

  6. Advances of radioiodine therapy of tumor induced by sodium iodide symporter gene

    International Nuclear Information System (INIS)

    As a kind of membrane protein that mainly mediates iodide transport into thyroid follicular cells, sodium iodide symporter (NIS) plays a key role in radioiodine therapy of both thyroid and other cancers. Studies show that decreased NIS expression level or intracellular localization in thyroid carcinomas lead to low iodine uptake. So NIS gene therapy is a new method to overcome this problem. To be therapeutically effective, radioiodine has to be remained in the tumor cells for sufficient long time; this is still a problem which reduces therapeutic effect. It should increase iodide retention and decrease iodide efflux in tumor cells to optimize therapeutic scheme. This article reviews the studies on advances of radioiodine therapy of tumor induced by sodium iodide symporter gene. (authors)

  7. Mediastinal Yolk Sac Tumor Producing Protein Induced by Vitamin K Absence or Antagonist-II.

    Science.gov (United States)

    Akutsu, Noriyuki; Adachi, Yasushi; Isosaka, Mai; Mita, Hiroaki; Takagi, Hideyasu; Sasaki, Shigeru; Yamamoto, Hiroyuki; Arimura, Yoshiaki; Ishii, Yoshifumi; Masumori, Naoya; Endo, Takao; Shinomura, Yasuhisa

    2015-01-01

    Extragonadal yolk sac tumors (YSTs) are rare. We herein report the case of a 66-year-old man with mediastinal, lung and liver tumors. The largest mass was located in the liver and contained a high concentration of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein. Therefore, the lesion was difficult to distinguish from hepatocellular carcinoma. Finally, YST was diagnosed based on the results of a liver biopsy. Although chemotherapy was effective, the patient died of respiratory failure. The autopsy revealed primary mediastinal YST. In the current report, we describe this case of PIVKA-II-producing YST and review previous cases of PIVKA-II-producing tumors other than hepatoma. PMID:26073245

  8. Vaccination with Necroptotic Cancer Cells Induces Efficient Anti-tumor Immunity

    Directory of Open Access Journals (Sweden)

    Tania Løve Aaes

    2016-04-01

    Full Text Available Successful immunogenic apoptosis in experimental cancer therapy depends on the induction of strong host anti-tumor responses. Given that tumors are often resistant to apoptosis, it is important to identify alternative molecular mechanisms that elicit immunogenic cell death. We have developed a genetic model in which direct dimerization of FADD combined with inducible expression of RIPK3 promotes necroptosis. We report that necroptotic cancer cells release damage-associated molecular patterns and promote maturation of dendritic cells, the cross-priming of cytotoxic T cells, and the production of IFN-γ in response to tumor antigen stimulation. Using both FADD-dependent and FADD-independent RIPK3 induction systems, we demonstrate the efficient vaccination potential of immunogenic necroptotic cells. Our study broadens the current concept of immunogenic cell death and opens doors for the development of new strategies in cancer therapy.

  9. Peroxisome Proliferator-Activated Receptors (PPARs as Potential Inducers of Antineoplastic Effects in CNS Tumors

    Directory of Open Access Journals (Sweden)

    Lars Tatenhorst

    2008-01-01

    Full Text Available The peroxisome proliferator-activated receptors (PPARs are ligand-inducible transcription factors which belong to the superfamily of nuclear hormone receptors. In recent years it turned out that natural as well as synthetic PPAR agonists exhibit profound antineoplastic as well as redifferentiation effects in tumors of the central nervous system (CNS. The molecular understanding of the underlying mechanisms is still emerging, with partially controverse findings reported by a number of studies dealing with the influence of PPARs on treatment of tumor cells in vitro. Remarkably, studies examining the effects of these drugs in vivo are just beginning to emerge. However, the agonists of PPARs, in particular the thiazolidinediones, seem to be promising candidates for new approaches in human CNS tumor therapy.

  10. The influence of patients age, type of tumor growth, hematocrit, and radiation-induced tumor regression on the prognosis of advanced uterine cervix carcinoma

    International Nuclear Information System (INIS)

    The age of patients, type of tumor growth, pretreatment hematocrit, and radiation-induced tumor regression were evaluated as possible prognostic factors in 222 patients with advanced cervical cancer treated at the Institute of Clinical Oncology in Bratislava in the period from 1960 through 1980. The five-year disease-free survival rate for Stage IIb patients was 50%, for Stage III patients 23.1%, and for Stage IV patients 13%. Radiatoin-induced tumor regression and type of tumor growth were noted to be a significant prognostic factor with regard to the control of disease in the pelvis. Age of the patients and pretreatment hematocrit were found to be a weak prognostic factor. (author). 4 figs., 6 tabs., 25 refs

  11. Tumor-induced osteomalacia with elevated fibroblast growth factor 23: a case of phosphaturic mesenchymal tumor mixed with connective tissue variants and review of the literature

    Institute of Scientific and Technical Information of China (English)

    Fang-Ke Hu; Fang Yuan; Cheng-Ying Jiang; Da-Wei Lv; Bei-Bei Mao; Qiang Zhang; Zeng-Qiang Yuan; Yan Wang

    2011-01-01

    Tumor-induced osteomalacia (TIO),or oncogenic osteomalacia (OOM),is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia.Recent evidence shows that tumor-overexpressed fibroblast growth factor 23 (FGF23) is responsible for the hypophosphatemia and osteomalacia.The tumors associated with TIO are usually phosphaturic mesenchymal tumor mixed connective tissue variants (PMTMCT).Surgical removal of the responsible tumors is clinically essential for the treatment of TIO.However,identifying the responsible tumors is often difficult.Here,we report a case of a TIO patient with elevated serum FGF23 levels suffering from bone pain and hypophosphatemia for more than three years.A tumor was finally located in first metacarpal bone by octreotide scintigraphy and she was cured by surgery.After complete excision of the tumor,serum FGF23 levels rapidly decreased,dropping to 54.7% of the preoperative level one hour after surgery and eventually to a little below normal.The patient's serum phosphate level rapidly improved and returned to normal level in four days.Accordingly,her clinical symptoms were greatly improved within one month after surgery.There was no sign of tumor recurrence during an 18-month period of follow-up.According to pathology,the tumor was originally diagnosed as “glomangioma” based upon a biopsy sample,“proliferative giant cell tumor of tendon sheath” based upon sections of tumor,and finally diagnosed as PMTMCT by consultation one year after surgery.In conclusion,although an extremely rare disease,clinicians and pathologists should be aware of the existence of TIO and PMTMCT,respectively.

  12. Soy isoflavone exposure through all life stages accelerates 17β-estradiol-induced mammary tumor onset and growth, yet reduces tumor burden, in ACI rats.

    Science.gov (United States)

    Möller, Frank Josef; Pemp, Daniela; Soukup, Sebastian T; Wende, Kathleen; Zhang, Xiajie; Zierau, Oliver; Muders, Michael H; Bosland, Maarten C; Kulling, Sabine E; Lehmann, Leane; Vollmer, Günter

    2016-08-01

    There is an ongoing debate whether the intake of soy-derived isoflavones (sISO) mediates beneficial or adverse effects with regard to breast cancer risk. Therefore, we investigated whether nutritional exposure to a sISO-enriched diet from conception until adulthood impacts on 17β-estradiol (E2)-induced carcinogenesis in the rat mammary gland (MG). August-Copenhagen-Irish (ACI) rats were exposed to dietary sISO from conception until postnatal day 285. Silastic tubes containing E2 were used to induce MG tumorigenesis. Body weight, food intake, and tumor growth were recorded weekly. At necropsy, the number, position, size, and weight of each tumor were determined. Plasma samples underwent sISO analysis, and the morphology of MG was analyzed. Tumor incidence and multiplicity were reduced by 20 and 56 %, respectively, in the sISO-exposed rats compared to the control rats. Time-to-tumor onset was shortened from 25 to 20 weeks, and larger tumors developed in the sISO-exposed rats. The histological phenotype of the MG tumors was independent of the sISO diet received, and it included both comedo and cribriform phenotypes. Morphological analyses of the whole-mounted MGs also showed no diet-dependent differences. Lifelong exposure to sISO reduced the overall incidence of MG carcinomas in ACI rats, although the time-to-tumor was significantly shortened. PMID:26861028

  13. [Viral transfer of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in gene therapy].

    Science.gov (United States)

    Wędrowska, Ewelina; Wandtke, Tomasz; Dyczek, Andrzej; Woźniak, Joanna

    2015-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces carcinoma cell death through the extrinsic pathway of apoptosis. Preclinical trials of gene therapy have been conducted using viral transfer of the TRAIL transgene into prostate, bladder, breast, kidney, liver, non-small cell lung cancer and also glioblastoma cells. Experiments in vitro demonstrated the extensive apoptosis of target cells as well as frequent disease regression or remission. TRAIL transfer did not show any side effects, opposite to chemotherapy. Encouraging results of TRAIL-related gene therapy were observed in rheumatoid arthritis and type 1 diabetes. Adenoviral vectors (AdV) encoding TRAIL are the most promising tool in anti-tumor therapy. They have undergone numerous modifications by increasing transfection efficiency and transgene expression in target cells. However, only one clinical phase I trial has been performed. AdV encoding the TRAIL transgene caused local inflammation and apoptosis in patients with prostate cancer. PMID:27259213

  14. HF-LPLI-treated tumor cells induce NO production in macrophage

    Science.gov (United States)

    Lu, Cuixia; Zhou, Feifan; Wu, Shengnan; Xing, Da

    2013-02-01

    High fluence low-power laser irradiation (HF-LPLI) provides a new stimulator to trigger cell apoptosis, and it is well known that apoptotic cells provide antigens to effectively trigger recognition by the immune system. In order to investigate the effect of HF-LPLI on the professional antigen-presenting cell (APC) function, in our primary study, we focused our attention on the effect of HF-LPLI-treated tumor cells on macrophages phagocytosis and NO production. Both confocal microscopy and flowcytometry analysis showed that HF-LPLI (120 J/cm2) induced significantly EMT6 death. Further experiments showed that HF-LPLI-treated EMT6 cells could be phagocyted by the murine macrophage cells RAW264.7, and could induce NO production in macrophages. Taken together, our results indicate that HF-LPLI-treated tumor cells effectively regulated the immune system. The HF-LPLI effect on the APC function needs to be further studied.

  15. Subacute brain atrophy induced by radiation therapy to the malignant brain tumors

    International Nuclear Information System (INIS)

    In order to analyze brain atrophy after radiation therapy to the brain tumors, we calculated a CSF-cranial volume ratio on CT scan as an index of brain atrophy, and estimated dementia-score by Hasegawa's method in 91 post-irradiated patients with malignant brain tumors. Radiation-induced brain atrophy was observed in 51 out of 91 patients (56 %) and dementia in 23 out of 47 patients (49 %). These two conditions were closely related, and observed significantly more often in aged and whole-brain-irradiated patients. As radiation-induced brain atrophy accompanied by dementia appeared 2 - 3 months after the completion of radiation therapy, it should be regarded as a subacute brain injury caused by radiation therapy. (author)

  16. Overexpression and amplification of the c-myc gene in mouse tumors induced by chemical and radiations

    International Nuclear Information System (INIS)

    We examined expression of the c-myc gene by the dot blot hybridization of total cellular RNA from mouse primary tumors induced by chemicals and radiations. Expression of the c-myc gene was found to be elevated in 69 cases among 177 independently induced tumors of 12 different types. DNA from tumors overexpressing the myc gene was analyzed by Southern blotting. No case of rearrangement was detected. However, amplification of the c-myc gene was found in 7 cases of primary sarcomas. These included 4 cases out of 24 methylcholanthrene-induced sarcomas and 3 cases out of 7 α-tocopherol-induced sacromas. We also analyzed 8 cases of sarcomas induced by radiations, but could not find changes in the gene structure of the c-myc gene. Thus, our data indicate tumor type specificity and agent specificity of c-myc gene amplification. (author)

  17. Suppression of tumor growth by designed dimeric epidithiodiketopiperazine targeting hypoxia-inducible transcription factor complex.

    Science.gov (United States)

    Dubey, Ramin; Levin, Michael D; Szabo, Lajos Z; Laszlo, Csaba F; Kushal, Swati; Singh, Jason B; Oh, Philip; Schnitzer, Jan E; Olenyuk, Bogdan Z

    2013-03-20

    Hypoxia is a hallmark of solid tumors, is associated with local invasion, metastatic spread, resistance to chemo- and radiotherapy, and is an independent, negative prognostic factor for a diverse range of malignant neoplasms. The cellular response to hypoxia is primarily mediated by a family of transcription factors, among which hypoxia-inducible factor 1 (HIF1) plays a major role. Under normoxia, the oxygen-sensitive α subunit of HIF1 is rapidly and constitutively degraded but is stabilized and accumulates under hypoxia. Upon nuclear translocation, HIF1 controls the expression of over 100 genes involved in angiogenesis, altered energy metabolism, antiapoptotic, and pro-proliferative mechanisms that promote tumor growth. A designed transcriptional antagonist, dimeric epidithiodiketopiperazine (ETP 2), selectively disrupts the interaction of HIF1α with p300/CBP coactivators and downregulates the expression of hypoxia-inducible genes. ETP 2 was synthesized via a novel homo-oxidative coupling of the aliphatic primary carbons of the dithioacetal precursor. It effectively inhibits HIF1-induced activation of VEGFA, LOX, Glut1, and c-Met genes in a panel of cell lines representing breast and lung cancers. We observed an outstanding antitumor efficacy of both (±)-ETP 2 and meso-ETP 2 in a fully established breast carcinoma model by intravital microscopy. Treatment with either form of ETP 2 (1 mg/kg) resulted in a rapid regression of tumor growth that lasted for up to 14 days. These results suggest that inhibition of HIF1 transcriptional activity by designed dimeric ETPs could offer an innovative approach to cancer therapy with the potential to overcome hypoxia-induced tumor growth and resistance. PMID:23448368

  18. Peroxisome Proliferator-Activated Receptors (PPARs) as Potential Inducers of Antineoplastic Effects in CNS Tumors

    OpenAIRE

    Lars Tatenhorst; Eric Hahnen; Heneka, Michael T

    2008-01-01

    The peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors which belong to the superfamily of nuclear hormone receptors. In recent years it turned out that natural as well as synthetic PPAR agonists exhibit profound antineoplastic as well as redifferentiation effects in tumors of the central nervous system (CNS). The molecular understanding of the underlying mechanisms is still emerging, with partially controverse findings reported by a number of studie...

  19. Simultaneous Targeting of Tumor Antigens and the Tumor Vasculature using T Lymphocyte Transfer Synergize to Induce Regression of Established Tumors in Mice

    Science.gov (United States)

    Chinnasamy, Dhanalakshmi; Tran, Eric; Yu, Zhiya; Morgan, Richard A.; Restifo, Nicholas P.; Rosenberg, Steven A.

    2013-01-01

    Most systemic cancer therapies target tumor cells directly though there is increasing interest in targeting the tumor stroma that can comprise a substantial portion of the tumor mass. We report here a synergy between two T cell therapies, one directed against the stromal tumor vasculature and the other directed against antigens expressed on the tumor cell. Simultaneous transfer of genetically engineered syngeneic T cells expressing a chimeric antigen receptor targeting the Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2; KDR) that is over expressed on tumor vasculature and T cells specific for the tumor antigens gp100 (PMEL), TRP-1 (TYRP1), or TRP-2 (DCT) synergistically eradicated established B16 melanoma tumors in mice and dramatically increased the tumor-free survival of mice compared to treatment with either cell type alone or T cells coexpressing these two targeting molecules. Host lymphodepletion prior to cell transfer was required to mediate the anti-tumor effect. The synergistic antitumor response was accompanied by a significant increase in the infiltration and expansion and/or persistence of the adoptively transferred tumor antigen-specific T cells in the tumor microenvironment and thus enhanced their anti-tumor potency. The data presented here emphasize the possible beneficial effects of combining anti-angiogenic with tumor-specific immunotherapeutic approaches for the treatment of patients with cancer. PMID:23633494

  20. Nitric Oxide Synthase Inhibition by NG-Nitro-l-Arginine Methyl Ester Inhibits Tumor-Induced Angiogenesis in Mammary Tumors

    OpenAIRE

    Jadeski, Lorraine C.; Lala, Peeyush K.

    1999-01-01

    Using a murine breast cancer model, we earlier found a positive correlation between the expression of nitric oxide synthase (NOS) and tumor progression; treatment with inhibitors of NOS, NG-methyl-l-arginine (NMMA) and NG-nitro-l-arginine methyl ester (L-NAME), had antitumor and antimetastatic effects that were partly attributed to reduced tumor cell invasiveness. In the present study, we used a novel in vivo model of tumor angiogenesis using subcutaneous implants of tumor cells suspended in ...

  1. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation.

    Directory of Open Access Journals (Sweden)

    Adam D Cohen

    Full Text Available In vivo GITR ligation has previously been shown to augment T-cell-mediated anti-tumor immunity, yet the underlying mechanisms of this activity, particularly its in vivo effects on CD4+ foxp3+ regulatory T cells (Tregs, have not been fully elucidated. In order to translate this immunotherapeutic approach to the clinic it is important gain better understanding of its mechanism(s of action. Utilizing the agonist anti-GITR monoclonal antibody DTA-1, we found that in vivo GITR ligation modulates regulatory T cells (Tregs directly during induction of melanoma tumor immunity. As a monotherapy, DTA-1 induced regression of small established B16 melanoma tumors. Although DTA-1 did not alter systemic Treg frequencies nor abrogate the intrinsic suppressive activity of Tregs within the tumor-draining lymph node, intra-tumor Treg accumulation was significantly impaired. This resulted in a greater Teff:Treg ratio and enhanced tumor-specific CD8+ T-cell activity. The decreased intra-tumor Treg accumulation was due both to impaired infiltration, coupled with DTA-1-induced loss of foxp3 expression in intra-tumor Tregs. Histological analysis of B16 tumors grown in Foxp3-GFP mice showed that the majority of GFP+ cells had lost Foxp3 expression. These "unstable" Tregs were absent in IgG-treated tumors and in DTA-1 treated TDLN, demonstrating a tumor-specific effect. Impairment of Treg infiltration was lost if Tregs were GITR(-/-, and the protective effects of DTA-1 were reduced in reconstituted RAG1(-/- mice if either the Treg or Teff subset were GITR-negative and absent if both were negative. Our results demonstrate that DTA-1 modulates both Teffs and Tregs during effective tumor treatment. The data suggest that DTA-1 prevents intra-tumor Treg accumulation by altering their stability, and as a result of the loss of foxp3 expression, may modify their intra-tumor suppressive capacity. These findings provide further support for the continued development of agonist

  2. Re-examine tumor-induced alterations in hemodynamic responses of BOLD fMRI. Implications in presurgical brain mapping

    International Nuclear Information System (INIS)

    Background: Blood oxygenation level dependent (BOLD) fMRI is used for presurgical functional mapping of brain tumor patients. Abnormal tumor blood supply may affect hemodynamic responses and BOLD fMRI signals. Purpose: To perform a multivariate and quantitative investigation of the effect of brain tumors on the hemodynamic responses and its impact on BOLD MRI signal time course, data analysis in order to better understand tumor-induced alterations in hemodynamic responses, and accurately mapping cortical regions in brain tumor patients. Material and Methods: BOLD fMRI data from 42 glioma patients who underwent presurgical mapping of the primary motor cortex (PMC) with a block designed finger tapping paradigm were analyzed, retrospectively. Cases were divided into high grade (n = 24) and low grade (n = 18) groups based on pathology. The tumor volume and distance to the activated PMCs were measured. BOLD signal time courses from selected regions of interest (ROIs) in the PMCs of tumor affected and contralateral unaffected hemispheres were obtained from each patient. Tumor-induced changes of BOLD signal intensity and time to peak (TTP) of BOLD signal time courses were analyzed statistically. Results: The BOLD signal intensity and TTP in the tumor-affected PMCs are altered when compared to that of the unaffected hemisphere. The average BOLD signal level is statistically significant lower in the affected PMCs. The average TTP in the affected PMCs is shorter in the high grade group, but longer in the low grade tumor group compared to the contralateral unaffected hemisphere. Degrees of alterations in BOLD signal time courses are related to both the distance to activated foci and tumor volume with the stronger effect in tumor distance to activated PMC. Conclusion: Alterations in BOLD signal time courses are strongly related to the tumor grade, the tumor volume, and the distance to the activated foci. Such alterations may impair accurate mapping of tumor-affected functional

  3. Expression profile of microRNAs in c-Myc induced mouse mammary tumors

    OpenAIRE

    Sun, Yuan; Wu, Jack; Wu, Si-hung; Thakur, Archana; Bollig, Aliccia; Huang, Yong; Liao, D. Joshua

    2008-01-01

    c-Myc is a transcription factor overexpression of which induces mammary cancer in transgenic mice. To explore whether certain microRNAs (mirRNA) mediate c-Myc induced mammary carcinogenesis, we studied mir-RNA expression profile in mammary tumors developed from MMTV-c-myc transgenic mice, and found 50 and 59 mirRNAs showing increased and decreased expression, respectively, compared with lactating mammary glands of wild type mice. Twenty-four of these mirRNAs could be grouped into eight cluste...

  4. Cellular Mechanism of Newly Synthesized Indoledione Derivative-induced Immunological Death of Tumor Cell

    OpenAIRE

    Oh, Su-Jin; Ryu, Chung-Kyu; Baek, So-Young; Lee, Hyunah

    2011-01-01

    Background EY-6 is one of the newly synthesized indoledione derivatives to induce tumor cell-specific cell death. In this study, we investigated the mechanism of immunological death induced by EY-6 at mouse colon cancer cell as well as at the normal immune cell represented by dendritic cell. Methods C57BL/6 mouse syngeneic colon cancer cell MC38 was treated with EY-6, and analyzed by MTT for viability test, flow cytometry for confirming surface expressing molecules and ELISA for detection of ...

  5. Novel interferon-λs induce antiproliferative effects in neuroendocrine tumor cells

    International Nuclear Information System (INIS)

    Interferon-α (IFN-α) is used for biotherapy of neuroendocrine carcinomas. The interferon-λs (IL-28A/B and IL-29) are a novel group of interferons. In this study, we investigated the effects of the IFN-λs IL-28A and IL-29 on human neuroendocrine BON1 tumor cells. Similar to IFN-α, incubation of BON1 cells with IL-28A (10 ng/ml) and IL-29 (10 ng/ml) induced phosphorylation of STAT1, STAT2, and STAT3, significantly decreased cell numbers in a proliferation assay, and induced apoptosis as demonstrated by poly(ADP-ribose) polymerase (PARP)-cleavage, caspase-3-cleavage, and DNA-fragmentation. Stable overexpression of suppressor of cytokine signaling proteins (SOCS1 and SOCS3) completely abolished the aforementioned effects indicating that SOCS proteins act as negative regulators of IFN-λ signaling in BON1 cells. In conclusion, the novel IFN-λs IL-28A and IL-29 potently induce STAT signaling and antiproliferative effects in neuroendocrine BON1 tumor cells. Thus, IFN-λs may hint a promising new approach in the antiproliferative therapy of neuroendocrine tumors

  6. ANTICANCER EFFECTS OF CARICA PAPAYA IN EXPERIMENTAL INDUCED MAMMARY TUMORS IN RATS

    Directory of Open Access Journals (Sweden)

    Gurudatta M, Deshmukh YA, Naikwadi A A

    2015-07-01

    Full Text Available Objective: To evaluate the anticancer effect of Carica papaya in DMBA induced mammary tumors in rats. Methods: Wistar rats were divided in to five groups (n=6, Group-I (Normal control administered vehicle olive oil, Group-II, Group-III ,Group-IV and V induced mammary tumors by administering single dose of DMBA (7,12 Dimethyl benz(Aanthracene orally 65 mg/kg. Group-III was administered aqueous leaf extract of Carica papaya (ALQECP in a dose of 200 mg/kg body wt for a period of 3 months, group-IV has given ALQECP 200 mg/kg body wt for a period of 21 days post 3 months of tumor induction, group-V rats were administered a small dose of Carica papaya extract intra tumor locally in the region of tumor. Results: Values of CA15-3 were increased in group-II rats (tumor control significantly, whereas in group-III (prevention group the levels of CA15-3 were found to be reduced substantially and the P value < 0.001. Similarly, CA-15-3 levels were reduced significantly in group-IV (treatment groupand P<0.005. The levels of LDH were seen to be increased in group-II, where as in group-III LDH levels were decreased and P<0.001.similarly group-IV LDH levels also reduced significantly but not to the level of group-III. Conclusion: Among the various markers for the detection of cancer antigen-15(CA15-3 and lactate dehydrogenase (LDH are important biochemical parameters that give a clear understanding of the progression and proliferation of cancer cells. In this study it was found that there is increase in the levels of markers such as CA15-3 and LDH and also the tumor volume in tumor control, these marker levels were decreased by the administration of aqueous leaf extract of Carica papaya in a dose of 200 mg/kg body wt. ALQECP not only prevented the progression of cancer growth but also has significant effect in reducing the both CA15-3 and LDH levels in treatment group.

  7. Tumor-promoting macrophages induce the expression of the macrophage-specific receptor CD163 in malignant cells

    DEFF Research Database (Denmark)

    Maniecki, Maciej Bogdan; Etzerodt, Anders; Ulhøi, Benedicte Parm; Steiniche, Torben; Borre, Michael; Andersen, Lars Dyrskjøt; Orntoft, Torben Falck; Moestrup, Søren Kragh; Møller, Holger Jon

    2012-01-01

    Tumor-associated macrophages (TAMs) represent a distinct malignancy-promoting phenotype suggested to play a key role in tumor formation and metastasis. We aimed to investigate the expression of the monocyte/macrophage-restricted receptor CD163 in bladder tumor biopsies and assess the potential...... and histologically advanced disease. In 39% of the biopsies, CD163 immunoreactivity was also observed in tumor cells, and CD163-expressing metastatic cells were identified in lymph node biopsies (n = 8). Bladder cancer cell lines did not express CD163; however, when cocultured with macrophages the...... expressed by a significant portion of the malignant cells in both tumors and lymph nodes. CD163 expressing tumor cells may constitute a subpopulation of tumor cells with a phenotypic shift associated with epithelial-to-mesenchymal transition (EMT) and increased metastatic activity induced by TAMs....

  8. Effects of 900 MHz GSM wireless communication signals on DMBA-induced mammary tumors in rats.

    Science.gov (United States)

    Yu, Da; Shen, Yonghao; Kuster, Niels; Fu, Yiti; Chiang, Huai

    2006-02-01

    The purpose of the study was to investigate whether exposure to 900 MHz GSM wireless communication signals enhances mammary tumor development and growth induced by low-dose DMBA. Five hundred female Sprague-Dawley rats were treated with a single dose of 35 mg/kg DMBA and then divided into five groups in a blinded fashion: one cage control group and four exposure groups, including three microwave exposure groups and one sham exposure with specific absorption rates (SARs) of 4.0, 1.33, 0.44 and 0 W/kg, respectively. Exposure started on the day after DMBA administration and lasted 4 h/day, 5 days/week for 26 weeks. Rats were weighed and palpated weekly for the presence of tumors and were killed humanely at the end of the 26-week exposure period. All mammary glands were examined histologically. There were no statistically significant differences in body weight between sham- and GSM microwave-exposed groups. No significant differences in overall mammary tumor incidence, latency to tumor onset, tumor multiplicity, or tumor size were observed between microwave- and sham-exposed groups. There was a tendency for reduction of mammary adenocarcinoma incidence in the lowest microwave exposure group (0.44 W/ kg) compared with the sham-exposed group (P = 0.058). Additionally, a higher incidence of adenocarcinoma was noticed in the 4.0 W/kg group from the 15th to 26th weeks, especially in the 19th week (P = 0.358 compared to sham). However, neither tendency was statistically significant; thus this study does not provide evidence that GSM microwave exposure promotes mammary tumor development in rats. In the present study there were significant differences between the cage controls and the experimental groups (sham and exposure). Body weight and mammary tumor (malignant plus benign) incidence in the cage control group were significantly higher than in the sham- and GSM microwave-exposed groups. The latency to the mammary tumor onset was significantly shorter in the cage control

  9. Host genetic influence on papillomavirus-induced tumors in the horse.

    Science.gov (United States)

    Staiger, Elizabeth A; Tseng, Chia T; Miller, Donald; Cassano, Jennifer M; Nasir, Lubna; Garrick, Dorian; Brooks, Samantha A; Antczak, Douglas F

    2016-08-15

    The common equine skin tumors known as sarcoids have been causally associated with infection by bovine papillomavirus (BPV). Additionally, there is evidence for host genetic susceptibility to sarcoids. We investigated the genetic basis of susceptibility to sarcoid tumors on a cohort of 82 affected horses and 270 controls genotyped on a genome-wide platform and two custom panels. A Genome Wide Association Study (GWAS) identified candidate regions on six chromosomes. Bayesian probability analysis of the same dataset verified only the regions on equine chromosomes (ECA) 20 and 22. Fine mapping using custom-produced SNP arrays for ECA20 and ECA22 regions identified two marker loci with high levels of significance: SNP BIEC2-530826 (map position 32,787,619) on ECA20 in an intron of the DQA1 gene in the Major Histocompatibility Complex (MHC) class II region (p = 4.6e-06), and SNP BIEC2-589604 (map position 25,951,536) on ECA22 in a 200 kb region containing four candidate genes: PROCR, EDEM2, EIF6 and MMP24 (p = 2.14e-06). The marker loci yielded odds ratios of 5.05 and 4.02 for ECA20 and ECA22, respectively. Associations between genetic MHC class II variants and papillomavirus-induced tumors have been reported for human papillomavirus and cottontail rabbit papillomavirus infections. This suggests a common mechanism for susceptibility to tumor progression that may involve subversion of the host immune response. This study also identified a genomic region other than MHC that influenced papillomavirus-induced tumor development in the studied population. PMID:27037728

  10. Immunological and viral aspects of radiation-induced tumors. Third annual report

    International Nuclear Information System (INIS)

    We have attempted to induce bone sarcoma with FBJ virus in a total of 140 newborn mice. FBJ tumors have developed in CF1 mice, but not in mice of the other strains. Attempts to transplant FBJ tumors in CF1 mice have failed, since these mice are random bred. Because C57BL/6 mice are healthy, long-lived mice that have a low incidence of spontaneous tumors, we have used them for our initial work on strontium-90 carcinogenesis. The last of nine mice injected at the beginning of the study with 0.5 μc/gm body weight of strontium-90 has now died. Two of these mice developed bone sarcoma, of which one has been transplanted isogenically through eight transplant generations. Immunological experiments to test the antigenicity of this transplantable tumor are in progress. An extensive experiment in which 700 C57BL/6 female mice were divided into nineteen groups is now in its second year. Mice were given the following treatments: 0, 0.032, 0.01, 0.32, 1.0 and 2.0 μc/gm of strontium-90, 0, 0.032, 0.01, 0.32 and 1.0 μc/gm of strontium-90 plus 300 rad total body cesium-137 irradiation; and injection of active FBJ virus, inactive FBJ virus, and irradiated (10,000 rad) transplantable strontium-90-induced C57BL/6 osteosarcoma, all three modes of treatment given to groups that did and that did not receive prior injection of 1.0 μc/gm of strontium-90. To date, we have serially transplanted four osteogenic sarcomas that developed in these mice. We have also in serial passage a lymphoma that developed in a control C57BL/6 mouse that received no treatment. All these transplantable C57BL/6 tumor lines are intended for use in immunological experiments

  11. Dexamethasone-induced enhancement of resistance to ionizing radiation and chemotherapeutic agents in human tumor cells

    International Nuclear Information System (INIS)

    Background: Dexamethasone-induced changes in radioresistance have previously been observed by several authors. Here, we examined effects of dexamethasone on resistance to ionizing radiation in 10 additional human cell lines and strains, and on resistance to carboplatin and paclitaxel in 13 fresh tumor samples. Material and Methods: Eight human carcinoma cell lines, a glioblastoma cell line and a strain of normal human diploid fibroblasts were arbitrarily chosen for these in-vitro studies. Effects on radiosensitivity were assessed using a conventional colony formation assay. Effects on resistance to the drugs were investigated prospectively (ATP cell viability assay) using 13 fresh tumor samples from consecutive patients operated for ovarian cancer within the context of a Swiss nation-wide randomized prospective clinical trial (SAKK 45/94). Results: Dexamethasone promoted proliferation of 1 of the cell lines without affecting radiosensitivity, while it completely inhibited proliferation of another cell line (effects on radiosensitivity could thus not be examined). Furthermore, dexamethasone induced enhanced radioresistance in 1 of the 8 carcinoma cell lines examined. In the glioblastoma cell line, there was no effect on growth or radioresistance, nor in the fibroblasts. Treatment with dexamethasone enhanced resistance of the malignant cells to carboplatin in 4 of the 13 fresh tumor samples examined, while no enhancement in resistance to paclitaxel was observed. Conclusions: In agreement with previous reports, we found that dexamethasone may induce radioresistance in human carcinoma cells. Including the published data from the literature, dexamethasone induced enhancement in radioresistance in 4 of 12 carcinoma cell lines (33%), but not in 3 glioblastoma cell lines, nor in 3 fibroblast strains. Dexamethasone also induced enhanced resistance to carboplatin with a similar probability in fresh samples of ovarian cancer evaluated prospectively (in 4 of 13 samples; 31

  12. Frequency filtering based analysis on the cardiac induced lung tumor motion and its impact on the radiotherapy management

    International Nuclear Information System (INIS)

    Purpose/objectives: Lung tumor motion may be impacted by heartbeat in addition to respiration. This study seeks to quantitatively analyze heart-motion-induced tumor motion and to evaluate its impact on lung cancer radiotherapy. Methods/materials: Fluoroscopy images were acquired for 30 lung cancer patients. Tumor, diaphragm, and heart were delineated on selected fluoroscopy frames, and their motion was tracked and converted into temporal signals based on deformable registration propagation. The clinical relevance of heart impact was evaluated using the dose volumetric histogram of the redefined target volumes. Results: Correlation was found between tumor and cardiac motion for 23 patients. The heart-induced motion amplitude ranged from 0.2 to 2.6 mm. The ratio between heart-induced tumor motion and the tumor motion was inversely proportional to the amplitude of overall tumor motion. When the heart motion impact was integrated, there was an average 9% increase in internal target volumes for 17 patients. Dose coverage decrease was observed on redefined planning target volume in simulated SBRT plans. Conclusions: The tumor motion of thoracic cancer patients is influenced by both heart and respiratory motion. The cardiac impact is relatively more significant for tumor with less motion, which may lead to clinically significant uncertainty in radiotherapy for some patients

  13. INDOLEAMINE 2,3-DIOXYGENASE INDUCES EXPRESSION OF A NOVEL TRYPTOPHAN TRANSPORTER IN MOUSE AND HUMAN TUMOR CELLS1

    OpenAIRE

    Silk, Jonathan D.; Lakhal, Samira; Laynes, Robert; Vallius, Laura; Karydis, Ioannis; Marcea, Cornelius; Boyd, C. A. Richard; Cerundolo, Vincenzo

    2011-01-01

    Indoleamine 2,3 dioxygenase (IDO) is the rate-limiting enzyme in the kynurenine pathway, catabolizing tryptophan to kynurenine. Tryptophan depletion by IDO expressing tumors is a common mechanism of immune evasion inducing regulatory T cells and inhibiting effector T cells. As mammalian cells cannot synthesize tryptophan, it remains unclear how IDO positive tumor cells overcome the detrimental effects of local tryptophan depletion.

  14. Manipulation of gene expression by an ecdysone-inducible gene switch in tumor xenografts

    Directory of Open Access Journals (Sweden)

    Gulding Kathryn M

    2001-12-01

    Full Text Available abstract Background Rapid, robust and reversible induction of transgene expression would significantly facilitate cancer gene therapy as well as allow the in vivo functional study of newly discovered genes in tumor formation and progression. The popularity of the ecdysone inducible gene switch system has led us to investigate whether such a system can successfully regulate gene expression in a syngeneic tumor system in vivo. Results MBT-2 and Panc02 carcinoma cells were transfected with components of a modification of the ecdysone switch system driving firefly luciferase (F-Luc. In vitro luciferase expression ± ecdysone analog GS-E indicated a robust induction with minimal baseline activity and complete decay after 24 hours without drug. In vitro selection of MBT-2 transfected cell clones which had complete absence of F-Luc expression in the absence of stimulation but which expressed this gene at high levels in response to GS-E were chosen for in vivo evaluation. Tumors from engineered MBT-2 cells were grown to 5 mm in diameter prior to GS-E administration, animals euthanized and tumors removed at 6, 12 and 24 hours after GS-E administration and assayed for F-Luc activity. GS-E resulted in a maximal induction of F-Luc activity at 6 hours in tumor tissue with almost complete reversion to control levels by 12 hours. Conclusions This study is the first demonstration that robust and reversible transgene expression in tumors is feasible using the ecdysone system, allowing future rapid in vivo functional characterization of gene function or gene therapy applications.

  15. Aloe vera non-decolorized whole leaf extract-induced large intestinal tumors in F344 rats share similar molecular pathways with human sporadic colorectal tumors.

    Science.gov (United States)

    Pandiri, Arun R; Sills, Robert C; Hoenerhoff, Mark J; Peddada, Shyamal D; Ton, Thai-Vu T; Hong, Hue-Hua L; Flake, Gordon P; Malarkey, David E; Olson, Greg R; Pogribny, Igor P; Walker, Nigel J; Boudreau, Mary D

    2011-12-01

    Aloe vera is one of the most commonly used botanicals for various prophylactic and therapeutic purposes. Recently, NTP/NCTR has demonstrated a dose-dependent increase in large intestinal tumors in F344 rats chronically exposed to Aloe barbadensis Miller (Aloe vera) non-decolorized whole leaf extract (AVNWLE) in drinking water. The morphological and molecular pathways of AVNWLE-induced large intestinal tumors in the F344 rats were compared to human colorectal cancer (hCRC) literature. Defined histological criteria were used to compare AVNWLE-induced large intestinal tumors with hCRC. The commonly mutated genes (Kras, Ctnnb1, and Tp53) and altered signaling pathways (MAPK, WNT, and TGF-β) important in hCRC were evaluated within AVNWLE-induced large intestinal tumors. Histological evaluation of the large intestinal tumors indicated eight of twelve adenomas (Ads) and four of twelve carcinomas (Cas). Mutation analysis of eight Ads and four Cas identified point mutations in exons 1 and 2 of the Kras gene (two of eight Ads, two of four Cas), and in exon 2 of the Ctnnb1 gene (three of eight Ads, one of four Cas). No Tp53 (exons 5-8) mutations were found in Ads or Cas. Molecular pathways important in hCRC such as MAPK, WNT, and TGF-β signaling were also altered in AVNWLE-induced Ads and Cas. In conclusion, the AVNWLE-induced large intestinal tumors in F344 rats share several similarities with hCRC at the morphological and molecular levels. PMID:21937742

  16. Anti-ganglioside antibody-induced tumor cell death by loss of membrane integrity.

    Science.gov (United States)

    Roque-Navarro, Lourdes; Chakrabandhu, Krittalak; de León, Joel; Rodríguez, Sandra; Toledo, Carlos; Carr, Adriana; de Acosta, Cristina Mateo; Hueber, Anne-Odile; Pérez, Rolando

    2008-07-01

    Gangliosides have been involved in multiple cellular processes such as growth, differentiation and adhesion, and more recently as regulators of cell death signaling pathways. Some of these molecules can be considered as tumor-associated antigens, in particular, N-glycolyl sialic acid-containing gangliosides, which are promising candidates for cancer-targeted therapy because of their low expression in normal human tissues. In this study, we provided the molecular and cellular characterization of a novel cell death mechanism induced by the anti-NGcGM3 14F7 monoclonal antibody (mAb) in L1210 murine tumor cell line but not in mouse normal cells (B and CD4(+) T lymphocytes) that expressed the antigen. Impairment of ganglioside synthesis in tumor cells abrogated the 14F7 mAb cytotoxic effect; however, exogenous reincorporation of the ganglioside did not restore tumor cell sensitivity to 14F7 mAb-induced cytotoxicity. 14F7 F(ab')(2) but not Fab fragments retained the cytotoxic capacity of the whole mAb. By contrary, other mAb, which recognizes N-glycolylated gangliosides, did not show any cytotoxic effect. These mAbs showed quite different capacities to bind NGcGM3-positive cell lines measured by binding inhibition experiments. Interestingly, this complement-independent cell death mechanism did not resemble apoptosis, because no DNA fragmentation, caspase activation, or Fas mediation were observed. However, NGcGM3 ganglioside-mediated 14F7 mAb-induced cell death was accompanied by cellular swelling, membrane lesion formation, and cytoskeleton activation, suggesting an oncosis-like phenomenon. This novel mechanism of cell death lets us to support further therapeutic approaches using NGcGM3 as a molecular target for antibody-based cancer immunotherapy. PMID:18645013

  17. Xanthine crystals induced by topiroxostat, a xanthine oxidoreductase inhibitor, in rats, cause transitional cell tumors.

    Science.gov (United States)

    Shimo, Takeo; Moto, Mitsuyoshi; Ashizawa, Naoki; Matsumoto, Koji; Iwanaga, Takashi; Saito, Kazuhiro

    2014-04-01

    The present study was performed to elucidate the underlying mechanism of transitional cell tumors found in the carcinogenicity testing of topiroxostat, a xanthine oxidoreductase inhibitor, in which topiroxostat was orally given to F344 rats at 0.3, 1, and 3 mg/kg for 2 years. In the urinary bladder, transitional cell papillomas and/or carcinomas were seen in males receiving 0.3, 1, and 3 mg/kg (1/49, 3/49, and 10/50, respectively). In the kidney, transitional cell papillomas and/or carcinomas in the pelvis were seen in 2/50 males and 1/50 females receiving 3 mg/kg. In the mechanistic study by 52-week oral treatment with topiroxostat at 3 mg/kg to F344 male rats, with and without citrate, simple and papillary transitional cell hyperplasias of the urinary bladder epithelium were observed in 5/17 in the topiroxostat-alone treatment group, along with xanthine-induced nephropathy, in contrast to neither xanthine crystals nor lesions in urinary organs by co-treatment group with citrate. As for sex differences of urinary bladder tumors, the BrdU labeling index for epithelial cells of the urinary bladder by 5-week oral treatment with topiroxostat at 10 mg/kg to F344 rats was increased in males only, showing consistency with histopathological findings. Therefore, the present study indicates that transitional cell tumors induced by topiroxostat in rats were due to physical stimulation to transitional cells of xanthine crystals/calculi and provides that other factors were not implicated in this tumorigenesis. Furthermore, the present study suggests that such tumors do not predict for humans since topiroxostat-induced xanthine deposition is a rodent-specific event. PMID:24448833

  18. M-CSF from Cancer Cells Induces Fatty Acid Synthase and PPARβ/δ Activation in Tumor Myeloid Cells, Leading to Tumor Progression

    Directory of Open Access Journals (Sweden)

    Jonghanne Park

    2015-03-01

    Full Text Available We investigate crosstalk between cancer cells and stromal myeloid cells. We find that Lewis lung carcinoma cells significantly induce PPARβ/δ activity in myeloid cells in vitro and in vivo. Myeloid cell-specific knockout of PPARβ/δ results in impaired growth of implanted tumors, and this is restored by adoptive transfer of wild-type myeloid cells. We find that IL-10 is a downstream effector of PPARβ/δ and facilitates tumor cell invasion and angiogenesis. This observation is supported by the finding that the CD11blowIL-10+ pro-tumoral myeloid cell is scarcely detected in tumors from myeloid-cell-specific PPARβ/δ knockout mice, where vessel densities are also decreased. Fatty acid synthase (FASN is shown to be an upstream regulator of PPARβ/δ in myeloid cells and is induced by M-CSF secreted from tumor cells. Our study gives insight into how cancer cells influence myeloid stromal cells to get a pro-tumoral phenotype.

  19. A dicyanotriterpenoid induces cytoprotective enzymes and reduces multiplicity of skin tumors in UV-irradiated mice

    International Nuclear Information System (INIS)

    Inducible phase 2 enzymes constitute a primary line of cellular defense. The oleanane dicyanotriterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile (TP-225) is a very potent inducer of these systems. Topical application of TP-225 to SKH-1 hairless mice increases the levels of NAD(P)H-quinone acceptor oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO-1) and protects against UV radiation-induced dermal thickening. Daily topical treatments of 10 nmol of TP-225 to the backs of mice that were previously subjected to low-level chronic UVB radiation (30 mJ/cm2/session, twice a week for 17 weeks), led to 50% reduction in multiplicity of skin tumors. In addition, the total tumor burden of squamous cell carcinomas was reduced by 5.5-fold. The identification of new agents for protection against UV radiation-induced skin cancer and understanding of their mechanism(s) of action is especially important in view of the fact that human skin cancers represent a significant source of increasing morbidity and mortality

  20. Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone Hsp70

    OpenAIRE

    Maheswaran, Shyamala; Englert, Christoph; Zheng, Gang; Lee, Sean Bong; Wong, Jenise; Harkin, D Paul; Bean, James; Ezzell, Robert; Garvin, A. Julian; McCluskey, Robert T.; DeCaprio, James A.; Haber, Daniel A.

    1998-01-01

    The Wilms tumor suppressor WT1 encodes a zinc finger transcription factor that is expressed in glomerular podocytes during a narrow window in kidney development. By immunoprecipitation and protein microsequencing analysis, we have identified a major cellular protein associated with endogenous WT1 to be the inducible chaperone Hsp70. WT1 and Hsp70 are physically associated in embryonic rat kidney cells, in primary Wilms tumor specimens and in cultured cells with inducible expression of WT1. Co...

  1. [Management of metabolic disorders induced by everolimus in patients with differentiated neuroendocrine tumors: expert proposals].

    Science.gov (United States)

    Lombard-Bohas, Catherine; Cariou, Bertrand; Vergès, Bruno; Coriat, Romain; N'guyen, Thierry; François, Eric; Hammel, Pascal; Niccoli, Patricia; Hentic, Olivia

    2014-02-01

    Medical management of pancreatic neuroendocrine tumors has recently been improved by new molecules of which the mTOR inhibitor everolimus. If digestive neuroendocrine tumors are rare, the incidence is in constant increase and the prevalence in digestive cancers put them right behind colorectal cancers. Everolimus has demonstrated efficacy in unresectable and progressive pancreatic neuroendocrine tumors, by doubling the median progression free survival (11 versus 4.6 months), with a median time of exposure to everolimus of nine months. Everolimus is generally maintained until progression or intolerance and some patients are treated during several years. Potential metabolic disorders induced by everolimus (dyslipidemia, hyperglycemia) in patients with life expectancy of several years, justify monitoring of these parameters and accurate treatment management algorithm. These will avoid worsening patient's prognostic, but also prematurely discontinue potentially effective treatment or contraindicate other therapeutic weapons, in a pathology in which there are multiple therapeutic options in metastatic phase. We propose a standard practice in terms of initial assessment, monitoring, care threshold, and therapeutic objectives to manage metabolic disorders, fitted to our patients with advanced pancreatic neuroendocrine tumors. PMID:24557872

  2. Novel allelic mutations in murine Serca2 induce differential development of squamous cell tumors.

    Science.gov (United States)

    Toki, Hideaki; Minowa, Osamu; Inoue, Maki; Motegi, Hiromi; Karashima, Yuko; Ikeda, Ami; Kaneda, Hideki; Sakuraba, Yoshiyuki; Saiki, Yuriko; Wakana, Shigeharu; Suzuki, Hiroshi; Gondo, Yoichi; Shiroishi, Toshihiko; Noda, Tetsuo

    2016-08-01

    Dominant mutations in the Serca2 gene, which encodes sarco(endo)plasmic reticulum calcium-ATPase, predispose mice to gastrointestinal epithelial carcinoma [1-4] and humans to Darier disease (DD) [14-17]. In this study, we generated mice harboring N-ethyl-N-nitrosourea (ENU)-induced allelic mutations in Serca2: three missense mutations and one nonsense mutation. Mice harboring these Serca2 mutations developed tumors that were categorized as either early onset squamous cell tumors (SCT), with development similar to null-type knockout mice [2,4] (aggressive form; M682, M814), or late onset tumors (mild form; M1049, M1162). Molecular analysis showed no aberration in Serca2 mRNA or protein expression levels in normal esophageal cells of any of the four mutant heterozygotes. There was no loss of heterozygosity at the Serca2 locus in the squamous cell carcinomas in any of the four lines. The effect of each mutation on Ca(2+)-ATPase activity was predicted using atomic-structure models and accumulated mutated protein studies, suggesting that putative complete loss of Serca2 enzymatic activity may lead to early tumor onset, whereas mutations in which Serca2 retains residual enzymatic activity result in late onset. We propose that impaired Serca2 gene product activity has a long-term effect on squamous cell carcinogenesis from onset to the final carcinoma stage through an as-yet unrecognized but common regulatory pathway. PMID:27131742

  3. Reprogramming of Melanoma Tumor-Infiltrating Lymphocytes to Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Hidehito Saito

    2016-01-01

    Full Text Available Induced pluripotent stem cells (iPSCs derived from somatic cells of patients hold great promise for autologous cell therapies. One of the possible applications of iPSCs is to use them as a cell source for producing autologous lymphocytes for cell-based therapy against cancer. Tumor-infiltrating lymphocytes (TILs that express programmed cell death protein-1 (PD-1 are tumor-reactive T cells, and adoptive cell therapy with autologous TILs has been found to achieve durable complete response in selected patients with metastatic melanoma. Here, we describe the derivation of human iPSCs from melanoma TILs expressing high level of PD-1 by Sendai virus-mediated transduction of the four transcription factors, OCT3/4, SOX2, KLF4, and c-MYC. TIL-derived iPSCs display embryonic stem cell-like morphology, have normal karyotype, express stem cell-specific surface antigens and pluripotency-associated transcription factors, and have the capacity to differentiate in vitro and in vivo. A wide variety of T cell receptor gene rearrangement patterns in TIL-derived iPSCs confirmed the heterogeneity of T cells infiltrating melanomas. The ability to reprogram TILs containing patient-specific tumor-reactive repertoire might allow the generation of patient- and tumor-specific polyclonal T cells for cancer immunotherapy.

  4. Volume changes of A-Mel 3 tumor cells induced by photodynamic treatment

    International Nuclear Information System (INIS)

    PhotoDynamic Therapy has shown promising results in treatment of super-ficial malignant T1/T2 tumors through combining systematically administered photosensitizing HematoPorhyrin-Derivative and local application of light. Mechanisms leading to tumor destruction during PDT are still not completely understood. Generation of singlet oxygen by a type II photochemical reaction is reported to be primarily responsible for the cytotoxicity induced by PDT. Besides significant effects on microcirculation damage to plasma membranes, cytoplasmic organelles and enzymes, as well as to nuclear structures and enzymes, was observed following exposure cells to PDT. A phenomenon probably proceeding these events might be cell swelling. Already Meyer-Betz showed that a time- and dose-dependent swelling and edema formation of healthy skin occurs after PDT. Direct correlation between ear swelling response of albino mice and the concentration of Photofrin II in the blood at the same time of light exposure has been reported recently. Various studies indicating tumor tissue swelling following PDT without being able to discriminate if this is due to cell swelling or interstitial fluid accumulation. Therefore the influence was studied of treatment with HPD and laser light on volume changes of tumor cells and its relation to cell viability. (author). 20 refs

  5. Role of Tertiary Lymphoid Structures (TLS) in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Pimenta, Erica M. [Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, Newark, NJ 07103 (United States); Barnes, Betsy J., E-mail: barnesbe@njms.rutgers.edu [Department of Biochemistry and Molecular Biology, Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, Newark, NJ 07103 (United States)

    2014-04-23

    Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin{sup ®}) and rituximab (Rituxan{sup ®})) and the first approved cancer vaccine, Provenge{sup ®} (sipuleucel-T), investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS) within the tumor microenvironment may be used to enhance immunotherapy response.

  6. Role of Tertiary Lymphoid Structures (TLS) in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

    International Nuclear Information System (INIS)

    Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin®) and rituximab (Rituxan®)) and the first approved cancer vaccine, Provenge® (sipuleucel-T), investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS) within the tumor microenvironment may be used to enhance immunotherapy response

  7. Role of Tertiary Lymphoid Structures (TLS in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

    Directory of Open Access Journals (Sweden)

    Erica M. Pimenta

    2014-04-01

    Full Text Available Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin® and rituximab (Rituxan® and the first approved cancer vaccine, Provenge® (sipuleucel-T, investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS within the tumor microenvironment may be used to enhance immunotherapy response.

  8. Ursolic acid-loaded chitosan nanoparticles induce potent anti-angiogenesis in tumor.

    Science.gov (United States)

    Jin, Hua; Pi, Jiang; Yang, Fen; Wu, Chaomin; Cheng, Xueli; Bai, Haihua; Huang, Dan; Jiang, Jinhuan; Cai, Jiye; Chen, Zheng W

    2016-08-01

    Angiogenesis provides necessary nutrients and oxygen for tumor growth and metastasis; thus, every stage of angiogenesis process is the potential target for cancer therapies. Ursolic acid (UA) is reported to decrease tumor burden through anti-angiogenesis pathway, but its poor water solubility greatly limits its efficiency and clinical application. Here, a simple method for preparing UA-loaded chitosan nanoparticles (CH-UA-NPs) with anti-angiogenesis and anti-tumor activity was demonstrated. In vitro, CH-UA-NPs could significantly inhibit the proliferation, migration, and tube formation of human umbilical vascular endothelial cells (HUVECs). After uptake by HUVECs, CH-UA-NPs were mainly localized in lysosomes and mitochondria, but not nuclei. CH-UA-NPs induced the destruction of lysosome membrane integrity, collapse of mitochondrial membrane potential, and reorganization of cell cytoskeleton. All these changes led to the apoptosis or necrosis in HUVECs. In vivo, CH-UA-NPs could inhibit the angiogenesis in chicken chorioallantoic membrane (CAM) model and H22 xenograft model. Notably, comparing with free UA, such synthesized CH-UA-NPs could save about tenfold of UA doses, implying that this could significantly decrease the side effects induced by high doses of UA in biological organism. Our data showed that CH-UA-NPs and this nanoparticle-based drug delivery system could be as a potential drug candidate for anti-angiogenesis treatment. PMID:26883344

  9. Molecular and cytogenetic characterization of radon-induced lung tumors in the rat

    International Nuclear Information System (INIS)

    Radon is a natural radioactive gas. This radioelement, which is an α-particle emitter, is omnipresent in the environment. Inhalation of atmospheric radon is the major exposure route in man of natural radioactivity which results in respiratory tract contamination. An increased lung cancer risk associated with radon inhalation has been shown both in humans and animals by epidemiological and experimental studies, respectively. In rats, characterization of dose-effect relationships has led to the construction of statistical models that may help theoretically in the prediction of human health involvements of both occupational and domestic chronic exposure to radon. However, little is known about the cellular and molecular mechanisms of radon-induced lung carcinogenesis. In the laboratory, a model of lung cancers induced in rats after radon inhalation is available. This model represents a good tool to identify and characterize the genetic events contributing to the development of radon-induced lung tumors. Carrying out a global approach based on the combined use of classical and molecular cytogenetic methods, the analysis of 17 neoplasms allowed the identification of chromosomal regions frequently altered in these tumors. Numerous similarities have been found between our results and the cytogenetic data for human lung cancers, suggesting common underlying genetic molecular mechanisms for lung cancer development in both species. Moreover, our study has allowed to point to tumor suppressor genes and proto-oncogenes potentially involved in radon-induced lung carcinogenesis. Thus, our results may aid further molecular studies aimed either at confirming the role of these candidate genes or at demonstrating the involvement of yet to be identified genes. (author)

  10. Novel molecular and computational methods improve the accuracy of insertion site analysis in Sleeping Beauty-induced tumors.

    Directory of Open Access Journals (Sweden)

    Benjamin T Brett

    Full Text Available The recent development of the Sleeping Beauty (SB system has led to the development of novel mouse models of cancer. Unlike spontaneous models, SB causes cancer through the action of mutagenic transposons that are mobilized in the genomes of somatic cells to induce mutations in cancer genes. While previous methods have successfully identified many transposon-tagged mutations in SB-induced tumors, limitations in DNA sequencing technology have prevented a comprehensive analysis of large tumor cohorts. Here we describe a novel method for producing genetic profiles of SB-induced tumors using Illumina sequencing. This method has dramatically increased the number of transposon-induced mutations identified in each tumor sample to reveal a level of genetic complexity much greater than previously appreciated. In addition, Illumina sequencing has allowed us to more precisely determine the depth of sequencing required to obtain a reproducible signature of transposon-induced mutations within tumor samples. The use of Illumina sequencing to characterize SB-induced tumors should significantly reduce sampling error that undoubtedly occurs using previous sequencing methods. As a consequence, the improved accuracy and precision provided by this method will allow candidate cancer genes to be identified with greater confidence. Overall, this method will facilitate ongoing efforts to decipher the genetic complexity of the human cancer genome by providing more accurate comparative information from Sleeping Beauty models of cancer.

  11. Immunogenic Cell Death Induced by Ginsenoside Rg3: Significance in Dendritic Cell-based Anti-tumor Immunotherapy.

    Science.gov (United States)

    Son, Keum-Joo; Choi, Ki Ryung; Lee, Seog Jae; Lee, Hyunah

    2016-02-01

    Cancer is one of the leading causes of morbidity and mortality worldwide; therefore there is a need to discover new therapeutic modules with improved efficacy and safety. Immune-(cell) therapy is a promising therapeutic strategy for the treatment of intractable cancers. The effectiveness of certain chemotherapeutics in inducing immunogenic tumor cell death thus promoting cancer eradication has been reported. Ginsenoside Rg3 is a ginseng saponin that has antitumor and immunomodulatory activity. In this study, we treated tumor cells with Rg3 to verify the significance of inducing immunogenic tumor cell death in antitumor therapy, especially in DC-based immunotherapy. Rg3 killed the both immunogenic (B16F10 melanoma cells) and non-immunogenic (LLC: Lewis Lung Carcinoma cells) tumor cells by inducing apoptosis. Surface expression of immunogenic death markers including calreticulin and heat shock proteins and the transcription of relevant genes were increased in the Rg3-dying tumor. Increased calreticulin expression was directly related to the uptake of dying tumor cells by dendritic cells (DCs): the proportion of CRT(+) CD11c(+) cells was increased in the Rg3-treated group. Interestingly, tumor cells dying by immunogenic cell death secreted IFN-γ, an effector molecule for antitumor activity in T cells. Along with the Rg3-induced suppression of pro-angiogenic (TNF-α) and immunosuppressive cytokine (TGF-β) secretion, IFN-γ production from the Rg3-treated tumor cells may also indicate Rg3 as an effective anticancer immunotherapeutic strategy. The data clearly suggests that Rg3-induced immunogenic tumor cell death due its cytotoxic effect and its ability to induce DC function. This indicates that Rg3 may be an effective immunotherapeutic strategy. PMID:26937234

  12. Amplification of tumor inducing putative cancer stem cells (CSCs) by vitamin A/retinol from mammary tumors

    International Nuclear Information System (INIS)

    Highlights: •Vitamin A supports self renewal of putative CSCs from mammary tumors. •These cells exhibit impaired retinol metabolism into retinoic acid. •CSCs from mammary tumors differentiate into mammary specific cell lineages. •The cells express mammary stem cell specific CD29 and CD49f markers. •Putative CSCs form highly metastatic tumors in NOD SCID mouse. -- Abstract: Solid tumors contain a rare population of cancer stem cells (CSCs) that are responsible for relapse and metastasis. The existence of CSC however, remains highly controversial issue. Here we present the evidence for putative CSCs from mammary tumors amplified by vitamin A/retinol signaling. The cells exhibit mammary stem cell specific CD29hi/CD49fhi/CD24hi markers, resistance to radiation and chemo therapeutic agents and form highly metastatic tumors in NOD/SCID mice. The cells exhibit indefinite self renewal as cell lines. Furthermore, the cells exhibit impaired retinol metabolism and do not express enzymes that metabolize retinol into retinoic acid. Vitamin A/retinol also amplified putative CSCs from breast cancer cell lines that form highly aggressive tumors in NOD SCID mice. The studies suggest that high purity putative CSCs can be isolated from solid tumors to establish patient specific cell lines for personalized therapeutics for pre-clinical translational applications. Characterization of CSCs will allow understanding of basic cellular and molecular pathways that are deregulated, mechanisms of tumor metastasis and evasion of therapies that has direct clinical relevance

  13. Mitochondrial-derived ROS in edelfosine-induced apoptosis in yeasts and tumor cells

    Institute of Scientific and Technical Information of China (English)

    Hui ZHANG; Consuelo GAJATE; Li-ping YU; Yun-xiang FANG; Faustino MOLLINEDO

    2007-01-01

    Aim: To investigate whether a similar process mediates cytotoxicity of 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET- 18-OCH3, edelfosine) in both yeasts and human tumor cells.Methods: A modified version of a previously described assay for the intracellular conversion of nitro blue tetrazolium to formazan by superoxide anion was used to measure the generation of reactive oxygen spe-cies (ROS). Apoptotic yeast cells were detected using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. DNA fragmenta-tion and the generation of ROS were measured by cytofluorimetric analysis in Jurkat cells.Results: Edelfosine induced apoptosis in Saccharomyces cerevisiae,as assessed by TUNEL assay. Meanwhile, edelfosine induced a time- and con-centration-dependent generation of ROS in yeasts. Rotenone, an inhibitor of the mitochondrial electron transport chain, prevented ROS generation and apoptosis in response to edelfosine in S cerevisiae, α-Tocopherol abrogated the edelfosine-induced generation of intracellular ROS and apoptosis. Edelfosine also induced an increase of ROS in human leukemic cells that preceded apoptosis. The overexpression of Bcl-2 by gene transfer abrogated both ROS generation and apoptosis induced by edelfosine in leukemic cells. Changes in the relative mito-chondrial membrane potential were detected in both yeasts and Jurkat cells.Conclusion: These results indicate that edelfosine induces apoptosis in yeasts in addition to human tumor cells, and this apoptotic process involves mitochondria,likely through mitochondrial-derived ROS. These data also suggest that yeasts can be used as a suitable cell model in elucidating the antitumor mechanism of action of edelfosine.

  14. Coupling of discrete random walks and continuous modeling for three-dimensional tumor-induced angiogenesis

    Science.gov (United States)

    Vilanova, Guillermo; Colominas, Ignasi; Gomez, Hector

    2014-03-01

    The growth of new vascular networks from pre-existing capillaries (angiogenesis) plays a pivotal role in tumor development. Mathematical modeling of tumor-induced angiogenesis may help understand the underlying biology of the process and provide new hypotheses for experimentation. Here, we couple an existing deterministic continuum theory with a discrete random walk, proposing a new model that accounts for chemotactic and haptotactic cellular migration. We propose an efficient numerical method to approximate the solution of the model. The accuracy, stability and effectiveness of our algorithms permitted us to perform large-scale three-dimensional simulations which, in contrast to two-dimensional calculations, show a topological complexity similar to that found in experiments. Finally, we use our model and simulations to investigate the role of haptotaxis and chemotaxis in the mobility of tip endothelial cells and its influence in the final vascular patterns.

  15. Active adjoint modeling method in microwave induced thermoacoustic tomography for breast tumor.

    Science.gov (United States)

    Zhu, Xiaozhang; Zhao, Zhiqin; Wang, Jinguo; Chen, Guoping; Liu, Qing Huo

    2014-07-01

    To improve the model-based inversion performance of microwave induced thermoacoustic tomography for breast tumor imaging, an active adjoint modeling (AAM) method is proposed. It aims to provide a more realistic breast acoustic model used for tumor inversion as the background by actively measuring and reconstructing the structural heterogeneity of human breast environment. It utilizes the reciprocity of acoustic sensors, and adapts the adjoint tomography method from seismic exploration. With the reconstructed acoustic model of breast environment, the performance of model-based inversion method such as time reversal mirror is improved significantly both in contrast and accuracy. To prove the advantage of AAM, a checkerboard pattern model and anatomical realistic breast models have been used in full wave numerical simulations. PMID:24956614

  16. Electron microscopic observations and DNA chain fragmentation studies on apoptosis in bone tumor cells induced by 153Sm—EDTMP

    Institute of Scientific and Technical Information of China (English)

    ZhuShou-Peng; XiaoDong; 等

    1997-01-01

    The morphological changes observed by electron microscopy indicate that after internal irradiation with 153Sm-ESTMP bone tumor cells displayed feature of apoptosis,such as margination of condensed chromatin,chromatin fragmentation.as well as the membranebouded apoptotic bodies formation.THe quantification analysis of fragmentation DNA for bone tumor cells induced by 153Sm-EDTMP shows that the DNA fragmentation is enhanced with the prolongation of internally irradiated time.These characteristics suggest that 153Sm-EDTMP internal irradiation could induce bone tumor cells to go9 to apoptosis.

  17. Electron microscopic observations and DNA chain fragmentation studies on apoptosis in bone tumor cells induced by 153Sm-EDTMP

    International Nuclear Information System (INIS)

    The morphological changes observed by electron microscopy indicate that after internal irradiation with 153Sm-EDTMP bone tumor cells displayed feature of apoptosis, such as margination of condensed chromatin, chromatin fragmentation, as well as the membrane bounded apoptotic bodies formation. The quantification analysis of fragmentation DNA for bone tumor cells induced by 153Sm-EDTMP shows that the DNA fragmentation is enhanced with the prolongation of internally irradiated time. These characteristics suggest that 153Sm-EDTMP internal irradiation could induce bone tumor cells to go to apoptosis

  18. Advances in identification and application of tumor antigen inducing anti-cancer responses

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    @@ Tumor antigen is one of the important bases of tumor immunotherapy[1]. With the discovery of novel tumor antigens, interest in specific immunotherapy for treatment of malignancies has increased substantially. Nowadays more and more scientists paid close attention to various tumor antigens with their roles or/and applications in anti-cancer immune responses, immune tolerance, tumor markers, tumor immunotherapy and so on. Here we discussed the classification of tumor antigens and summarized the technologies of identification and application of tumor antigens.

  19. Comparison of bone tumors induced by beta-emitting or alpha-emitting radionuclides: Schemes of pathogenesis

    International Nuclear Information System (INIS)

    Life-span studies in Beagle dogs have documented the occurrence of bone tumors following exposure to bone-seeking alpha- or beta-emitting radionuclides administered by different routes of exposure. Bone tumors from dogs in four different life-span studies were analyzed according to tumor phenotype, tumor location, radiographic appearance, incidence of metastasis, and association with radiation osteodystrophy. Marked differences in these parameters were observed that did not correlate with differences in radionuclide type, route of exposure, or duration of radionuclide uptake. Radiation osteodystrophy, which is postulated to be a preneoplastic lesion, was not a significant component in one of the studies. Analysis of the data from these four studies suggests that at least two different mechanisms of bone tumor pathogenesis occur for radiation-induced bone tumors. (author)

  20. Enhancement of tumor necrosis factor-induced endothelial cell injury by cycloheximide

    International Nuclear Information System (INIS)

    Tumor necrosis factor (TNF), a potent polypeptide mediator released by activated monocytes and macrophages, has a number of proinflammatory effects on endothelial cells. TNF is cytotoxic to tumor cells in vivo and in vitro, but TNF-induced toxicity to endothelial cells is less well established. We now report that cycloheximide (CHX), an inhibitor of protein synthesis, renders endothelial cells highly susceptible to TNF-induced lysis. TNF alone did not change the overall rate of protein synthesis by endothelial cells, whereas the addition of CHX completely abolished protein synthesis. Endothelial cells incubated in TNF alone in high concentrations (up to 1,000 U/ml) showed minimal rounding up and release of 51Cr. Likewise, CHX alone (5 micrograms/ml) had no significant effect on endothelial cell morphology and release of 51Cr. However, incubation of endothelial cells in both CHX and TNF caused injury in a dose-dependent manner. Morphological evidence of cell retraction, rounding, and detachment began within 2 h, but specific 51Cr release did not begin to rise until after 4 h. These changes were not observed when endothelial cells were incubated with TNF/CHX at 4 degrees C. The combination of TNF/CHX was lethal to all endothelial cells tested (bovine pulmonary artery, human umbilical vein, and human aorta), with human aortic cells showing the most pronounced changes. We conclude that healthy endothelial cells are resistant to TNF-induced lysis, but inhibition of their ability to make protein renders them highly susceptible

  1. Cks1 is required for tumor cell proliferation but not sufficient to induce hematopoietic malignancies.

    Science.gov (United States)

    Kratzat, Susanne; Nikolova, Viktoriya; Miething, Cornelius; Hoellein, Alexander; Schoeffmann, Stephanie; Gorka, Oliver; Pietschmann, Elke; Illert, Anna-Lena; Ruland, Jürgen; Peschel, Christian; Nilsson, Jonas; Duyster, Justus; Keller, Ulrich

    2012-01-01

    The Cks1 component of the SCF(Skp2) complex is necessary for p27(Kip1) ubiquitylation and degradation. Cks1 expression is elevated in various B cell malignancies including Burkitt lymphoma and multiple myeloma. We have previously shown that loss of Cks1 results in elevated p27(Kip1) levels and delayed tumor development in a mouse model of Myc-induced B cell lymphoma. Surprisingly, loss of Skp2 in the same mouse model also resulted in elevated p27(Kip1) levels but exhibited no impact on tumor onset. This raises the possibility that Cks1 could have other oncogenic activities than suppressing p27(Kip1). To challenge this notion we have targeted overexpression of Cks1 to B cells using a conditional retroviral bone marrow transduction-transplantation system. Despite potent ectopic overexpression, Cks1 was unable to promote B cell hyperproliferation or B cell malignancies, indicating that Cks1 is not oncogenic when overexpressed in B cells. Since Skp2 overexpression can drive T-cell tumorigenesis or other cancers we also widened the quest for oncogenic activity of Cks1 by ubiquitously expressing Cks1 in hematopoetic progenitors. At variance with c-Myc overexpression, which caused acute myeloid leukemia, Cks1 overexpression did not induce myeloproliferation or leukemia. Therefore, despite being associated with a poor prognosis in various malignancies, sole Cks1 expression is insufficient to induce lymphoma or a myeloproliferative disease in vivo. PMID:22624029

  2. A case of radiation-induced mucoepidermoid carcinoma of the lung following radiotherapy for pulmonary metastasis of Wilms' tumor

    International Nuclear Information System (INIS)

    Radiotherapy is one of the main therapeutic methods for malignant tumors, but on the other hand it can also induce new malignant tumors. Recently, we experienced a case of a 22-year-old woman with triple cancers (Wilms' tumor, thyroid cancer and mucoepidermoid carcinoma of the lung). She had been treated repeatedly for right-sided pulmonary metastases from the Wilms' tumor. The last cancer arose from a different organ in the field irradiated to treat the first cancer, after a latent period of about 20 years. Therefore, this case is classified as highly probable radiation-induced cancer (A-I group) by the diagnostic criteria for radiation-induced cancer proposed by Sakai et al. Second cancers (radiation-induced cancers) mainly consist of soft tissue sarcomas, leukemias, skin cancers, urinary bladder cancers, large bowel cancers and other tumors. The occurrence of mucoepidermoid carcinoma of the lung as a radiation-induced tumor had not been reported. This patient also showed poor growth of the right breast and marked deformity of the right side of the thorax as late damage from irradiation. We must make efforts to decrease late damage from radiotherapy for pediatric cancers. (author)

  3. Oncogene amplification detected by in situ hybridization in radiation induced rat skin tumors

    International Nuclear Information System (INIS)

    Oncogene activation may play an important role in radiation induced carcinogenesis. C-myc oncogene amplification was detected by in situ hybridization in radiation-induced rat skin tumors, including squamous and basal cell carcinomas. In situ hybridization was performed with a biotinylated human c-myc third exon probe, visualized with an avidin-biotinylated alkaline phosphate detection system. No c-myc oncogene amplification was detected in normal rat skin at very early times after exposure to ionizing radiation, which is consistent with the view that c-myc amplification is more likely to be related to carcinogenesis than to normal cell proliferation. The incorporation of tritiated thymidine into the DNA of rat skin cells showed that the proliferation of epidermal cells reached a peak on the seventh day after exposure to ionizing radiation and then decreased. No connection between the proliferation of epidermal cell and c-myc oncogene amplification in normal or irradiated rat skin was found. The results indicated that c-myc amplification as measured by in situ hybridization was correlated with the Southern bolt results, but only some of the cancer cells were amplified. The c-myc positive cells were distributed randomly within regions of the tumor and exhibited a more uniform nuclear structure in comparison to the more vacuolated c-myc negative cells. No c-myc signal was detected in unirradiated normal skin or in irradiated skin cells near the tumors. C-myc amplification appears to be cell or cell cycle specific within radiation-induced carcinomas. 28 refs., 3 figs., 3 tabs

  4. Three-dimensional imaging of the metabolic state of c-MYC-induced mammary tumor with the cryo-imager

    Science.gov (United States)

    Zhang, Zhihong; Liu, Qian; Luo, Qingming; Zhang, Min Z.; Blessington, Dana M.; Zhou, Lanlan; Chodosh, Lewis A.; Zheng, Gang; Chance, Britton

    2003-07-01

    This study imaged the metabolic state of a growing tumor and the relationship between energy metabolism and the ability of glucose uptake in whole tumor tissue with cryo-imaging at 77° K. A MTB/TOM mouse model, bearing c-MYC-induced mammary tumor, was very rapidly freeze-trapped 2 hrs post Pyro-2DG injection. The fluorescence signals of oxidized flavoprotein (Fp), reduced pyridine nucleotide (PN), pyro-2DG, and the reflection signal of deoxy-hemoglobin were imaged every 100 μm from the top surface to the bottom of the tumor sequentially, 9 sections in total. Each of the four signals was constructed into 3D images with Amira software. Both Fp and PN signals could be detected in the growing tumor regions, and a higher reduction state where was shown in the ratio images. The necrotic tumor regions displayed a very strong Fp signal and weak PN signal. In the bloody extravasation regions, Fp and PN signals were observably diminished. Therefore, the regions of high growth and necrosis in the tumor could be determined according to the Fp and PN signals. The content of deoxy-hemoglobin (Hb) in the tumor was positively correlated with the reduced PN signal. Pyro-2DG signal was only evident in the growing condition region in the tumor. Normalized 3D cross-correlation showed that Pyro-2DG signal was similar to the redox ratio. The results indicated that glucose uptake in the tumor was consistent with the redox state of the tumor. And both Pyro-2DG and mitochondrial NADH fluorescence showed bimodal histograms suggesting that the two population of c-MYC induced mammary tumor, one of which could be controlled by c-MYC transgene.

  5. The inducible costimulator augments Tc17 cell responses to self and tumor tissue

    OpenAIRE

    Nelson, Michelle H.; Kundimi, Sreenath; Bowers, Jacob S.; Rogers, Carolyn E.; Huff, Logan W.; Schwartz, Kristina M.; Thyagarajan, Krishnamurthy; Little, Elizabeth C.; Mehrotra, Shikhar; Cole, David J.; Rubinstein, Mark P.; Paulos, Chrystal M.

    2015-01-01

    The inducible costimulator (ICOS) plays a key role in CD4+ Th17 cell development, but its role in CD8+ Tc17 cell development and self/tumor immunity remains unknown. We found that ICOS co-stimulation was important for the functional maintenance but not differentiation of Tc17 cells in vitro. Blocking the ICOS pathway using an antagonist antibody or by using mice genetically deficient in the ICOS ligand (ICOSL) reduced the antitumor activity of adoptively transferred Tc17 cells. Conversely, ac...

  6. Tumor Associated Macrophages Protect Colon Cancer Cells from TRAIL-Induced Apoptosis through IL-1β- Dependent Stabilization of Snail in Tumor Cells

    OpenAIRE

    Kaler, Pawan; Galea, Vincent; Augenlicht, Leonard; Klampfer, Lidija

    2010-01-01

    Background We recently reported that colon tumor cells stimulate macrophages to release IL-1β, which in turn inactivates GSK3β and enhances Wnt signaling in colon cancer cells, generating a self-amplifying loop that promotes the growth of tumor cells. Principal Findings Here we describe that macrophages protect HCT116 and Hke-3 colon cancer cells from TRAIL-induced apoptosis. Inactivation of IL-1β by neutralizing IL-1β antibody, or silencing of IL-1β in macrophages inhibited their ability to ...

  7. Amplification of tumor inducing putative cancer stem cells (CSCs) by vitamin A/retinol from mammary tumors

    Energy Technology Data Exchange (ETDEWEB)

    Sharma, Rohit B. [Department of Microbiology and Molecular Genetics, University of Pittsburgh, PA 15261 (United States); Wang, Qingde [Department of Surgery, University of Pittsburgh, PA 15261 (United States); Khillan, Jaspal S., E-mail: khillan@pitt.edu [Department of Microbiology and Molecular Genetics, University of Pittsburgh, PA 15261 (United States)

    2013-07-12

    Highlights: •Vitamin A supports self renewal of putative CSCs from mammary tumors. •These cells exhibit impaired retinol metabolism into retinoic acid. •CSCs from mammary tumors differentiate into mammary specific cell lineages. •The cells express mammary stem cell specific CD29 and CD49f markers. •Putative CSCs form highly metastatic tumors in NOD SCID mouse. -- Abstract: Solid tumors contain a rare population of cancer stem cells (CSCs) that are responsible for relapse and metastasis. The existence of CSC however, remains highly controversial issue. Here we present the evidence for putative CSCs from mammary tumors amplified by vitamin A/retinol signaling. The cells exhibit mammary stem cell specific CD29{sup hi}/CD49f{sup hi}/CD24{sup hi} markers, resistance to radiation and chemo therapeutic agents and form highly metastatic tumors in NOD/SCID mice. The cells exhibit indefinite self renewal as cell lines. Furthermore, the cells exhibit impaired retinol metabolism and do not express enzymes that metabolize retinol into retinoic acid. Vitamin A/retinol also amplified putative CSCs from breast cancer cell lines that form highly aggressive tumors in NOD SCID mice. The studies suggest that high purity putative CSCs can be isolated from solid tumors to establish patient specific cell lines for personalized therapeutics for pre-clinical translational applications. Characterization of CSCs will allow understanding of basic cellular and molecular pathways that are deregulated, mechanisms of tumor metastasis and evasion of therapies that has direct clinical relevance.

  8. 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

    International Nuclear Information System (INIS)

    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 (IC50=25±0.38) when compared to reference compound PTER (IC50=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

  9. 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

    Energy Technology Data Exchange (ETDEWEB)

    Nikhil, Kumar; Sharan, Shruti; Chakraborty, Ajanta [Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand (India); Bodipati, Naganjaneyulu; Krishna Peddinti, Rama [Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand (India); Roy, Partha, E-mail: paroyfbs@iitr.ernet.in [Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand (India)

    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.

  10. Human tumor-derived genomic DNA transduced into a recipient cell induces tumor-specific immune responses ex vivo

    OpenAIRE

    Whiteside, Theresa L.; Gambotto, Andrea; Albers, Andreas; Stanson, Joanna; Cohen, Edward P.

    2002-01-01

    This article describes a DNA-based vaccination strategy evaluated ex vivo with human cells. The vaccine was prepared by transferring tumor-derived genomic DNA to PCI-13 cells, a highly immunogenic tumor cell line (“recipient cell”), which had been genetically modified to secrete IL-2 (PCI-13/IL-2). PCI-13 cells expressed class I MHC determinants (HLA-A2) shared with the tumor from which the DNA was obtained as well as allogeneic determinants. DNA from a gp100+ melanoma ce...

  11. The natural product peiminine represses colorectal carcinoma tumor growth by inducing autophagic cell death

    Energy Technology Data Exchange (ETDEWEB)

    Lyu, Qing [School of Life Sciences, Tsinghua University, Beijing, 100084 (China); Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055 (China); Tou, Fangfang [Jiangxi Provincial Key Lab of Oncology Translation Medicine, Jiangxi Cancer Hospital, Nanchang, 330029 (China); Su, Hong; Wu, Xiaoyong [First Affiliated Hospital, Guiyang College of Traditional Chinese Medicine, Guiyang, 550002 (China); Chen, Xinyi [Department of Hematology and Oncology, Beijing University of Chinese Medicine, Beijing, 100029 (China); Zheng, Zhi, E-mail: zheng_sheva@hotmail.com [Jiangxi Provincial Key Lab of Oncology Translation Medicine, Jiangxi Cancer Hospital, Nanchang, 330029 (China)

    2015-06-19

    Autophagy is evolutionarily conservative in eukaryotic cells that engulf cellular long-lived proteins and organelles, and it degrades the contents through fusion with lysosomes, via which the cell acquires recycled building blocks for the synthesis of new molecules. In this study, we revealed that peiminine induces cell death and enhances autophagic flux in colorectal carcinoma HCT-116 cells. We determined that peiminine enhances the autophagic flux by repressing the phosphorylation of mTOR through inhibiting upstream signals. Knocking down ATG5 greatly reduced the peiminine-induced cell death in wild-type HCT-116 cells, while treating Bax/Bak-deficient cells with peiminine resulted in significant cell death. In summary, our discoveries demonstrated that peiminine represses colorectal carcinoma cell proliferation and cell growth by inducing autophagic cell death. - Highlights: • Peiminine induces autophagy and upregulates autophagic flux. • Peiminine represses colorectal carcinoma tumor growth. • Peiminine induces autophagic cell death. • Peiminine represses mTOR phosphorylation by influencing PI3K/Akt and AMPK pathway.

  12. The natural product peiminine represses colorectal carcinoma tumor growth by inducing autophagic cell death

    International Nuclear Information System (INIS)

    Autophagy is evolutionarily conservative in eukaryotic cells that engulf cellular long-lived proteins and organelles, and it degrades the contents through fusion with lysosomes, via which the cell acquires recycled building blocks for the synthesis of new molecules. In this study, we revealed that peiminine induces cell death and enhances autophagic flux in colorectal carcinoma HCT-116 cells. We determined that peiminine enhances the autophagic flux by repressing the phosphorylation of mTOR through inhibiting upstream signals. Knocking down ATG5 greatly reduced the peiminine-induced cell death in wild-type HCT-116 cells, while treating Bax/Bak-deficient cells with peiminine resulted in significant cell death. In summary, our discoveries demonstrated that peiminine represses colorectal carcinoma cell proliferation and cell growth by inducing autophagic cell death. - Highlights: • Peiminine induces autophagy and upregulates autophagic flux. • Peiminine represses colorectal carcinoma tumor growth. • Peiminine induces autophagic cell death. • Peiminine represses mTOR phosphorylation by influencing PI3K/Akt and AMPK pathway

  13. Granuloma induced by sustained-release fluorouracil implants misdiagnosed as a hepatic tumor: A case report.

    Science.gov (United States)

    Bai, Dou-Sheng; Jin, Sheng-Jie; He, Rong; Jiang, Guo-Qing; Yao, Jie

    2014-08-01

    Sustained-release fluorouracil (FU) implants have been extensively used in peritoneal interstitial chemotherapy, and during surgery for gastrointestinal tumors, breast cancer and hepatic tumors. Currently, studies regarding the complications associated with sustained-release FU implants are rare. The present study describes the case of a 61-year-old male who presented with a space-occupying lesion of the left lobe of the liver six months after undergoing a radical total gastrectomy. Thus, laparoscopic exploration was performed to remove the tumor. Postoperative histological examination demonstrated that the lesion in the left lobe comprised of necrotic tissue with granulation tissue hyperplasia. Based on the surgical and postoperative histological findings, the mass was proposed to be due to a high concentration of local sustained-release FU implants. Furthermore, the drug was partially surrounded and had been insufficiently metabolized over a long time period, which was proposed to have caused necrosis, proliferation and fibrillation, and induced granuloma. In conclusion, local high concentrations of sustained-release FU implants may be associated with granuloma and this finding may enable improved management of sustained-release FU implants during surgery. PMID:25013494

  14. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression.

    Science.gov (United States)

    Laklai, Hanane; Miroshnikova, Yekaterina A; Pickup, Michael W; Collisson, Eric A; Kim, Grace E; Barrett, Alex S; Hill, Ryan C; Lakins, Johnathon N; Schlaepfer, David D; Mouw, Janna K; LeBleu, Valerie S; Roy, Nilotpal; Novitskiy, Sergey V; Johansen, Julia S; Poli, Valeria; Kalluri, Raghu; Iacobuzio-Donahue, Christine A; Wood, Laura D; Hebrok, Matthias; Hansen, Kirk; Moses, Harold L; Weaver, Valerie M

    2016-05-01

    Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype. PMID:27089513

  15. Latent period and antigenicity of murine tumors induced in C3H mice by short-wavelength ultraviolet radiation

    International Nuclear Information System (INIS)

    Skin tumors were induced in C3H/HeNCr1BR mice with chronic short-wavelength ultraviolet (UVC) irradiation using a germicidal lamp (254 nm). Fifty percent of mice had developed tumors by 9 1/2 months (range 8-12 months). With progressive irradiation, mice developed multiple tumors on the back reaching a mean of 2.9 tumors/mouse at 11 1/2 months. No tumors developed on the ears. Of 83 lesions examined histologically 66 (80%) were squamous cell carcinomas, 6 (7%) were fibrosarcomas, and 10 (12%) were proliferative squamous lesions without evident invasion. Twenty-two squamous cell carcinomas were transplanted s.c. into normal syngeneic mice and into mice immunosuppressed by adult thymectomy, lethal x-irradiation, and bone marrow or neonatal liver reconstitution. Transplantation of squamous cell carcinomas was successful in a total of 17/22 (77%) cases. Only 11/22 (50%) tumors grew progressively in normal mice. Six of 22 (27%) tumors grew progressively in immunosuppressed mice but not normal syngeneic recipients. Three fibrosarcomas were also transplanted. All 3 grew progressively in immunosuppressed hosts but failed to grow in normal syngeneic recipients. Two fibrosarcomas that were induced by a germicidal lamp were found to grow significantly better in UVB-irradiated (280-320 nm) mice than in normal mice. Conversely, a UVB-induced fibrosarcoma showed enhanced growth in UVC-irradiated mice compared to growth in normal, age-matched controls

  16. Detection of irradiation-induced, membrane heat shock protein 70 (Hsp70) in mouse tumors using Hsp70 Fab fragment

    International Nuclear Information System (INIS)

    Background and purpose: The major stress-inducible heat shock protein 70 (Hsp70) is frequently overexpressed in highly aggressive tumors, and elevated intracellular Hsp70 levels mediate protection against apoptosis. Following therapeutic intervention, such as ionizing irradiation, translocation of cytosolic Hsp70 to the plasma membrane is selectively increased in tumor cells and therefore, membrane Hsp70 might serve as a therapy-inducible, tumor-specific target structure. Materials and methods: Based on the IgG1 mouse monoclonal antibody (mAb) cmHsp70.1, we produced the Hsp70-specific recombinant Fab fragment (Hsp70 Fab), as an imaging tool for the detection of membrane Hsp70 positive tumor cells in vitro and in vivo. Results: The binding characteristics of Hsp70 Fab towards mouse colon (CT26) and pancreatic (1048) carcinoma cells at 4 deg. C were comparable to that of cmHsp70.1 mAb, as determined by flow cytometry. Following a temperature shift to 37 deg. C, Hsp70 Fab rapidly translocates into subcellular vesicles of mouse tumor cells. Furthermore, in tumor-bearing mice Cy5.5-conjugated Hsp70 Fab, but not unrelated IN-1 control Fab fragment (IN-1 ctrl Fab), gradually accumulates in CT26 tumors between 12 and 55 h after i.v. injection. Conclusions: In summary, the Hsp70 Fab provides an innovative, low immunogenic tool for imaging of membrane Hsp70 positive tumors, in vivo.

  17. Pertussis toxin inhibits somatostatin-induced K+ conductance in human pituitary tumor cells

    International Nuclear Information System (INIS)

    The effect of pertussis toxin on somatostatin-induced K+ current was examined in dissociated human pituitary tumor cells obtained from two acromegalic patients. Somatostatin-induced hyperpolarization or K+ current was observed in 20 of 23 cells in adenoma 1 and 10 of 11 cells in adenoma 2. After treatment with pertussis toxin for 24 h, these responses were completely suppressed (0/14 in adenoma, 1, 0/10 in adenoma 2). Spontaneous action potentials, K+, Na+, and Ca2+ currents were well preserved after pertussis toxin treatment. When crude membrane fraction was incubated with [32P]NAD, a 41K protein was ADP-ribosylated by pertussis toxin. Hormone release was inhibited by somatostatin and this inhibition was blocked by pertussis toxin treatment

  18. Hypoxia-inducible factor 1 alpha expression increases during colorectal carcinogenesis and tumor progression

    International Nuclear Information System (INIS)

    Hypoxia-inducible factor 1 alpha (HIF-1α) is involved in processes promoting carcinogenesis of many tumors. However, its role in the development of colorectal cancer is unknown. To investigate the significance of HIF-1α during colorectal carcinogenesis and progression we examined its expression in precursor lesions constituting the conventional and serrated pathways, as well as in non-metastatic and metastatic adenocarcinomas. Immunohistochemistry and Western blot is used to analyse HIF-1α expression in normal colonic mucosa, hyperplastic polyps (HPP), sessile serrated adenomas (SSA), low-grade (TA-LGD) and high-grade (TA-HGD) traditional adenomas as well as in non-metastatic and metastatic colorectal adenocarcinomas. Eight colorectal carcinoma cell lines are tested for their HIF-1α inducibility after lipopolysaccharide (LPS) stimulation using western blot and immunocytochemistry. In normal mucosa, HPP and TA-LGD HIF-1α was not expressed. In contast, perinuclear protein accumulation and nuclear expression of HIF-1α were shown in half of the examined SSA and TA-HGD. In all investigated colorectal carcinomas a significant nuclear HIF-1α overexpression compared to the premalignant lesions was observed but a significant correlation with the metastatic status was not found. Nuclear HIF-1α expression was strongly accumulated in perinecrotic regions. In these cases HIF-1α activation was seen in viable cohesive tumor epithelia surrounding necrosis and in dissociated tumor cells, which subsequently die. Enhanced distribution of HIF-1α was also seen in periiflammatory regions. In additional in vitro studies, treatment of diverse colorectal carcinoma cell lines with the potent pro-inflammatory factor lipopolysaccharide (LPS) led to HIF-1α expression and nuclear translocation. We conclude that HIF-1α expression occurs in early stages of colorectal carcinogenesis and achieves a maximum in the invasive stage independent of the metastatic status. Perinecrotic

  19. INDUCEMENT OF ANTITUMOR-IMMUNITY BY DC ACTIVATED BY HSP70-H22 TUMOR ANTIGEN PEPTIDE

    Institute of Scientific and Technical Information of China (English)

    冯作化; 黄波; 张桂梅; 李东; 王洪涛

    2003-01-01

    Objective: To investigate the feasibility of decreasing the dosage of tumor antigen peptides by dendritic cell (DC)-presenting and the characteristics of modification of DC by heat shock protein (Hsp70) and antigen peptides. Methods: Peptides were bound to Hsp70 and used to modify DC in vitro. The metabolism of the modified DC and the cytokines secreted by the modified DC were determined. The activation of lymphocytes by the modified DC and Hsp70-H22 peptides was tested. The cytotoxicity of the activated lymphocytes to H22 tumor cells was analyzed. The inhibitory effect of tumor in mice by the injection of DC and Hsp70-H22 peptides was tested. Results: 0.15μg of H22 peptides bound with Hsp70 could make 2×105 DC mature. 4×103 matured DC could activate 2×106 lymphocytes. The same amount of lymphocytes could be activated to produce similar cytotoxicity to tumor cells by either DC modified by 0.003μg of peptides bound with Hsp70 or by direct stimulation with 0.15μg of peptides bound with Hsp70. The dosage of peptides could be reduced by about 50 folds if the modified DC was used for injection instead of Hsp70-peptides. Peptides from normal hepatocytes, bound with Hsp70, could not make DC mature, nor activate lymphocytes through DC. Conclusion: The dosage of Hsp70-H22 peptides can be reduced significantly by DC-presenting to activate lymphocytes. Peptides from normal cells could not activate lymphocytes by either Hsp70-presenting or DC-presenting and they have little chance to induce autoimmunity.

  20. N,N'-dimethylnitrosourea-induced tumors in mice and Syrian hamsters

    Directory of Open Access Journals (Sweden)

    Hiraki,Shunkichi

    1974-10-01

    Full Text Available Carcinogenic effect of N, N'-dimethylnitrosourea (DMNU on mice and hamsters was studied. Repeated subcutaneous injections of DMNU resulted in the induction of malignant lymphomas with an incidence of 100 per cent in adult C3HjBifBjKi mice and induced malignant tumors of forestomach, mammary gland and uterus with a high incidence in adult hamsters. Control animals showed no pathological changes. Electron microscopy revealed the presence of murine type C virus particles in some of the tissues examined. Many type C virus particles were found in a transplant of DMNU.induced malig. nant lymphoma. Some type C virus particles were shown in malignant lymphomas and lymph nodes of malignant lymphoma-bearing mice. A very small number of type C virus particles were observed in thymus of control mice and bone marrow of a malignant lymphoma.bearing mouse. A few particles, quite similar to murine type C virus particles, were detected in DMNU.induced mammary adenocarcinoma of hamster. No virus-like particles were seen in mammary glands of control hamsters. Whether these particles are merely passengers or are playing a significant role in the carcinogenesis of these tumors remains to be determined.

  1. Modulatory influence of Phyllanthus niruri on oxidative stress, antioxidant defense and chemically induced skin tumors.

    Science.gov (United States)

    Sharma, Priyanka; Parmar, Jyoti; Verma, Preeti; Goyal, Pradeep Kumar

    2011-01-01

    The present study evaluates the modulatory potential of Phyllanthus niruri on chemically induced skin carcinogenesis, and its influence on oxidative stress and the antioxidant defense system. Oral administration of P. niruri extract (PNE), during peri- (Gr. III), post- (Gr. IV), or peri- and post- (Gr. V) initiational stages of 7,12-dimethylbenz(a) anthracene (DMBA)-croton oil–induced papillomagenesis considerably reduced tumor burden to 4.20, 4.00, and 3.33(positive control value 6.20); cumulative number of papillomas to 21, 16, and 10, respectively, (positive control value 62); and incidence of mice bearing papillomas to 50, 40, and 30%, respectively (positive control value 100%), but significantly increased the average latent period to 10.14, 10.62, and 11.60, and inhibition of tumor multiplicity to 66, 74,and 83%, respectively. Enzyme analysis of skin and liver showed a significant (p ≤ 0.05, ≤ 0.01, ≤ 0.001) elevation in antioxidant parameters such as superoxide dismutase, catalase, glutathione, and vitamin C in PNE-treated groups (Gr. III–V) when compared with the carcinogen-treated control (Gr. II). The elevated level of lipid peroxidation in the carcinogen-treated positive control group was significantly (p ≤ 0.05, ≤ 0.01, ≤ 0.001) inhibited by PNE administration. These results indicate that P. niruri extract has potentiality to reduce skin papillomas by enhancing antioxidant defense system. PMID:21609315

  2. Epithelial-mesenchymal transition induces endoplasmic-reticulum-stress response in human colorectal tumor cells.

    Directory of Open Access Journals (Sweden)

    Evelyn Zeindl-Eberhart

    Full Text Available Tumor cells are stressed by unfavorable environmental conditions like hypoxia or starvation. Driven by the resulting cellular stress tumor cells undergo epithelial-mesenchymal transition. Additionally, cellular stress is accompanied by endoplasmic reticulum-stress which induces an unfolded protein response. It is unknown if epithelial-mesenchymal transition and endoplasmic reticulum-stress are occurring as independent parallel events or if an interrelationship exists between both of them. Here, we show that in colorectal cancer cells endoplasmic reticulum-stress depends on the induction of ZEB-1, which is a main factor of epithelial-mesenchymal transition. In the absence of ZEB-1 colorectal cancer cells cannot mount endoplasmic reticulum-stress as a reaction on cellular stress situations like hypoxia or starvation. Thus, our data suggest that there is a hierarchy in the development of cellular stress which starts with the presence of environmental stress that induces epithelial-mesenchymal transition which allows finally endoplasmic reticulum-stress. This finding highlights the central role of epithelial-mesenchymal transition during the process of tumorigenesis as epithelial-mesenchymal transition is also associated with chemoresistance and cancer stemness. Consequently, endoplasmic reticulum-stress might be a well suited target for chemotherapy of colorectal cancers.

  3. Reduction of DMH-induced colon tumors in rats fed psyllium husk or cellulose.

    Science.gov (United States)

    Roberts-Andersen, J; Mehta, T; Wilson, R B

    1987-01-01

    The effect of feeding psyllium husk, a water-soluble fiber, and cellulose, a water-insoluble fiber, against chemically induced colon cancer was investigated in rats. Adult male rats were fed semipurified diets containing 20% fat, no fiber, or 10% psyllium husk or cellulose for 22 weeks. Tumors were induced in one-half of the rats fed each diet by the gastric intubation of 1,2-dimethylhydrazine (DMH) during Weeks 3-11. In terms of the number of animals with tumors in each group, psyllium strongly reduced the tumorigenicity of DMH and cellulose moderately reduced tumorigenicity, whereas the two fibers did not differ significantly from each other with respect to tumorigenicity. Psyllium-fed rats had the highest fecal aerobic counts, lowest beta-glucuronidase, and highest 7-alpha-dehydroxylase activities. The psyllium diet also resulted in increased fecal output and percent moisture. Rats fed cellulose tended to have greater fecal bulk and lower beta-glucuronidase activity compared with rats fed no fiber and lower 7-alpha-dehydroxylase activity compared with rats fed psyllium husk. PMID:2819829

  4. Type-1-cytokines synergize with oncogene inhibition to induce tumor growth arrest

    Science.gov (United States)

    Acquavella, Nicolas; Clever, David; Yu, Zhiya; Roelke-Parker, Melody; Palmer, Douglas C.; Xi, Liqiang; Pflicke, Holger; Ji, Yun; Gros, Alena; Hanada, Ken-ichi; Goldlust, Ian S.; Mehta, Gautam U.; Klebanoff, Christopher A.; Crompton, Joseph G.; Sukumar, Madhusudhanan; Morrow, James J.; Franco, Zulmarie; Gattinoni, Luca; Liu, Hui; Wang, Ena; Marincola, Francesco; Stroncek, David F.; Lee, Chyi-Chia R.; Raffeld, Mark; Bosenberg, Marcus W.; Roychoudhuri, Rahul; Restifo, Nicholas P.

    2014-01-01

    Both targeted inhibition of oncogenic driver mutations and immune-based therapies show efficacy in treatment of patients with metastatic cancer but responses can be either short-lived or incompletely effective. Oncogene inhibition can augment the efficacy of immune-based therapy but mechanisms by which these two interventions might cooperate are incompletely resolved. Using a novel transplantable BRAFV600E-mutant murine melanoma model (SB-3123), we explore potential mechanisms of synergy between the selective BRAFV600E inhibitor vemurafenib and adoptive cell transfer (ACT)-based immunotherapy. We found that vemurafenib cooperated with ACT to delay melanoma progression without significantly affecting tumor infiltration or effector function of endogenous or adoptively transferred CD8+ T cells as previously observed. Instead, we found that the T-cell cytokines IFNγ and TNFα synergized with vemurafenib to induce cell-cycle arrest of tumor cells in vitro. This combinatorial effect was recapitulated in human melanoma-derived cell lines and was restricted to cancers bearing a BRAFV600E-mutation. Molecular profiling of treated SB-3123 indicated that the provision of vemurafenib promoted the sensitization of SB-3123 to the anti-proliferative effects of T-cell effector cytokines. The unexpected finding that immune cytokines synergize with oncogene inhibitors to induce growth arrest have major implications for understanding cancer biology at the intersection of oncogenic and immune signaling and provides a basis for design of combinatorial therapeutic approaches for patients with metastatic cancer. PMID:25358764

  5. Lentivirus-Mediated Oncogene Introduction into Mammary Cells In Vivo Induces Tumors

    Directory of Open Access Journals (Sweden)

    Stefan K. Siwko

    2008-07-01

    Full Text Available We recently reported the introduction of oncogene-expressing avian retroviruses into somatic mammary cells in mice susceptible to infection by transgenic expression of tva, encoding the receptor for subgroup A avian leukosis-sarcoma virus (ALSV. Because ALSV-based vectors poorly infect nondividing cells, they are inadequate for studying carcinogenesis initiated from nonproliferative cells (e.g., stem cells. Lentivirus pseudotyped with the envelope protein of ALSV infects nondividing TVA-producing cells in culture but has not previously been tested for introducing genes in vivo. Here, we demonstrate that these vectors infected mammary cells in vivo when injected into the mammary ductal lumen of mice expressing tva under the control of the keratin 19 promoter. Furthermore, intraductal injection of this lentiviral vector carrying the polyoma middle T antigen gene induced atypical ductal hyperplasia and ductal carcinoma in situ-like premalignant lesions in 30 days and palpable invasive tumors at a median latency of 3.3 months. Induced tumors were a mixed epithelial/myoepithelial histologic diagnosis, occasionally displayed squamous metaplasia, and were estrogen receptor-negative. This work demonstrates the first use of a lentiviral vector to introduce oncogenes for modeling cancer in mice, and this vector system may be especially suitable for introducing genetic alterations into quiescent cells in vivo.

  6. Clonal T cell expansion induced by interleukin 2 therapy in blood and tumors.

    Science.gov (United States)

    Kumar, A; Farace, F; Gaudin, C; Triebel, F

    1996-01-01

    In a phase I clinical trial on the effects of preoperative adjuvant IL-2 therapy given to patients undergoing hepatic resection of colorectal adenocarcinoma metastases, we monitored the putative induction of T cell clonal expansion in both tissues and blood. The presence of T cell clonotypes was analyzed with a PCR-based method that determines V-D-J junction size patterns in T cell receptor (TCR) V beta subfamilies in samples before and after a 5-d IL-2 infusion. This high resolution method analyzing CDR3 sizes of TCR transcripts was used in conjunction with FACS analysis of the corresponding T cell subpopulations with TCR V beta-specific mAb. At time of surgery (day 8 after starting IL-2), we found in the three patients analyzed with V beta-C beta primers multiple dominant T cell clonotypes in the tumor and peritumoral tissues which had probably expanded as a result of therapy. In three control patients not treated with IL-2, multiple oligoclonal patterns were not observed with this set of primers. In the fourth control patient a unique V beta 21-C beta CDR3 pattern which corresponds to two dominant clonotypes was found in the tumor. The same dominant clonotypes identified in the tumor after IL-2 were also detectable in the blood and comparison of the profiles obtained before and after IL-2 therapy indicates that they were induced by IL-2. The relative expansion of the corresponding T cell subpopulations was maintained for varying periods of time after surgery (4-7 d and almost 2 yr in one case). Together, these results indicate that IL-2 induces marked expansion of several T cell clones. Systemic IL-2 administration may represent, either alone or as a vaccine adjuvant, an appropriate way of boosting antigen-specific immune responses. PMID:8636433

  7. Repercussion of mitochondria deformity induced by anti-Hsp90 drug 17AAG in human tumor cells

    KAUST Repository

    Vishal, Chaturvedi

    2011-06-07

    Inhibiting Hsp90 chaperone roles using 17AAG induces cytostasis or apoptosis in tumor cells through destabilization of several mutated cancer promoting proteins. Although mitochondria are central in deciding the fate of cells, 17AAG induced effects on tumor cell mitochondria were largely unknown. Here, we show that Hsp90 inhibition with 17AAG first affects mitochondrial integrity in different human tumor cells, neuroblastoma, cervical cancer and glial cells. Using human neuroblastoma tumor cells, we found the early effects associated with a change in mitochondrial membrane potential, elongation and engorgement of mitochondria because of an increased matrix vacuolization. These effects are specific to Hsp90 inhibition as other chemotherapeutic drugs did not induce similar mitochondrial deformity. Further, the effects are independent of oxidative damage and cytoarchitecture destabilization since cytoskeletal disruptors and mitochondrial metabolic inhibitors also do not induce similar deformity induced by 17AAG. The 1D PAGE LC MS/ MS mitochondrial proteome analysis of 17AAG treated human neuroblastoma cells showed a loss of 61% proteins from membrane, metabolic, chaperone and ribonucleoprotein families. About 31 unmapped protein IDs were identified from proteolytic processing map using Swiss-Prot accession number, and converted to the matching gene name searching the ExPASy proteomics server. Our studies display that Hsp90 inhibition effects at first embark on mitochondria of tumor cells and compromise mitochondrial integrity. the author(s), publisher and licensee Libertas Academica Ltd.

  8. Electron microscopic morphology and DNA chain fragmentation studies on apoptosis in bone tumor cells induced by 153Sm

    International Nuclear Information System (INIS)

    Objective: To study the apoptosis and fraction of DNA chain fragmentation in bone tumor cells induced by 153Sm-EDTMP. Methods: Apoptosis in bone tumor cells exposed to different time periods of 153Sm-EDTMP internal irradiation was observed by electron microscopic morphology and DNA chain fragmentation studies. Results: It was demonstrated that the bone tumor cells internally exposed to 153Sm-EDTMP displayed nuclear fragmentation, margination of condensed chromatin, and formation of membrane bounded apoptotic bodies. The study showed that the percentage of DNA chain fragmentation increases in direct proportion to the duration of internal exposure to 153Sm-EDTMP. Conclusion: Apoptosis induced by 153Sm-EDTMP in bone tumor cells was dependent on the time of 153Sm-EDTMP exposure

  9. Matrix metalloproteinase 13 is induced in fibroblasts in polyomavirus middle T antigen-driven mammary carcinoma without influencing tumor progression

    DEFF Research Database (Denmark)

    Nielsen, Boye S; Egeblad, Mikala; Rank, Fritz;

    2008-01-01

    intraepithelial neoplasias. To determine if MMP13 plays a role in tumor progression, we crossed MMTV-PyMT mice with Mmp13 deficient mice. The absence of MMP13 did not influence tumor growth, vascularization, progression to more advanced tumor stages, or metastasis to the lungs, and the absence of MMP13 was not......Matrix metalloproteinase (MMP) 13 (collagenase 3) is an extracellular matrix remodeling enzyme that is induced in myofibroblasts during the earliest invasive stages of human breast carcinoma, suggesting that it is involved in tumor progression. During progression of mammary carcinomas in the...... polyoma virus middle T oncogene mouse model (MMTV-PyMT), Mmp13 mRNA was strongly upregulated concurrently with the transition to invasive and metastatic carcinomas. As in human tumors, Mmp13 mRNA was found in myofibroblasts of invasive grade II and III carcinomas, but not in benign grade I and II mammary...

  10. The tumor suppressor gene RBM5 inhibits lung adenocarcinoma cell growth and induces apoptosis

    Directory of Open Access Journals (Sweden)

    Shao Chen

    2012-08-01

    Full Text Available Abstract Background The loss of tumor suppressor gene (TSG function is a critical step in the pathogenesis of human lung cancer. RBM5 (RNA-binding motif protein 5, also named H37/LUCA-15 gene from chromosome 3p21.3 demonstrated tumor suppressor activity. However, the role of RBM5 played in the occurrence and development of lung cancer is still not well understood. Method Paired non-tumor and tumor tissues were obtained from 30 adenocarcinomas. The expression of RBM5 mRNA and protein was examined by RT-PCR and Western blot. A549 cell line was used to determine the apoptotic function of RBM5 in vitro. A549 cells were transiently transfected with pcDNA3.1-RBM5. AnnexinV analysis was performed by flow cytometry. Expression of Bcl-2, cleaved caspase-3, caspase-9 and PAPP proteins in A549 lung cancer cells and the A549 xenograft BALB/c nude mice model was determined by Western blot. Tumor suppressor activity of RBM5 was also examined in the A549 xenograft model treated with pcDNA3.1-RBM5 plasmid carried by attenuated Salmonella typhi Ty21a. Result The expression of RBM5 mRNA and protein was decreased significantly in adenocarcinoma tissues compared to that in the non-tumor tissues. In addition, as compared to the vector control, a significant growth inhibition of A549 lung cancer cells was observed when transfected with pcDNA3.1-RBM5 as determined by cell proliferation assay. We also found that overexpression of RBM5 induced both early and late apoptosis in A549 cells using AnnexinV/PI staining as determined by flow cytometry. Furthermore, the expression of Bcl-2 protein was decreased, whereas the expression of cleaved caspase-3, caspase-9 and PARP proteins was significantly increased in the RBM5 transfected cells; similarly, expression of decreased Bcl-2 and increased cleaved caspase-3 proteins was also examined in the A549 xenograft model. More importantly, we showed that accumulative and stable overexpression of RBM5 in the A549 xenograft BALB

  11. Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through Toll Like Receptor 9

    Science.gov (United States)

    Liu, Yao; Yan, Wei; Tohme, Samer; Chen, Man; Fu, Yu; Tian, Dean; Lotze, Michael; Tang, Daolin; Tsung, Allan

    2015-01-01

    Background and aims The mechanisms of hypoxia-induced tumor growth remain unclear. Hypoxia induces intracellular translocation and release of a variety of damage associated molecular patterns (DAMPs) such as nuclear HMGB1 and mitochondrial DNA (mtDNA). In inflammation, Toll-like receptor (TLR)-9 activation by DNA-containing immune complexes has been shown to be mediated by HMGB1. We thus hypothesize that HMGB1 binds mtDNA in the cytoplasm of hypoxic tumor cells and promotes tumor growth through activating TLR9 signaling pathways. Methods C57BL6 mice were injected with Hepa1-6 cancer cells. TLR9 and HMGB1 were inhibited using shRNA or direct antagonists. Huh7 and Hepa1-6 cancer cells were investigated in vitro to investigate how the interaction of HMGB1 and mtDNA activates TLR9 signaling pathways. Results During hypoxia, HMGB1 translocates from the nucleus to the cytosol and binds to mtDNA released from damaged mitochondria. This complex subsequently activates TLR9 signaling pathways to promote tumor cell proliferation. Loss of HMGB1 or mtDNA leads to a defect in TLR9 signaling pathways in response to hypoxia, resulting in decreased tumor cell proliferation. Also, the addition of HMGB1 and mtDNA leads to the activation of TLR-9 and subsequent tumor cell proliferation. Moreover, TLR9 is overexpressed in both hypoxic tumor cells in vitro and in human hepatocellular cancer (HCC) specimens; and, knockdown of either HMGB1 or TLR9 from HCC cells suppressed tumor growth in vivo after injection in mice. Conclusions Our data reveals a novel mechanism by which the interactions of HMGB1 and mtDNA activate TLR9 signaling during hypoxia to induce tumor growth. PMID:25681553

  12. Gastrointestinal stromal tumor of the pelvic soft tissue presenting with symptomatic hypoglycemia: A case report and brief review of current literature of non-islet cell tumor-induced hypoglycemia

    OpenAIRE

    Dean, Kathleen; Hsieh, Jessica; Morosky, Christopher; Hoffman, James

    2012-01-01

    ► Presentation of a rare case of pelvic gastrointestinal stromal tumor. ► Non-islet cell induced hypoglycemia causing severe hypoglycemia. ► The pathogenesis of non-islet cell induced hypoglycemia due to over-production of precursors of insulin-like growth factor-II. ► Complete resolution of hypoglycemia following resection of the tumor.

  13. Carcinogenic alterations in murine liver, lung, and uterine tumors induced by in utero exposure to ionizing radiation.

    Science.gov (United States)

    Lumniczky, K; Antal, S; Unger, E; Wunderlich, L; Hidvégi, E J; Sáfrány, G

    1998-02-01

    The atomic bombing of Hiroshima and Nagasaki and the nuclear accident at Chernobyl raised the question of prenatal sensitivity to ionizing radiation-induced cancer. In this study, mice were exposed to single doses of gamma-radiation (0.2-2.0 Gy) at different embryonic stages. The tumor incidence increased with dose from 15% in control mice to 35% in mice irradiated with 2.0 Gy on 18 d of prenatal life. Various oncogenic events were investigated in lymphoid, liver, lung, and uterine tumors. We observed threefold to fivefold increases in myc expression in 25% of the lymphomas, and the expression of Ha-ras and p53 genes decreased in 40% and 60% of the lung tumors by twofold to fivefold. Point mutations were tissue specific: Ha-ras codon 61 mutations were found in about 40% of the liver adenocarcinomas, Ki-ras codon 12 mutations in about 17% of lung tumors, and p53 mutations in about 15% of the lymphomas. Amplification and rearrangement of the p53, myc, and Ha-, Ki- and N-ras genes were not detected. Loss of heterozygosity on chromosome 4 at the multiple tumor suppressor 1 and 2 genes was observed in all types of malignancies. Allelic losses on chromosome 11 at the p53 locus were found in lymphoid, liver, and lung tumors, but they were absent from uterine tumors. Multiple oncogenic changes were often detected. The frequency of carcinogenic alterations was similar in spontaneous and radiation-induced lymphoid, liver, and uterine tumors. In radiation-induced lung adenocarcinomas, however, the incidences of many oncogenic changes were different from those found in their spontaneous counterparts. This suggests that different oncogenic pathways are activated during spontaneous and in utero gamma-radiation-induced murine lung carcinogenesis. PMID:9496910

  14. Experimental study on radiation-inducible expression and anti-tumor effect of pEgr-IFN γ recombinant plasmid

    International Nuclear Information System (INIS)

    Objective: To study the radiation-inducible expression and the anti-tumor effect of pEgr-IFN γ recombinant plasmid in mice bearing melanoma. Methods: The pEgr-IFN γ plasmid was injected locally into the tumor in the mice, and the tumors were irradiated with X-rays 36 hours later. The tumor growth rate at different times and mean survival period of the mice were observed. The IFN γmRNA level in the tumor was detected with RT-PCR, 3 days after irradiation, and the concentration of IFNγ in the serum of the mice was detected by ELISA 1, 3 and 5 days after irradiation. Results: The IFNγ mRNA level in the tumor of mice in the gene-radiotherapy group was significantly higher than that in the recombinant plasmid group 3 days after irradiation. The IFNγ concentration in the serum of mice in the gene-radiotherapy group was higher than that in the recombinant plasmid group and the control group 1 and 3 days after irradiation. The tumor growth rate in the group of plasmid injection followed by 5 Gy irradiation for four times was significantly lower than that in the group of plasmid injection followed by 20 Gy irradiation 9-15 days after irradiation, and the mean survival period was also longer. Conclusions: The anti-tumor effect of plasmid injection followed by lower dose irradiation for several times is better than that by higher dose irradiation. By inducing higher expression of IFNγ gene in the tumor, pEgr-IFN γ gene-radiotherapy could increase the concentration of IFNγ in the serum, and therefore the body's immunologic function and anti-tumor ability are enhanced

  15. Hypoxia upregulates Bcl-2 expression and suppresses interferon-gamma induced antiangiogenic activity in human tumor derived endothelial cells.

    LENUS (Irish Health Repository)

    Wang, Jiang Huai

    2012-02-03

    BACKGROUND: Hypoxia in solid tumors potentially stimulates angiogenesis by promoting vascular endothelial growth factor (VEGF) production and upregulating VEGF receptor expression. However, it is unknown whether hypoxia can modulate the effect of anti-angiogenic treatment on tumor-derived endothelium. METHODS: Human tumor-derived endothelial cells (HTDEC) were freshly isolated from surgically removed human colorectal tumors by collagenase\\/DNase digestion and Percol gradient sedimentation. Cell proliferation was assessed by measuring BrdU incorporation, and capillary tube formation was measured using Matrigel. Cell apoptosis was assessed by flow cytometry and ELISA, and Bcl-2 expression was detected by Western blot analysis. RESULTS: Under aerobic culture conditions (5% CO2 plus 21% O2) HTDEC expressed less Bcl-2 and were more susceptible to IFN-gamma-induced apoptosis with significant reductions in both cell proliferation and capillary tube formation, when compared with normal human macrovascular and microvascular EC. Following exposure of HTDEC to hypoxia (5% CO2 plus 2% O2), IFN-gamma-induced cell apoptosis, and antiangiogenic activity (i.e. an inhibition in cell proliferation and capillary tube formation) in HTDEC were markedly attenuated. This finding correlated with hypoxia-induced upregulation of Bcl-2 expression in HTDEC. CONCLUSIONS: These results indicate that hypoxia can protect HTDEC against IFN-gamma-mediated cell death and antiangiogenic activity, and suggest that improvement of tumor oxygenation may potentiate the efficacy of anti-cancer therapies specifically targeting the inhibition of tumor angiogenesis.

  16. Down-regulation of HSP27 sensitizes TRAIL-resistant tumor cell to TRAIL-induced apoptosis

    DEFF Research Database (Denmark)

    Zhuang, Hongqin; Jiang, Weiwei; Cheng, Wei;

    2010-01-01

    oxygen species or anticancer drugs. Their elevated expressions facilitate cells to survive in stress circumstances. The HSP27 expression is enhanced in many tumor cells, implying that it is involved in tumor progression and the development of treatment resistance in various tumors, including lung cancer...... HSP27 siRNA on drug sensitization of A549 cells to TRAIL treatment. The results showed that treatment of A549 cells with HSP27 siRNA down-regulated HSP27 expression but did not induce significant apoptosis. However, combination of HSP27 siRNA with TRAIL-induced significant apoptosis in TRAIL......-resistant A549 cells. In addition to inducing caspases activation and apoptosis, combined treatment with HSP27 siRNA and TRAIL also increased JNK and p53 expression and activity. Collectively, these findings provide a conclusion that siRNA targeting of the HSP27 gene specifically down-regulated HSP27...

  17. Microarray analysis of tumor necrosis factor α induced gene expression in U373 human glioblastoma cells

    Directory of Open Access Journals (Sweden)

    Prüllage Maria

    2003-11-01

    Full Text Available Abstract Background Tumor necrosis factor α (TNF is able to induce a variety of biological responses in the nervous system including inflammation and neuroprotection. Human astrocytoma cells U373 have been widely used as a model for inflammatory cytokine actions in the nervous system. Here we used cDNA microarrays to analyze the time course of the transcriptional response from 1 h up to 12 h post TNF treatment in comparison to untreated U373 cells. TNF activated strongly the NF-κB transcriptional pathway and is linked to other pathways via the NF-κB target genes JUNB and IRF-1. Part of the TNF-induced gene expression could be inhibited by pharmacological inhibition of NF-κB with pyrrolidine-dithiocarbamate (PDTC. NF-κB comprises a family of transcription factors which are involved in the inducible expression of genes regulating neuronal survival, inflammatory response, cancer and innate immunity. Results In this study we show that numerous genes responded to TNF (> 880 from 7500 tested with a more than two-fold induction rate. Several novel TNF-responsive genes (about 60% of the genes regulated by a factor ≥ 3 were detected. A comparison of our TNF-induced gene expression profiles of U373, with profiles from 3T3 and Hela cells revealed a striking cell-type specificity. SCYA2 (MCP-1, CCL2, MCAF was induced in U373 cells in a sustained manner and at the highest level of all analyzed genes. MCP-1 protein expression, as monitored with immunofluorescence and ELISA, correlated exactly with microarray data. Based on these data and on evidence from literature we suggest a model for the potential neurodegenerative effect of NF-κB in astroglia: Activation of NF-κB via TNF results in a strongly increased production of MCP-1. This leads to a exacerbation of neurodegeneration in stoke or Multiple Sclerosis, presumably via infiltration of macrophages. Conclusions The vast majority of genes regulated more than 3-fold were previously not linked to

  18. Tumor cell death induced by the inhibition of mitochondrial electron transport: The effect of 3-hydroxybakuchiol

    International Nuclear Information System (INIS)

    Changes in mitochondrial ATP synthesis can affect the function of tumor cells due to the dependence of the first step of glycolysis on mitochondrial ATP. The oxidative phosphorylation (OXPHOS) system is responsible for the synthesis of approximately 90% of the ATP in normal cells and up to 50% in most glycolytic cancers; therefore, inhibition of the electron transport chain (ETC) emerges as an attractive therapeutic target. We studied the effect of a lipophilic isoprenylated catechol, 3-hydroxybakuchiol (3-OHbk), a putative ETC inhibitor isolated from Psoralea glandulosa. 3-OHbk exerted cytotoxic and anti-proliferative effects on the TA3/Ha mouse mammary adenocarcinoma cell line and induced a decrease in the mitochondrial transmembrane potential, the activation of caspase-3, the opening of the mitochondrial permeability transport pore (MPTP) and nuclear DNA fragmentation. Additionally, 3-OHbk inhibited oxygen consumption, an effect that was completely reversed by succinate (an electron donor for Complex II) and duroquinol (electron donor for Complex III), suggesting that 3-OHbk disrupted the electron flow at the level of Complex I. The inhibition of OXPHOS did not increase the level of reactive oxygen species (ROS) but caused a large decrease in the intracellular ATP level. ETC inhibitors have been shown to induce cell death through necrosis and apoptosis by increasing ROS generation. Nevertheless, we demonstrated that 3-OHbk inhibited the ETC and induced apoptosis through an interaction with Complex I. By delivering electrons directly to Complex III with duroquinol, cell death was almost completely abrogated. These results suggest that 3-OHbk has antitumor activity resulting from interactions with the ETC, a system that is already deficient in cancer cells. - Highlights: • We studied the anticancer activity of a natural compound, 3-OHbk, on TA3/Ha cells. • 3-OHbk inhibited mitochondrial electron flow by interacting with Complex I. • Complex I inhibition did

  19. Tumor cell death induced by the inhibition of mitochondrial electron transport: The effect of 3-hydroxybakuchiol

    Energy Technology Data Exchange (ETDEWEB)

    Jaña, Fabián [Clinical and Molecular Pharmacology Program, University of Chile, Santiago (Chile); Faini, Francesca [Department of Chemistry, Faculty of Sciences, University of Chile, Santiago (Chile); Lapier, Michel; Pavani, Mario [Clinical and Molecular Pharmacology Program, University of Chile, Santiago (Chile); Kemmerling, Ulrike [Anatomy and Developmental Biology Program, ICBM, Faculty of Medicine, University of Chile, Santiago (Chile); Morello, Antonio; Maya, Juan Diego; Jara, José [Clinical and Molecular Pharmacology Program, University of Chile, Santiago (Chile); Parra, Eduardo [Laboratory of Experimental Biomedicine, University of Tarapaca, Campus Esmeralda, Iquique (Chile); Ferreira, Jorge, E-mail: jferreir@med.uchile.cl [Clinical and Molecular Pharmacology Program, University of Chile, Santiago (Chile)

    2013-10-15

    Changes in mitochondrial ATP synthesis can affect the function of tumor cells due to the dependence of the first step of glycolysis on mitochondrial ATP. The oxidative phosphorylation (OXPHOS) system is responsible for the synthesis of approximately 90% of the ATP in normal cells and up to 50% in most glycolytic cancers; therefore, inhibition of the electron transport chain (ETC) emerges as an attractive therapeutic target. We studied the effect of a lipophilic isoprenylated catechol, 3-hydroxybakuchiol (3-OHbk), a putative ETC inhibitor isolated from Psoralea glandulosa. 3-OHbk exerted cytotoxic and anti-proliferative effects on the TA3/Ha mouse mammary adenocarcinoma cell line and induced a decrease in the mitochondrial transmembrane potential, the activation of caspase-3, the opening of the mitochondrial permeability transport pore (MPTP) and nuclear DNA fragmentation. Additionally, 3-OHbk inhibited oxygen consumption, an effect that was completely reversed by succinate (an electron donor for Complex II) and duroquinol (electron donor for Complex III), suggesting that 3-OHbk disrupted the electron flow at the level of Complex I. The inhibition of OXPHOS did not increase the level of reactive oxygen species (ROS) but caused a large decrease in the intracellular ATP level. ETC inhibitors have been shown to induce cell death through necrosis and apoptosis by increasing ROS generation. Nevertheless, we demonstrated that 3-OHbk inhibited the ETC and induced apoptosis through an interaction with Complex I. By delivering electrons directly to Complex III with duroquinol, cell death was almost completely abrogated. These results suggest that 3-OHbk has antitumor activity resulting from interactions with the ETC, a system that is already deficient in cancer cells. - Highlights: • We studied the anticancer activity of a natural compound, 3-OHbk, on TA3/Ha cells. • 3-OHbk inhibited mitochondrial electron flow by interacting with Complex I. • Complex I inhibition did

  20. Adrenomedullin mediates tumor necrosis factor-α-induced responses in dorsal root ganglia in rats.

    Science.gov (United States)

    Chen, Yajuan; Zhang, Yan; Huo, Yuanhui; Wang, Dongmei; Hong, Yanguo

    2016-08-01

    Adrenomedullin (AM), a member of the calcitonin gene-related peptide (CGRP) family, has been demonstrated to be a pain peptide. This study investigated the possible involvement of AM in tumor necrosis factor-alpha (TNF-α)-induced responses contributing to neuronal plasticity in the dorsal root ganglia (DRG). Exposure of the DRG explant cultures to TNF-α (5nM) for 48h upregulated the expression of AM mRNA. The treatment with TNF-α also increased the level of CGRP, CCL-2 and MMP-9 mRNA in the cultured DRG. This increase was attenuated by the co-treatment with the selective AM receptor antagonist AM22-52 (2μM). The blockade of AM receptors inhibited TNF-α-induced increase of the glial fibrillary acidic protein (GFAP), interleukin-1β (IL-1β), phosphorylated cAMP response element binding protein (pCREB) and nuclear factor kappa B (pNF-κB) proteins. On the other hand, the treatment with the AM receptor agonist AM1-50 (10nM) for 96h induced an increase in the level of GFAP, IL-1β, pCREB and pNF-κB proteins. The inhibition of AM activity did not change TNF-α-induced phosphorylation of extracellular signal-related kinase (pERK) while the treatment with AM1-50 still increased the level of pERK in the cultured DRG. Immunofluorescence assay showed the colocalization of AM-like immunoreactivity (IR) with TNF-α-IR in DRG neurons. The present study suggests that the increased AM receptor signaling mediated the many, but not all, TNF-α-induced activities, contributing to peripheral sensitization in neuropathic pain. PMID:27184601

  1. Radiation-Inducible Caspase-8 Gene Therapy for Malignant Brain Tumors

    International Nuclear Information System (INIS)

    Purpose: Patients with malignant gliomas have a poor prognosis. To explore a novel and more effective approach for the treatment of patients with malignant gliomas, we designed a strategy that combines caspase-8 (CSP8) gene therapy and radiation treatment (RT). In addition, the specificity of the combined therapy was investigated to decrease the unpleasant effects experienced by the surrounding normal tissue. Methods and Materials: We constructed the plasmid pEGR-green fluorescence protein that included the radiation-inducible early growth response gene-1 (Egr-1) promoter and evaluated its characteristics. The pEGR-CSP8 was constructed and included the Egr-1 promoter and CSP8 complementary DNA. Assays that evaluated the apoptosis inducibility and cytotoxicity caused by CSP8 gene therapy combined with RT were performed using U251 and U87 glioma cells. The pEGR-CSP8 was transfected into the subcutaneous U251 glioma cells of nude mice by means of in vivo electroporation. The in vivo effects of CSP8 gene therapy combined with RT were evaluated. Results: The Egr-1 promoter yielded a better response with fractionated RT than with single-dose RT. In the assay of apoptosis inducibility and cytotoxicity, pEGR-CSP8 showed response for RT. The pEGR-CSP8 combined with RT is capable of inducing cell death effectively. In mice treated with pEGR-CSP8 and RT, apoptotic cells were detected in pathologic sections, and a significant difference was observed in tumor volumes. Conclusions: Our results indicate that radiation-inducible gene therapy may have great potential because this can be spatially or temporally controlled by exogenous RT and is safe and specific

  2. Tumor-associated antigens identified by mRNA expression profiling induce protective anti-tumor immunity

    DEFF Research Database (Denmark)

    Mathiassen, Søren; Lauemøller, S L; Ruhwald, Morten;

    2001-01-01

    to identify TAA, mice were immunized with mixtures of peptides representing putative cytotoxic T cell epitopes derived from one of the gene products. Indeed, such immunized mice were partially protected against subsequent tumor challenge. Despite being immunized with bona fide self antigens, no...

  3. Surface expressed nucleolin is constantly induced in tumor cells to mediate calcium-dependent ligand internalization.

    Directory of Open Access Journals (Sweden)

    Ara G Hovanessian

    Full Text Available BACKGROUND: Nucleolin is one of the major proteins of the nucleolus, but it is also expressed on the cell surface where is serves as a binding protein for variety of ligands implicated in tumorigenesis and angiogenesis. Emerging evidence suggests that the cell-surface expressed nucleolin is a strategic target for an effective and nontoxic cancer therapy. METHODOLOGY/PRINCIPAL FINDINGS: By monitoring the expression of nucleolin mRNA, and by measuring the level of nucleolin protein recovered from the surface and nucleus of cells, here we show that the presence of nucleolin at the cell surface is dependent on the constant induction of nucleolin mRNA. Indeed, inhibitors of RNA transcription or translation block expression of surface nucleolin while no apparent effect is observed on the level of nucleolin in the nucleus. The estimated half-life of surface nucleolin is less than one hour, whereas that of nuclear nucleolin is more than 8 hours. Nucleolin mRNA induction is reduced markedly in normal fibroblasts that reach confluence, while it occurs continuously even in post-confluent epithelial tumor cells consistent with their capacity to proliferate without contact inhibition. Interestingly, cold and heat shock induce nucleolin mRNA concomitantly to enhanced mRNA expression of the heat shock protein 70, thus suggesting that surface nucleolin induction also occurs in response to an environmental insult. At the cell surface, one of the main functions of nucleolin is to shuttle specific extracellular ligands by an active transport mechanism, which we show here to be calcium dependent. CONCLUSION/SIGNIFICANCE: Our results demonstrate that the expression of surface nucleolin is an early metabolic event coupled with tumor cell proliferation and stress response. The fact that surface nucleolin is constantly and abundantly expressed on the surface of tumor cells, makes them a preferential target for the inhibitory action of anticancer agents that target

  4. Sequence tags of provirus integration sites in DNAs of tumors induced by the murine retrovirus SL3-3.

    OpenAIRE

    Sørensen, A B; Duch, M.; Amtoft, H W; Jørgensen, P; Pedersen, F S

    1996-01-01

    The murine retrovirus SL3-3 is a potent inducer of T-cell lymphomas when inoculated into susceptible newborn mice. The proviral integration site sequences were surveyed in tumor DNAs by a simple two-step PCR method. From 20 SL3-3-induced tumors a total of 39 provirus-host junctions were amplified and sequenced. Seven showed homology to known sequences. These included the known common integration site c-myc as well as genes not previously identified as targets of provirus integration, namely N...

  5. Tumor Necrosis Factor-α-Induced Ototoxicity in Mouse Cochlear Organotypic Culture.

    Directory of Open Access Journals (Sweden)

    Qian Wu

    Full Text Available Tumor necrosis factor (TNF-α is a cytokine involved in acute inflammatory phase reactions, and is the primary upstream mediator in the cochlear inflammatory response. Treatment of the organ of Corti with TNF-α can induce hair cell damage. However, the resulting morphological changes have not been systematically examined. In the present study, cochlear organotypic cultures from neonatal mice were treated with various concentrations and durations of TNF-α to induce inflammatory responses. Confocal microscopy was used to evaluate the condition of hair cells and supporting cells following immunohistochemical staining. In addition, the ultrastructure of the stereocilia bundle, hair cells, and supporting cells were examined by scanning and transmission electron microscopy. TNF-α treatment resulted in a fusion and loss of stereocilia bundles in hair cells, swelling of mitochondria, and vacuolation and degranulation of the endoplasmic reticulum. Disruption of tight junctions between hair cells and supporting cells was also observed at high concentrations. Hair cell loss was preceded by apoptosis of Deiters' and pillar cells. Taken together, these findings detail the morphological changes in the organ of Corti after TNF-α treatment, and provide an in vitro model of inflammatory-induced ototoxicity.

  6. Human Adipose Derived Stem Cells Induced Cell Apoptosis and S Phase Arrest in Bladder Tumor

    Directory of Open Access Journals (Sweden)

    Xi Yu

    2015-01-01

    Full Text Available The aim of this study was to determine the effect of human adipose derived stem cells (ADSCs on the viability and apoptosis of human bladder cancer cells. EJ and T24 cells were cocultured with ADSCs or cultured with conditioned medium of ADSCs (ADSC-CM, respectively. The cell counting and colony formation assay showed ADSCs inhibited the proliferation of EJ and T24 cells. Cell viability assessment revealed that the secretions of ADSCs, in the form of conditioned medium, were able to decrease cancer cell viability. Wound-healing assay suggested ADSC-CM suppressed migration of T24 and EJ cells. Moreover, the results of the flow cytometry indicated that ADSC-CM was capable of inducing apoptosis of T24 cells and inducing S phase cell cycle arrest. Western blot revealed ADSC-CM increased the expression of cleaved caspase-3 and cleaved PARP, indicating that ADSC-CM induced apoptosis in a caspase-dependent way. PTEN/PI3K/Akt pathway and Bcl-2 family proteins were involved in the mechanism of this reaction. Our study indicated that ADSCs may provide a promising and practicable manner for bladder tumor therapy.

  7. Fer tyrosine kinase oligomer mediates and amplifies Src-induced tumor progression.

    Science.gov (United States)

    Oneyama, C; Yoshikawa, Y; Ninomiya, Y; Iino, T; Tsukita, S; Okada, M

    2016-01-28

    c-Src is upregulated in various human cancers, suggesting its role in malignant progression. However, the molecular circuits of c-Src oncogenic signaling remain elusive. Here we show that Fer tyrosine kinase oligomer mediates and amplifies Src-induced tumor progression. Previously, we showed that transformation of fibroblasts is promoted by the relocation of c-Src to non-raft membranes. In this study, we identified Fer and ezrin as non-raft c-Src targets. c-Src directly activated Fer by initiating its autophosphorylation, which was further amplified by Fer oligomerization. Fer interacted with active c-Src at focal adhesion membranes and activated Fer-phosphorylated ezrin to induce cell transformation. Fer was also crucial for cell transformation induced by v-Src or epidermal growth-factor receptor activation. Furthermore, Fer activation was required for tumorigenesis and invasiveness in some cancer cells in which c-Src is upregulated. We propose that the Src-Fer axis represents a new therapeutic target for treatment of a subset of human cancers. PMID:25867068

  8. Frankincense oil derived from Boswellia carteri induces tumor cell specific cytotoxicity

    Directory of Open Access Journals (Sweden)

    Ashley Richard A

    2009-03-01

    Full Text Available Abstract Background Originating from Africa, India, and the Middle East, frankincense oil has been important both socially and economically as an ingredient in incense and perfumes for thousands of years. Frankincense oil is prepared from aromatic hardened gum resins obtained by tapping Boswellia trees. One of the main components of frankincense oil is boswellic acid, a component known to have anti-neoplastic properties. The goal of this study was to evaluate frankincense oil for its anti-tumor activity and signaling pathways in bladder cancer cells. Methods Frankincense oil-induced cell viability was investigated in human bladder cancer J82 cells and immortalized normal bladder urothelial UROtsa cells. Temporal regulation of frankincense oil-activated gene expression in bladder cancer cells was identified by microarray and bioinformatics analysis. Results Within a range of concentration, frankincense oil suppressed cell viability in bladder transitional carcinoma J82 cells but not in UROtsa cells. Comprehensive gene expression analysis confirmed that frankincense oil activates genes that are responsible for cell cycle arrest, cell growth suppression, and apoptosis in J82 cells. However, frankincense oil-induced cell death in J82 cells did not result in DNA fragmentation, a hallmark of apoptosis. Conclusion Frankincense oil appears to distinguish cancerous from normal bladder cells and suppress cancer cell viability. Microarray and bioinformatics analysis proposed multiple pathways that can be activated by frankincense oil to induce bladder cancer cell death. Frankincense oil might represent an alternative intravesical agent for bladder cancer treatment.

  9. Tumor vaccines

    International Nuclear Information System (INIS)

    Tumor vaccines have several potential advantages over standard anticancer regiments. They represent highly specific anticancer therapy. Inducing tumor-specific memory T-lymphocytes, they have potential for long-lived antitumor effects. However, clinical trials, in which cancer patients were vaccinated with tumor vaccines, have been so far mainly disappointing. There are many reasons for the inefficiency of tumor vaccines. Most cancer antigens are normal self-molecules to which immune tolerance exists. That is why the population of tumor-specific lymphocytes is represented by a small number of low-affinity T-lymphocytes that induce weak antitumor immune response. Simultaneously, tumors evolve many mechanisms to actively evade immune system, what makes them poorly immunogenic or even tolerogenic. Novel immunotherapeutic strategies are directed toward breaking immune tolerance to tumor antigens, enhancing immunogenicity of tumor vaccines and overcoming mechanisms of tumor escape. There are several approaches, unfortunately, all of them still far away from an ideal tumor vaccine that would reject a tumor. Difficulties in the activation of antitumor immune response by tumor vaccines have led to the development of alternative immunotherapeutic strategies that directly focus on effector mechanisms of immune system (adoptive tumor- specific T-lymphocyte transfer and tumor specific monoclonal antibodies). (author)

  10. Phosphoinositide 3-kinase accelerates postoperative tumor growth by inhibiting apoptosis and enhancing resistance to chemotherapy-induced apoptosis. Novel role for an old enemy.

    LENUS (Irish Health Repository)

    Coffey, J Calvin

    2012-02-03

    Tumor removal remains the principal treatment modality in the management of solid tumors. The process of tumor removal may potentiate the resurgent growth of residual neoplastic tissue. Herein, we describe a novel murine model in which flank tumor cytoreduction is followed by accelerated local tumor recurrence. This model held for primary and recurrent tumors generated using a panel of human and murine (LS174T, DU145, SW480, SW640, and 3LL) cell lines and replicated accelerated tumor growth following excisional surgery. In investigating this further, epithelial cells were purified from LS174T primary and corresponding recurrent tumors for comparison. Baseline as well as tumor necrosis factor apoptosis-inducing ligand (TRAIL)-induced apoptosis were significantly reduced in recurrent tumor epithelia. Primary and recurrent tumor gene expression profiles were then compared. This identified an increase and reduction in the expression of p110gamma and p85alpha class Ia phosphoinositide 3-kinase (PI3K) subunits in recurrent tumor epithelia. These changes were further confirmed at the protein level. The targeting of PI3K ex vivo, using LY294002, restored sensitivity to TRAIL in recurrent tumor epithelia. In vivo, adjuvant LY294002 prolonged survival and significantly attenuated recurrent tumor growth by greatly enhancing apoptosis levels. Hence, PI3K plays a role in generating the antiapoptotic and chemoresistant phenotype associated with accelerated local tumor recurrence.

  11. The role of UV induced lesions in skin carcinogenesis: an overview of oncogene and tumor suppressor gene modifications in xeroderma pigmentosum skin tumors

    Energy Technology Data Exchange (ETDEWEB)

    Daya-Grosjean, Leela [Laboratory of Genetic Instability and Cancer, UPR2169 CNRS, IFR 54, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif Cedex (France)]. E-mail: daya@igr.fr; Sarasin, Alain [Laboratory of Genetic Instability and Cancer, UPR2169 CNRS, IFR 54, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif Cedex (France)

    2005-04-01

    Xeroderma pigmentosum (XP), a rare hereditary syndrome, is characterized by a hypersensitivity to solar irradiation due to a defect in nucleotide excision repair resulting in a predisposition to squamous and basal cell carcinomas as well as malignant melanomas appearing at a very early age. The mutator phenotype of XP cells is evident by the higher levels of UV specific modifications found in key regulatory genes in XP skin tumors compared to those in the same tumor types from the normal population. Thus, XP provides a unique model for the study of unrepaired DNA lesions, mutations and skin carcinogenesis. The high level of ras oncogene activation, Ink4a-Arf and p53 tumor suppressor gene modifications as well as alterations of the different partners of the mitogenic sonic hedgehog signaling pathway (patched, smoothened and sonic hedgehog), characterized in XP skin tumors have clearly demonstrated the major role of the UV component of sunlight in the development of skin tumors. The majority of the mutations are C to T or tandem CC to TT UV signature transitions, occurring at bipyrimidine sequences, the specific targets of UV induced lesions. These characteristics are also found in the same genes modified in sporadic skin cancers but with lower frequencies confirming the validity of studying the XP model. The knowledge gained by studying XP tumors has given us a greater perception of the contribution of genetic predisposition to cancer as well as the consequences of the many alterations which modulate the activities of different genes affecting crucial pathways vital for maintaining cell homeostasis.

  12. The role of UV induced lesions in skin carcinogenesis: an overview of oncogene and tumor suppressor gene modifications in xeroderma pigmentosum skin tumors

    International Nuclear Information System (INIS)

    Xeroderma pigmentosum (XP), a rare hereditary syndrome, is characterized by a hypersensitivity to solar irradiation due to a defect in nucleotide excision repair resulting in a predisposition to squamous and basal cell carcinomas as well as malignant melanomas appearing at a very early age. The mutator phenotype of XP cells is evident by the higher levels of UV specific modifications found in key regulatory genes in XP skin tumors compared to those in the same tumor types from the normal population. Thus, XP provides a unique model for the study of unrepaired DNA lesions, mutations and skin carcinogenesis. The high level of ras oncogene activation, Ink4a-Arf and p53 tumor suppressor gene modifications as well as alterations of the different partners of the mitogenic sonic hedgehog signaling pathway (patched, smoothened and sonic hedgehog), characterized in XP skin tumors have clearly demonstrated the major role of the UV component of sunlight in the development of skin tumors. The majority of the mutations are C to T or tandem CC to TT UV signature transitions, occurring at bipyrimidine sequences, the specific targets of UV induced lesions. These characteristics are also found in the same genes modified in sporadic skin cancers but with lower frequencies confirming the validity of studying the XP model. The knowledge gained by studying XP tumors has given us a greater perception of the contribution of genetic predisposition to cancer as well as the consequences of the many alterations which modulate the activities of different genes affecting crucial pathways vital for maintaining cell homeostasis

  13. Doxycyclin ameliorates a starvation-induced germline tumor in C. elegans daf-18/PTEN mutant background.

    Science.gov (United States)

    Wolf, Tim; Qi, Wenjing; Schindler, Verena; Runkel, Eva Diana; Baumeister, Ralf

    2014-08-01

    Managing available resources is a key necessity of each organism to cope with the environment. The nematode C. elegans responds to nutritional deprivation or harsh environmental conditions with a multitude of developmental adaptations, among them a starvation-induced quiescence at early larval development (L1). daf-18, the C. elegans homolog of the human tumor suppressor gene PTEN, is essential for the maintenance of survival and germline stem cell arrest during the L1 diapause. We show here that daf-18 mutants, independently to their failure to maintain G2 arrest of the primordial germ cells, develop a gonad phenotype after refeeding. This highly penetrant gonadal phenotype is further enhanced by a mutation in shc-1, encoding a protein homologous to the human adaptor ShcA. Features of this phenotype are a tumor-like phenotype encompassing hyper-proliferation of germ cell nuclei and disruption/invasion of the basement membrane surrounding the gonad. The penetrance of this phenotype is reduced by decreasing starvation temperature. In addition, it is also ameliorated in a dose-dependent way by exposure to the antibiotic doxycyclin either during starvation or during subsequent refeeding. Since, in eukaryotic cells, doxycyclin specifically blocks mitochondrial translation, our results suggest that daf-18 and shc-1;daf-18 mutants fail to adapt mitochondrial activity to reduced nutritional availability during early larval developing. PMID:24746511

  14. Staphylococcal Superantigen-like 10 Inhibits CXCL12-Induced Human Tumor Cell Migration

    Directory of Open Access Journals (Sweden)

    Annemiek M.E. Walenkamp

    2009-04-01

    Full Text Available Purpose: Tumor cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. CXCR4 is the most widely expressed chemokine receptor in many different types of cancer and has been linked to tumor dissemination and poor prognosis. Several CXCR4 antagonists have been synthesized. A totally novel approach to discover chemokine receptor antagonists is the use of bacteria. Bacteria produce chemokine receptor inhibitors to prevent neutrophil extravasation and migration toward the infection site to escape clearance by innate immune cells. The aim of the current study was to find and identify the mechanism of a bacterial protein that specifically targets CXCR4, a chemokine receptor shared by neutrophils and cancer cells. Experimental Design: Several staphylococcal proteins were screened for their capacity to prevent binding of a function-blocking antibody against CXCR4. Results: Staphylococcal superantigen-like 10 was found to bind CXCR4 expressed on human T acute lymphoblastic leukemia, lymphoma, and cervical carcinoma cell lines. It potently inhibited CXCL12-induced calcium mobilization and cell migration. Conclusions: Staphylococcal superantigen-like 10 is a potential lead in the development of new anticancer compounds preventing metastasis by targeting CXCR4.

  15. Optical signature of multicellular tumor spheroid using index-mismatch-induced spherical aberrations

    Science.gov (United States)

    Le Corre, G.; Weiss, P.; Ducommun, B.; Lorenzo, C.

    2014-02-01

    The development of new cancer treatments and the early prediction of their therapeutic potential are often made difficult by the lack of predictive pharmacological models. The 3D multicellular tumor spheroid (MCTS) model offers a level of complexity that recapitulates the three-dimensional organization of a tumor and appears to be fairly predictive of therapeutic efficiency. The use of spheroids in large-scale automated screening was recently reported to link the power of a high throughput analysis to the predictability of a 3D cell model. The spheroid has a radial symmetry; this simple geometry allows establishing a direct correlation between structure and function. The outmost layers of MCTS are composed of proliferating cells and form structurally uniform domain with an approximate thickness of 100 microns. The innermost layers are composed of quiescent cells. Finally, cells in the center of the spheroid can form a necrotic core. This latest region is structurally heterogeneous and is poorly characterized. These features make the spheroid a model of choice and a paradigm to study the optical properties of various epithelial tissues. In this study, we used an in-vitro optical technique for label-free characterization of multicellular systems based on the index- mismatch induced spherical aberrations. We achieve to monitor and characterize the optical properties of MCTS. This new and original approach might be of major interest for the development of innovative screening strategies dedicated to the identification of anticancer drugs.

  16. Low-temperature plasma-induced antiproliferative effects on multi-cellular tumor spheroids

    International Nuclear Information System (INIS)

    Biomedical applications of low-temperature plasmas are of growing interest, especially in the field of plasma-induced anti-tumor effects. The present work is aimed at investigating the regionalized antiproliferative effects of low-temperature plasmas on a multicellular tumor spheroid (MCTS), a model that mimics the 3D organization and regionalization of a microtumor region. We report that a low-temperature plasma jet, using helium flow in open air, inhibits HCT116 colon carcinoma MCTS growth in a dose-dependent manner. This growth inhibition is associated with the loss of Ki67, and the regionalized accumulation of DNA damage detected by histone H2AX phosphorylation. This regionalized genotoxic effect leads to massive cell death and loss of the MCTS proliferative region. The use of reactive oxygen species (ROS), scavenger N-acetyl cysteine (NAC) and plasma-conditioned media demonstrate that the ROS generated in the media after exposure to low-temperature plasma play a major role in these observed effects. These findings strengthen the interest in the use of MCTS for the evaluation of antiproliferative strategies, and open new perspectives for studies dedicated to demonstrate the potential of low-temperature plasma in cancer therapy

  17. Low-temperature plasma-induced antiproliferative effects on multi-cellular tumor spheroids

    Science.gov (United States)

    Plewa, Joseph-Marie; Yousfi, Mohammed; Frongia, Céline; Eichwald, Olivier; Ducommun, Bernard; Merbahi, Nofel; Lobjois, Valérie

    2014-04-01

    Biomedical applications of low-temperature plasmas are of growing interest, especially in the field of plasma-induced anti-tumor effects. The present work is aimed at investigating the regionalized antiproliferative effects of low-temperature plasmas on a multicellular tumor spheroid (MCTS), a model that mimics the 3D organization and regionalization of a microtumor region. We report that a low-temperature plasma jet, using helium flow in open air, inhibits HCT116 colon carcinoma MCTS growth in a dose-dependent manner. This growth inhibition is associated with the loss of Ki67, and the regionalized accumulation of DNA damage detected by histone H2AX phosphorylation. This regionalized genotoxic effect leads to massive cell death and loss of the MCTS proliferative region. The use of reactive oxygen species (ROS), scavenger N-acetyl cysteine (NAC) and plasma-conditioned media demonstrate that the ROS generated in the media after exposure to low-temperature plasma play a major role in these observed effects. These findings strengthen the interest in the use of MCTS for the evaluation of antiproliferative strategies, and open new perspectives for studies dedicated to demonstrate the potential of low-temperature plasma in cancer therapy.

  18. Sophoridinol derivative 05D induces tumor cells apoptosis by topoisomerase1-mediated DNA breakage

    Directory of Open Access Journals (Sweden)

    Zhao W

    2016-05-01

    Full Text Available Wuli Zhao, Caixia Zhang, Chongwen Bi, Cheng Ye, Danqing Song, Xiujun Liu, Rongguang Shao Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of China Abstract: Sophoridine is a quinolizidine natural product of Sophora alopecuroides and has been applied for treatment of malignant trophoblastic tumors. Although characterized by low toxicity, the limited-spectrum antitumor activity hinders its further applications. 05D, a derivative of sophoridine, exhibits a better anticancer activity on diverse cancer cells, including solid tumors, and hematologic malignancy. It could inhibit topoisomerase 1 (top1 activity by stabilizing DNA–top1 complex and induce mitochondria-mediated apoptosis by promoting DNA single- and double-strand breakage mediated by top1. Also, 05D induced HCT116 cells arrest at G1 phase by inactivating CDK2/CDK4–Rb–E2F and cyclinD1–CDK4–p21 checkpoint signal pathways. 05D suppressed the ataxia telangiectasia mutated (ATM and ATM and Rad3-related (ATR activation and decreased 53BP level, which contributed to DNA damage repair, suggesting that the novel compound 05D might be helpful to improve the antitumor activity of DNA damaging agent by repressing ATM and ATR activation and 53BP level. In addition, the priorities in molecular traits and druggability, such as a simple structure and formulation for oral administration, further prove 05D to be a promising targeting topoisomerase agent. Keywords: topoisomerase inhibitor, topoisomerase 1, DNA breakage, sophoridinol, anticancer, apoptosis, cell cycle

  19. How to Use MR-Contrast Agent in Tumor Induced Epilepsis

    OpenAIRE

    Aliakbar Ameri; Mohammad Shirazi; Hamid Mohammadpour; Ali Noroozi; Jalal Jalalshokouhi

    2010-01-01

    By year of 1990, second MRI revolution has hap-pened in the diagnosis of infection and tumor assessment "first revolution was made by clinical MRI invention in the early 1980's"."nTumor-associated epilepsis is an important contributor to morbidity in patients with brain tumors. Perilesional tissue changes play a vital role in the generation of tumor-associated seizures.Tumor-associated seizure is usually focal with secondary generalization and often resistant to antiepileptic drugs....

  20. Tumor Growth Inhibition via Occlusion of Tumor Vasculature Induced by N-Terminally PEGylated Retargeted Tissue Factor tTF-NGR.

    Science.gov (United States)

    Brand, Caroline; Fröhlich, Max; Ring, Janine; Schliemann, Christoph; Kessler, Torsten; Mantke, Verena; König, Simone; Lücke, Martin; Mesters, Rolf M; Berdel, Wolfgang E; Schwöppe, Christian

    2015-10-01

    tTF-NGR retargets the extracellular domain of tissue factor via a C-terminal peptide GNGRAHA, a ligand of the surface protein aminopeptidase N (CD13) and upon deamidation of integrin αvβ3, to tumor vasculature. tTF-NGR induces tumor vascular infarction with consecutive antitumor activity against xenografts and selectively inhibits tumor blood flow in cancer patients. Since random PEGylation resulted in favorable pharmacodynamics of tTF-NGR, we performed site-directed PEGylation of PEG units to the N-terminus of tTF-NGR to further improve the antitumor profile of the molecule. Mono-PEGylation to the N-terminus did not change the procoagulatory activity of the tTF-NGR molecule as measured by Factor X activation. Experiments to characterize pharmacokinetics in mice showed a more than 1 log step higher mean area under the curve of PEG20k-tTF-NGR over tTF-NGR. Acute (24 h) tolerability upon intravenous application for the mono-PEGylated versus non-PEGylated tTF-NGR compounds was comparable. PEG20k-tTF-NGR showed clear antitumor efficacy in vivo against human tumor xenografts when systemically applied. However, site-directed mono-PEGylation to the N-terminus does not unequivocally improve the therapeutic profile of tTF-NGR. PMID:26310827

  1. Cryo-thermal therapy elicits potent anti-tumor immunity by inducing extracellular Hsp70-dependent MDSC differentiation

    Science.gov (United States)

    Zhu, Jun; Zhang, Yan; Zhang, Aili; He, Kun; Liu, Ping; Xu, Lisa X.

    2016-06-01

    Achieving control of metastatic disease is a long-sought goal in cancer therapy. Treatments that encourage a patient’s own immune system are bringing new hopes in reaching such a goal. In clinic, local hyperthermia and cryoablation have been explored to induce anti-tumor immune responses against tumors. We have also developed a novel therapeutic modality of cryo-thermal treatment by alternating liquid nitrogen (LN2) cooling and radio frequency (RF) heating, and better therapeutic effect was achieved in treating metastatic cancer in animal model. In this study, we investigated the mechanism of systemic immune response elicited by cryo-thermal therapy. In the 4T1 murine mammary carcinoma model, we found that local cryo-thermal therapy resulted in a considerable reduction of distant lung metastases, and improved long-term survival. Moreover, results of tumor re-challenge experiments indicated generation of a strong tumor-specific immune memory after the local treatment of primary tumors. Our further study indicated that cryo-thermal therapy caused an elevated extracellular release of Hsp70. Subsequently, Hsp70 induced differentiation of MDSCs into mature DCs, contributing to the relief of MDSCs-mediated immunosuppression and ultimately the activation of strong anti-tumor immune response. Our findings reveal new insight into the mechanism of robust therapeutic effects of cryo-thermal therapy against metastatic cancers.

  2. Cryo-thermal therapy elicits potent anti-tumor immunity by inducing extracellular Hsp70-dependent MDSC differentiation.

    Science.gov (United States)

    Zhu, Jun; Zhang, Yan; Zhang, Aili; He, Kun; Liu, Ping; Xu, Lisa X

    2016-01-01

    Achieving control of metastatic disease is a long-sought goal in cancer therapy. Treatments that encourage a patient's own immune system are bringing new hopes in reaching such a goal. In clinic, local hyperthermia and cryoablation have been explored to induce anti-tumor immune responses against tumors. We have also developed a novel therapeutic modality of cryo-thermal treatment by alternating liquid nitrogen (LN2) cooling and radio frequency (RF) heating, and better therapeutic effect was achieved in treating metastatic cancer in animal model. In this study, we investigated the mechanism of systemic immune response elicited by cryo-thermal therapy. In the 4T1 murine mammary carcinoma model, we found that local cryo-thermal therapy resulted in a considerable reduction of distant lung metastases, and improved long-term survival. Moreover, results of tumor re-challenge experiments indicated generation of a strong tumor-specific immune memory after the local treatment of primary tumors. Our further study indicated that cryo-thermal therapy caused an elevated extracellular release of Hsp70. Subsequently, Hsp70 induced differentiation of MDSCs into mature DCs, contributing to the relief of MDSCs-mediated immunosuppression and ultimately the activation of strong anti-tumor immune response. Our findings reveal new insight into the mechanism of robust therapeutic effects of cryo-thermal therapy against metastatic cancers. PMID:27256519

  3. Relationship of doxorubicin- and radiation-induced apoptosis with Ki-67 labeling index in human tumors in vivo

    International Nuclear Information System (INIS)

    In the use of doxorubicin and radiation for treatment of human malignant tumors in vivo, the relationship between treatment-induced apoptosis and Ki-67 labeling index was investigated. Four human tumor xenografts (ependymoblastoma, NNE; primitive neuroectodermal tumor, YKP; small cell lung carcinoma, GLS; glioblastoma, KYG) were transplanted under the skin of thigh of the nude mice (BALB/cA JcL-nu). The mice were given a single radiation dose of 1 Gy, or doxorubicin alone intraperitoneally at a dose of 8 mg/kg. After treatment, sections of tumor specimens were prepared from paraffin-embedded tissues. Hematoxylin and eosin staining, TUNEL staining, and immunohistochemical analysis of Ki-67 were performed. In NNE, apoptotic cells appeared most frequently after treatment compared with all other tumors, and the incidence of apoptosis in the radiation-treated group was much higher than in the doxorubicintreated group. As the incidence of apoptosis in NNE increased, the Ki-67 labeling index tended to decrease. In GLS and KYG, there was a low incidence of treatment-induced apoptosis, although the Ki-67 labeling index decreased transiently after treatment. In YKP, few apoptotic cells appeared and Ki-67 the labeling index was unchanged throughout the time course after treatment. Ki-67 labeling index in malignant tumors after treatment may be affected by various kinds of cell deaths and treatment methods. (author)

  4. Survivin selective inhibitor YM155 induce apoptosis in SK-NEP-1 Wilms tumor cells

    Directory of Open Access Journals (Sweden)

    Tao Yan-Fang

    2012-12-01

    Full Text Available Abstract Background Survivin, a member of the family of inhibitor of apoptosis proteins, functions as a key regulator of mitosis and programmed cell death. YM155, a novel molecular targeted agent, suppresses survivin, which is overexpressed in many tumor types. The aim of this study was to determine the antitumor activity of YM155 in SK-NEP-1 cells. Methods SK-NEP-1 cell growth in vitro and in vivo was assessed by MTT and nude mice experiments. Annexin V/propidium iodide staining followed by flow cytometric analysis was used to detect apoptosis in cell culture. Then gene expression profile of tumor cells treated with YM155 was analyzed with real-time PCR arrays. We then analyzed the expression data with MEV (Multi Experiment View cluster software. Datasets representing genes with altered expression profile derived from cluster analyses were imported into the Ingenuity Pathway Analysis tool. Results YM155 treatment resulted in inhibition of cell proliferation of SK-NEP-1cells in a dose-dependent manner. Annexin V assay, cell cycle, and activation of caspase-3 demonstrates that YM155 induced apoptosis in SK-NEP-1 cells. YM155 significantly inhibited growth of SK-NEP-1 xenografts (YM155 5 mg/kg: 1.45 ± 0.77 cm3; YM155 10 mg/kg: 0.95 ± 0.55 cm3 compared to DMSO group (DMSO: 3.70 ± 2.4 cm3 or PBS group cells (PBS: 3.78 ± 2.20 cm3, ANOVA P Conclusions The present study demonstrates that YM155 treatment resulted in apoptosis and inhibition of cell proliferation of SK-NEP-1cells. YM155 had significant role and little side effect in the treatment of SK-NEP-1 xenograft tumors. Real-time PCR array analysis firstly showed expression profile of genes dyes-regulated after YM155 treatment. IPA analysis also represents new molecule mechanism of YM155 treatment, such as NR3C1 and dexamethasone may be new target of YM155. And our results may provide new clues of molecular mechanism of apoptosis induced by YM155.

  5. Dendritic cells loaded with killed breast cancer cells induce differentiation of tumor-specific cytotoxic T lymphocytes

    International Nuclear Information System (INIS)

    Early clinical trials, mostly in the setting of melanoma, have shown that dendritic cells (DCs) expressing tumor antigens induce some immune responses and some clinical responses. A major difficulty is the extension to other tumors, such as breast carcinoma, for which few defined tumor-associated antigens are available. We have demonstrated, using both prostate carcinoma and melanoma as model systems, that DCs loaded with killed allogeneic tumor cell lines can induce CD8+ T cells to differentiate into cytotoxic T lymphocytes (CTLs) specific for shared tumor antigens. The present study was designed to determine whether DCs would capture killed breast cancer cells and present their antigens to autologous CD4+ and CD8+ T cells. We show that killed breast cancer cells are captured by immature DCs that, after induced maturation, can efficiently present MHC class I and class II peptides to CD8+ and CD4+ T lymphocytes. The elicited CTLs are able to kill the target cells without a need for pretreatment with interferon gamma. CTLs can be obtained by culturing the DCs loaded with killed breast cancer cells with unseparated peripheral blood lymphocytes, indicating that the DCs can overcome any potential inhibitory effects of breast cancer cells. Loading DCs with killed breast cancer cells may be considered a novel approach to breast cancer immunotherapy and to identification of shared breast cancer antigens

  6. Sesquiterpene lactones isolated from indigenous Middle Eastern plants inhibit tumor promoter-induced transformation of JB6 cells

    Directory of Open Access Journals (Sweden)

    Saikali Melody

    2012-07-01

    Full Text Available Abstract Background Sesquiterpene lactones (SL are plant secondary metabolites that are known for their anti-fungal, anti-bacterial, anti-inflammatory, and anti-tumor properties. Considering that several SL-derived drugs are currently in cancer clinical trials, we have tested two SL molecules, 3-β-methoxy-iso-seco-tanapartholide (β-tan isolated from Achillea falcata and salograviolide A (Sal A isolated from Centaurea ainetensis, for their anti-tumor properties. We used the mouse epidermal JB6P + cells as a model for tumor promotion and cellular transformation. Key players that are involved in cellular transformation and tumorigenesis are the AP-1 and NF-κB transcription factors; therefore, we assessed how β-tan and Sal A modulate their signaling pathways in JB6P + cells. Methods The effects of β-tan and Sal A on the growth of normal and neoplastic keratinocytes and on the tumor promotion-responsive JB6P + cells were determined using the MTT assay. Anchorage-independent cell growth transformation assays were used to evaluate the anti-tumor promoting properties of these SL molecules in JB6P + cells and dual luciferase reporter assays and western blot analysis were used to investigate their effects on tumor promoter-induced AP-1 and NF-κB activities and protein levels of key AP-1 and NF-кB target genes. Results β-tan and Sal A selectively inhibited tumor promoter-induced cell growth and transformation of JB6P + cells at concentrations that do not affect JB6P + and primary keratinocytes basal cell growth. In addition, both molecules reduced basal and tumor promoter-induced NF-κB transcriptional activities, differentially regulated basal and tumor promoter-induced AP-1 transcriptional activities, and modulated key players of the AP-1 and NF-κB signaling pathways. Conclusions These results highlight the anti-tumor promoting properties of β-tan and Sal A. These SL molecules isolated from two plant species native to

  7. Human Cytomegalovirus Infection of Tumor Cells Downregulates NCAM (CD56: A Novel Mechanism for Virus-Induced Tumor Invasiveness'

    Directory of Open Access Journals (Sweden)

    Roman A. Blaheta

    2004-07-01

    Full Text Available Pathologic data indicate that human cytomegalovirus (HCMV infection might be associated with the pathogenesis of several human malignancies. However, no definitive evidence of a causal link between HCMV infection and cancer dissemination has been established to date. This study describes the modulation of the invasive behavior of NCAM-expressing tumor cell lines by HCMV. Neuroblastoma (NB cells, persistently infected with the HCMV strain AD169 (UKF-NB-4AD169 and MHH-NB-11AD169, were added to endothelial cell monolayers and adhesion and penetration kinetics were measured. The 140- and 180-kDa isoforms of the adhesion receptor NCAM were evaluated by flow cytometry, Western blot, and reverse transcriptionpolymerase chain reaction (RT-PCR. The relevance of NCAM for tumor cell binding was proven by treating NB with NCAM antisense oligonucleotides or NCAM transfection. HCMV infection profoundly increased the number of adherent and penetrated NB, compared to controls. Surface expression of NCAM was significantly lower on UKF-NB-4AD169 and MHH-NB-11AD169, compared to mock-infected cells. Western-blot and RT-PCR demonstrated reduced protein and RNA levels of the 140- and 180-kDa isoform. An inverse correlation between NCAM expression and adhesion capacity of NB has been shown by antisense and transfection experiments. We conclude that HCMV infection leads to downregulation of NCAM receptors, which is associated with enhanced tumor cell invasiveness.

  8. NUMERICAL SIMULATION OF HEMODYNAMICS IN THE HOST BLOOD VESSEL AND MICROVASCULAR NETWORK GENERATED FROM TUMOR-INDUCED ANGIOGENESIS

    Institute of Scientific and Technical Information of China (English)

    ZHAO Gai-ping; WU Jie; XU Shi-xiong; COLLINS M.W.; JIANG Yu-ping; WANG Jian

    2006-01-01

    Numerical simulation of hemodynamics under the combined effects of both the host blood vessel and the microvascular network,which is based on a 2-D tumor inside and outside vascular network generated from a discrete mathematical model of tumor-induced angiogenesis, is performed systemically. And a "microvascular network-transport across microvascular network-flow in interstitium" model is developed to study the flow in solid tumor. Simulations are carried out to examine the effects of the variations of the inlet Reynolds number in the host blood vessel, the hydraulic conductivity of the microvascular wall, and interstitial hydraulic conductivity coefficient on the fluid flow in tumor microcirculation. The results are consistent with data obtained in terms of physiology. These results may provide some theoretical references and the bases for further clinical experimental research.

  9. Hypoxia-inducible miR-210 regulates the susceptibility of tumor cells to lysis by cytotoxic T cells.

    Science.gov (United States)

    Noman, Muhammad Zaeem; Buart, Stéphanie; Romero, Pedro; Ketari, Sami; Janji, Bassam; Mari, Bernard; Mami-Chouaib, Fathia; Chouaib, Salem

    2012-09-15

    Hypoxia in the tumor microenvironment plays a central role in the evolution of immune escape mechanisms by tumor cells. In this study, we report the definition of miR-210 as a miRNA regulated by hypoxia in lung cancer and melanoma, documenting its involvement in blunting the susceptibility of tumor cells to lysis by antigen-specific cytotoxic T lymphocytes (CTL). miR-210 was induced in hypoxic zones of human tumor tissues. Its attenuation in hypoxic cells significantly restored susceptibility to autologous CTL-mediated lysis, independent of tumor cell recognition and CTL reactivity. A comprehensive approach using transcriptome analysis, argonaute protein immunoprecipitation, and luciferase reporter assay revealed that the genes PTPN1, HOXA1, and TP53I11 were miR-210 target genes regulated in hypoxic cells. In support of their primary importance in mediating the immunosuppressive effects of miR-210, coordinate silencing of PTPN1, HOXA1, and TP53I11 dramatically decreased tumor cell susceptibility to CTL-mediated lysis. Our findings show how miR-210 induction links hypoxia to immune escape from CTL-mediated lysis, by providing a mechanistic understanding of how this miRNA mediates immunosuppression in oxygen-deprived regions of tumors where cancer stem-like cells and metastatic cellular behaviors are known to evolve. PMID:22962263

  10. Accurate sequential detection of primary tumor and metastatic lymphatics using a temperature-induced phase transition nanoparticulate system

    Directory of Open Access Journals (Sweden)

    Oh KS

    2014-06-01

    Full Text Available Keun Sang Oh,1 Ji Young Yhee,2 Dong-Eun Lee,3 Kwangmeyung Kim,2 Ick Chan Kwon,2 Jae Hong Seo,4 Sang Yoon Kim,5 Soon Hong Yuk1,4 1College of Pharmacy, Korea University, Sejong, 2Biomedical Research Center, Korea Institute of Science and Technology, Seoul, 3Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeonbuk, 4Biomedical Research Center, Korea University Guro Hospital, Seoul, 5Department of Otolaryngology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Republic of Korea Abstract: Primary tumor and tumor-associated metastatic lymphatics have emerged as new targets for anticancer therapy, given that these are difficult to treat using traditional chemotherapy. In this study, docetaxel-loaded Pluronic nanoparticles with Flamma™ (FPR-675, fluorescence molecular imaging dye; DTX/FPR-675 Pluronic NPs were prepared using a temperature-induced phase transition for accurate detection of metastatic lymphatics. Significant accumulation was seen at the primary tumor and in metastatic lymph nodes within a short time. Particle size, maximum drug loading capacity, and drug encapsulation efficiency of the docetaxel-loaded Pluronic NPs were approximately 10.34±4.28 nm, 3.84 wt%, and 94±2.67 wt%, respectively. Lymphatic tracking after local and systemic delivery showed that DTX/FPR-675 Pluronic NPs were more potent in tumor-bearing mice than in normal mice, and excised mouse lymphatics showed stronger near-infrared fluorescence intensity on the tumor-bearing side than on the non-tumor-bearing side at 60 minutes post-injection. In vivo cytotoxicity and efficacy data for the NPs demonstrated that the systemically administered NPs caused little tissue damage and had minimal side effects in terms of slow renal excretion and prolonged circulation in tumor-bearing mice, and rapid renal excretion in non-tumor-bearing mice using an in vivo real-time near-infrared fluorescence imaging system. These results

  11. PPARδ INDUCES CELL PROLIFERATION BY A CYCLIN E1-DEPENDENT MECHANISM AND IS UPREGULATED IN THYROID TUMORS

    OpenAIRE

    Zeng, Lingchun; Geng, Yan; Tretiakova, Maria; Yu, Xuemei; Sicinski, Peter; Kroll, Todd G.

    2008-01-01

    Peroxisome proliferator-activated receptors (PPARs) are lipid sensing nuclear receptors that have been implicated in multiple physiologic processes including cancer. Here, we determine that PPARδ induces cell proliferation through a novel cyclin E1-dependent mechanism and is upregulated in many human thyroid tumors. The expression of PPARδ was induced coordinately with proliferation in primary human thyroid cells by activation of serum, TSH/cAMP/pKa or EGF/MEK/ERK mitogenic signaling pathways...

  12. High-fat-diet-induced obesity causes an inflammatory and tumor-promoting microenvironment in the rat kidney

    OpenAIRE

    Kerstin Stemmer; Diego Perez-Tilve; Gayathri Ananthakrishnan; Anja Bort; Seeley, Randy J.; Tschöp, Matthias H.; Dietrich, Daniel R.; Pfluger, Paul T.

    2012-01-01

    SUMMARY Obesity and concomitant comorbidities have emerged as public health problems of the first order. For instance, obese individuals have an increased risk for kidney cancer. However, direct mechanisms linking obesity with kidney cancer remain elusive. We hypothesized that diet-induced obesity (DIO) promotes renal carcinogenesis by inducing an inflammatory and tumor-promoting microenvironment. We compared chow-fed lean Wistar rats with those that were sensitive (DIOsens) or partially r...

  13. Effect of peripheral benzodiazepine receptor ligands on lipopolysaccharide-induced tumor necrosis factor activity in thioglycolate-treated mice.

    OpenAIRE

    Matsumoto, T.; Ogata, M.; Koga, K.; Shigematsu, A

    1994-01-01

    To investigate the effect of peripheral and central benzodiazepine receptor ligands on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) activity in mouse macrophages, three types of ligands, 4'-chlorodiazepam (pure peripheral), midazolam (mixed), and clonazepam (pure central), were compared. Midazolam and 4'-chlorodiazepam significantly suppressed LPS (1-microgram/ml)-induced TNF activity in thioglycolate-elicited mouse macrophages. In every concentration examined (0.001 to 100 mi...

  14. ANTI-TUMOR ACTIVITY AND IMMUNE RESPONSES INDUCED BY HUMAN CANCER-ASSOCIATED MUCIN CORE PEPTIDE

    Institute of Scientific and Technical Information of China (English)

    Ma Yunguo; Yuan Mei; Fei Lihua; Li Li

    1998-01-01

    Objective: To investigate the immune responses induced by apomucin which is a mixture of mucin core peptide, in mice for elucidating the role of mucin core peptide in the modulation of cancers. Methods:Apomucin was isolated from human pancreatic cancer cell line SW1990. The mice were immunized with this apomucin (10μg/time×6) plus DETOX. Results: When immunized, all mice developed delayed-type hypersensitivity (DTH) after challenged with apomucin or synthetic peptide MUC-2 or MUC-3, while the mice immunized with apomucin alone did not develop DTH.No antibodies were detected by ELISA after immunization. When the spleen cells of vaccinated mice were cocultured with this apomucin (10-50μg/ml) and rhIL-2(50U/ml) in vitro, the proliferated lymphocytes showed cytotoxicity against human cancer cells, including colon cancer, gastric cancer, pancreatic cancer and leukemia as measured by Cr-51 release assay. Antibodies against MUC-2 and MUC-3 could block the cytotoxicity. Conclusion: It was identified that a vaccine combined of apomucin and immune adjuvant DETOX can induce cellular immune response and anti-tumor cytotoxicity in mice.

  15. Bone tumors induced by inhalation of 238PuO2 in dogs

    International Nuclear Information System (INIS)

    Plutonium-238, an alpha-emitting radionuclide, is used as a heat source in thermoelectric power generators such as have been employed on lunar expeditions of communications satellites and in cardiac pacemakers. It has an 86.4 year half-life and emits 5.5 MeV alpha particles. Beagle dogs were given single 10 to 30 minute exposures to 238PuO2 aerosols to study the long-term translocation of plutonium and biologicl effects. Dogs with a terminal body burden ranging from 7 to 260 MuCi were euthanized due to respiratory insufficiency related to plutonium-induced pneumonitis during the first 3 years after exposure. Nine of the 11 dogs euthanized during the 4 to 6 year postexposure period had osteosarcomas. The terminal plutonium body burden in the tumor-bearing dogs ranged from 0.5 to 2.6 muCi with 30 to 55 percent of the plutonium in the skeleton. Experiments are in progress to further define the dose-effect relationship of inhaled 238PuO2 and investigate the mechanisms of plutonium-induced neoplasia

  16. Tumor Necrosis Factor Induces Developmental Stage-Dependent Structural Changes in the Immature Small Intestine

    Directory of Open Access Journals (Sweden)

    Kathryn S. Brown

    2014-01-01

    Full Text Available Background. Premature infants are commonly subject to intestinal inflammation. Since the human small intestine does not reach maturity until term gestation, premature infants have a unique challenge, as either acute or chronic inflammation may alter the normal development of the intestinal tract. Tumor necrosis factor (TNF has been shown to acutely alter goblet cell numbers and villus length in adult mice. In this study we tested the effects of TNF on villus architecture and epithelial cells at different stages of development of the immature small intestine. Methods. To examine the effects of TNF-induced inflammation, we injected acute, brief, or chronic exposures of TNF in neonatal and juvenile mice. Results. TNF induced significant villus blunting through a TNF receptor-1 (TNFR1 mediated mechanism, leading to loss of villus area. This response to TNFR1 signaling was altered during intestinal development, despite constant TNFR1 protein expression. Acute TNF-mediated signaling also significantly decreased Paneth cells. Conclusions. Taken together, the morphologic changes caused by TNF provide insight as to the effects of inflammation on the developing intestinal tract. Additionally, they suggest a mechanism which, coupled with an immature immune system, may help to explain the unique susceptibility of the immature intestine to inflammatory diseases such as NEC.

  17. Novel Principles of Gamma-Retroviral Insertional Transcription Activation in Murine Leukemia Virus-induced End-stage Tumors

    DEFF Research Database (Denmark)

    Sokol, Martin; Wabl, Matthias; Rius Ruiz, Irene; Pedersen, Finn Skou

    2014-01-01

    Background Insertional mutagenesis screens of retrovirus-induced mouse tumors have proven valuable in human cancer research and for understanding adverse effects of retroviral-based gene therapies. In previous studies, the assignment of mouse genes to individual retroviral integration sites has b...... understanding fundamental cellular regulatory principles and retroviral biology....

  18. Staphylococcus aureus and Salmonella enterica Serovar Dublin Induce Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Expression by Normal Mouse and Human Osteoblasts

    OpenAIRE

    Alexander, Emily H; Bento, Jennifer L.; Hughes, Francis M.; Marriott, Ian; Hudson, Michael C.; Bost, Kenneth L

    2001-01-01

    Staphylococcus aureus and Salmonella enterica serovar Dublin invade osteoblasts and are causative agents of human bone disease. In the present study, we examined the ability of S. aureus and Salmonella serovar Dublin to induce the production of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by normal osteoblasts. Normal mouse and human osteoblasts were cocultured with S. aureus or Salmonella serovar Dublin at different multiplicities of infection. Following initial incubation...

  19. The relationship of bone-tumor-induced spinal cord astrocyte activation and aromatase expression to mechanical hyperalgesia and cold hypersensitivity in intact female and ovariectomized mice.

    Science.gov (United States)

    Smeester, B A; O'Brien, E E; Michlitsch, K S; Lee, J-H; Beitz, A J

    2016-06-01

    Recently, our group established a relationship between tumor-induced spinal cord astrocyte activation and aromatase expression and the development of bone tumor nociception in male mice. As an extension of this work, we now report on the association of tumor-induced mechanical hyperalgesia and cold hypersensitivity to changes in spinal cord dorsal horn GFAP and aromatase expression in intact (INT) female mice and the effect of ovariectomy on these parameters. Implantation of fibrosarcoma cells produced robust mechanical hyperalgesia in INT animals, while ovariectomized (OVX) females had significantly less mechanical hyperalgesia. Cold hypersensitivity was apparent by post-implantation day 7 in INT and OVX females compared to their saline-injected controls and increased throughout the experiment. The decrease in mechanical hyperalgesia in OVX females was mirrored by significant decreases in spinal astrocyte activity in laminae I-II, III-IV, V-VI and X and aromatase expression in laminae V-VI and X in the dorsal horn of tumor-bearing animals. Administration of the aromatase inhibitor letrozole reduced tumor-induced hyperalgesia in INT females only suggesting that the tumor-induced increase in aromatase expression and its associated increase in spinal estrogen play a role in the development of bone tumor-induced hyperalgesia. Finally, intrathecal (i.t.) administration of 17β-estradiol caused a significant increase in tumor-induced hyperalgesia in INT tumor-bearing females. Since i.t. 17β-estradiol increases tumor pain and ovariectomy significantly decreases tumor pain, as well as spinal aromatase, estrogen may play a critical role in the spinal cord response to the changing tumor environment and the development of tumor-induced nociception. PMID:26995084

  20. In vitro generation of cytotoxic lymphocytes against radiation-and radiation leukemia virus-induced tumors. III. Suppression of anti-tumor immunity in vitro by lymphocytes of mice undergoing radiation leukemia virus-induced leukemogenesis

    International Nuclear Information System (INIS)

    Adult C57BL/6 mice exposed to fractionated irradiation or inoculated with the radiation leukemia virus (RadLV), develop high incidence (80 to 100%) of lymphatic leukemias within 3 to 6 months. RadLV-induced lymphomas can elicit cytotoxic responses in vitro in lymphocytes of preimmunized syngeneic mice. As soon as 5 d after RadLV inoculation, and during the entire leukemogenic process, suppressor T cells are detectable in the spleen that are capable of specifically abrogating generation of syngeneic anti-tumor cytotoxic cells in vitro. Mice exposed to fractionated x irradiation do not develop suppressor cells. These findings suggest that although RadLV has been isolated from radiation-induced leukemias, x-ray- and RadLV-induced leukemogenesis do not seem to involve a common viral etilogy, and that induction of suppressor cells during RadLV leukemogenesis may be essential for tumor progression

  1. 5α-reductase inhibition suppresses testosterone-induced initial regrowth of regressed xenograft prostate tumors in animal models.

    Science.gov (United States)

    Masoodi, Khalid Z; Ramos Garcia, Raquel; Pascal, Laura E; Wang, Yujuan; Ma, Hei M; O'Malley, Katherine; Eisermann, Kurtis; Shevrin, Daniel H; Nguyen, Holly M; Vessella, Robert L; Nelson, Joel B; Parikh, Rahul A; Wang, Zhou

    2013-07-01

    Androgen deprivation therapy (ADT) is the standard treatment for patients with prostate-specific antigen progression after treatment for localized prostate cancer. An alternative to continuous ADT is intermittent ADT (IADT), which allows recovery of testosterone during off-cycles to stimulate regrowth and differentiation of the regressed prostate tumor. IADT offers patients a reduction in side effects associated with ADT, improved quality of life, and reduced cost with no difference in overall survival. Our previous studies showed that IADT coupled with 5α-reductase inhibitor (5ARI), which blocks testosterone conversion to DHT could prolong survival of animals bearing androgen-sensitive prostate tumors when off-cycle duration was fixed. To further investigate this clinically relevant observation, we measured the time course of testosterone-induced regrowth of regressed LuCaP35 and LNCaP xenograft tumors in the presence or absence of a 5ARI. 5α-Reductase inhibitors suppressed the initial regrowth of regressed prostate tumors. However, tumors resumed growth and were no longer responsive to 5α-reductase inhibition several days after testosterone replacement. This finding was substantiated by bromodeoxyuridine and Ki67 staining of LuCaP35 tumors, which showed inhibition of prostate tumor cell proliferation by 5ARI on day 2, but not day 14, after testosterone replacement. 5α-Reductase inhibitors also suppressed testosterone-stimulated proliferation of LNCaP cells precultured in androgen-free media, suggesting that blocking testosterone conversion to DHT can inhibit prostate tumor cell proliferation via an intracrine mechanism. These results suggest that short off-cycle coupled with 5α-reductase inhibition could maximize suppression of prostate tumor growth and, thus, improve potential survival benefit achieved in combination with IADT. PMID:23671262

  2. BAC CGH-array identified specific small-scale genomic imbalances in diploid DMBA-induced rat mammary tumors

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    Samuelson Emma

    2012-08-01

    Full Text Available Abstract Background Development of breast cancer is a multistage process influenced by hormonal and environmental factors as well as by genetic background. The search for genes underlying this malignancy has recently been highly productive, but the etiology behind this complex disease is still not understood. In studies using animal cancer models, heterogeneity of the genetic background and environmental factors is reduced and thus analysis and identification of genetic aberrations in tumors may become easier. To identify chromosomal regions potentially involved in the initiation and progression of mammary cancer, in the present work we subjected a subset of experimental mammary tumors to cytogenetic and molecular genetic analysis. Methods Mammary tumors were induced with DMBA (7,12-dimethylbenz[a]anthrazene in female rats from the susceptible SPRD-Cu3 strain and from crosses and backcrosses between this strain and the resistant WKY strain. We first produced a general overview of chromosomal aberrations in the tumors using conventional kartyotyping (G-banding and Comparative Genome Hybridization (CGH analyses. Particular chromosomal changes were then analyzed in more details using an in-house developed BAC (bacterial artificial chromosome CGH-array platform. Results Tumors appeared to be diploid by conventional karyotyping, however several sub-microscopic chromosome gains or losses in the tumor material were identified by BAC CGH-array analysis. An oncogenetic tree analysis based on the BAC CGH-array data suggested gain of rat chromosome (RNO band 12q11, loss of RNO5q32 or RNO6q21 as the earliest events in the development of these mammary tumors. Conclusions Some of the identified changes appear to be more specific for DMBA-induced mammary tumors and some are similar to those previously reported in ACI rat model for estradiol-induced mammary tumors. The later group of changes is more interesting, since they may represent anomalies that involve

  3. BAC CGH-array identified specific small-scale genomic imbalances in diploid DMBA-induced rat mammary tumors

    International Nuclear Information System (INIS)

    Development of breast cancer is a multistage process influenced by hormonal and environmental factors as well as by genetic background. The search for genes underlying this malignancy has recently been highly productive, but the etiology behind this complex disease is still not understood. In studies using animal cancer models, heterogeneity of the genetic background and environmental factors is reduced and thus analysis and identification of genetic aberrations in tumors may become easier. To identify chromosomal regions potentially involved in the initiation and progression of mammary cancer, in the present work we subjected a subset of experimental mammary tumors to cytogenetic and molecular genetic analysis. Mammary tumors were induced with DMBA (7,12-dimethylbenz[a]anthrazene) in female rats from the susceptible SPRD-Cu3 strain and from crosses and backcrosses between this strain and the resistant WKY strain. We first produced a general overview of chromosomal aberrations in the tumors using conventional kartyotyping (G-banding) and Comparative Genome Hybridization (CGH) analyses. Particular chromosomal changes were then analyzed in more details using an in-house developed BAC (bacterial artificial chromosome) CGH-array platform. Tumors appeared to be diploid by conventional karyotyping, however several sub-microscopic chromosome gains or losses in the tumor material were identified by BAC CGH-array analysis. An oncogenetic tree analysis based on the BAC CGH-array data suggested gain of rat chromosome (RNO) band 12q11, loss of RNO5q32 or RNO6q21 as the earliest events in the development of these mammary tumors. Some of the identified changes appear to be more specific for DMBA-induced mammary tumors and some are similar to those previously reported in ACI rat model for estradiol-induced mammary tumors. The later group of changes is more interesting, since they may represent anomalies that involve genes with a critical role in mammary tumor development. Genetic

  4. Impacts of autophagy-inducing ingredient of areca nut on tumor cells.

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    Ching-Yu Yen

    Full Text Available Areca nut (AN is a popular carcinogen used by about 0.6-1.2 billion people worldwide. Although AN contains apoptosis-inducing ingredients, we previously demonstrated that both AN extract (ANE and its 30-100 kDa fraction (ANE 30-100K predominantly induce autophagic cell death in both normal and malignant cells. In this study, we further explored the action mechanism of ANE 30-100K-induced autophagy (AIA in Jurkat T lymphocytes and carcinoma cell lines including OECM-1 (mouth, CE81T/VGH (esophagus, SCC25 (tongue, and SCC-15 (tongue. The results showed that chemical- and small hairpin RNA (shRNA-mediated inhibition of AMP-activated protein kinase (AMPK resulted in the attenuation of AIA in Jurkat T but not in OECM-1 cells. Knockdown of Atg5 and Beclin 1 expressions ameliorated AIA in OECM-1/CE81T/VGH/Jurkat T and OECM-1/SCC25/SCC-15, respectively. Furthermore, ANE 30-100K could activate caspase-3 after inhibition of Beclin 1 expression in OECM-1/SCC25/SCC15 cells. Meanwhile, AMPK was demonstrated to be the upstream activator of the extracellular-regulated kinase (ERK in Jurkat T cells, and inhibition of MEK attenuated AIA in Jurkat T/OECM-1/CE81T/VGH cells. Finally, we also found that multiple myeloma RPMI8226, lymphoma U937, and SCC15 cells survived from long-term non-cytotoxic ANE 30-100K treatment exhibited stronger resistance against serum deprivation through upregulated autophagy. Collectively, our studies indicate that Beclin-1 and Atg5 but not AMPK are commonly required for AIA, and MEK/ERK pathway is involved in AIA. Meanwhile, it is also suggested that long-term AN usage might increase the resistance of survived tumor cells against serum-limited conditions.

  5. Survivin selective inhibitor YM155 induce apoptosis in SK-NEP-1 Wilms tumor cells

    International Nuclear Information System (INIS)

    Survivin, a member of the family of inhibitor of apoptosis proteins, functions as a key regulator of mitosis and programmed cell death. YM155, a novel molecular targeted agent, suppresses survivin, which is overexpressed in many tumor types. The aim of this study was to determine the antitumor activity of YM155 in SK-NEP-1 cells. SK-NEP-1 cell growth in vitro and in vivo was assessed by MTT and nude mice experiments. Annexin V/propidium iodide staining followed by flow cytometric analysis was used to detect apoptosis in cell culture. Then gene expression profile of tumor cells treated with YM155 was analyzed with real-time PCR arrays. We then analyzed the expression data with MEV (Multi Experiment View) cluster software. Datasets representing genes with altered expression profile derived from cluster analyses were imported into the Ingenuity Pathway Analysis tool. YM155 treatment resulted in inhibition of cell proliferation of SK-NEP-1cells in a dose-dependent manner. Annexin V assay, cell cycle, and activation of caspase-3 demonstrates that YM155 induced apoptosis in SK-NEP-1 cells. YM155 significantly inhibited growth of SK-NEP-1 xenografts (YM155 5 mg/kg: 1.45 ± 0.77 cm3; YM155 10 mg/kg: 0.95 ± 0.55 cm3) compared to DMSO group (DMSO: 3.70 ± 2.4 cm3) or PBS group cells (PBS: 3.78 ± 2.20 cm3, ANOVA P < 0.01). YM155 treatment decreased weight of tumors (YM155 5 mg/kg: 1.05 ± 0.24 g; YM155 10 mg/kg: 0.72 ± 0.17 g) compared to DMSO group (DMSO: 2.06 ± 0.38 g) or PBS group cells (PBS: 2.36 ± 0.43 g, ANOVA P < 0.01). Real-time PCR array analysis showed between Test group and control group there are 32 genes significantly up-regulated and 54 genes were significantly down-regulated after YM155 treatment. Ingenuity pathway analysis (IPA) showed cell death was the highest rated network with 65 focus molecules and the significance score of 44. The IPA analysis also groups the differentially expressed genes into biological mechanisms that are related to cell death

  6. Berberine suppresses tumorigenicity and growth of nasopharyngeal carcinoma cells by inhibiting STAT3 activation induced by tumor associated fibroblasts

    International Nuclear Information System (INIS)

    Cortidis rhizoma (Huanglian) and its major therapeutic component, berberine, have drawn extensive attention in recent years for their anti-cancer properties. Growth inhibitory effects of berberine on multiple types of human cancer cells have been reported. Berberine inhibits invasion, induces cell cycle arrest and apoptosis in human cancer cells. The anti-inflammatory property of berberine, involving inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) activation, has also been documented. In this study, we have examined the effects of berberine on tumorigenicity and growth of nasopharyngeal carcinoma (NPC) cells and their relationship to STAT3 signaling using both in vivo and in vitro models. Berberine effectively inhibited the tumorigenicity and growth of an EBV-positive NPC cell line (C666-1) in athymic nude mice. Inhibition of tumorigenic growth of NPC cells in vivo was correlated with effective inhibition of STAT3 activation in NPC cells inside the tumor xenografts grown in nude mice. In vitro, berberine inhibited both constitutive and IL-6-induced STAT3 activation in NPC cells. Inhibition of STAT3 activation by berberine induced growth inhibition and apoptotic response in NPC cells. Tumor-associated fibroblasts were found to secret IL-6 and the conditioned medium harvested from the fibroblasts also induced STAT3 activation in NPC cells. Furthermore, STAT3 activation by conditioned medium of tumor-associated fibroblasts could be blocked by berberine or antibodies against IL-6 and IL-6R. Our observation that berberine effectively inhibited activation of STAT3 induced by tumor-associated fibroblasts suggests a role of berberine in modulating the effects of tumor stroma on the growth of NPC cells. The effective inhibition of STAT3 activation in NPC cells by berberine supports its potential use in the treatment of NPC

  7. Expression of tumor necrosis factor related apoptosis inducing ligand receptor in glioblastoma

    Institute of Scientific and Technical Information of China (English)

    Dongling Gao; Zhongwei Zhao; Hongxin Zhang; Lan Zhang; Kuisheng Chen; Yunhan Zhang

    2008-01-01

    BACKGROUND: Receptors for tumor necrosis factor related apoptosis inducing ligand (TRAIL) include death receptor 4, death receptor 5, decoy receptor 1, and decoy receptor 2. Activation of death receptor 4 and 5 selectively kills tumor cells.OBJECTIVE: To detect TRAIL receptor expression in glioblastoma by immunohistochemistry and RT-PCR and to compare this expression to that in normal brain tissue.DESIGN: Observational analysis.SETTING: Department of Pathology, the First Affiliated Hospital of Zhengzhou University; Henan Tumor Pathology Key Laboratory.PARTICIPANTS: Twenty-five patients (17 males and 8 females) who received glioblastoma resection were selected from the Fifth Affiliated Hospital of Zhengzhou University, between September 2003 to June 2004. All glioblastoma samples were diagnosed pathologically. Twenty patients (12 males and 8 females) with craniocerebral injury who received normal brain tissue resection were selected in the same time period. There were no significant differences in sex and age between glioblastoma patients or between craniocerebral injury patients (P>0.05). All patients and appropriate relatives provided informed consent, and this study was approved by the local research ethics committee.METHODS: Polyclonal antibody against TRAIL receptors and an immunohistochemical kit (batch number: 200502) were purchased from Boster Company, Wuhan. Immunohistochemistry: Expression of death receptor 4, death receptor 5, decoy receptor 1, and decoy receptor 2 were observed in both glioblastoma and normal brain tissue. The experiment was performed according to the kit instructions, and positive staining was brown-yellow. Assessment: There were no positive signals (-); weakly positive signals, positive cells75% (++++). Evaluation: Expression levels of TRAIL receptors were estimated in both normal brain tissue and glioblastoma. Expression of decoy receptor 1 and decoy receptor 2 mRNA in glioblastoma were detected by reverse transcription polymerase

  8. Pulmonary tumor thrombotic microangiopathy induced by gastric carcinoma: Morphometric and immunohistochemical analysis of six autopsy cases

    Directory of Open Access Journals (Sweden)

    Shinozaki Minoru

    2011-03-01

    Full Text Available Abstract Background Pulmonary tumor thrombotic microangiopathy (PTTM has been known as a rare and serious cancer-related pulmonary complication. However, the pathogenesis and pathophysiology of this debilitating condition still remains obscure and no effective management was recommended. The present study aims to elucidate the pathophysiology of PTTM. Methods Autopsy records were searched to extract cases of pulmonary tumor embolism induced by metastasis of gastric carcinoma in the Toho University Omori Medical Center from 2000 to 2006. And then, tissue sections of extracted cases were prepared for not only light microscopic observation but morphometric analysis with the use of selected PTTM cases. Results Six autopsies involved PTTM and clinicopathological data of them were summarized. There was a significant negative association between pulmonary arterial diameter and stenosis rate in four cases. Although all cases showed an increase of stenosis rate to some degree, the degree of stenosis rate varied from case to case. Significant differences were found for average stenosis rate between the under 100 micrometer group or the 100 to 300 micrometer group and the 300 micrometer group in four cases. However, no significant differences were found for average stenosis rate between the under 100 micrometer group and the 100 to 300 micrometer group in all cases. Meanwhile, all cases showed positive reactivity for tissue factor (TF, five showed positive reactivity for vascular endothelial growth factor (VEGF, and three showed positive reactivity for osteopontin (OPN. Conclusions In the present study, we revealed that the degree of luminal narrowing of the pulmonary arteries varied from case to case, and our results suggested that pulmonary hypertension in PTTM occurs in selected cases which have a widespread pulmonary lesion with severe luminal narrowing in the smaller arteries. Furthermore, our immunohistochemical examination indicated that gastric

  9. Expression of dynamin immunoreactivity in experimental pancreatic tumors induced in rat by mancozeb-nitrosomethylurea.

    Science.gov (United States)

    Valentich, M A; Cook, T; Urrutia, R

    1996-04-19

    Dynamins are GTPases which support receptor-mediated endocytosis and bind to several tyrosine kinase receptor-associated proteins known to mediate cell proliferation and differentiation. We have recently established that dynamin expression correlates with normal neuronal (Torre et al., J. Biol. Chem., 269 (1994) 32411-32417) and acinar pancreatic cell differentiation (Cook et al., Mol. Biol. Cell, 6 (1995) 405a). To begin to understand the role of dynamin in neoplastic pancreatic cell differentiation, we have followed the expression of this protein by immunohistochemistry during the development of pancreatic tumors in a mancozeb-nitrosomethylurea (NMU)-based carcinogenesis model recently developed in our laboratory (Monis and Valentich, Carcinogenesis, 14 (1993) 929-933). After a single intraperitoneal injection (50 mg/g body wt) of this carcinogen, rats fed with mancozeb develop pancreatic focal acinar hyperplasia (FACH), dysplastic foci (DYF) displaying acinar-like and ductular-like structures, and ductular-like carcinoma in situ (CIS). After histochemical staining using a monoclonal anti-dynamin antibody, high levels of this protein are consistently observed in well-differentiated acinar tumors (FACH). In contrast, dynamin immunoreactivity is almost undetectable in more advanced lesions showing a ductular-like phenotype (ductular-like DYF and CIS). This change in the expression pattern of dynamin during the progression of acinar into ductular-like DYF and CIS lesions correlates with recent findings from our laboratory showing a differential expression pattern for dynamin in pancreatic cells during embryonic development, with ductular-like precursor cells expressing low levels of this protein. Based upon these results, we conclude that more advanced ductular-like neoplastic cells induced by the carcinogen NMU in rat pancreas behave phenotypically like pancreatic precursor cells in their pattern of expression for dynamin. PMID:8603375

  10. Methylation of the estrogen receptor CpG island distinguishes spontaneous and plutonium-induced tumors from nitrosamine-induced lung tumors

    Energy Technology Data Exchange (ETDEWEB)

    Belinsky, S.A.; Baylin, S.B.; Issa, J.J. [Johns Hopkins Univ., Baltimore, MD (United States)

    1995-12-01

    CpG islands located in the promoter region of genes constitute one mechanism for regulating transcription. These islands are normally free of methylation, regardless of the expression state of the gene. Hypermethylation of CpG islands, the addition of a methyl group to the internal cytosine within CpG dinucleotides, can cause silencing of a gene. Hypermethylation has been detected as an early event at specific chromosome loci during the development of colon cancer and represents one mechanism used by neoplatic cells to inactivate tumor suppressor genes. Recent studies have demonstrated this mechanism in inactivation of the VHL tumor suppressor gene in 19% of sporadic renal tumors and the p16 {sup INK4a} tumor suppressor gene in 30% of non-small cell lung cancers. A recent report indicates that the estrogen receptor gene could also be inactivated through methylation. In addition, estrogen receptor CpG island methylation arises as a direct function of age in normal colonic mucosa and is present in virtually all colonic tumors. In cultured colon cancer cells, methylation-associated loss of expression of the estrogen receptor gene results in deregulated growth, suggesting a role for the estrogen receptor in colon cancer development. These results provide further evidence that gene silencing through methylation could be a predominant epigenetic mechanism underlying the development of many different types of cancer. The purpose of the current investigation was to determine whether estrogen receptor CpG island methylation is involved in the development of lung cancer. The frequency for methylation of the estrogen receptor CpG island in rodent lung tumors is summarized.

  11. Electron microscopic features of a brain tumor induced in hamster by BK virus, a human papova virus.

    Directory of Open Access Journals (Sweden)

    Tsuboi,Masahiro

    1979-12-01

    Full Text Available In order to locate the target cells for malignant transformation by BK virus (a human papova virus in hamster brain, electron microscopic observation of tumor originally induced in hamster brain by BK virus was performed. With light microscopy, the BK virus-induced tumor (Vn 17 bore a close resemblance to human malignant ependymoma. Under the electron microscope, numerous microvilli and few cilia were visible on the surface of the tumor cells. These tumor cells were joined to each other by desmosomes. Gap junctions were not observed. Multilayered cuboidal cells were observed around the lumen and blood vessels in the tumor. With regard to fine structure, three types of Vn 17 cells were recognized; ependymal like cells, tanycytes with prominent cell processes, and undifferentiated cells with few cytoplasmic organelles. There was no basal lamina between the ependymal cells and the connective tissue stroma. The Vn 17 cells showed some similarity to the ultrastructural features of the epemdymal cells of newborn rabbits, suggesting that the target cells for Vn 17 may be cells related to ependyma. Malignant transformation of the cells would be initiated in the early stages after BK virus inoculation into the brain of newborn hamsters.

  12. Metabolic changes detected by in vivo magnetic resonance studies of HEPA-1 wild-type tumors and tumors deficient in hypoxia-inducible factor-1beta (HIF-1beta): evidence of an anabolic role for the HIF-1 pathway.

    Science.gov (United States)

    Griffiths, John R; McSheehy, Paul M J; Robinson, Simon P; Troy, Helen; Chung, Yuen-Li; Leek, Russell D; Williams, Kaye J; Stratford, Ian J; Harris, Adrian L; Stubbs, Marion

    2002-02-01

    Hypoxia-inducible factor-1 (HIF-1) regulates many pathways potentially important for tumor growth, including angiogenesis and glycolysis. Most attention has focused on its role in the response to hypoxia, but HIF-1 is also constitutively expressed in many tumors. To analyze the role of this pathway in vivo, we used magnetic resonance (MR) methods and complementary techniques to monitor metabolic changes in tumors derived from HEPA-1 mouse hepatoma lines that were either wild type (WT) or deficient in hypoxia-inducible transcription factor HIF-1beta (c4). The c4 tumors grew significantly more slowly than the WT tumors (P < 0.05), but were examined at a similar size (0.4-0.6 g). At the tumor size used in these studies, no differences in vascularity were observed, and MR parameters measured that related to tumor blood flow, vascularity, and oxygenation demonstrated no significant differences between the two tumor types. Unexpectedly, the ATP content of the c4 tumor was approximately 5 times less than in the WT tumor [measured in tumor extracts (P < 0.001) and by metabolic imaging (P < 0.05)]. Noninvasive (31)P MR spectroscopy showed that the nucleoside triphosphate/P(i) ratio of the two tumor types was similar, so the low ATP content of the c4 tumors was not caused by (or a cause of) impaired cellular bioenergetics. Rather, glycine, an essential precursor for de novo purine formation, was significantly lower in the c4 tumors (P < 0.05), suggesting that ATP synthesis was impaired in the mutant tumor cells. Supporting evidence for this hypothesis came from the significantly lower concentrations of betaine, phosphocholine, and choline in the c4 tumors (P < 0.05); these are intermediates in an alternative pathway for glycine synthesis. No significant differences were seen in lactate or glucose content. MR resonances from phosphodiesters, which relate to the metabolic turnover of phospholipid membranes, were significantly lower in the WT tumors than in the c4 tumors, both

  13. Butylated Hydroxyanisole Blocks the Occurrence of Tumor Associated Macrophages in Tobacco Smoke Carcinogen-Induced Lung Tumorigenesis

    International Nuclear Information System (INIS)

    Tumor-associated macrophages (TAMs) promote tumorigenesis because of their proangiogenic and immune-suppressive functions. Here, we report that butylated hydroxyanisole (BHA) blocks occurrence of tumor associated macrophages (TAMs) in tobacco smoke carcinogen-induced lung tumorigenesis. Continuous administration of butylated hydroxyanisole (BHA), a ROS inhibitor, before or after NNK treatment significantly blocked tumor development, although less effectively when BHA is administered after NNK treatment. Strikingly, BHA abolished the occurrence of F4/80+ macrophages with similar efficiency no matter whether it was administered before or after NNK treatment. Detection of cells from bronchioalveolar lavage fluid (BALF) confirmed that BHA markedly inhibited the accumulation of macrophages while slightly reducing the number of lymphocytes that were induced by NNK. Immunohistological staining showed that BHA specifically abolished the occurrence of CD206+ TAMs when it was administered before or after NNK treatment. Western blot analysis of TAMs markers, arginase I and Ym-1, showed that BHA blocked NNK-induced TAMs accumulation. Our study clearly demonstrated that inhibiting the occurrence of TAMs by BHA contributes to the inhibition of tobacco smoke carcinogen-induced tumorigenesis, suggesting ROS inhibitors may serve as a therapeutic target for treating smoke-induced lung cancer

  14. Butylated Hydroxyanisole Blocks the Occurrence of Tumor Associated Macrophages in Tobacco Smoke Carcinogen-Induced Lung Tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yan; Choksi, Swati; Liu, Zheng-Gang, E-mail: zgliu@helix.nih.gov [Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States)

    2013-12-04

    Tumor-associated macrophages (TAMs) promote tumorigenesis because of their proangiogenic and immune-suppressive functions. Here, we report that butylated hydroxyanisole (BHA) blocks occurrence of tumor associated macrophages (TAMs) in tobacco smoke carcinogen-induced lung tumorigenesis. Continuous administration of butylated hydroxyanisole (BHA), a ROS inhibitor, before or after NNK treatment significantly blocked tumor development, although less effectively when BHA is administered after NNK treatment. Strikingly, BHA abolished the occurrence of F4/80{sup +} macrophages with similar efficiency no matter whether it was administered before or after NNK treatment. Detection of cells from bronchioalveolar lavage fluid (BALF) confirmed that BHA markedly inhibited the accumulation of macrophages while slightly reducing the number of lymphocytes that were induced by NNK. Immunohistological staining showed that BHA specifically abolished the occurrence of CD206{sup +} TAMs when it was administered before or after NNK treatment. Western blot analysis of TAMs markers, arginase I and Ym-1, showed that BHA blocked NNK-induced TAMs accumulation. Our study clearly demonstrated that inhibiting the occurrence of TAMs by BHA contributes to the inhibition of tobacco smoke carcinogen-induced tumorigenesis, suggesting ROS inhibitors may serve as a therapeutic target for treating smoke-induced lung cancer.

  15. Butylated Hydroxyanisole Blocks the Occurrence of Tumor Associated Macrophages in Tobacco Smoke Carcinogen-Induced Lung Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Yan Zhang

    2013-12-01

    Full Text Available Tumor-associated macrophages (TAMs promote tumorigenesis because of their proangiogenic and immune-suppressive functions. Here, we report that butylated hydroxyanisole (BHA blocks occurrence of tumor associated macrophages (TAMs in tobacco smoke carcinogen-induced lung tumorigenesis. Continuous administration of butylated hydroxyanisole (BHA, a ROS inhibitor, before or after NNK treatment significantly blocked tumor development, although less effectively when BHA is administered after NNK treatment. Strikingly, BHA abolished the occurrence of F4/80+ macrophages with similar efficiency no matter whether it was administered before or after NNK treatment. Detection of cells from bronchioalveolar lavage fluid (BALF confirmed that BHA markedly inhibited the accumulation of macrophages while slightly reducing the number of lymphocytes that were induced by NNK. Immunohistological staining showed that BHA specifically abolished the occurrence of CD206+ TAMs when it was administered before or after NNK treatment. Western blot analysis of TAMs markers, arginase I and Ym-1, showed that BHA blocked NNK-induced TAMs accumulation. Our study clearly demonstrated that inhibiting the occurrence of TAMs by BHA contributes to the inhibition of tobacco smoke carcinogen-induced tumorigenesis, suggesting ROS inhibitors may serve as a therapeutic target for treating smoke-induced lung cancer.

  16. Participation of the NO/cGMP/K+ATP pathway in the antinociception induced by Walker tumor bearing in rats

    International Nuclear Information System (INIS)

    Implantation of Walker 256 tumor decreases acute systemic inflammation in rats. Inflammatory hyperalgesia is one of the most important events of acute inflammation. The L-arginine/NO/cGMP/K+ATP pathway has been proposed as the mechanism of peripheral antinociception mediated by several drugs and physical exercise. The objective of this study was to investigate a possible involvement of the NO/cGMP/K+ATP pathway in antinociception induced in Walker 256 tumor-bearing male Wistar rats (180-220 g). The groups consisted of 5-6 animals. Mechanical inflammatory hypernociception was evaluated using an electronic version of the von Frey test. Walker tumor (4th and 7th day post-implantation) reduced prostaglandin E2- (PGE2, 400 ng/paw; 50 µL; intraplantar injection) and carrageenan-induced hypernociception (500 µg/paw; 100 µL; intraplantar injection). Walker tumor-induced analgesia was reversed (99.3% for carrageenan and 77.2% for PGE2) by a selective inhibitor of nitric oxide synthase (L-NAME; 90 mg/kg, ip) and L-arginine (200 mg/kg, ip), which prevented (80% for carrageenan and 65% for PGE2) the effect of L-NAME. Treatment with the soluble guanylyl cyclase inhibitor ODQ (100% for carrageenan and 95% for PGE2; 8 µg/paw) and the ATP-sensitive K+ channel (KATP) blocker glibenclamide (87.5% for carrageenan and 100% for PGE2; 160 µg/paw) reversed the antinociceptive effect of tumor bearing in a statistically significant manner (P < 0.05). The present study confirmed an intrinsic peripheral antinociceptive effect of Walker tumor bearing in rats. This antinociceptive effect seemed to be mediated by activation of the NO/cGMP pathway followed by the opening of KATP channels

  17. The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis

    International Nuclear Information System (INIS)

    Osteosarcoma is the most frequent primary malignant bone tumor, notorious for its lung metastasis. Shikonin, an effective constituent extracted from Chinese medicinal herb, was demonstrated to induce necroptosis in some cancers. MTT assay was performed to detect cell survival rate in vitro. Flow cytometry was used to analyze cell cycle and cell death. Western blot was performed to determine the expression levels of RIP1, RIP3, caspase-3, caspase-6 and PARP. The tibial primary and lung metastatic osteosarcoma models were used to evaluate the anti-tumor effect of shikonin in vivo. The cell survival rate was decreased in a dose and time dependent manner when treated with shikonin. No major change in cell cycle was observed after shikonin treatment. The cell death induced by shikonin could be mostly rescued by specific necroptosis inhibitor necrostatin-1, but not by general caspase inhibitor Z-VAD-FMK. The number of necrotic cells caused by shikonin was decreased after being pretreated with Nec-1 detected by flow cytometry in K7 cells. After 8-hour treatment of shikonin, the expression levels of RIP1 and RIP3 were increased while caspase-3, caspase-6 and PARP were not activated in K7 and U2OS cells determined by Western blot. Size of primary tumor and lung metastasis in shikonin treated group were significantly reduced. The protein levels of RIP1 and RIP3 in primary tumor tissues were increased by shikonin. The overall survival of lung metastatic models was longer compared with control group (p < 0.001). Shikonin had prompt but profound anti-tumor effect on both primary and metastatic osteosarcoma, probably by inducing RIP1 and RIP3 dependent necroptosis. Shikonin would be a potential anti-tumor agent on the treatment of primary and metastatic osteosarcoma

  18. miR-21 modulates tumor outgrowth induced by human adipose tissue-derived mesenchymal stem cells in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Keun Koo; Lee, Ae Lim; Kim, Jee Young [Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870 (Korea, Republic of); Medical Research Center for Ischemic Tissue Engineering, Pusan National University, Yangsan, Gyeongnam 626-870 (Korea, Republic of); BK21 Medical Science Education Center, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870 (Korea, Republic of); Lee, Sun Young [Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870 (Korea, Republic of); Medical Research Center for Ischemic Tissue Engineering, Pusan National University, Yangsan, Gyeongnam 626-870 (Korea, Republic of); Bae, Yong Chan [Department of Plastic Surgery, School of Medicine, Pusan National University, Pusan 602-739 (Korea, Republic of); Jung, Jin Sup, E-mail: jsjung@pusan.ac.kr [Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870 (Korea, Republic of); Medical Research Center for Ischemic Tissue Engineering, Pusan National University, Yangsan, Gyeongnam 626-870 (Korea, Republic of); BK21 Medical Science Education Center, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870 (Korea, Republic of); Medical Research Institute, Pusan National University, Pusan 602-739 (Korea, Republic of)

    2012-06-15

    Highlights: Black-Right-Pointing-Pointer miR-21 modulates hADSC-induced increase of tumor growth. Black-Right-Pointing-Pointer The action is mostly mediated by the modulation of TGF-{beta} signaling. Black-Right-Pointing-Pointer Inhibition of miR-21 enhances the blood flow recovery in hindlimb ischemia. -- Abstract: Mesenchymal stem cells (MSCs) have generated a great deal of interest in clinical situations, due principally to their potential use in regenerative medicine and tissue engineering applications. However, the therapeutic application of MSCs remains limited, unless the favorable effects of MSCs on tumor growth in vivo, and the long-term safety of the clinical applications of MSCs, can be more thoroughly understood. In this study, we determined whether microRNAs can modulate MSC-induced tumor outgrowth in BALB/c nude mice. Overexpression of miR-21 in human adipose-derived stem cells (hADSCs) inhibited hADSC-induced tumor growth, and inhibition of miR-21 increased it. Downregulation of transforming growth factor beta receptor II (TGFBR2), but not of signal transducer and activator of transcription 3, in hADSCs showed effects similar to those of miR-21 overexpression. Downregulation of TGFBR2 and overexpression of miR21 decreased tumor vascularity. Inhibition of miR-21 and the addition of TGF-{beta} increased the levels of vascular endothelial growth factor and interleukin-6 in hADSCs. Transplantation of miR-21 inhibitor-transfected hADSCs increased blood flow recovery in a hind limb ischemia model of nude mice, compared with transplantation of control oligo-transfected cells. These findings indicate that MSCs might favor tumor growth in vivo. Thus, it is necessary to study the long-term safety of this technique before MSCs can be used as therapeutic tools in regenerative medicine and tissue engineering.

  19. miR-21 modulates tumor outgrowth induced by human adipose tissue-derived mesenchymal stem cells in vivo

    International Nuclear Information System (INIS)

    Highlights: ► miR-21 modulates hADSC-induced increase of tumor growth. ► The action is mostly mediated by the modulation of TGF-β signaling. ► Inhibition of miR-21 enhances the blood flow recovery in hindlimb ischemia. -- Abstract: Mesenchymal stem cells (MSCs) have generated a great deal of interest in clinical situations, due principally to their potential use in regenerative medicine and tissue engineering applications. However, the therapeutic application of MSCs remains limited, unless the favorable effects of MSCs on tumor growth in vivo, and the long-term safety of the clinical applications of MSCs, can be more thoroughly understood. In this study, we determined whether microRNAs can modulate MSC-induced tumor outgrowth in BALB/c nude mice. Overexpression of miR-21 in human adipose-derived stem cells (hADSCs) inhibited hADSC-induced tumor growth, and inhibition of miR-21 increased it. Downregulation of transforming growth factor beta receptor II (TGFBR2), but not of signal transducer and activator of transcription 3, in hADSCs showed effects similar to those of miR-21 overexpression. Downregulation of TGFBR2 and overexpression of miR21 decreased tumor vascularity. Inhibition of miR-21 and the addition of TGF-β increased the levels of vascular endothelial growth factor and interleukin-6 in hADSCs. Transplantation of miR-21 inhibitor-transfected hADSCs increased blood flow recovery in a hind limb ischemia model of nude mice, compared with transplantation of control oligo-transfected cells. These findings indicate that MSCs might favor tumor growth in vivo. Thus, it is necessary to study the long-term safety of this technique before MSCs can be used as therapeutic tools in regenerative medicine and tissue engineering.

  20. Targeted expression of tumor necrosis factor-related apoptosis-inducing ligand TRAIL in skin protects mice against chemical carcinogenesis

    Directory of Open Access Journals (Sweden)

    Gronemeyer Hinrich

    2011-04-01

    Full Text Available Abstract Background Gene ablation studies have revealed that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo2L, TNFSF10 plays a crucial role in tumor surveillance, as TRAIL-deficient mice exhibit an increased sensitivity to different types of tumorigenesis. In contrast, possible tumor-protective effect of increased levels of endogenous TRAIL expression in vivo has not been assessed yet. Such models will provide important information about the efficacy of TRAIL-based therapies and potential toxicity in specific tissues. Methods To this aim, we engineered transgenic mice selectively expressing TRAIL in the skin and subjected these mice to a two-step chemical carcinogenesis protocol that generated benign and preneoplastic lesions. We were therefore able to study the effect of increased TRAIL expression at the early steps of skin tumorigenesis. Results Our results showed a delay of tumor appearance in TRAIL expressing mice compared to their wild-type littermates. More importantly, the number of tumors observed in transgenic animals was significantly lower than in the control animals, and the lesions observed were mostly benign. Interestingly, Wnt/β-catenin signaling differed between tumors of wild-type and TRAIL transgenics. Conclusion Altogether, these data reveal that, at least in this model, TRAIL is able on its own to act on pre-transformed cells, and reduce their tumorigenic potential.

  1. Down-expression of tumor protein p53-induced nuclear protein 1 in human gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Pei-Hong Jiang; Yoshiharu Motoo; Stéphane Garcia; Juan Lucio Iovanna; Marie-Josèphe Pébusque; Norio Sawabu

    2006-01-01

    AIM: Overexpression of tumor protein p53-induced nuclear protein 1 (TP53INP1) induces G1 cell cycle arrest and increases p53-mediated apoptosis. To clarify the clinical importance of TP53INP1, we analyzed TP53INP1and p53 expression in gastric cancer.METHODS: TP53INP1 and p53 expression were examined using immunohistochemistry in 142 cases of gastric cancer. The apoptosis of gastric cancer cells was analyzed using the TUNEL method. The relationship between the expression of TP53INP1 and clinicopathological factors was statistically analyzed.RESULTS: TP53INP1 was expressed in 98% (139/142cases) of non-cancerous gastric tissues and was downexpressed in 64% (91/142 cases) of gastric cancer lesions from the same patients. TP53INP1 expression was significantly decreased (43.9%) in poorly differentiated adenocarcinoma compared with well or moderately differentiated adenocarcinoma (81.6%).Cancers invading the submucosa or deeper showed lower positively (59.1%) compared with mucosal cancers (85.2%). Decrease or loss of TP53INP1 expression was significantly correlated with lymphatic invasion (54.3%vs 82.0% without lymphatic invasion) and node-positive patients (31.3% vs 68.3% in node-negative patients).P53 was expressed in 68 (47.9%) patients of gastric cancer, whereas it was absent in normal gastric tissues.A significant association was also observed between TP53INP1 status and the level of apoptosis in tumor cells: the apoptotic index in TP53INP1-positive tissues was significantly higher than that in TP53INP1-negative portions. Finally, when survival data were analyzed,loss of TP53INP1 expression had a significant effect in predicting a poor prognosis (P= 0.0006).CONCLUSION: TP53INP1-positive rate decreases with the progression of gastric cancer. TP53INP1 protein negativity is significantly associated with aggressive pathological phenotypes of gastric cancer. TP53INP1is related to the apoptosis of gastric cancer cells. The decreased expression of the TP53INP1 protein may

  2. Berberine Induces Caspase-Independent Cell Death in Colon Tumor Cells through Activation of Apoptosis-Inducing Factor

    OpenAIRE

    Lihong Wang; Liping Liu; Yan Shi; Hanwei Cao; Rupesh Chaturvedi; M Wade Calcutt; Tianhui Hu; Xiubao Ren; Wilson, Keith T.; Brent Polk, D.; Fang Yan

    2012-01-01

    Berberine, an isoquinoline alkaloid derived from plants, is a traditional medicine for treating bacterial diarrhea and intestinal parasite infections. Although berberine has recently been shown to suppress growth of several tumor cell lines, information regarding the effect of berberine on colon tumor growth is limited. Here, we investigated the mechanisms underlying the effects of berberine on regulating the fate of colon tumor cells, specifically the mouse immorto-Min colonic epithelial (IM...

  3. Bleomycin-induced pulmonary fibrosis after tumor lysis syndrome in a case of advanced yolk sac tumor treated with bleomycin, etoposide and cisplatin (BEP) chemotherapy.

    Science.gov (United States)

    Doi, Mihoko; Okamoto, Yohei; Yamauchi, Masami; Naitou, Hiroyuki; Shinozaki, Katsunori

    2012-10-01

    Ovarian yolk sac tumor (YST) is a highly aggressive malignancy arising in young women. Chemotherapy has dramatically improved the prognosis, and bleomycin, etoposide, and cisplatin (BEP) combination chemotherapy appears to be the most effective combination regimen. A 23-year-old woman was admitted to our hospital with worsening abdominal distention and a lower abdominal mass. She was diagnosed with a stage IIIc pure YST of the right ovary, and right salpingo-oophorectomy was performed; there were numerous disseminated peritoneal tumors within the abdominal cavity. A few days postoperatively, massive ascites developed, and right hydronephrosis occurred. Chemotherapy with BEP was started, and after 24 h of administration, oliguria and tumor lysis syndrome (TLS) developed. Continuous hemodiafiltration was started, and hemodialysis was initiated following full-dose standard cisplatin and etoposide on days 2-5 of the 1st cycle. After the electrolyte abnormalities and the elevation of creatinine became normal, the patient received an additional three cycles of BEP and achieved complete remission. However, she also suffered from severe non-hematological toxicities, including grade 3 left ventricular dysfunction and grade 4 pulmonary fibrosis. In the case of rapidly progressing and high-volume YST treated with BEP chemotherapy, special attention should be paid to bleomycin-induced pulmonary toxicity following TLS. Further study is required to optimize drug exposure to ensure efficacy and reduce the risk of side effects in this population. PMID:22127348

  4. THE NADPH OXIDASE INHIBITOR VAS2870 IMPAIRS CELL GROWTH AND ENHANCES TGF-?-INDUCED APOPTOSIS OF LIVER TUMOR CELLS

    OpenAIRE

    Sancho, Patricia; Fabregat, Isabel

    2011-01-01

    Abstract Liver tumor cells show several molecular alterations which favor pro-survival signaling. Among those, we have proposed the NADPH oxidase NOX1 as a prosurvival signal for liver tumor cells. On the one side, we have described that FaO rat hepatoma cells show NOX1-dependent partial resistance to apoptosis induced by Transforming Growth Factor beta (TGF-?). On the other side, we have shown that FaO cells, as well as different human hepatocellular carcinoma (HCC) cell lines, ar...

  5. Study of arsenic trioxide-induced vascular shutdown and enhancement with radiation in solid tumor

    International Nuclear Information System (INIS)

    Arsenic trioxide (ATO) has been reported to be an effective chemotherapeutic agent for acute promyelocytic leukemia (APL), and, recently, anti-tumor effect has been demonstrated in solid tumors. However, little is known about the mechanism of action of the ATO effect on solid tumor. We investigated the anti-vascular effect of ATO and the potential of combining ATO with radiation therapy. We studied the anti-vascular effect of ATO and radiosensitization of squamous cell carcinoma (SCC) VII murine tumors of C3H mice. The anti-vascular effect was examined using magnetic resonance imaging (MRI), and radiosensitivity was studied by clonogenic assay and tumor growth delay. Histopathological changes of the tumors after various treatments were also observed with hematoxylin and eosin (H and E) staining. Necrosis and blood flow changes in the central region of tumors in the hind limbs of the animals were observed on T2-weighted imaging after an intraperitoneal (i.p.) injection of 8 mg/kg of ATO alone. ATO exposure followed by radiation decreased the clonogenic survival of SCC VII cells compared with either treatment alone. Tumor growth delay after 10-20 Gy of radiation alone was increased slightly compared with control tumors, but the combination of ATO injection 2 hours before exposure to 20 Gy of radiation significantly prolonged tumor growth delay by almost 20 days. The results suggest that ATO and radiation can enhance the radiosensitivity of solid tumor. (author)

  6. Distinct malignant behaviors of mouse myogenic tumors induced by different oncogenetic lesions.

    Directory of Open Access Journals (Sweden)

    Simone eHettmer

    2015-02-01

    Full Text Available Rhabdomyosarcomas (RMS are heterogeneous cancers with myogenic differentiation features. The cytogenetic and mutational aberrations in RMS are diverse. This study examined differences in the malignant behavior of two genetically distinct and disease-relevant mouse myogenic tumor models. Kras; p1619null myogenic tumors, initiated by expression of oncogenic Kras in p16p19null mouse satellite cells, were metastatic to the lungs of the majority of tumor-bearing animals and repopulated tumors in 7 of 9 secondary recipients. In contrast, SmoM2 tumors, initiated by ubiquitous expression of a mutant Smoothened allele, did not metastasize and repopulated tumors in 2 of 18 recipients only. In summary, genetically distinct myogenic tumors in mice exhibit marked differences in malignant behavior.

  7. Transcription-coupled repair: Impact on UV-induced mutagenesis in cultured rodent cells and mouse skin tumors

    International Nuclear Information System (INIS)

    UV-induced cyclobutane pyrimidine dimers (CPDs) are removed with accelerated speed from the transcribed strand of expressed genes in cultured mammalian cells by a process called transcription-coupled repair (TCR). It has been previously shown that this phenomenon has consequences for the molecular nature of the mutations induced by UV-light. Here, we review these data and show that TCR has not only a clear impact on UV-induced mutations in cultured mammalian cells but also on genes involved in tumor formation in the skin of UV-exposed mice. Mutations observed in the p53 gene in UV-induced squamous cell carcinoma are predominantly found at sites of dipyrimidines in the non-transcribed strand. In contrast, in UVC-irradiated Csb -/- Chinese hamster cells and in UVB-induced tumors in the Csb -/- mouse, almost all mutations are at positions of dipyrimidine sites in the transcribed strand of the mutated gene. Csb -/- mice appear to be susceptible to UVB-induced skin cancer in contrast to the human CSB patients. We speculate that the UVB-induced cancer susceptibility of Csb -/- mice is related to the absence of TCR as well as to a lack of a compensating global genome repair system for CPDs in mice

  8. Glucocorticoid-induced tumor necrosis factor receptor expression in patients with cervical human papillomavirus infection

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    Cacilda Tezelli Junqueira Padovani

    2013-06-01

    Full Text Available Introduction The progression of human papillomavirus (HPV infection in the anogenital tract has been associated with the involvement of cells with regulatory properties. Evidence has shown that glucocorticoid-induced tumor necrosis factor receptor (GITR is an important surface molecule for the characterization of these cells and proposes that GITR ligand may constitute a rational treatment for many cancer types. We aimed to detect the presence of GITR and CD25 in cervical stroma cells with and without pathological changes or HPV infection to better understand the immune response in the infected tissue microenvironment. Methods We subjected 49 paraffin-embedded cervical tissue samples to HPV DNA detection and histopathological analysis, and subsequently immunohistochemistry to detect GITR and CD25 in lymphocytes. Results We observed that 76.9% of all samples with high GITR expression were HPV-positive regardless of histopathological findings. High GITR expression (77.8% was predominant in samples with ≥1,000 RLU/PCB. Of the HPV-positive samples negative for intraepithelial lesion and malignancy, 62.5% had high GITR expression. High GITR expression was observed in both carcinoma and high-grade squamous intraepithelial lesion (HSIL samples (p = 0.16. CD25 was present in great quantities in all samples. Conclusions The predominance of high GITR expression in samples with high viral load that were classified as HSIL and carcinoma suggests that GITR+ cells can exhibit regulatory properties and may contribute to the progression of HPV-induced cervical neoplasia, emphasizing the importance of GITR as a potential target for immune therapy of cervical cancer and as a disease evolution biomarker.

  9. Heat-inducible translationally controlled tumor protein of Trichinella pseudospiralis: cloning and regulation of gene expression.

    Science.gov (United States)

    Mak, C H; Poon, M W; Lun, H M; Kwok, P Y; Ko, R C

    2007-04-01

    To elucidate the mechanism of inducing translationally controlled tumor protein (TCTP) in stress adaptation of adenophorean nematodes, the complete coding sequence of TCTP of the infective-stage larvae of Trichinella pseudospiralis was characterized. Two cDNA clones with different 3' untranslated region were identified. Tp-TCTP contained an open reading frame of 534 bp encoding 177 residues. The gene with five introns was expressed as histidine-tagged fusion protein having a molecular mass of 17.5 kDa. Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed that TCTP RNA was not accumulated when the infective-stage larvae were heat-shocked for 1 h at 45 or 60 degrees C. Using enzyme-linked immunosorbent assay and antiserum against the fusion protein, the expression of TCTP was found to be up-regulated at the translational level. The data suggest that translational regulation of TCTP may play an important role in the early heat-stress adaptation of the trichinellid. Cluster analysis demonstrated that the TCTP sequence of T. pseudospiralis is closely related to that of T. spiralis, but is diverged from the secernentean species. PMID:17149606

  10. Epidermal growth factor, like tumor promoters, enhances viral and radiation-induced cell transformation

    International Nuclear Information System (INIS)

    The polypeptide hormone epidermal growth factor (EGF) has been shown to enhance adenovirus type 5 transformation of a cloned culture of rat embryo cells (CREF) and X-ray or u.v.-light induced transformation of 10T1/2 mouse embryo cells. In both systems, the degree of enhancement was quantitatively similar to that observed in treated cells grown in the presence of the potent tumor promoting agent 12-0-tetradecanoylphorbol-13-acetate (TPA). An increase in viral transformation was also observed in cells continuously exposed to phorbol esters with known promoting activity on mouse skin, but not structurally related analogs, inactive or weakly active in the two-stage mouse skin carcinogenesis assay. In addition, the appearance of transformed foci was accelerated and colonies tended to be larger in cultures grown in the presence of EGF or TPA. These studies suggest the possibility that EGF may function as an endogenous promoter of carcinogenesis and further indicates that in vitro cell transformation systems may prove useful in identifying such agents. (author)

  11. Epidermal growth factor, little tumor promoters, enhances viral and radiation-induced cell transformation

    International Nuclear Information System (INIS)

    The polypeptide hormone epidermal growth factor (EGF) has been shown to enhance adenovirus type 5 transformation of a cloned culture of rat embryo cells (CREF) and X-ray or u.v.-light induced transformation of 10T1/2 mouse embryo cells. In both systems, the degree of enhancement was quantitatively similar to that observed in treated rats grown in the presence of the potent tumor promoting agent 12-O-tetradecanoyl-phorbol-13-acetate (TPA). An increase in viral transformation was also observed in cells continuously exposed to phorbol esters with known promoting activity on mouse skin, but not structurally related analogs, inactive or weakly active in the two-stage mouse skin carcinogenesis assay. In addition, the appearance of transformed foci was accelerated and colonies tended to be larger in cultures grown in the presence of EGF or TPA. The present studies suggest the possibility that EGF may function as an endogenous promoter of carcinogenesis and further indicates that in vitro cell transformation systems may prove useful in identifying such agents

  12. Tumor necrosis factor-α-induced protein 1 and immunity to hepatitis B virus

    Institute of Scientific and Technical Information of China (English)

    Marie C Lin; Nikki P Lee; Ning Zheng; Pai-Hao Yang; Oscar G Wong; Hsiang-Fu Kung; Chee-Kin Hui; John M Luk; George Ka-Kit Lau

    2005-01-01

    AIM: To compare the gene expression profile in a pair of HBV-infected twins.METHODS: The gene expression profile was compared in a pair of HBV-infected twins.RESULTS: The twins displayed different disease outcomes. One acquired natural immunity against HBV,whereas the other became a chronic HBV carrier. Eightyeight and forty-six genes were found to be up- or downregulated in their PBMCs, respectively. Tumor necrosis factor-alpha-induced protein 1 (TNF-αIP1) that expressed at a higher level in the HBV-immune twins was identified and four pairs of siblings with HBV immunity by RTPCR. However, upon HBV core antigen stimulation,TNF-αIP1 was downregulated in PBMCs from subjects with immunity, whereas it was slightly upregulated in HBV carriers. Bioinformatics analysis revealed a K+channel tetramerization domain in TNF-αIP1 that shares a significant homology with some human, mouse, and C elegan proteins.CONCLUSION: TNF-αIP1 may play a role in the innate immunity against HBV.

  13. A histological evaluation and in vivo assessment of intratumoral near infrared photothermal nanotherapy-induced tumor regression

    Directory of Open Access Journals (Sweden)

    Green HN

    2014-11-01

    Full Text Available Hadiyah N Green,1,2 Stephanie D Crockett,3 Dmitry V Martyshkin,1 Karan P Singh,2,4 William E Grizzle,2,5 Eben L Rosenthal,2,6 Sergey B Mirov11Department of Physics, Center for Optical Sensors and Spectroscopies, 2Comprehensive Cancer Center, 3Department of Pediatrics, Division of Neonatology, 4Department of Medicine, Division of Preventive Medicine, Biostatistics and Bioinformatics Shared Facility, 5Department of Pathology, 6Department of Surgery, Division of Otolaryngology, Head and Neck Surgery, The University of Alabama at Birmingham, Birmingham, AL, USAPurpose: Nanoparticle (NP-enabled near infrared (NIR photothermal therapy has realized limited success in in vivo studies as a potential localized cancer therapy. This is primarily due to a lack of successful methods that can prevent NP uptake by the reticuloendothelial system, especially the liver and kidney, and deliver sufficient quantities of intravenously injected NPs to the tumor site. Histological evaluation of photothermal therapy-induced tumor regression is also neglected in the current literature. This report demonstrates and histologically evaluates the in vivo potential of NIR photothermal therapy by circumventing the challenges of intravenous NP delivery and tumor targeting found in other photothermal therapy studies.Methods: Subcutaneous Cal 27 squamous cell carcinoma xenografts received photothermal nanotherapy treatments, radial injections of polyethylene glycol (PEG-ylated gold nanorods and one NIR 785 nm laser irradiation for 10 minutes at 9.5 W/cm2. Tumor response was measured for 10–15 days, gross changes in tumor size were evaluated, and the remaining tumors or scar tissues were excised and histologically analyzed.Results: The single treatment of intratumoral nanorod injections followed by a 10 minute NIR laser treatment also known as photothermal nanotherapy, resulted in ~100% tumor regression in ~90% of treated tumors, which was statistically significant in a

  14. Evidence that tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits angiogenesis by inducing vascular endothelial cell apoptosis

    International Nuclear Information System (INIS)

    Tumor necrosis factor (TNF) and its related ligands TNF-related apoptosis inducing ligand (TRAIL) and Fas ligand (FasL) play roles in the regulation of vascular responses, but their effect on the formation of new blood vessels (angiogenesis) is unclear. Therefore, we have examined the effects of these ligands on angiogenesis modeled with primary cultures of human umbilical vein endothelial cells (HUVEC). To examine angiogenesis in the context of the central nervous system, we have also modeled cerebral angiogenesis with the human brain endothelial cell line hCMEC/D3. Parameters studied were bromodeoxyuridine (BrdU) incorporation and cell number (MTT) assay (to assess endothelial proliferation), scratch assay (migration) and networks on Matrigel (tube formation). In our hands, neither TRAIL nor FasL (1, 10, and 100 ng/ml) had an effect on parameters of angiogenesis in the HUVEC model. In hCMEC/D3 cells by contrast, TRAIL inhibited all parameters (10-100 ng/ml, 24 h). This was due to apoptosis, since its action was blocked by the pan-caspase inhibitor zVADfmk (5 x 10-5 mol/l) and TRAIL increased caspase-3 activity 1 h after application. However FasL (100 ng/ml) increased BrdU uptake without other effects. We conclude that TRAIL has different effects on in vitro angiogenesis depending on which model is used, but that FasL is generally ineffective when applied in vitro. The data suggest that TRAIL primarily influences angiogenesis by the induction of vascular endothelial apoptosis, leading to vessel regression.

  15. Over-expression of Adenine Nucleotide Translocase 1 (ANT1) Induces Apoptosis and Tumor Regression in vivo

    International Nuclear Information System (INIS)

    Adenine nucleotide translocase (ANT) is located in the inner mitochondrial membrane and catalyzes the exchange of mitochondrial ATP for cytosolic ADP. ANT has been known to be a major component of the permeability transition pore complex of mitochondria and contributes to mitochondria-mediated apoptosis. Human ANT has four isoforms (ANT1, ANT2, ANT3, and ANT4), and the expression of the ANT isoforms is variable depending on the tissue and cell type, developmental stage, and proliferation status. Among the isoforms, ANT1 is highly expressed in terminally-differentiated tissues, but expressed in low levels in proliferating cells, such as cancer cells. In particular, over-expression of ANT1 induces apoptosis in cultured tumor cells. We applied an ANT1 gene transfer approach to induce apoptosis and to evaluate the anti-tumor effect of ANT1 in a nude mouse model. We demonstrated that ANT1 transfection induced apoptosis of MDA-MB-231 cells, inactivated NF-κB activity, and increased Bax expression. ANT1-inducing apoptosis was accompanied by the disruption of mitochondrial membrane potential, cytochrome c release and the activation of caspases-9 and -3. Moreover, ANT1 transfection significantly suppressed tumor growth in vivo. Our results suggest that ANT1 transfection may be a useful therapeutic modality for the treatment of cancer

  16. Over-expression of Adenine Nucleotide Translocase 1 (ANT1 Induces Apoptosis and Tumor Regression in vivo

    Directory of Open Access Journals (Sweden)

    Kim Chul-Woo

    2008-06-01

    Full Text Available Abstract Background Adenine nucleotide translocase (ANT is located in the inner mitochondrial membrane and catalyzes the exchange of mitochondrial ATP for cytosolic ADP. ANT has been known to be a major component of the permeability transition pore complex of mitochondria and contributes to mitochondria-mediated apoptosis. Human ANT has four isoforms (ANT1, ANT2, ANT3, and ANT4, and the expression of the ANT isoforms is variable depending on the tissue and cell type, developmental stage, and proliferation status. Among the isoforms, ANT1 is highly expressed in terminally-differentiated tissues, but expressed in low levels in proliferating cells, such as cancer cells. In particular, over-expression of ANT1 induces apoptosis in cultured tumor cells. Methods We applied an ANT1 gene transfer approach to induce apoptosis and to evaluate the anti-tumor effect of ANT1 in a nude mouse model. Results We demonstrated that ANT1 transfection induced apoptosis of MDA-MB-231 cells, inactivated NF-κB activity, and increased Bax expression. ANT1-inducing apoptosis was accompanied by the disruption of mitochondrial membrane potential, cytochrome c release and the activation of caspases-9 and -3. Moreover, ANT1 transfection significantly suppressed tumor growth in vivo. Conclusion Our results suggest that ANT1 transfection may be a useful therapeutic modality for the treatment of cancer.

  17. Boosting high-intensity focused ultrasound-induced anti-tumor immunity using a sparse-scan strategy that can more effectively promote dendritic cell maturation

    Directory of Open Access Journals (Sweden)

    Zhong Pei

    2010-01-01

    Full Text Available Abstract Background The conventional treatment protocol in high-intensity focused ultrasound (HIFU therapy utilizes a dense-scan strategy to produce closely packed thermal lesions aiming at eradicating as much tumor mass as possible. However, this strategy is not most effective in terms of inducing a systemic anti-tumor immunity so that it cannot provide efficient micro-metastatic control and long-term tumor resistance. We have previously provided evidence that HIFU may enhance systemic anti-tumor immunity by in situ activation of dendritic cells (DCs inside HIFU-treated tumor tissue. The present study was conducted to test the feasibility of a sparse-scan strategy to boost HIFU-induced anti-tumor immune response by more effectively promoting DC maturation. Methods An experimental HIFU system was set up to perform tumor ablation experiments in subcutaneous implanted MC-38 and B16 tumor with dense- or sparse-scan strategy to produce closely-packed or separated thermal lesions. DCs infiltration into HIFU-treated tumor tissues was detected by immunohistochemistry and flow cytometry. DCs maturation was evaluated by IL-12/IL-10 production and CD80/CD86 expression after co-culture with tumor cells treated with different HIFU. HIFU-induced anti-tumor immune response was evaluated by detecting growth-retarding effects on distant re-challenged tumor and tumor-specific IFN-γ-secreting cells in HIFU-treated mice. Results HIFU exposure raised temperature up to 80 degrees centigrade at beam focus within 4 s in experimental tumors and led to formation of a well-defined thermal lesion. The infiltrated DCs were recruited to the periphery of lesion, where the peak temperature was only 55 degrees centigrade during HIFU exposure. Tumor cells heated to 55 degrees centigrade in 4-s HIFU exposure were more effective to stimulate co-cultured DCs to mature. Sparse-scan HIFU, which can reserve 55 degrees-heated tumor cells surrounding the separated lesions, elicited an

  18. Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis.

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    Pierre Sonveaux

    Full Text Available Switching to a glycolytic metabolism is a rapid adaptation of tumor cells to hypoxia. Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating tumor cells, it also creates a gradient of lactate that mirrors the gradient of oxygen in tumors. More than a metabolic waste, the lactate anion is known to participate to cancer aggressiveness, in part through activation of the hypoxia-inducible factor-1 (HIF-1 pathway in tumor cells. Whether lactate may also directly favor HIF-1 activation in endothelial cells (ECs thereby offering a new druggable option to block angiogenesis is however an unanswered question. In this study, we therefore focused on the role in ECs of monocarboxylate transporter 1 (MCT1 that we previously identified to be the main facilitator of lactate uptake in cancer cells. We found that blockade of lactate influx into ECs led to inhibition of HIF-1-dependent angiogenesis. Our demonstration is based on the unprecedented characterization of lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in vascular endothelial growth factor receptor 2 (VEGFR2 and basic fibroblast growth factor (bFGF expression. Furthermore, using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of tumor angiogenesis through intravital microscopy and immunohistochemistry, we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects. Together with the previous demonstration of MCT1 being a key regulator of lactate exchange between tumor cells, the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities.

  19. Anti-tumor effect of pEgr-1-endostatin-TNF-α recombinant plasmid expression induced by ionizing radiation

    International Nuclear Information System (INIS)

    Objective: To study the anti-tumor effects of pEgr-1-endostatin-TNF-α gene-radiotherapy on mice bearing Lewis lung carcinoma, and to explore the mechanism involved. Methods: 240 mice with Lewis lung carcinoma were randomly divided into four groups, including control group, irradiation group, liposome group, and liposome combined irradiation group. The plasmids packed by liposome were injected locally into the tumors of the mice, and the tumors of liposome combined irradiation group were irradiated with 10 Gy γ-rays 24 h later. The expression levels of TNF-α and endostatin in mouse serum were measured by ELISA. Then the tumor growth rates at different time were observed. Tumor angiogenesis density were estimated on frozen sections stained with CD31 by using the Chalkley counting method to vessel hot-spots. The tumor inhibition rates were also calculated. Results: Radiation induced the expression of pEgr-1-endostatin-TNFα. The endostatin and TNF-α were expressed steadily for about 4 weeks. The highest levels of expression of the endostatin and TNF-α were (52.64±4.19) and (12.01±0.87) ng/ml at 2 week. The expression levels of TNF-α and endostatin were higher in combined therapy group than those in other groups (F=29.726, P3, F=16.415, P<0.05]. Conclusions: The expression of pEgr-1-endostatin-TNFα could be induced by irradiation in dose- and time- dependent manner. The effect of antitumor and angiogenesis inhibition may be more significant than irradiation. (authors)

  20. A preclinical model for noninvasive imaging of hypoxia-induced gene expression; comparison with an exogenous marker of tumor hypoxia

    Energy Technology Data Exchange (ETDEWEB)

    Wen Bixiu; Burgman, Paul; Zanzonico, Pat; O' Donoghue, Joseph; Li, Gloria C.; Ling, C. Clifton [Memorial Sloan-Kettering Cancer Center, Department of Medical Physics, New York (United States); Cai Shangde; Finn, Ron [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York (United States); Serganova, Inna [Memorial Sloan-Kettering Cancer Center, Department of Neurology, New York (United States); Blasberg, Ronald; Gelovani, Juri [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York (United States); Memorial Sloan-Kettering Cancer Center, Department of Neurology, New York (United States)

    2004-11-01

    Hypoxia is associated with tumor aggressiveness and is an important cause of resistance to radiation therapy and chemotherapy. Assays of tumor hypoxia could provide selection tools for hypoxia-modifying treatments. The purpose of this study was to develop and characterize a rodent tumor model with a reporter gene construct that would be transactivated by the hypoxia-inducible molecular switch, i.e., the upregulation of HIF-1. The reporter gene construct is the herpes simplex virus 1-thymidine kinase (HSV1-tk) fused with the enhanced green fluorescent protein (eGFP) under the regulation of an artificial hypoxia-responsive enhancer/promoter. In this model, tumor hypoxia would up-regulate HIF-1, and through the hypoxia-responsive promoter transactivate the HSV1-tkeGFPfusion gene. The expression of this reporter gene can be assessed with the {sup 124}I-labeled reporter substrate 2'-fluoro-2'-deoxy-1-{beta}-d-arabinofuranosyl-5-iodouracil ({sup 124}I-FIAU), which is phosphorylated by the HSV1-tk enzyme and trapped in the hypoxic cells. Animal positron emission tomography (microPET) and phosphor plate imaging (PPI) were used in this study to visualize the trapped {sup 124}I-FIAU, providing a distribution of the hypoxia-induced molecular events. The distribution of {sup 124}I-FIAU was also compared with that of an exogenous hypoxic cell marker, {sup 18}F-fluoromisonidazole (FMISO). Our results showed that {sup 124}I-FIAU microPET imaging of the hypoxia-induced reporter gene expression is feasible, and that the intratumoral distributions of {sup 124}I-FIAU and {sup 18}F-FMISO are similar. In tumor sections, detailed radioactivity distributions were obtained with PPI which also showed similarity between {sup 124}I-FIAU and {sup 18}F-FMISO. This reporter system is sufficiently sensitive to detect hypoxia-induced transcriptional activation by noninvasive imaging and might provide a valuable tool in studying tumor hypoxia and in validating existing and future

  1. A preclinical model for noninvasive imaging of hypoxia-induced gene expression; comparison with an exogenous marker of tumor hypoxia

    International Nuclear Information System (INIS)

    Hypoxia is associated with tumor aggressiveness and is an important cause of resistance to radiation therapy and chemotherapy. Assays of tumor hypoxia could provide selection tools for hypoxia-modifying treatments. The purpose of this study was to develop and characterize a rodent tumor model with a reporter gene construct that would be transactivated by the hypoxia-inducible molecular switch, i.e., the upregulation of HIF-1. The reporter gene construct is the herpes simplex virus 1-thymidine kinase (HSV1-tk) fused with the enhanced green fluorescent protein (eGFP) under the regulation of an artificial hypoxia-responsive enhancer/promoter. In this model, tumor hypoxia would up-regulate HIF-1, and through the hypoxia-responsive promoter transactivate the HSV1-tkeGFPfusion gene. The expression of this reporter gene can be assessed with the 124I-labeled reporter substrate 2'-fluoro-2'-deoxy-1-β-d-arabinofuranosyl-5-iodouracil (124I-FIAU), which is phosphorylated by the HSV1-tk enzyme and trapped in the hypoxic cells. Animal positron emission tomography (microPET) and phosphor plate imaging (PPI) were used in this study to visualize the trapped 124I-FIAU, providing a distribution of the hypoxia-induced molecular events. The distribution of 124I-FIAU was also compared with that of an exogenous hypoxic cell marker, 18F-fluoromisonidazole (FMISO). Our results showed that 124I-FIAU microPET imaging of the hypoxia-induced reporter gene expression is feasible, and that the intratumoral distributions of 124I-FIAU and 18F-FMISO are similar. In tumor sections, detailed radioactivity distributions were obtained with PPI which also showed similarity between 124I-FIAU and 18F-FMISO. This reporter system is sufficiently sensitive to detect hypoxia-induced transcriptional activation by noninvasive imaging and might provide a valuable tool in studying tumor hypoxia and in validating existing and future exogenous markers for tumor hypoxia. (orig.)

  2. Tumor Lymphangiogenesis and Metastasis to Lymph Nodes Induced by Cancer Cell Expression of Podoplanin

    OpenAIRE

    Cueni, Leah N.; Hegyi, Ivan; Shin, Jay W.; Albinger-Hegyi, Andrea; Gruber, Silke; Kunstfeld, Rainer; Moch, Holger; Detmar, Michael

    2010-01-01

    The membrane glycoprotein podoplanin is expressed by several types of human cancers and might be associated with their malignant progression. Its exact biological function and molecular targets are unclear, however. Here, we assessed the relevance of tumor cell expression of podoplanin in cancer metastasis to lymph nodes, using a human MCF7 breast carcinoma xenograft model. We found that podoplanin expression promoted tumor cell motility in vitro and, unexpectedly, increased tumor lymphangiog...

  3. Defective TGFβ signaling in bone marrow-derived cells prevents Hedgehog-induced skin tumors

    OpenAIRE

    Fan, Qipeng; Gu, Dongsheng; Liu, Hailan; Yang, Ling; Zhang, Xiaoli; Yoder, Mervin C.; Kaplan, Mark H.; Xie, Jingwu

    2013-01-01

    Hedgehog (Hh) signaling in cancer cells drives changes in the tumor microenvironment that are incompletely understood. Here we report that Hh- driven tumors exhibit an increase in myeloid-derived suppressor cells (MDSC) and a decrease in T cells, indicative of an immune suppressive tumor microenvironment. This change was associated with activated TGFβ signaling in several cell types in BCCs. We determined that TGFβ signaling in bone marrow (BM)-derived cells, not keratinocytes, regulates MDSC...

  4. A case of virilization induced by a Krukenberg tumor from gastric cancer

    OpenAIRE

    Schlitt Hans-Jürgen; Schubert Thomas; Vogel Peter; Hornung Matthias; Bolder Ulrich

    2008-01-01

    Abstract Background The Krukenberg tumor represents ovarian metastases associated with gastric cancer or other gastrointestinal malignancies. Histology shows typical mucus-production and numerous signet-ring cells. Occasionally Krukenberg tumors have endocrine function and, as a consequence, some patients demonstrate hirsutism and virilization. Case presentation Here we report a case of virilization associated with an extensive gastric adenocarcinoma and Krukenberg tumor in a premenopausal wo...

  5. Stochastic resonance in the growth of a tumor induced by correlated noises

    Institute of Scientific and Technical Information of China (English)

    ZHONG Weirong; SHAO Yuanzhi; HE Zhenhui

    2005-01-01

    Multiplicative noise is found to divide the growth law of tumors into two parts in a logistic model, which is driven by additive and multiplicative noises simultaneously. The Fokker-Planck equation was also derived to explain the fact that the influence of the intensity of multiplicative noise on the growth of tumor cells has a stochastic resonance-like characteristic. An appropriate intensity of multiplicative noise is benefit to the growth of the tumor cells. The correlation between two sorts of noises weakens the stochastic resonance-like characteristic. Homologous noises promote the growth of the tumor cells.

  6. Fructose as a carbon source induces an aggressive phenotype in MDA-MB-468 breast tumor cells

    Science.gov (United States)

    MONZAVI-KARBASSI, BEHJATOLAH; HINE, R. JEAN; STANLEY, JOSEPH S.; RAMANI, VISHNU PRAKASH; CARCEL-TRULLOLS, JAIME; WHITEHEAD, TRACY L.; KELLY, THOMAS; SIEGEL, ERIC R.; ARTAUD, CECILE; SHAAF, SAEID; SAHA, RINKU; JOUSHEGHANY, FARIBA; HENRY-TILLMAN, RONDA; KIEBER-EMMONS, THOMAS

    2012-01-01

    Aberrant glycosylation is a universal feature of cancer cells, and certain glycan structures are well-known markers for tumor progression. Availability and composition of sugars in the microenvironment may affect cell glycosylation. Recent studies of human breast tumor cell lines indicate their ability to take up and utilize fructose. Here we tested the hypothesis that adding fructose to culture as a carbon source induces phenotypic changes in cultured human breast tumor cells that are associated with metastatic disease. MDA-MB-468 cells were adapted to culture media in which fructose was substituted for glucose. Changes in cell surface glycan structures, expression of genes related to glycan assembly, cytoskeleton F-actin, migration, adhesion and invasion were determined. Cells cultured in fructose expressed distinct cell-surface glycans. The addition of fructose affected sialylation and fucosylation patterns. Fructose feeding also increased binding of leukoagglutinating Phaseolus vulgaris isolectin, suggesting a possible rise in expression of branching β-1, 6 GlcNAc structures. Rhodamine-phalloidin staining revealed an altered F-actin cytoskeletal system. Fructose accelerated cellular migration and increased invasion. These data suggest that changing the carbon source of the less aggressive MDA-MB-468 cell line induced characteristics associated with more aggressive phenotypes. These data could be of fundamental importance due to the markedly increased consumption of sweeteners containing free fructose in recent years, as they suggest that the presence of fructose in nutritional micro-environment of tumor cells may negatively affect the outcome for some breast cancer patients. PMID:20664930

  7. Prognostic Significance of Tumor Hypoxia Inducible Factor-1α Expression for Outcome After Radiotherapy in Oropharyngeal Cancer

    International Nuclear Information System (INIS)

    Purpose: Head-and-neck squamous cell carcinoma (HNSCC) represents a heterogeneous group of patients in terms of subsite, treatment, and biology. Currently most management decisions are based on clinical parameters with little appreciation of patient differences in underlying tumor biology. We investigated the prognostic significance of clinicopathologic features and tumor hypoxia-inducible factor-1α (HIF-1α) expression in a homogeneous series of patients who underwent radiotherapy. Methods and Materials: An audit identified 133 consecutive patients with histologically proven squamous cell carcinoma of the tonsil or tongue base. All patients received primary radiotherapy between 1996 and 2001. Tumor HIF-1α expression was examined in 79 patients. Results: Features associated with poor locoregional control were low Hb level (p = 0.05) and advancing T (p = 0.008), N (p = 0.03), and disease (p = 0.008) stage. HIF-1α expression was a more significant adverse prognostic factor in the tonsil (hazard ratio [HR], 23.1; 95% confidence interval [CI]. 3.04-176.7) than the tongue-base tumor (HR, 2.86; 95% CI, 1.14-7.19) group (p = 0.03, test for interaction). High tumor HIF-1α expression was associated with low blood Hb levels (p = 0.03). In a multivariate analysis HIF-1α expression retained prognostic significance for locoregional control (HR, 7.10; 95% CI, 3.07-16.43) and cancer-specific survival (HR, 9.19; 95% CI, 3.90-21.6). Conclusions: There are significant differences in radiation therapy outcome within a homogeneous subsite of the oropharynx related to molecular marker expression. The work highlights the importance of studying homogeneous groups of patients in HNSCC, and the complex interrelationships between tumor biology and clinicopathologic factors. The establishment of tumor-type specific markers would represent a major advance in this area

  8. Dynamic Contrast-Enhanced Magnetic Resonance Imaging Reveals Stress-Induced Angiogenesis in MCF7 Human Breast Tumors

    Science.gov (United States)

    Furman-Haran, Edna; Margalit, Raanan; Grobgeld, Dov; Degani, Hadassa

    1996-06-01

    The mechanism of contrast enhancement of tumors using magnetic resonance imaging was investigated in MCF7 human breast cancer implanted in nude mice. Dynamic contrast-enhanced images recorded at high spatial resolution were analyzed by an image analysis method based on a physiological model, which included the blood circulation, the tumor, the remaining tissues, and clearance via the kidneys. This analysis enabled us to map in rapidly enhancing regions within the tumor, the capillary permeability factor (capillary permeability times surface area per voxel volume) and the fraction of leakage space. Correlation of these maps with T2-weighted spin echo images, with histopathology, and with immunohistochemical staining of endothelial cells demonstrated the presence of dense permeable microcapillaries in the tumor periphery and in intratumoral regions that surrounded necrotic loci. The high leakage from the intratumoral permeable capillaries indicated an induction of a specific angiogenic process associated with stress conditions that cause necrosis. This induction was augmented in tumors responding to tamoxifen treatment. Determination of the distribution and extent of this stress-induced angiogenic activity by contrast-enhanced MRI might be of diagnostic and of prognostic value.

  9. Anti-tumor activity of Phyllanthus niruri (a medicinal plant) on chemical-induced skin carcinogenesis in mice.

    Science.gov (United States)

    Sharma, Priyanka; Parmar, Jyoti; Verma, Preeti; Sharma, Priyanka; Goyal, P K

    2009-01-01

    Chemoprevention is an important strategy to control the process of carcinogenesis. The potential of using medicinal herbs as cancer chemopreventive nutraceuticals and functional food is promising. Thus, there is a need for exploring drugs/agents which act as chemopreventive agents. Phyllanthus niruri is a well known medicinal plant which has been used in Ayurvedic medicine as hepatoprotective, antiviral, antibacterial, analgesic, antispasmodic and antidiabetic. The present study was carried out to evaluate the anti-tumor activity of a hydro-alcoholic extract of the whole plant, in 7-9 week old male Swiss albino mice, on the two stage process of skin carcinogenesis induced by a single topical application of 7, 12-dimethylbenz (a)anthracene (100 microg/100 microl acetone) and two weeks later promoted by repeated application of croton oil (1% in acetone/three times a week) till the end of experiment (16 weeks). The oral administration of P. niruri at a dose of 1000 mg/kg/b.wt. at peri- (i.e. 7 days before and 7 days after DMBA application) and post- (i.e. starting from the croton oil application) initiational phase of papillomagenesis caused significant reduction in tumor incidence, tumor yield, tumor burden and cumulative number of papillomas as compared to carcinogen-treated controls. Furthermore, the average latent period was significantly increased in the PNE treated group. The results thus suggest that P. niruri extract exhibits significant anti-tumor activity, which supports the traditional medicinal utilization of this plant. PMID:20192590

  10. Mammalian Target of Rapamycin Inhibitors Induce Tumor Cell Apoptosis In Vivo Primarily by Inhibiting VEGF Expression and Angiogenesis

    Directory of Open Access Journals (Sweden)

    Patrick Frost

    2013-01-01

    Full Text Available We found that rapalog mTOR inhibitors induce G1 arrest in the PTEN-null HS Sultan B-cell lymphoma line in vitro, but that administration of rapalogs in a HS Sultan xenograft model resulted in significant apoptosis, and that this correlated with induction of hypoxia and inhibition of neoangiogenesis and VEGF expression. Mechanistically, rapalogs prevent cap-dependent translation, but studies have shown that cap-independent, internal ribosome entry site (IRES-mediated translation of genes, such as c-myc and cyclin D, can provide a fail-safe mechanism that regulates tumor survival. Therefore, we tested if IRES-dependent expression of VEGF could likewise regulate sensitivity of tumor cells in vivo. To achieve this, we developed isogenic HS Sultan cell lines that ectopically express the VEGF ORF fused to the p27 IRES, an IRES sequence that is insensitive to AKT-mediated inhibition of IRES activity and effective in PTEN-null tumors. Mice challenged with p27-VEGF transfected tumor cells were more resistant to the antiangiogenic and apoptotic effects of the rapalog, temsirolimus, and active site mTOR inhibitor, pp242. Our results confirm the critical role of VEGF expression in tumors during treatment with mTOR inhibitors and underscore the importance of IRES activity as a resistance mechanism to such targeted therapy.

  11. Radiation-induced intracerebral cavernous angiomas in children with malignant brain tumors. A report of two cases

    International Nuclear Information System (INIS)

    Cavernous angiomas forming in the brain after radiation therapy for pediatric brain tumors have recently attracted special interest as a late complication of radiation therapy. We report here on two children with malignant brain tumors who developed intracerebral cavernous angiomas 4 to 5 years after radiation therapy. A 14-year-old girl with a primitive neuroectodermal tumor developed a cavernous angioma in the hypothalamus after being irradiated with 55 Gy 4 years ago. The second case, 13-year-old boy with a pineal mixed germ cell tumor showed a cavernous angioma at the thalamus 5 years after receiving radiation therapy with a dose of 60 Gy. Both patients did not show any abnormal symptoms and the cavernous angiomas diagnoses were made with MRI findings. A review of 20 reported cases of radiation-induced cavernous angiomas in the brain revealed some characteristic findings. Eighteen of the 20 cases were children, fourteen cases developed hemorrhage, the radiation dose administered was distributed between 18-60 Gy (median dose of 43.5 Gy), and the median latent period was 7.5 years (range: 2-21 years). As a differential diagnosis for the recurrent tumor is guite difficult in most cases, it is necessary to observe patients who developed angioma-like lesions in the irradiated area carefully. (author)

  12. Porous Silicon Microparticle Potentiates Anti-Tumor Immunity by Enhancing Cross-Presentation and Inducing Type I Interferon Response

    Directory of Open Access Journals (Sweden)

    Xiaojun Xia

    2015-05-01

    Full Text Available Micro- and nanometer-size particles have become popular candidates for cancer vaccine adjuvants. However, the mechanism by which such particles enhance immune responses remains unclear. Here, we report a porous silicon microparticle (PSM-based cancer vaccine that greatly enhances cross-presentation and activates type I interferon (IFN-I response in dendritic cells (DCs. PSM-loaded antigen exhibited prolonged early endosome localization and enhanced cross-presentation through both proteasome- and lysosome-dependent pathways. Phagocytosis of PSM by DCs induced IFN-I responses through a TRIF- and MAVS-dependent pathway. DCs primed with PSM-loaded HER2 antigen produced robust CD8 T cell-dependent anti-tumor immunity in mice bearing HER2+ mammary gland tumors. Importantly, this vaccination activated the tumor immune microenvironment with elevated levels of intra-tumor IFN-I and MHCII expression, abundant CD11c+ DC infiltration, and tumor-specific cytotoxic T cell responses. These findings highlight the potential of PSM as an immune adjuvant to potentiate DC-based cancer immunotherapy.

  13. The dissociation of tumor-induced weight loss from hypoglycemia in a transplantable pluripotent rat islet tumor results in the segregation of stable alpha- and beta-cell tumor phenotypes

    DEFF Research Database (Denmark)

    Madsen, O D; Karlsen, C; Nielsen, E;

    1993-01-01

    We previously established pluripotent transformed rat islet cell lines, MSL-cells, of which certain clones have been used to study processes of islet beta-cell maturation, including the transcriptional activation of the insulin gene induced by in vivo passage. Thus, successive sc transplantation in...... phenotype. Tumor necrosis factor (cachectin) was not produced by any of the tumors. Proglucagon was processed as in the fetal islet to products representative of both pancreatic alpha-cell and intestinal L-cell phenotypes, with glucagon and Glp-1 (7-36)amide as the major extractable products. In contrast to...... derived from a common clonal origin of pluripotent MSL cells, thus supporting the existence of a cell lineage relationship between islet alpha- and beta-cell during ontogeny; and 2) that our glucagonomas release an anorexigenic substance(s) of unknown nature that causes a severe weight loss comparable to...

  14. Disrupted sleep without sleep curtailment induces sleepiness and cognitive dysfunction via the tumor necrosis factor-α pathway

    OpenAIRE

    Ramesh Vijay; Nair Deepti; Zhang Shelley X L; Hakim Fahed; Kaushal Navita; Kayali Foaz; Wang Yang; Li Richard C; Carreras Alba; Gozal David

    2012-01-01

    Abstract Background Sleepiness and cognitive dysfunction are recognized as prominent consequences of sleep deprivation. Experimentally induced short-term sleep fragmentation, even in the absence of any reductions in total sleep duration, will lead to the emergence of excessive daytime sleepiness and cognitive impairments in humans. Tumor necrosis factor (TNF)-α has important regulatory effects on sleep, and seems to play a role in the occurrence of excessive daytime sleepiness in children who...

  15. Inhibitors of the cytochrome P-450 enzymes block the secretagogue-induced release of corticotropin in mouse pituitary tumor cells.

    OpenAIRE

    Luini, A G; Axelrod, J

    1985-01-01

    A mouse pituitary tumor cell line (AtT-20) releases corticotropin (ACTH) in response to a number of secretagogues, including corticotropin-releasing factor (CRF), beta-adrenergic agents, N6,O2'-dibutyryladenosine 3',5'-cyclic monophosphate (Bt2 cAMP), and potassium. The stimulation of ACTH secretion induced by the secretagogues can be blocked by inhibitors of the enzymes that generate (phospholipase A2) and metabolize (lipoxygenase and epoxygenase) arachidonic acid. The phospholipase A2 block...

  16. Mechanism regulating reactive oxygen species in tumor induced myeloid-derived suppressor cells1: MDSC and ROS in cancer

    OpenAIRE

    Corzo, Cesar A.; Cotter, Matthew J.; Cheng, Pingyan; Cheng, Fendong; Kusmartsev, Sergei; Sotomayor, Eduardo; Padhya, Tapan; McCaffrey, Thomas V.; McCaffrey, Judith C.; Gabrilovich, Dmitry I.

    2009-01-01

    Myeloid-derived suppressor cells (MDSC) are a major component of the immune suppressive network described in cancer and many other pathological conditions. Recent studies have demonstrated that one of the major mechanisms of MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). However, the mechanism of this phenomenon remained unknown. In this study we observed a substantial up-regulation of ROS by MDSC in all of seven different tumor models and in patients with head ...

  17. JNK inhibition sensitizes tumor cells to radiation-induced premature senescence via Bcl-2/ROS/DDR signaling pathway

    International Nuclear Information System (INIS)

    Premature senescence is considered as a cellular defense mechanism to prevent tumorigenesis. Although recent evidences demonstrate that c-Jun N-terminal kinase (JNK) is involved in the senescence process, the target and exact mechanism of JNK signaling in the regulation of cell proliferation has yet to be defined. In this study, we investigated the role of JNK in premature senescence and demonstrated JNK inhibition sensitized tumor cells to radiation-induced premature senescence

  18. Hypodipsic hypernatremia with intact AVP response to non-osmotic stimuli induced by hypothalamic tumor: a case report.

    OpenAIRE

    Kang, M. J.; Yoon, K. H.; S. S. Lee; Lee, J. M.; Ahn, Y. B.; Chang, S. A.; Kang, M. I.; Cha, B. Y.; Lee, K.W.; Son, H. Y.; Kang, S K; Hong, Y K

    2001-01-01

    Anatomical lesions of hypothalamic area associated with hypodipsic hypernatremia have been reported only rarely. We report here a case of hypodipsic hypernatremia induced by a hypothalamic lesion. A 25-yr-old man, who had been treated with radiation for hypothalamic tumor 5-yr before, was admitted for evaluation of hypernatremia and hypokalemia. He never felt thirst despite the elevated plasma osmolality and usually refused to drink intentionally. Plasma arginine vasopressin (AVP) level was n...

  19. Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

    Directory of Open Access Journals (Sweden)

    Ana-Maria Florea

    2011-03-01

    Full Text Available Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs and might provide new therapeutic strategies and reduce side effects.

  20. Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

    Energy Technology Data Exchange (ETDEWEB)

    Florea, Ana-Maria [Department of Neuropathology, Heinrich-Heine University, Düsseldorf (Germany); Büsselberg, Dietrich, E-mail: dib2015@qatar-med.cornell.edu [Weil Cornell Medical College in Qatar, Qatar Foundation-Education City, P.O. Box 24144, Doha (Qatar)

    2011-03-15

    Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects.

  1. 1,10-Phenanthroline promotes copper complexes into tumor cells and induces apoptosis by inhibiting the proteasome activity.

    Science.gov (United States)

    Zhang, Zhen; Bi, Caifeng; Schmitt, Sara M; Fan, Yuhua; Dong, Lili; Zuo, Jian; Dou, Q Ping

    2012-12-01

    Indole-3-acetic acid and indole-3-propionic acid, two potent natural plant growth hormones, have attracted attention as promising prodrugs in cancer therapy. Copper is known to be a cofactor essential for tumor angiogenesis. We have previously reported that taurine, L-glutamine, and quinoline-2-carboxaldehyde Schiff base copper complexes inhibit cell proliferation and proteasome activity in human cancer cells. In the current study, we synthesized two types of copper complexes, dinuclear complexes and ternary complexes, to investigate whether a certain structure could easily carry copper into cancer cells and consequently inhibit tumor proteasome activity and induce apoptosis. We observed that ternary complexes binding with 1,10-phenanthroline are more potent proteasome inhibitors and apoptosis inducers than dinuclear complexes in PC-3 human prostate cancer cells. Furthermore, the ternary complexes potently inhibit proteasome activity before induction of apoptosis in MDA-MB-231 human breast cancer cells, but not in nontumorigenic MCF-10A cells. Our results suggest that copper complexes binding with 1,10-phenanthroline as the third ligand could serve as potent, selective proteasome inhibitors and apoptosis inducers in tumor cells, and that the ternary complexes may be good potential anticancer drugs. PMID:23053530

  2. Exposure to chromium (VI) in the drinking water increases susceptibility to UV-induced skin tumors in hairless mice

    International Nuclear Information System (INIS)

    Hexavalent chromium (Cr (VI)) is a well known-human carcinogen with exposures occurring in both occupational and environmental settings. Although lung carcinogenicity has been well documented for occupational exposure via inhalation, the carcinogenic hazard of drinking water exposure to Cr (VI) has yet to be established. We used a hairless mouse model to study the effects of K2CrO4 in the drinking water on ultraviolet radiation (UVR)-induced skin tumors. Hairless mice were unexposed or exposed to UVR alone (1.2 kJ/m2), K2CrO4 alone at 2.5 and 5.0 ppm, or the combination of UVR and K2CrO4 at 0.5, 2.5, and 5.0 ppm. Mice were observed on a weekly basis for the appearance of skin tumors larger than 2 mm. All the mice were euthanized on day 182. The skin tumors were excised and subsequently analyzed microscopically for malignancy by histopathology. There was a total absence of observable skin tumors in untreated mice and in mice exposed to chromate alone. However, there was a dose-dependent increase in the number of skin tumors greater than 2 mm in mice exposed to K2CrO4 and UV compared with mice exposed to UV alone. The increase in tumors larger than 2 mm was statistically significant (P 2CrO4 at the two highest K2CrO4 doses (2.5 and 5.0 ppm), and there was a statistically significant increase in the numbers of malignant tumors per mouse in the UVR plus K2CrO4 (5 ppm) group compared with UV alone. The data presented here indicate that K2CrO4 increases the number of UV-induced skin tumors in a dose-dependent manner, and these results support the concern that regulatory agencies have relative to the carcinogenic health hazards of widespread human exposure to Cr (VI) in drinking water

  3. Activation of Nerve Growth Factor-Induced Bα by Methylene-Substituted Diindolylmethanes in Bladder Cancer Cells Induces Apoptosis and Inhibits Tumor GrowthS⃞

    OpenAIRE

    Dae Cho, Sung; Lee, Syng-Ook; Chintharlapalli, Sudhakar; Abdelrahim, Maen; Khan, Shaheen; Yoon, Kyungsil; Kamat, Ashish M.; Safe, Stephen

    2010-01-01

    Nerve growth factor-induced B (NGFI-B) genes are orphan nuclear receptors, and NGFI-Bα (Nur77, TR3) is overexpressed in bladder tumors and bladder cancer cells compared with nontumorous bladder tissue. 1,1-Bis(3′-indolyl)-1-(p-methoxyphenyl)-methane (DIM-C-pPhOCH3) and 1,1-bis(3′-indolyl)-1-(p-phenyl)methane have previously been identified as activators of Nur77, and both compound...

  4. A case of virilization induced by a Krukenberg tumor from gastric cancer

    Directory of Open Access Journals (Sweden)

    Schlitt Hans-Jürgen

    2008-02-01

    Full Text Available Abstract Background The Krukenberg tumor represents ovarian metastases associated with gastric cancer or other gastrointestinal malignancies. Histology shows typical mucus-production and numerous signet-ring cells. Occasionally Krukenberg tumors have endocrine function and, as a consequence, some patients demonstrate hirsutism and virilization. Case presentation Here we report a case of virilization associated with an extensive gastric adenocarcinoma and Krukenberg tumor in a premenopausal woman. Virilization occurred three months after diagnosis of gastric cancer and the ovarian tumors. Palliative chemotherapy was initiated as primary therapy, but gastric outlet obstruction required a gastrojejunostomy. In addition, oopherectomy was performed to relieve abdominal tension and to abate hormonal effects. It is likely that virilization of the patient could have been prevented by earlier oopherectomy prior to development of hormone production. Conclusion Despite the limitation in survival time early oopherectomy should be considered to prevent the development of virilization even in palliative situations if a Krukenberg tumor is diagnosed with gastric cancer.

  5. Exenatide Reduces Tumor Necrosis Factor-α-induced Apoptosis in Cardiomyocytes by Alleviating Mitochondrial Dysfunction

    Institute of Scientific and Technical Information of China (English)

    Yuan-Yuan Cao; Zhang-Wei Chen; Yan-Hua Gao; Xing-Xu Wang; Jian-Ying Ma; Shu-Fu Chang; Ju-Ying Qian

    2015-01-01

    Background: Tumor necrosis factor-α (TNF-α) plays an important role in progressive contractile dysfunction in several cardiac diseases.The cytotoxic effects of TNF-α are suggested to be partly mediated by reactive oxygen species (ROS)-and mitochondria-dependent apoptosis.Glucagon-like peptide-1 (GLP-1) or its analogue exhibits protective effects on the cardiovascular system.The objective of the study was to assess the effects of exenatide, a GLP-1 analogue, on oxidative stress, and apoptosis in TNF-c-treated cardiomyocytes in vitro.Methods: Isolated neonatal rat cardiomyocytes were divided into three groups: Control group, with cells cultured in normal conditions without intervention;TNF-α group, with cells incubated with TNF-c (40 ng/ml) for 6, 12, or 24 h without pretreatment with exenatide;and exenatide group, with cells pretreated with exenatide (100 nmol/L) 30 mins before TNF-α (40 ng/ml) stimulation.We evaluated apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and flow cytometry, measured ROS production and mitochondrial membrane potential (MMP) by specific the fluorescent probes, and assessed the levels of proteins by Western blotting for all the groups.Results: Exenatide pretreatment significantly reduced cardiomyocyte apoptosis as measured by flow cytometry and TUNEL assay at 12 h and 24 h.Also, exenatide inhibited excessive ROS production and maintained MMP.Furthermore, declined cytochrome-c release and cleaved caspase-3 expression and increased bcl-2 expression with concomitantly decreased Bax activation were observed in exenatide-pretreated cultures.Conclusion: These results suggested that exenatide exerts a protective effect on cardiomyocytes, preventing TNF-α-induced apoptosis;the anti-apoptotic effects may be associated with protection of mitochondrial function.

  6. Pituitary Tumors

    Science.gov (United States)

    ... Tumors Oligoastrocytoma Oligodendroglioma Pineal Tumor Pituitary Tumor PNET Schwannoma Risk Factors Brain Tumor Facts Brain Tumor Dictionary ... Tumors Oligoastrocytoma Oligodendroglioma Pineal Tumor Pituitary Tumor PNET Schwannoma Risk Factors Brain Tumor Facts Brain Tumor Dictionary ...

  7. Inducible and transmissible genetic events and pediatric tumors of the nervous system

    International Nuclear Information System (INIS)

    Tumors of the nervous system most often occur in both children and adults as sporadic events with no family history of the disease, but they are also among the clinical manifestations of a significant number of familial cancer syndromes, including familial retinoblastoma, neurofibromatosis 1 and 2, tuberous sclerosis, and Cowden, Turcot, Li-Fraumeni and nevoid basal cell carcinoma (Gorlin) syndromes. All of these syndromes involve transmissible genetic risk resulting from loss of a functional allele, or inheritance of a structurally defective allele, of a specific gene. These genes include RB1, NF1, NF2, TSC1, TSC2, TP53, PTEN, APC, hMLH1, hPSM2, and PTCH, most of which function as tumor suppressor genes. The same genes are also observed in mutated and inactive forms, or are deleted, in tumor cells in sporadic cases of the same tumors. The nature of the mutational events that give rise to these inactivated alleles suggests a possible role of environmental mutagens in their causation. However, only external ionizing radiation at high doses is clearly established as an environmental cause of brain, nerve and meningeal tumors in humans. Transplacental carcinogenesis studies in rodents and other species emphasize the extraordinary susceptibility of the developing mammalian nervous system to carcinogenesis, but the inverse relationship of latency to dose suggests that low transplacental exposures to genotoxicants are more likely to result in brain tumors late in life, rather than in childhood. While not all neurogenic tumor-related genes in humans have similar effects in experimental rodents, genetically engineered mice (GEM) increasingly provide useful insights into the combined effects of multiple tumor suppressor genes and of gene-environment interactions in the genesis of brain tumors, especially pediatric brain tumors such as medulloblastoma. (author)

  8. Promising markers for the detection of premature senescence tumor cells induced by ionizing radiation: Cathepsin D and eukaryotic translation elongation factor 1

    International Nuclear Information System (INIS)

    Recently, it has been proved that induction of senescence could be a promising way of tumor treatment. Senescence was originally described in normal human cells undergoing a finite number of divisions before permanent growth arrest. It has now become regarded more broadly as a general biological program of terminal growth arrest. A variety of stresses such as ionizing radiation (IR), oxidative stress, oncogenic transformation, DNA damaging agents triggers stress-induced premature senescence, i.e. rapid and permanent cell growth arrest. Therefore, premature senescence is bona fide barrier to tumorigenesis and hallmark of premalignant tumors. However, there is lack of obvious markers for senescent tumor cells. To identify useful premature senescence markers for tumor cells, we monitored the changes of protein expression profile in IR-induced premature senescence MCF7 human breast cancer cells. We identified biomarkers which evidently changed their expression levels in ionizing radiation-induced senescenct tumor cells

  9. NI-49SMART SUCKER: NEXT GENERATION SMART SURGICAL TOOL FOR INTRAOPERATIVE BRAIN TUMOR RESECTION USING TIME RESOLVED LASER INDUCED FLUORESCENCE SPECTROSCOPY

    OpenAIRE

    Kittle, David S.; Butte, Pramod V.; Vasefi, Fartash; Patil, Chirag G.; Black, Keith

    2014-01-01

    Primary brain tumors are highly lethal tumors where surgical resection is the primary treatment of choice. It has been shown that survival rate is directly related to the extent of tumor resection. In order to aid the surgeon in achieving near-complete resection, novel technologies are required. Time-resolved laser induced fluorescence spectroscopy (TRLIFS) promises to be one such technology, where the tissue is excited using an ultra-short laser and the corresponding fluorescence intensity d...

  10. Metabolic effects of cachectin/tumor necrosis factor are modified by site of production. Cachectin/tumor necrosis factor-secreting tumor in skeletal muscle induces chronic cachexia, while implantation in brain induces predominantly acute anorexia.

    OpenAIRE

    Tracey, K J; Morgello, S; Koplin, B; Fahey, T J; Fox, J; Aledo, A; Manogue, K. R.; Cerami, A

    1990-01-01

    We have developed a murine model of wasting by injecting intracerebrally cells which continuously secrete h-cachectin/TNF (CHO-TNF) to: (a) determine the effects of cachectin/TNF produced continuously in the central nervous system (CNS), and (b) compare the metabolic effects of cachectin/TNF-secreting tumor in the brain to the cachexia caused by CHO-TNF tumor in peripheral tissue (IM). Intracerebral CHO-TNF tumors produced increased serum h-cachectin/TNF levels with lethal hypophagia and weig...

  11. Radium-induced malignant tumors of the mastoid and paranasal sinuses

    International Nuclear Information System (INIS)

    In the records of 5,058 persons with therapeutic or occupational exposure to radium, 21 patients with carcinoma of the mastoid and 11 with malignant tumors of the paranasal sinuses were identified. Tumor induction times were 21 to 50 years for mastoid tumors (median, 33) and 19 to 52 years for paranasal sinus tumors (median, 34). Dosimetric data are given for the patients whose body burdens of radium have been measured. We found a high proportion of mucoepidermoid carcinoma, comprising 38% of the mastoid and 36% of the paranasal sinus tumors. Three patients had antecedent bone sarcoma at 20, 11, and 5 years, respectively, and a bone sarcoma was discovered at autopsy in a fourth patient. Radiographic changes in the mastoid and paranasal sinuses were similar to those seen in nonradium malignant tumors. More than 800 known persons exposed to radium before 1930 and another group of unknown size who received radium water or injections of radium from physicians are still alive and at risk of developing malignant tumors of the mastoid and paranasal sinuses

  12. Knock-down of hypoxia-induced carbonic anhydrases IX and XII radiosensitizes tumor cells by increasing intracellular acidosis

    Directory of Open Access Journals (Sweden)

    Jérôme eDoyen

    2013-01-01

    Full Text Available The relationship between acidosis within the tumor microenvironment and radioresistance of hypoxic tumor cells remains unclear. Previously we reported that hypoxia-induced carbonic anhydrases CAIX and CAXII constitute a robust pHi-regulating system that confers a survival advantage on hypoxic human colon carcinoma LS174Tr cells in acidic microenvironments. Here we investigate the role of acidosis, CAIX and CAXII knock-down in combination with ionizing radiation. Fibroblasts cells (-/+ CAIX and LS174Tr cells (inducible knock-down for ca9/ca12 were analyzed for cell cycle phase distribution and survival after irradiation in extracellular pHo manipulations and hypoxia (1% O2 exposure. Radiotherapy was used to target ca9/ca12-silenced LS174Tr tumors grown in nude mice. We found that diminishing the pHi-regulating capacity of fibroblasts through inhibition of NHE-1 sensitize cells to radiation-induced cell death. Secondly, the pHi-regulating function of CAIX plays a key protective role in irradiated fibroblasts in an acidic environment as accompanied by a reduced number of cells in the radiosensitive phases of the cell cycle. Thirdly, we demonstrate that irradiation of LS174Tr spheroids, silenced for either ca9 or both ca9/ca12, showed a respective 50% and 75% increase in cell death as a result of a decrease in cell number in the radioresistant S phase and a disruption of CA-mediated pHi regulation. Finally, LS174Tr tumor progression was strongly decreased when ca9/ca12 silencing was combined with irradiation in vivo. These findings highlight the combinatory use of radiotherapy with targeting of the pHi-regulating carbonic anhydrases as an anti-cancer strategy.

  13. Interleukin-15-induced CD56(+) myeloid dendritic cells combine potent tumor antigen presentation with direct tumoricidal potential.

    Science.gov (United States)

    Anguille, Sébastien; Lion, Eva; Tel, Jurjen; de Vries, I Jolanda M; Couderé, Karen; Fromm, Phillip D; Van Tendeloo, Viggo F; Smits, Evelien L; Berneman, Zwi N

    2012-01-01

    Dendritic cells (DCs) are the quintessential antigen-presenting cells of the human immune system and play a prime role in coordinating innate and adaptive immune responses, explaining the strong and still growing interest in their application for cancer immunotherapy. Much current research in the field of DC-based immunotherapy focuses on optimizing the culture conditions for in vitro DC generation in order to assure that DCs with the best possible immunogenic qualities are being used for immunotherapy. In this context, monocyte-derived DCs that are alternatively induced by interleukin-15 (IL-15 DCs) have attracted recent attention due to their superior immunostimulatory characteristics. In this study, we show that IL-15 DCs, in addition to potent tumor antigen-presenting function, possess tumoricidal potential and thus qualify for the designation of killer DCs. Notwithstanding marked expression of the natural killer (NK) cell marker CD56 on a subset of IL-15 DCs, we found no evidence of a further phenotypic overlap between IL-15 DCs and NK cells. Allostimulation and antigen presentation assays confirmed that IL-15 DCs should be regarded as bona fide myeloid DCs not only from the phenotypic but also from the functional point of view. Concerning their cytotoxic activity, we demonstrate that IL-15 DCs are able to induce apoptotic cell death of the human K562 tumor cell line, while sparing tumor antigen-specific T cells. The cytotoxicity of IL-15 DCs is predominantly mediated by granzyme B and, to a small extent, by tumor necrosis factor-α (TNF-α)-related apoptosis-inducing ligand (TRAIL) but is independent of perforin, Fas ligand and TNF-α. In conclusion, our data provide evidence of a previously unappreciated role for IL-15 in the differentiation of human monocytes towards killer DCs. The observation that IL-15 DCs have killer DC capacity lends further support to their implementation in DC-based immunotherapy protocols. PMID:23284789

  14. Radium-induced malignant tumors of the mastoid and paranasal sinuses

    International Nuclear Information System (INIS)

    In the records of 5058 persons with therapeutic or occupational exposure to radium, 21 patients with carcinoma of the mastoid and 11 with malignant tumors of the paranasal sinuses were identified. Induction time for mastoid tumors was 21 to 50 years, median 33; for paranasal sinus tumors it was 10 to 52 years, median 34. Dosimetric data are given for the patients whose body burdens of radium have been measured. Observations and theoretical considerations strongly suggest that radon in the air of sinuses may be an important or perhaps a major factor in the induction of paranasal sinus malignancies in the radium cases

  15. Pure Multiplicative Noises Induced Population Extinction in an Anti-tumor Model under Immune Surveillance

    International Nuclear Information System (INIS)

    The dynamical characters of a theoretical anti-tumor model under immune surveillance subjected to a pure multiplicative noise are investigated. The effects of pure multiplicative noise on the stationary probability distribution (SPD) and the mean first passage time (MFPT) are analysed based on the approximate Fokker-Planck equation of the system in detail. For the anti-tumor model, with the multiplicative noise intensity D increasing, the tumor population move towards to extinction and the extinction rate can be enhanced. Numerical simulations are carried out to check the approximate theoretical results. Reasonably good agreement is obtained.

  16. Metabolic effects of cachectin/tumor necrosis factor are modified by site of production. Cachectin/tumor necrosis factor-secreting tumor in skeletal muscle induces chronic cachexia, while implantation in brain induces predominantly acute anorexia.

    Science.gov (United States)

    Tracey, K J; Morgello, S; Koplin, B; Fahey, T J; Fox, J; Aledo, A; Manogue, K R; Cerami, A

    1990-12-01

    We have developed a murine model of wasting by injecting intracerebrally cells which continuously secrete h-cachectin/TNF (CHO-TNF) to: (a) determine the effects of cachectin/TNF produced continuously in the central nervous system (CNS), and (b) compare the metabolic effects of cachectin/TNF-secreting tumor in the brain to the cachexia caused by CHO-TNF tumor in peripheral tissue (IM). Intracerebral CHO-TNF tumors produced increased serum h-cachectin/TNF levels with lethal hypophagia and weight loss (mean survival time of 11 d); these changes were not observed in association with nonsecretory control brain tumors. The metabolic consequences of intracerebral cachectin/TNF production were indistinguishable from acute, lethal starvation: whole-body lipid content was decreased significantly but protein was conserved. Although intramuscular cachectin/TNF-secreting tumors caused similar increases of serum h-cachectin/TNF levels, profound anorexia did not develop; wasting developed after a longer period of tumor burden (50 d) with classical signs of cachexia (i.e., anemia and depletion of both protein and lipid). These studies provide a reproducible animal model of site-specific cytokine production and suggest that, regardless of serum levels, cachectin/TNF produced locally in brain influences both the rate of development of wasting and its net metabolic effects. PMID:2254457

  17. Semiallogenic fusions of MSI+ tumor cells and activated B cells induce MSI-specific T cell responses

    Directory of Open Access Journals (Sweden)

    Klier Ulrike

    2011-09-01

    Full Text Available Abstract Background Various strategies have been developed to transfer tumor-specific antigens into antigen presenting cells in order to induce cytotoxic T cell responses against tumor cells. One approach uses cellular vaccines based on fusions of autologous antigen presenting cells and allogeneic tumor cells. The fusion cells combine antigenicity of the tumor cell with optimal immunostimulatory capacity of the antigen presenting cells. Microsatellite instability caused by mutational inactivation of DNA mismatch repair genes results in translational frameshifts when affecting coding regions. It has been shown by us and others that these mutant proteins lead to the presentation of immunogenic frameshift peptides that are - in principle - recognized by a multiplicity of effector T cells. Methods We chose microsatellite instability-induced frameshift antigens as ideal to test for induction of tumor specific T cell responses by semiallogenic fusions of microsatellite instable carcinoma cells with CD40-activated B cells. Two fusion clones of HCT116 with activated B cells were selected for stimulation of T cells autologous to the B cell fusion partner. Outgrowing T cells were phenotyped and tested in functional assays. Results The fusion clones expressed frameshift antigens as well as high amounts of MHC and costimulatory molecules. Autologous T cells stimulated with these fusions were predominantly CD4+, activated, and reacted specifically against the fusion clones and also against the tumor cell fusion partner. Interestingly, a response toward 6 frameshift-derived peptides (of 14 tested could be observed. Conclusion Cellular fusions of MSI+ carcinoma cells and activated B cells combine the antigen-presenting capacity of the B cell with the antigenic repertoire of the carcinoma cell. They present frameshift-derived peptides and can induce specific and fully functional T cells recognizing not only fusion cells but also the carcinoma cells. These

  18. Semiallogenic fusions of MSI+ tumor cells and activated B cells induce MSI-specific T cell responses

    International Nuclear Information System (INIS)

    Various strategies have been developed to transfer tumor-specific antigens into antigen presenting cells in order to induce cytotoxic T cell responses against tumor cells. One approach uses cellular vaccines based on fusions of autologous antigen presenting cells and allogeneic tumor cells. The fusion cells combine antigenicity of the tumor cell with optimal immunostimulatory capacity of the antigen presenting cells. Microsatellite instability caused by mutational inactivation of DNA mismatch repair genes results in translational frameshifts when affecting coding regions. It has been shown by us and others that these mutant proteins lead to the presentation of immunogenic frameshift peptides that are - in principle - recognized by a multiplicity of effector T cells. We chose microsatellite instability-induced frameshift antigens as ideal to test for induction of tumor specific T cell responses by semiallogenic fusions of microsatellite instable carcinoma cells with CD40-activated B cells. Two fusion clones of HCT116 with activated B cells were selected for stimulation of T cells autologous to the B cell fusion partner. Outgrowing T cells were phenotyped and tested in functional assays. The fusion clones expressed frameshift antigens as well as high amounts of MHC and costimulatory molecules. Autologous T cells stimulated with these fusions were predominantly CD4+, activated, and reacted specifically against the fusion clones and also against the tumor cell fusion partner. Interestingly, a response toward 6 frameshift-derived peptides (of 14 tested) could be observed. Cellular fusions of MSI+ carcinoma cells and activated B cells combine the antigen-presenting capacity of the B cell with the antigenic repertoire of the carcinoma cell. They present frameshift-derived peptides and can induce specific and fully functional T cells recognizing not only fusion cells but also the carcinoma cells. These hybrid cells may have great potential for cellular immunotherapy and

  19. Treatment of a supratentorial primitive neuroectodermal tumor using magnetic resonance-guided laser-induced thermal therapy.

    Science.gov (United States)

    Jethwa, Pinakin R; Lee, Jason H; Assina, Rachid; Keller, Irwin A; Danish, Shabbar F

    2011-11-01

    Supratentorial primitive neuroectodermal tumors (PNETs) are rare tumors that carry a poorer prognosis than those arising from the infratentorial compartment (such as medulloblastoma). The overall prognosis for these patients depends on several factors including the extent of resection, age at diagnosis, CSF dissemination, and site in the supratentorial space. The authors present the first case of a patient with a newly diagnosed supratentorial PNET in which cytoreduction was achieved with MR-guided laser-induced thermal therapy. A 10-year-old girl presented with left-sided facial weakness and a large right thalamic mass extending into the right midbrain. The diagnosis of supratentorial PNET was made after stereotactic biopsy. Therapeutic options for this lesion were limited because of the risks of postoperative neurological deficits with resection. The patient underwent MR-guided laser-induced thermal ablation of her tumor. Under real-time MR thermometry, thermal energy was delivered to the tumor at a core temperature of 90°C for a total of 960 seconds. The patient underwent follow-up MR imaging at regular intervals to evaluate the tumor response to the thermal ablation procedure. Initial postoperative scans showed an increase in the size of the lesion as well as the amount of the associated edema. Both the size of the lesion and the edema stabilized by 1 week and then decreased below preablation levels at the 3-month postsurgical follow-up. There was a slight increase in the size of the lesion and associated edema at the 6-month follow-up scan, presumably due to concomitant radiation she received as part of her postoperative care. The patient tolerated the procedure well and has had resolution of her symptoms since surgery. Further study is needed to assess the role of laser-induced thermal therapy for the treatment of intracranial tumors. As such, it is a promising tool in the neurosurgical armamentarium. Postoperative imaging has shown no evidence of definitive

  20. Perillyl Alcohol Protects against Fe-NTA-Induced Nephrotoxicity and Early Tumor Promotional Events in Rat Experimental Model

    Directory of Open Access Journals (Sweden)

    Tamanna Jahangir

    2007-01-01

    Full Text Available Plants have been widely used as protective agents against a wide variety of processes and compounds that damage tissues via free radical mechanisms. Perillyl alcohol (PA is a naturally occurring monoterpene found in the essential oils of numerous species of plants including mints, cherries and celery seeds. This monocyclic monoterpene has shown antioxidant and therapeutic activity in various studies against various xenobiotics. In this study, we have analyzed the effects of PA against single intraperitoneal dose of ferric nitrilotriacetate (Fe-NTA (9 mg iron per kg body weight-induced nephrotoxicity and early tumor promotional events. The pretreatment of Fe-NTA-treated rats with 0.5% per kg body weight dose and 1% per kg body weight dose of PA for seven consecutive days significantly reversed the Fe-NTA-induced malondialdehyde formation, xanthine oxidase activity (P < 0.001, ornithine decarboxylase activity (P < 0.001 and 3[H]thymidine incorporation in renal DNA (P < 0.001 with simultaneous significant depletion in serum toxicity markers blood urea nitrogen and creatinine (P < 0.001. Significant restoration at both the doses was recorded in depleted renal glutathione content, and its dependent enzymes with prophylactic treatment of PA. Present results suggest that PA potentially attenuates against Fe-NTA-induced oxidative damage and tumor promotional events that preclude its development as a future drug to avert the free radical-induced toxicity.

  1. Retinoid-induced expression and activity of an immediate early tumor suppressor gene in vascular smooth muscle cells.

    Directory of Open Access Journals (Sweden)

    Jeffrey W Streb

    Full Text Available Retinoids are used clinically to treat a number of hyper-proliferative disorders and have been shown in experimental animals to attenuate vascular occlusive diseases, presumably through nuclear receptors bound to retinoic acid response elements (RARE located in target genes. Here, we show that natural or synthetic retinoids rapidly induce mRNA and protein expression of a specific isoform of A-Kinase Anchoring Protein 12 (AKAP12β in cultured smooth muscle cells (SMC as well as the intact vessel wall. Expression kinetics and actinomycin D studies indicate Akap12β is a retinoid-induced, immediate-early gene. Akap12β promoter analyses reveal a conserved RARE mildly induced with atRA in a region that exhibits hyper-acetylation. Immunofluorescence microscopy and protein kinase A (PKA regulatory subunit overlay assays in SMC suggest a physical association between AKAP12β and PKA following retinoid treatment. Consistent with its designation as a tumor suppressor, inducible expression of AKAP12β attenuates SMC growth in vitro. Further, immunohistochemistry studies establish marked decreases in AKAP12 expression in experimentally-injured vessels of mice as well as atheromatous lesions in humans. Collectively, these results demonstrate a novel role for retinoids in the induction of an AKAP tumor suppressor that blocks vascular SMC growth thus providing new molecular insight into how retiniods may exert their anti-proliferative effects in the injured vessel wall.

  2. Salinomycin inhibits proliferation and induces apoptosis of human nasopharyngeal carcinoma cell in vitro and suppresses tumor growth in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Danxin; Zhang, Yu; Huang, Jie; Fan, Zirong; Shi, Fengrong; Wang, Senming, E-mail: wsenming@126.com

    2014-01-10

    Highlight: •We first evaluated the effect of salinomycin on nasopharyngeal carcinoma (NPC). •Salinomycin could inhibit Wnt/β-catenin signaling and induce apoptosis in NPC. •So salinomycin may be a good potential candidate for the chemotherapy of NPC. -- Abstract: Salinomycin (Sal) is a polyether ionophore antibiotic that has recently been shown to induce cell death in various human cancer cells. However, whether salinomycin plays a functional role in nasopharyngeal carcinoma (NPC) has not been determined to date. The present study investigated the chemotherapeutic efficacy of salinomycin and its molecular mechanisms of action in NPC cells. Salinomycin efficiently inhibited proliferation and invasion of 3 NPC cell lines (CNE-1, CNE-2, and CNE-2/DDP) and activated a extensive apoptotic process that is accompanied by activation of caspase-3 and caspase-9, and decreased mitochondrial membrane potential. Meanwhile, the protein expression level of the Wnt coreceptor lipoprotein receptor related protein 6 (LRP6) and β-catenin was down-regulated, which showed that the Wnt/β-catenin signaling was involved in salinomycin-induced apoptosis of NPC cells. In a nude mouse NPC xenograft model, the anti-tumor effect of salinomycin was associated with the downregulation of β-catenin expression. The present study demonstrated that salinomycin can effectively inhibit proliferation and invasion, and induce apoptosis of NPC cells in vitro and inhibit tumor growth in vivo, probably via the inhibition of Wnt/β-catenin signaling, suggesting salinomycin as a potential candidate for the chemotherapy of NPC.

  3. IGF binding protein-6 expression in vascular endothelial cells is induced by hypoxia and plays a negative role in tumor angiogenesis

    OpenAIRE

    ZHANG, CHUNYANG; Lu, Ling; Li, Yun; Wang, Xianlei; Zhou, Jianfeng; Liu, Yunzhang; Fu, Ping; Gallicchio, Marisa A; Bach, Leon A.; Duan, Cunming

    2011-01-01

    Hypoxia stimulates tumor angiogenesis by inducing the expression of angiogenic molecules. The negative regulators of this process, however, are not well understood. Here we report that hypoxia induced the expression of insulin-like growth factor binding protein-6 (IGFBP-6), a tumor repressor, in human and rodent vascular endothelial cells (VECs) via a HIF-mediated mechanism. Addition of human IGFBP-6 to cultured human VECs inhibited angiogenesis in vitro. An IGFBP-6 mutant with at least 10,00...

  4. Amblyomin-X induces ER stress, mitochondrial dysfunction, and caspase activation in human melanoma and pancreatic tumor cell.

    Science.gov (United States)

    Morais, Katia L P; Pacheco, Mario Thiego Fernandes; Berra, Carolina Maria; Bosch, Rosemary V; Sciani, Juliana Mozer; Chammas, Roger; de Freitas Saito, Renata; Iqbal, Asif; Chudzinski-Tavassi, Ana Marisa

    2016-04-01

    During the last two decades, new insights into proteasome function and its role in several human diseases made it a potential therapeutic target. In this context, Amblyomin-X is a Kunitz-type FXa inhibitor similar to endogenous tissue factor pathway inhibitor (TFPI) and is a novel proteasome inhibitor. Herein, we have demonstrated Amblyomin-X cytotoxicity to different tumor cells lines such as pancreatic (Panc1, AsPC1BxPC3) and melanoma (SK-MEL-5 and SK-MEL-28). Of note, Amblyomin-X was not cytotoxic to normal human fibroblast cells. In addition, Amblyomin-X promoted accumulation of ER stress markers (GRP78 and GADD153) in sensitive (SK-MEL-28) and bortezomib-resistant (Mia-PaCa-2) tumor cells. The intracellular calcium concentration [Ca(2+)] i was slightly modulated in human tumor cells (SK-MEL-28 and Mia-PaCa-2) after 24 h of Amblyomin-X treatment. Furthermore, Amblyomin-X induced mitochondrial dysfunction, cytochrome-c release, PARP cleavage, and activation of caspase cascade in both human tumor (SK-MEL-28 and Mia-PaCa-2) cells. These investigations might help in further understanding of the antitumor properties of Amblyomin-X. PMID:27015684

  5. Identification of glucocorticoid-induced leucine zipper as a key regulator of tumor cell proliferation in epithelial ovarian cancer

    Directory of Open Access Journals (Sweden)

    Fernandez Hervé

    2009-10-01

    Full Text Available Abstract Background Little is known about the molecules that contribute to tumor progression of epithelial ovarian cancer (EOC, currently a leading cause of mortality from gynecological malignancies. Glucocorticoid-Induced Leucine Zipper (GILZ, an intracellular protein widely expressed in immune tissues, has been reported in epithelial tissues and controls some of key signaling pathways involved in tumorigenesis. However, there has been no report on GILZ in EOC up to now. The objectives of the current study were to examine the expression of GILZ in EOC and its effect on tumor cell proliferation. Results GILZ expression was measured by immunohistochemical staining in tissue sections from 3 normal ovaries, 7 benign EOC and 50 invasive EOC. GILZ was not detected on the surface epithelium of normal ovaries and benign tumors. In contrast, it was expressed in the cytoplasm of tumor cells in 80% EOC specimens. GILZ immunostaining scores correlated positively to the proliferation marker Ki-67 (Spearman test in univariate analysis, P P Conclusion The present study is the first to identify GILZ as a molecule produced by ovarian cancer cells that promotes cell cycle progression and proliferation. Our findings clearly indicate that GILZ activates AKT, a crucial signaling molecule in tumorigenesis. GILZ thus appears as a potential key molecule in EOC.

  6. How to Use MR-Contrast Agent in Tumor Induced Epilepsis

    Directory of Open Access Journals (Sweden)

    Aliakbar Ameri

    2010-05-01

    Full Text Available By year of 1990, second MRI revolution has hap-pened in the diagnosis of infection and tumor assessment "first revolution was made by clinical MRI invention in the early 1980's"."nTumor-associated epilepsis is an important contributor to morbidity in patients with brain tumors. Perilesional tissue changes play a vital role in the generation of tumor-associated seizures.Tumor-associated seizure is usually focal with secondary generalization and often resistant to antiepileptic drugs."nFor studying the tumor well and diagnosis, contrast injection is a necessity and T1 pulse is used for demonstration. It needs pre-contrast T1 to compare with post contrast T1. "nContrast agent "Gadolinium" changes the relaxation time of tissue in T1 pulse "shortening the time". Contrast circulation in the body is in a close circuit from vein or artery to the capillary system, interstitial tissue and contrast does not go inside the normal cells except in hepatocytes, pituicytes and damaged cells "broken blood brain barrier"."nFor tumor diagnosis, MRI with and without Gadolinium is used more than x-ray CT techniques."nOther diagnostic techniques for tumor D.D.X and epilepsis are PET, SPECT, EEG, MEG "MSI" and ultrasound. "nTested Double Dose contrasted images "2 x 1mmol/kg" of Gadolinium by 1.5 Tesla machine increased the enhancement rate about 5-10% but needs double money for contrast. Using 3 Tesla machine also increases signal demonstration but today all imaging "95%" is sufficient by 1.5 Tesla and imaging by 3-Tesla is difficult and expensive. "nConclusion: 1/ Please request MRI with and without GD for tumor diagnosis "pre-contrast T1and post contrast T1 is necessary to diagnosis and D.D.X of any hemorrhage inside the tumor versus enhancement". 2/ Please do not request double dose contrast for imaging "it is more expensive and less effective". 3/ Please request your patients imaging by 1.5 Tesla "3 Tesla imaging is difficult and more expensive". 4/Requesting

  7. The analysis of respiration-induced pancreatic tumor motion based on reference measurement

    International Nuclear Information System (INIS)

    To evaluate pancreatic tumor motion and its dynamics during respiration. This retrospective study includes 20 patients with unresectable pancreatic cancer who were treated with stereotactic ablative radiotherapy. An online respiratory tumor tracking system was used. Periodical maximum and minimum tumor positions with respiration in superior-inferior (SI), latero-lateral (LL), and anterior-posterior (AP) directions were collected for tumor motion evaluation. The predictability of tumor motion in each axis, based on reference measurement, was analyzed. The use of a 20-mm and 5-mm constant margins for SI and LL/AP directions, avoids target underdosage, without the need for reference measurement. Pearson’s correlation coefficient indicated only a modest correlation between reference and subsequent measurements in the SI direction (r = 0.50) and no correlation in LL (r = 0.17) and AP (r = 0.35) directions. When margins based on the reference measurement of respiratory tumor motion are used, then 30% of patients have a risk zone of underdosage >3 mm (in average). ITV (internal target volume) optimization based on the reference measurement is possible, but allows only modest margin reduction (approximately from 20 mm to 16-17 mm) in SI direction and no reduction in AP and LL directions. Our results support the use of 20-mm margin in the SI direction and 5-mm margins in the LL and AP directions to account for respiratory motion without reference measurement. Single measurement of tumor motion allows only modest margin reduction. Further margin reduction is only possible when there is on-line tumor motion control according to internal markers

  8. Inducing pluripotency and immortality in prostate tumor cells : a stem cell model of cancer progression

    OpenAIRE

    Fiñones, Rita Roces

    2009-01-01

    The progression from local prostate tumor to lethal prostate cancer is not well understood. Although current treatments cure a majority of patients, a significant minority (̃12 %) of people are diagnosed with late-stage, hormone-independent disease. As yet, the origin of the hormone-independent prostate cancer cells is unknown. In the present study, the transition to the lethal form of this disease is hypothesized to occur when a genetically- compromised tumor cell undergoes (1) an immortaliz...

  9. Modulation of N-methyl-N-nitrosourea induced mammary tumors in Sprague–Dawley rats by combination of lysine, proline, arginine, ascorbic acid and green tea extract

    International Nuclear Information System (INIS)

    The limited ability of current treatments to control metastasis and the proposed antitumor properties of specific nutrients prompted us to examine the effect of a specific formulation (nutrient supplement [NS]) of lysine, proline, arginine, ascorbic acid, and green tea extract in vivo on the development of N-methyl-N-nitrosourea (MNU)-induced mammary tumors in rats. A single intraperitoneal dose of MNU was injected into each of 20 female Sprague–Dawley rats (aged 50 days) to induce tumors. Two weeks after MNU treatment, a time by which the animals had recovered from MNU-induced toxicity, the rats were divided into two groups. Rats in group 1 (n = 10) were fed Purina chow diet, whereas those in group 2 (n = 10) were fed the same diet supplemented with 0.5% NS. After a further 24 weeks, the rats were killed and tumors were excised and processed. NS reduced the incidence of MNU-induced mammary tumors and the number of tumors by 68.4%, and the tumor burden by 60.5%. The inhibitory effect of NS was also reflected by decreased tumor weight; the tumor weights per rat and per group were decreased by 41% and 78%, respectively. In addition, 30% of the control rats developed ulcerated tumors, in contrast to 10% in the nutrient supplemented rats. These findings suggest that the specific formulation of lysine, proline, arginine, ascorbic acid, and green tea extract tested significantly reduces the incidence and growth of MNU-induced mammary tumors, and therefore has strong potential as a useful therapeutic regimen for inhibiting breast cancer development

  10. Mechanism of inhibitory effect of atorvastatin on resistin expression induced by tumor necrosis factor-α in macrophages

    Directory of Open Access Journals (Sweden)

    Chua Su-Kiat

    2009-05-01

    Full Text Available Abstract Atorvastatin has been shown to reduce resistin expression in macrophages after pro-inflammatory stimulation. However, the mechanism of reducing resistin expression by atorvastatin is not known. Therefore, we sought to investigate the molecular mechanisms of atorvastatin for reducing resistin expression after proinflammatory cytokine, tumor necrosis factor-α (TNF-α stimulation in cultured macrophages. Cultured macrophages were obtained from human peripheral blood mononuclear cells. TNF-α stimulation increased resistin protein and mRNA expression and atorvastatin inhibited the induction of resistin by TNF-α. Addition of mevalonate induced resistin protein expression similar to TNF-α stimulation. However, atorvastatin did not have effect on resistin protein expression induced by mevalonate. SP600125 and JNK small interfering RNA (siRNA completely attenuated the resistin protein expression induced by TNF-α and mevalonate. TNF-α induced phosphorylation of Rac, while atorvastatin and Rac-1 inhibitor inhibited the phosphorylation of Rac induced by TNF-α. The gel shift and promoter activity assay showed that TNF-α increased AP-1-binding activity and resistin promoter activity, while SP600125 and atorvastatin inhibited the AP-1-binding activity and resistin promoter activity induced by TNF-α. Recombinant resistin and TNF-α significantly reduced glucose uptake in cultured macrophages, while atorvastatin reversed the reduced glucose uptake by TNF-α. In conclusion, JNK and Rac pathway mediates the inhibitory effect of atorvastatin on resistin expression induced by TNF-α.

  11. Comparison of Vaccine-Induced Effector CD8 T Cell Responses Directed against Self- and Non-Self-Tumor Antigens

    DEFF Research Database (Denmark)

    Pedersen, Sara R; Sørensen, Maria R; Buus, Søren;

    2013-01-01

    construct expressing a foreign (viral) TA induced efficient tumor control. Analyzing the self-TA-specific CD8 T cells, we observed that these could be activated to produce IFN-γ and TNF-α. In addition, surface expression of phenotypic markers and inhibitory receptors, as well as in vivo cytotoxicity and......It is generally accepted that CD8 T cells play a major role in tumor control, yet vaccination aimed at eliciting potent CD8 T cell responses are rarely efficient in clinical trials. To try and understand why this is so, we have generated potent adenoviral vectors encoding the endogenous tumor Ags....... Prophylactic vaccination with adenoviral vectors expressing either TRP-2 (Ad-Ii-TRP-2) or GP100 (Ad-Ii-GP100) had little or no effect on the growth of s.c. B16 melanomas, and only Ad-Ii-TRP-2 was able to induce a marginal reduction of B16 lung metastasis. In contrast, vaccination with a similar vector...

  12. Extracts of strawberry fruits induce intrinsic pathway of apoptosis in breast cancer cells and inhibits tumor progression in mice.

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    Ranganatha R Somasagara

    Full Text Available BACKGROUND: The consumption of berry fruits, including strawberries, has been suggested to have beneficial effects against oxidative stress mediated diseases. Berries contain multiple phenolic compounds and secondary metabolites that contribute to their biological properties. METHODOLOGY/PRINCIPAL FINDINGS: Current study investigates the anticancer activity of the methanolic extract of strawberry (MESB fruits in leukaemia (CEM and breast cancer (T47D cell lines ex vivo, and its cancer therapeutic and chemopreventive potential in mice models. Results of MTT, trypan blue and LDH assays suggested that MESB can induce cytotoxicity in cancer cells, irrespective of origin, in a concentration- and time-dependent manner. Treatment of mice bearing breast adenocarcinoma with MESB blocked the proliferation of tumor cells in a time-dependent manner and resulted in extended life span. Histological and immunohistochemical studies suggest that MESB treatment affected tumor cell proliferation by activating apoptosis and did not result in any side effects. Finally, we show that MESB can induce intrinsic pathway of apoptosis by activating p73 in breast cancer cells, when tumor suppressor gene p53 is mutated. CONCLUSIONS/SIGNIFICANCE: The present study reveals that strawberry fruits possess both cancer preventive and therapeutic values and we discuss the mechanism by which it is achieved.

  13. Cordycepin-enriched Cordyceps militaris induces immunomodulation and tumor growth delay in mouse-derived breast cancer.

    Science.gov (United States)

    Jeong, Min-Ho; Lee, Chang-Min; Lee, Sang-Wha; Seo, Su-Yeong; Seo, Min-Jeong; Kang, Byoung-Won; Jeong, Yong-Kee; Choi, Yoo-Jin; Yang, Kwang-Mo; Jo, Wol-Soon

    2013-10-01

    Cordyceps militaris (C. militaris) and its main functional component, cordycepin, has been shown to possess a number of pharmacological activities including immunological stimulation and antitumor effects. However, the pharmacological mechanisms of C. militaris on tumor immunity underlying its antitumor effect have yet to be elucidated. In the present study, we evaluated the antitumor and immunomodulatory effects of C. militaris on FM3A tumor-bearing C3H/He mice, comparing wild-type C. militaris and cordycepin-enriched C. militaris (JLM 0636). The concentration of cordycepin produced by crossbred JLM 0636 was 7.42 mg/g dry weight, which was 7-fold higher than that of wild-type C. militaris. Dietary administration of C. militaris revealed retardation of tumor growth as well as elongation of survival rates of tumor-bearing mice. This effect was more pronounced in JLM 0636. There was a cordycepin-dependent decrease in IL-2 and TGF-β secretion and an increase in IL-4 secretion without changes in the proliferative responses of concanavalin A-stimulated lymphocytes, which suggested that C. militaris feeding might induce changes in the subpopulations of tumor-derived T lymphocytes. CD4+CD25+ cell population was significantly reduced in the total splenocytes from JLM 0636-administered mice, while CD4+ T cell population remained unchanged. FoxP3+-expressing Treg cells among CD4+CD25+ population showed a similar pattern. On the contrary, CD8+ T cells as well as the IFN-γ expressing CD8+ T cells from tumor-bearing mice were significantly upregulated by the administration of JLM 0636. These results demonstrated the suppressive role of JLM 0636 on the function of Treg cells contributing to tumor specific IFN-γ-expressing CD8+ T cell responses in tumor-bearing mice, which explained the underlying mechanism of the antitumor immunity of cordycepin. Therefore, cordycepin-enriched C. militaris is a promising candidate for an adjuvant in cancer immunotherapy. PMID:23921598

  14. Tumor necrosis factor-α attenuates starvation-induced apoptosis through upregulation of ferritin heavy chain in hepatocellular carcinoma cells

    International Nuclear Information System (INIS)

    Tumor microenviroment is characteristic of inflammation, ischemia and starvation of nutrient. TNF-α, which is an extraordinarily pleiotropic cytokine, could be an endogenous tumor promoter in some tumor types. The basic objective of this study was to investigate the effects of TNF-α on the cell viability and apoptosis of hepatocellular carcinoma cells under serum starvation, and to identify the molecular mechanisms involved. For this purpose, five different concentrations of TNF-α and two different serum settings (serum-cultured and serum-deprived) were used to investigate the effects of TNF-α on the cell viability and apoptosis of Hep3B and SMMC-7721 cells. TNF-α (10 ng/ml) attenuated serum starvation-induced apoptosis of hepatocellular carcinoma cells, and autophagy conferred this process. BAY11-7082, a specific inhibitor of NF-κB, reversed the suppression of serum starvation-induced apoptosis by TNF-α. Moreover, TNF-α-induced NF-κB transactivation was suppressed by autophagy inhibitor 3-MA. In addition, TNF-α up-regulated Ferritin heavy chain (FHC) transiently by NF-κB activation and FHC levels were correlated with the TNF-α-induced protection against serum starvation-mediated apoptosis of hepatocellular carcinoma cells. Furthermore, FHC-mediated inhibition of apoptosis depended on suppressing ROS accumulation. Our findings suggested that autophagy conferred the TNF-α protection against serum starvation-mediated apoptosis of hepatocellular carcinoma cells, the mechanism involved with the activation of the TNF-α/ NF-κB /FHC signaling pathway

  15. The Hypoxia-Inducible Epigenetic Regulators Jmjd1a and G9a Provide a Mechanistic Link between Angiogenesis and Tumor Growth

    OpenAIRE

    Ueda, J.; Ho, J. C.; Lee, K. L.; Kitajima, S.; Yang, H.(Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, China; Department of Modern Physics, University of Science and Technology of China, Anhui, China; Department of Physics, Nanjing University, Jiangsu, China; School of Physics, Shandong University, Shandong, China; Department of Physics and Astronomy, Shanghai Key Laboratory for Particle Physics and Cosmology, Shanghai Jiao Tong University, Shanghai, China; Physics Department, Tsinghua University, 100084, Beijing, China); Sun, W; Fukuhara, N.; Zaiden, N.; Chan, S. L.; Tachibana, M.; Shinkai, Y; Kato, H.; Poellinger, L

    2014-01-01

    Hypoxia promotes stem cell maintenance and tumor progression, but it remains unclear how it regulates long-term adaptation toward these processes. We reveal a striking downregulation of the hypoxia-inducible histone H3 lysine 9 (H3K9) demethylase JMJD1A as a hallmark of clinical human germ cell-derived tumors, such as seminomas, yolk sac tumors, and embryonal carcinomas. Jmjd1a was not essential for stem cell self-renewal but played a crucial role as a tumor suppressor in opposition to the hy...

  16. An Inducible Lentiviral Guide RNA Platform Enables the Identification of Tumor-Essential Genes and Tumor-Promoting Mutations In Vivo

    Directory of Open Access Journals (Sweden)

    Brandon J. Aubrey

    2015-03-01

    Full Text Available The CRISPR/Cas9 technology enables the introduction of genomic alterations into almost any organism; however, systems for efficient and inducible gene modification have been lacking, especially for deletion of essential genes. Here, we describe a drug-inducible small guide RNA (sgRNA vector system allowing for ubiquitous and efficient gene deletion in murine and human cells. This system mediates the efficient, temporally controlled deletion of MCL-1, both in vitro and in vivo, in human Burkitt lymphoma cell lines that require this anti-apoptotic BCL-2 protein for sustained survival and growth. Unexpectedly, repeated induction of the same sgRNA generated similar inactivating mutations in the human Mcl-1 gene due to low mutation variability exerted by the accompanying non-homologous end-joining (NHEJ process. Finally, we were able to generate hematopoietic cell compartment-restricted Trp53-knockout mice, leading to the identification of cancer-promoting mutants of this critical tumor suppressor.

  17. Decrease in radio-sensitivity of the tumor by radiation-induced damage to immuno-related cells

    Energy Technology Data Exchange (ETDEWEB)

    Makidono, Reiko

    1987-08-01

    Immunological competence plays an important role in response of patients to radiation therapy and dose of radiation required for tumor control depends also on the immunocompetence of the individual patient. Radiation therapy (even localized irradiation) can, however, cause lymphopenia and induce an immunodeficient state. This may facilitate growth of residual tumor cells or metastatic foci, this negating benefits of the therapy. A brief overview of damage to T and B lymphocytes as well as macrophages and natural killer (NK) cells by radiation therapy was presented. The restoration and potentiation of the immunological competence of the patients by biological response modifiers (BRM) such as OK432 (a bacterial preparation), recombinant interferon (rIFN-..gamma..) and recombinant interleukin-2 (rIL-2) with or without lymphokine activated killer (LAK) cells, were discussed. (author) 61 refs.

  18. Histogenesis of lung tumors induced in rats by inhalation of α emitters. An overview

    International Nuclear Information System (INIS)

    Recent reviews have shown that simular risks coefficients for α irradiation of the lung in man could be deduced using epidemiological or experimental data in animals. Most experimental data were obtained in rats. In this overview the histogenesis and ultrastructure of lung tumors are presented. Only few tumors originating from lung parenchyma could be considered as non relevant for extrapolation to man. Most tumors arose from axial bronchus or bronchioles and their histogenesis was very similar to what is known in man. The only striking difference between the two species was related to the growth characteristics of the tumors. Tumors in rat, frequently papillary, acquired only slowly their full malignancy. They seem to be only potentially malignant. Two main types of tumors were considered: bronchogenic (B) and bronchiolo alveolar (b.a.) carcinomas. Survivals of the cancerous rats were log normal distribution in a given group of dose and were supposed to reflect latent period. No difference was found between B and b.a. carcinomas; geometric standard deviation did not increase when doses decrease. Since risk coefficients were found to increase when dose decreased, and through latent period fitted well with a power function of dose within the dose range studied, it is observed that the latent period can not be deduced by extrapolation at low doses. b.a. carcinomas prevailed at low doses; the relevance of this observation to man is however dubious since combined action with environmental carcinogens led to a high prevalence of B. carcinomas. Though genetic and immune surveillance are factors of some importance in the determination of the tumors it is suggested that critical individuals will be mostly multi-exposed individuals

  19. The Cell Death Inhibitor ARC Is Induced in a Tissue-Specific Manner by Deletion of the Tumor Suppressor Gene Men1, but Not Required for Tumor Development and Growth.

    Directory of Open Access Journals (Sweden)

    Wendy M McKimpson

    Full Text Available Multiple endocrine neoplasia type 1 (MEN1 is a genetic disorder characterized by tissue-specific tumors in the endocrine pancreas, parathyroid, and pituitary glands. Although tumor development in these tissues is dependent upon genetic inactivation of the tumor suppressor Men1, loss of both alleles of this gene is not sufficient to induce these cancers. Men1 encodes menin, a nuclear protein that influences transcription. A previous ChIP on chip analysis suggested that menin binds promoter sequences of nol3, encoding ARC, which is a cell death inhibitor that has been implicated in cancer pathogenesis. We hypothesized that ARC functions as a co-factor with Men1 loss to induce the tissue-restricted distribution of tumors seen in MEN1. Using mouse models that recapitulate this syndrome, we found that biallelic deletion of Men1 results in selective induction of ARC expression in tissues that develop tumors. Specifically, loss of Men1 in all cells of the pancreas resulted in marked increases in ARC mRNA and protein in the endocrine, but not exocrine, pancreas. Similarly, ARC expression increased in the parathyroid with inactivation of Men1 in that tissue. To test if ARC contributes to MEN1 tumor development in the endocrine pancreas, we generated mice that lacked none, one, or both copies of ARC in the context of Men1 deletion. Studies in a cohort of 126 mice demonstrated that, although mice lacking Men1 developed insulinomas as expected, elimination of ARC in this context did not significantly alter tumor load. Cellular rates of proliferation and death in these tumors were also not perturbed in the absence of ARC. These results indicate that ARC is upregulated by loss Men1 in the tissue-restricted distribution of MEN1 tumors, but that ARC is not required for tumor development in this syndrome.

  20. Triphala inhibits both in vitro and in vivo xenograft growth of pancreatic tumor cells by inducing apoptosis

    International Nuclear Information System (INIS)

    Triphala is commonly used in Ayurvedic medicine to treat variety of diseases; however its mechanism of action remains unexplored. This study elucidates the molecular mechanism of Triphala against human pancreatic cancer in the cellular and in vivo model. Growth-inhibitory effects of Triphala were evaluated in Capan-2, BxPC-3 and HPDE-6 cells by Sulphoradamine-B assay. Apoptosis was determined by cell death assay and western blotting. Triphala was administered orally to nude mice implanted with Capan-2 xenograft. Tumors were analyzed by immunohistochemistry and western blotting. Exposure of Capan-2 cells to the aqueous extract of Triphala for 24 h resulted in the significant decrease in the survival of cells in a dose-dependent manner with an IC50 of about 50 μg/ml. Triphala-mediated reduced cell survival correlated with induction of apoptosis, which was associated with reactive oxygen species (ROS) generation. Triphala-induced apoptosis was linked with phosphorylation of p53 at Ser-15 and ERK at Thr-202/Tyr-204 in Capan-2 cells. Above mentioned effects were significantly blocked when the cells were pretreated with an antioxidant N-acetylcysteine (NAC), suggesting the involvement of ROS generation. Pretreatment of cells with pifithrin-α or U0126, specific inhibitors of p53 or MEK-1/2, significantly attenuated Triphala-induced apoptosis. Moreover, NAC or U0126 pretreatment significantly attenuated Triphala-induced p53 transcriptional activity. Similarly, Triphala induced apoptosis in another pancreatic cancer cell line BxPC-3 by activating ERK. On the other hand, Triphala failed to induce apoptosis or activate ERK or p53 in normal human pancreatic ductal epithelial (HPDE-6) cells. Further, oral administration of 50 mg/kg or 100 mg/kg Triphala in PBS, 5 days/week significantly suppressed the growth of Capan-2 pancreatic tumor-xenograft. Reduced tumor-growth in Triphala fed mice was due to increased apoptosis in the tumors cells, which was associated with increased

  1. Deoxynivalenol induced mouse skin tumor initiation: Elucidation of molecular mechanisms in human HaCaT keratinocytes.

    Science.gov (United States)

    Mishra, Sakshi; Tewari, Prachi; Chaudhari, Bhushan P; Dwivedi, Premendra D; Pandey, Haushila P; Das, Mukul

    2016-11-01

    Among food contaminants, mycotoxins are toxic to both human and animal health. Our prior studies suggest that Deoxynivalenol (DON), a mycotoxin, behaves as a tumor promoter by inducing edema, hyperplasia, ODC activity and activation of MAPK's in mouse skin. In this study, topical application of DON, 336 and 672 nmol significantly enhanced ROS levels, DNA damage and apoptosis with concomitant downregulation of Ki-67, cyclin D, cyclin E, cyclin A and cyclin-dependent kinases (CDK4 and CDK2) thereby resulting in tumor initiation in mouse skin. Further, the elucidation of molecular mechanisms of tumor initiation by DON (0.42-3.37 nmol/ml) in HaCaT keratinocytes, revealed (i) enhanced ROS generation with cell cycle phase arrest in G0/G1 phase, (ii) increase in levels of 8-OxoG (6-24 hr) and γH2AX protein, (iii) significant enhancement in oxidative stress marker enzymes LPO, GSH, GR with concomitant decrease in antioxidant enzymes catalase, GPx, GST, SOD and mitochondrial membrane potential after DON (1.68 nmol) treatment, (iv) suppression of Nrf2 translocation to nucleus, enhanced phosphorylation with subsequent activation ERK1/2, p38 and JNK MAPK's following DON (1.68 nmol) treatment, (v) overexpression of c-jun, c-fos proteins, upregulation of Bax along with downregulation of Bcl-2 proteins, (vi) increase in cytochrome-c, caspase-9, caspase-3 and poly ADP ribose polymerase levels leads to apoptosis. Pretreatment of superoxide dismutase, mannitol and ethanol to HaCaT cells resulted in significant reduction in ROS levels and apoptosis indicating the role of superoxide and hydroxyl radicals in DON induced apoptosis as an early event and skin tumor initiation as a late event. PMID:27389473

  2. Role of cysteinyl leukotriene receptor-1 antagonists in treatment of experimentally induced mammary tumor: does montelukast modulate antitumor and immunosuppressant effects of doxorubicin?

    Science.gov (United States)

    El-Sisi, Alaa El-Din E; Sokar, Samia S; Salem, Tarek A; Abu Risha, Sally E

    2015-11-01

    It has been reported that a leukotriene (LT)-D4 receptor (i.e. cysteinyl LT1 receptor; CysLT1R) has an important role in carcinogenesis. The current study was carried out to assess the possible antitumor effects of montelukast (MON), a CysLT1R antagonist, in a mouse mammary carcinoma model, that is, a solid Ehrlich carcinoma (SEC). Effects of MON on tumor-induced immune dysfunction and the possibility that MON may modulate the antitumor and immunomodulatory effects of doxorubicin (DOX) were also studied. The effects in tumor-bearing hosts of several dosings with MON (10 mg/kg, per os), with and without the added presence of DOX (2 mg/kg, intraperitoneal), were investigated in vivo; end points evaluated included assessment of tumor volume, splenic lymphocyte profiles/functionality, tumor necrosis factor-α content, as well as apoptosis and expression of nuclear factor-κB (NF-κB) among the tumor cells. The data indicate that MON induced significant antitumor activity against the SEC. MON treatments also significantly mitigated both tumor- and DOX-induced declines in immune parameters assessed here. Moreover, MON led to decreased NF-κB nuclear expression and, in doing so, appeared to chemosensitize these tumor cells to DOX-induced apoptosis. PMID:26499992

  3. Tumor Infiltrating Lymphocytes Genetically Engineered with an Inducible Gene Encoding Interleukin-12 for the Immunotherapy of Metastatic Melanoma

    Science.gov (United States)

    Zhang, Ling; Morgan, Richard A.; D.Beane, Joal; Zheng, Zhili; Dudley, Mark E.; Kassim, Sadik H.; Nahvi, Azam V.; Ngo, Lien T.; Sherry, Richard M.; Phan, Giao Q.; Hughes, Marybeth S.; Kammula, Udai S.; Feldman, Steven A.; Toomey, Mary Ann; Kerkar, Sid. P.; Restifo, Nicholas P.; Yang, James C.; Rosenberg, Steven A.

    2015-01-01

    Purpose Infusion of interleukin-12 (IL-12) can mediate anti-tumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the anti-tumor activity of adoptively transferred human tumor infiltrating lymphocytes (TIL) genetically engineered to secrete single-chain IL-12 selectively at the tumor site. Experimental design Thirty-three patients with metastatic melanoma were treated in a cell-dose escalation trial of autologous TIL transduced with a gene encoding a single chain IL-12 driven by a nuclear factor of activated T cells promoter (NFAT.IL12). No IL-2 was administered. Results The administration of 0.001-0.1 X 109 NFAT.IL12 transduced TIL to 17 patients resulted in a single objective response (5.9%). However, at doses between 0.3-3 X 109 cells, 10 of 16 patients (63%) exhibited objective clinical responses. The responses tended to be short and the administered IL-12 producing cells rarely persisted at one month. Increasing cell doses were associated with high serum levels of IL-12 and gamma-interferon as well as clinical toxicities including liver dysfunction, high fevers and sporadic life threatening hemodynamic instability. Conclusions In this first-in-man trial, administration of TIL transduced with an inducible IL-12 gene mediated tumor responses in the absence of IL-2 administration using cell doses 10-100 fold lower than conventional TIL. However, due to toxicities, likely attributable to the secreted IL-12, further refinement will be necessary before this approach can be safely utilized in the treatment of cancer patients. PMID:25695689

  4. CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth.

    Science.gov (United States)

    Mathsyaraja, H; Thies, K; Taffany, D A; Deighan, C; Liu, T; Yu, L; Fernandez, S A; Shapiro, C; Otero, J; Timmers, C; Lustberg, M B; Chalmers, J; Leone, G; Ostrowski, M C

    2015-07-01

    Metastasis of solid tumors is associated with poor prognosis and bleak survival rates. Tumor-infiltrating myeloid cells (TIMs) are known to promote metastasis, but the mechanisms underlying their collaboration with tumor cells remain unknown. Here, we report an oncogenic role for microRNA (miR) in driving M2 reprogramming in TIMs, characterized by the acquisition of pro-tumor and pro-angiogenic properties. The expression of miR-21, miR-29a, miR-142-3p and miR-223 increased in myeloid cells during tumor progression in mouse models of breast cancer and melanoma metastasis. Further, we show that these miRs are regulated by the CSF1-ETS2 pathway in macrophages. A loss-of-function approach utilizing selective depletion of the miR-processing enzyme Dicer in mature myeloid cells blocks angiogenesis and metastatic tumor growth. Ectopic expression of miR-21 and miR-29a promotes angiogenesis and tumor cell proliferation through the downregulation of anti-angiogenic genes such as Col4a2, Spry1 and Timp3, whereas knockdown of the miRs impedes these processes. miR-21 and miR-29a are expressed in Csf1r+ myeloid cells associated with human metastatic breast cancer, and levels of these miRs in CD115+ non-classical monocytes correlates with metastatic tumor burden in patients. Taken together, our results suggest that miR-21 and miR-29a are essential for the pro-tumor functions of myeloid cells and the CSF1-ETS2 pathway upstream of the miRs serves as an attractive therapeutic target for the inhibition of M2 remodeling of macrophages during malignancy. In addition, miR-21 and miR-29a in circulating myeloid cells may potentially serve as biomarkers to measure therapeutic efficacy of targeted therapies for CSF1 signaling. PMID:25241894

  5. Astrocytes Upregulate Survival Genes in Tumor Cells and Induce Protection from Chemotherapy

    Directory of Open Access Journals (Sweden)

    Sun-Jin Kim

    2011-03-01

    Full Text Available In the United States, more than 40% of cancer patients develop brain metastasis. The median survival for untreated patients is 1 to 2 months, which may be extended to 6 months with conventional radiotherapy and chemotherapy. The growth and survival of metastasis depend on the interaction of tumor cells with host factors in the organ microenvironment. Brain metastases are surrounded and infiltrated by activated astrocytes and are highly resistant to chemotherapy. We report here that coculture of human breast cancer cells or lung cancer cells with murine astrocytes (but not murine fibroblasts led to the up-regulation of survival genes, including GSTA5, BCL2L1, and TWIST1, in the tumor cells. The degree of up-regulation directly correlated with increased resistance to all tested chemotherapeutic agents. We further show that the up-regulation of the survival genes and consequent resistance are dependent on the direct contact between the astrocytes and tumor cells through gap junctions and are therefore transient. Knocking down these genes with specific small interfering RNA rendered the tumor cells sensitive to chemotherapeutic agents. These data clearly demonstrate that host cells in the microenvironment influence the biologic behavior of tumor cells and reinforce the contention that the organ microenvironment must be taken into consideration during the design of therapy.

  6. Spontaneous squamous cell carcinoma induced by the somatic inactivation of retinoblastoma and Trp53 tumor suppressors.

    Science.gov (United States)

    Martínez-Cruz, Ana Belén; Santos, Mirentxu; Lara, M Fernanda; Segrelles, Carmen; Ruiz, Sergio; Moral, Marta; Lorz, Corina; García-Escudero, Ramón; Paramio, Jesús M

    2008-02-01

    Squamous cell carcinomas (SCC) represent the most aggressive type of nonmelanoma skin cancer. Although little is known about the causal alterations of SCCs, in organ-transplanted patients the E7 and E6 oncogenes of human papillomavirus, targeting the p53- and pRb-dependent pathways, have been widely involved. Here, we report the functional consequences of the simultaneous elimination of Trp53 and retinoblastoma (Rb) genes in epidermis using Cre-loxP system. Loss of p53, but not pRb, produces spontaneous tumor development, indicating that p53 is the predominant tumor suppressor acting in mouse epidermis. Although the simultaneous inactivation of pRb and p53 does not aggravate the phenotype observed in Rb-deficient epidermis in terms of proliferation and/or differentiation, spontaneous SCC development is severely accelerated in doubly deficient mice. The tumors are aggressive and undifferentiated and display a hair follicle origin. Detailed analysis indicates that the acceleration is mediated by premature activation of the epidermal growth factor receptor/Akt pathway, resulting in increased proliferation in normal and dysplastic hair follicles and augmented tumor angiogenesis. The molecular characteristics of this model provide valuable tools to understand epidermal tumor formation and may ultimately contribute to the development of therapies for the treatment of aggressive squamous cancer. PMID:18245467

  7. Thermal dosimetry studies of ultrasonically induced hyperthermia in normal dog brain and in experimental brain tumors

    International Nuclear Information System (INIS)

    In a series of 16 acute experiments on pentobarbital anesthetized dogs, thermal distributions generated by ultrasonic heating using a 1 MHz PZT transducer were compared with intensity distributions mapped in a test tank. Relatively flat distributions from 1 to 3 cm have been mapped in normal dog brain using ''shaped'' intensity distributions generated from ultrasonic emission patterns which are formed by the interaction between compressional, transverse and flexural modes activated within the crystal. In contrast, these same intensity distributions generated marked temperature variations in 3 malignant brain tumors presumably due to variations in tumor blood flow. The results of this study suggest that a practical clinical system for uniform heating of large tumor volumes with varying volumes and geometries is not an achievable goal. The author's laboratory is developing a scanning ultrasonic rapid hyperthermia treatment system which will be able to sequentially heat small volume of tumor tissue either to temperatures which will sterilize tumor or to a more conventional thermal dose. Time-temperature studies of threshold for thermal damage in normal dog brain are currently in progress

  8. Repression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL but not its receptors during oral cancer progression

    Directory of Open Access Journals (Sweden)

    Muller Susan

    2007-06-01

    Full Text Available Abstract Background TRAIL plays an important role in host immunosurveillance against tumor progression, as it induces apoptosis of tumor cells but not normal cells, and thus has great therapeutic potential for cancer treatment. TRAIL binds to two cell-death-inducing (DR4 and DR5 and two decoy (DcR1, and DcR2 receptors. Here, we compare the expression levels of TRAIL and its receptors in normal oral mucosa (NOM, oral premalignancies (OPM, and primary and metastatic oral squamous cell carcinomas (OSCC in order to characterize the changes in their expression patterns during OSCC initiation and progression. Methods DNA microarray, immunoblotting and immunohistochemical analyses were used to examine the expression levels of TRAIL and its receptors in oral epithelial cell lines and in archival tissues of NOM, OPM, primary and metastatic OSCC. Apoptotic rates of tumor cells and tumor-infiltrating lymphocytes (TIL in OSCC specimens were determined by cleaved caspase 3 immunohistochemistry. Results Normal oral epithelia constitutively expressed TRAIL, but expression was progressively lost in OPM and OSCC. Reduction in DcR2 expression levels was noted frequently in OPM and OSCC compared to respective patient-matched uninvolved oral mucosa. OSCC frequently expressed DR4, DR5 and DcR1 but less frequently DcR2. Expression levels of DR4, DR5 and DcR1 receptors were not significantly altered in OPM, primary OSCC and metastatic OSCC compared to patient-matched normal oral mucosa. Expression of proapoptotic TRAIL-receptors DR4 and DR5 in OSCC seemed to depend, at least in part, on whether or not these receptors were expressed in their parental oral epithelia. High DR5 expression in primary OSCC correlated significantly with larger tumor size. There was no significant association between TRAIL-R expression and OSSC histology grade, nodal status or apoptosis rates of tumor cells and TIL. Conclusion Loss of TRAIL expression is an early event during oral

  9. Repression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but not its receptors during oral cancer progression

    International Nuclear Information System (INIS)

    TRAIL plays an important role in host immunosurveillance against tumor progression, as it induces apoptosis of tumor cells but not normal cells, and thus has great therapeutic potential for cancer treatment. TRAIL binds to two cell-death-inducing (DR4 and DR5) and two decoy (DcR1, and DcR2) receptors. Here, we compare the expression levels of TRAIL and its receptors in normal oral mucosa (NOM), oral premalignancies (OPM), and primary and metastatic oral squamous cell carcinomas (OSCC) in order to characterize the changes in their expression patterns during OSCC initiation and progression. DNA microarray, immunoblotting and immunohistochemical analyses were used to examine the expression levels of TRAIL and its receptors in oral epithelial cell lines and in archival tissues of NOM, OPM, primary and metastatic OSCC. Apoptotic rates of tumor cells and tumor-infiltrating lymphocytes (TIL) in OSCC specimens were determined by cleaved caspase 3 immunohistochemistry. Normal oral epithelia constitutively expressed TRAIL, but expression was progressively lost in OPM and OSCC. Reduction in DcR2 expression levels was noted frequently in OPM and OSCC compared to respective patient-matched uninvolved oral mucosa. OSCC frequently expressed DR4, DR5 and DcR1 but less frequently DcR2. Expression levels of DR4, DR5 and DcR1 receptors were not significantly altered in OPM, primary OSCC and metastatic OSCC compared to patient-matched normal oral mucosa. Expression of proapoptotic TRAIL-receptors DR4 and DR5 in OSCC seemed to depend, at least in part, on whether or not these receptors were expressed in their parental oral epithelia. High DR5 expression in primary OSCC correlated significantly with larger tumor size. There was no significant association between TRAIL-R expression and OSSC histology grade, nodal status or apoptosis rates of tumor cells and TIL. Loss of TRAIL expression is an early event during oral carcinogenesis and may be involved in dysregulation of apoptosis and

  10. Squalene Selectively Protects Mouse Bone Marrow Progenitors Against Cisplatin and Carboplatin-Induced Cytotoxicity In Vivo Without Protecting Tumor Growth

    Directory of Open Access Journals (Sweden)

    Bikul Das

    2008-10-01

    Full Text Available Squalene, an isoprenoid antioxidant is a potential cytoprotective agent against chemotherapy-induced toxicity. We have previously published that squalene protects light-density bone marrow cells against cis-diamminedichloroplatinum( II (cisplatin-induced toxicity without protecting tumor cells in vitro. Here, we developed an in vivo mouse model of cisplatin and cis-diammine (cyclobutane-1,1-dicarboxylato platinum(II (carboplatin-induced toxicity to further investigate squalene-mediated LD-BM cytoprotection including the molecular mechanism behind selective cytoprotection. We found that squalene significantly reduced the body weight loss of cisplatin and carboplatin-treated mice. Light-density bone marrow cells from squalene-treated mice exhibited improved formation of hematopoietic colonies (colony-forming unit-granulocyte macrophage. Furthermore, squalene also protected mesenchymal stem cell colonies (colony-forming unit-fibroblast from cisplatin and carboplatin-induced toxicity. Squalene-induced protection was associated with decreased reactive oxygen species and increased levels of glutathione and glutathione peroxidase/glutathione-S-transferase. Importantly, squalene did not protect neuroblastoma, small cell carcinoma, or medulloblastoma xenografts against cisplatin-induced toxicity. These results suggest that squalene is a potential candidate for future development as a cytoprotective agent against chemotherapeutic toxicity.

  11. Ga-68 DOTATOC PET/CT-Guided Biopsy and Cryoablation with Autoradiography of Biopsy Specimen for Treatment of Tumor-Induced Osteomalacia.

    Science.gov (United States)

    Maybody, Majid; Grewal, Ravinder K; Healey, John H; Antonescu, Cristina R; Fanchon, Louise; Hwang, Sinchun; Carrasquillo, Jorge A; Kirov, Assen; Farooki, Azeez

    2016-09-01

    Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by small benign tumors of mesenchymal origin also known as phosphaturic mesenchymal tumors mixed connective tissue variant. Excellent prognosis is expected with eradication of the culprit tumor. These small tumors are notoriously difficult to localize with conventional imaging studies; this often leads to an extensive work up and prolonged morbidity. We report a patient with clinical diagnosis of TIO whose culprit tumor was localized with Ga-68 DOTATOC PET/CT and MRI. Biopsy and cryoablation were performed under Ga-68 DOTATOC PET/CT guidance. Autoradiography of the biopsy specimen was performed and showed in situ correlation between Ga-68 DOTATOC uptake and histopathology with millimeter resolution. PMID:27150801

  12. High-fat-diet-induced obesity causes an inflammatory and tumor-promoting microenvironment in the rat kidney

    Directory of Open Access Journals (Sweden)

    Kerstin Stemmer

    2012-09-01

    Obesity and concomitant comorbidities have emerged as public health problems of the first order. For instance, obese individuals have an increased risk for kidney cancer. However, direct mechanisms linking obesity with kidney cancer remain elusive. We hypothesized that diet-induced obesity (DIO promotes renal carcinogenesis by inducing an inflammatory and tumor-promoting microenvironment. We compared chow-fed lean Wistar rats with those that were sensitive (DIOsens or partially resistant (DIOres to DIO to investigate the impact of body adiposity versus dietary nutrient overload in the development of renal preneoplasia and activation of tumor-promoting signaling pathways. Our data clearly show a correlation between body adiposity, the severity of nephropathy, and the total number and incidence of preneoplastic renal lesions. However, similar plasma triglyceride, plasma free fatty acid and renal triglyceride levels were found in chow-fed, DIOres and DIOsens rats, suggesting that lipotoxicity is not a critical contributor to the renal pathology. Obesity-related nephropathy was further associated with regenerative cell proliferation, monocyte infiltration and higher renal expression of monocyte chemotactic protein-1 (MCP-1, interleukin (IL-6, IL-6 receptor and leptin receptor. Accordingly, we observed increased signal transducer and activator of transcription 3 (STAT3 and mammalian target of rapamycin (mTOR phosphorylation in tubules with preneoplastic phenotypes. In summary, our results demonstrate that high body adiposity induces an inflammatory and proliferative microenvironment in rat kidneys that promotes the development of preneoplastic lesions, potentially via activation of the STAT3 and mTOR signaling pathways.

  13. Tumor Necrosis Factor-related Apoptosis Ligand Induces Apoptosis in Prostate Cancer PC-3M Cell Line

    Institute of Scientific and Technical Information of China (English)

    CHEN Zhohui; WANG Huafang; GU Longjie; YE Zhewei; XIAO Yajun

    2005-01-01

    To study the effect of tumor necrosis factor-related apoptosis inducing ligand (TRAIL)on PC-3M cell line, PC-3M cell line was incubated with gradient concentrations of TRAIL for 4-24h. Annixin-Ⅴ fluorescence staining and TUNEL method were employed to detect the apoptosis of PC-3M cells. The morphology of apoptotic PC-3M cells was observed by electron microscopy. The relationship between TRAIL concentrations and the percentage of apoptotic cells was evaluated by flow cytometry. The proliferation inhibitory ratio was calculated by using MTT colorimetry. Our results showed that apoptosis of PC-3M cells could be induced by treatment with TRAIL for at most 4 h. The results of flow cytometry and MTT colorimetry demonstrated a time- and concentration-dependent relationship between cell apoptosis rate and TRAIL concentration. It is concluded that apoptosis of PC-3M cells can be induced by TRAIL. Because of the selective killing effect of TRAIL on tumor ceils, it may become a potential alternative for the treatment of advanced prostate cancer.

  14. Dietary proanthocyanidins inhibit UV radiation-induced skin tumor development through functional activation of the immune system.

    Science.gov (United States)

    Katiyar, Santosh K

    2016-06-01

    The incidence of skin cancer is equivalent to the incidence of malignancies in all other organs combined. The main risk factor for this disease is overexposure of the skin to solar ultraviolet (UV) radiation. UV irradiation induces inflammation, oxidative stress, DNA damage, and suppression of the immune system in the skin, which together contribute to carcinogenesis. The use of dietary phytochemicals shows great promise as a complementary and alternative strategy for skin cancer prevention. Grape seed proanthocyanidins (GSPs) have been tested extensively for their anti-skin cancer effect using in vivo animal models. Supplementation of an AIN76A control diet with GSPs (0.2 and 0.5%, w/w) significantly inhibits UV radiation-induced skin tumor development as well as malignant transformation of papillomas to carcinoma in mice. The inhibition of UVB-induced skin tumor development by GSPs is mediated through interrelated mechanisms of action including: (i) inhibition of inflammation, (ii) rapid repair of damaged DNA, and (iii) stimulation of immune system. Additionally, the chemopreventive effects of GSPs involve DNA repair-dependent functional activation of antigen-presenting cells and stimulation of CD8(+) effector T cells. These effects of GSPs could be useful in attenuation of the adverse effects of UV radiation and may have health benefits in humans. PMID:26991736

  15. Glutathione regulation of redox-sensitive signals in tumor necrosis factor-α-induced vascular endothelial dysfunction

    International Nuclear Information System (INIS)

    We investigated the regulatory role of glutathione in tumor necrosis factor-alpha (TNF-α)-induced vascular endothelial dysfunction as evaluated by using vascular endothelial adhesion molecule expression and monocyte-endothelial monolayer binding. Since TNF-α induces various biological effects on vascular cells, TNF-α dosage could be a determinant factor directing vascular cells into different biological fates. Based on the adhesion molecule expression patterns responding to different TNF-α concentrations, we adopted the lower TNF-α (0.2 ng/ml) to rule out the possible involvement of other TNF-α-induced biological effects. Inhibition of glutathione synthesis by L-buthionine-(S,R)-sulfoximine (BSO) resulted in down-regulations of the TNF-α-induced adhesion molecule expression and monocyte-endothelial monolayer binding. BSO attenuated the TNF-α-induced nuclear factor-kappaB (NF-κB) activation, however, with no detectable effect on AP-1 and its related mitogen-activated protein kinases (MAPKs). Deletion of an AP-1 binding site in intercellular adhesion molecule-1 (ICAM-1) promoter totally abolished its constitutive promoter activity and its responsiveness to TNF-α. Inhibition of ERK, JNK, or NF-κB attenuates TNF-α-induced ICAM-1 promoter activation and monocyte-endothelial monolayer binding. Our study indicates that TNF-α induces adhesion molecule expression and monocyte-endothelial monolayer binding mainly via activation of NF-κB in a glutathione-sensitive manner. We also demonstrated that intracellular glutathione does not modulate the activation of MAPKs and/or their downstream AP-1 induced by lower TNF-α. Although AP-1 activation by the lower TNF-α was not detected in our systems, we could not rule out the possible involvement of transiently activated MAPKs/AP-1 in the regulation of TNF-α-induced adhesion molecule expression

  16. A case of radiation-induced mucoepidermoid carcinoma of the lung following radiotherapy for pulmonary metastasis of Wilms' tumor

    Energy Technology Data Exchange (ETDEWEB)

    Kubota, Susumu; Kimura, Makoto; Inatsuki, Shinichi; Ohgushi, Ikuyo (National Shikoku Cancer Center, Matsuyama (Japan)); Hamamoto, Ken

    1990-11-01

    Radiotherapy is one of the main therapeutic methods for malignant tumors, but on the other hand it can also induce new malignant tumors. Recently, we experienced a case of a 22-year-old woman with triple cancers (Wilms' tumor, thyroid cancer and mucoepidermoid carcinoma of the lung). She had been treated repeatedly for right-sided pulmonary metastases from the Wilms' tumor. The last cancer arose from a different organ in the field irradiated to treat the first cancer, after a latent period of about 20 years. Therefore, this case is classified as highly probable radiation-induced cancer (A-I group) by the diagnostic criteria for radiation-induced cancer proposed by Sakai et al. Second cancers (radiation-induced cancers) mainly consist of soft tissue sarcomas, leukemias, skin cancers, urinary bladder cancers, large bowel cancers and other tumors. The occurrence of mucoepidermoid carcinoma of the lung as a radiation-induced tumor had not been reported. This patient also showed poor growth of the right breast and marked deformity of the right side of the thorax as late damage from irradiation. We must make efforts to decrease late damage from radiotherapy for pediatric cancers. (author).

  17. Intake of high-fat diet stimulates the risk of ultraviolet radiation-induced skin tumors and malignant progression of papillomas to carcinoma in SKH-1 hairless mice

    Energy Technology Data Exchange (ETDEWEB)

    Vaid, Mudit; Singh, Tripti; Prasad, Ram [Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Katiyar, Santosh K., E-mail: skatiyar@uab.edu [Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Birmingham Veterans Affairs Medical Center, Birmingham, AL 35294 (United States)

    2014-01-01

    Previously, we showed that administration of a high-fat diet (HF-diet) to C57BL/6 mice exacerbates their response to short-term UVB radiation-induced inflammation in the skin. To explore the effects of an HF-diet on UVB-induced tumorigenesis, we have used the SKH-1 hairless mouse model in which the mice are exposed to UVB radiation (180 mJ/cm{sup 2}) three times a week for 24 weeks. The development of UVB-induced skin tumors was rapid and the tumor multiplicity and tumor size were significantly higher (P < 0.01–0.005) in the mice fed an HF-diet than the mice fed a control-diet (C-diet). Moreover, the malignant progression of UVB-induced papillomas to carcinomas was higher in HF-diet-fed mice. On analysis of tumors and tumor-uninvolved skin samples from the tumor-bearing mice, we found that administration of an HF-diet significantly enhanced the levels of UVB-induced expression of cyclooxygenase-2 (COX-2), prostaglandin E{sub 2} (P < 0.01), and PGE{sub 2} receptors, and activation of NF-κB in the UVB-exposed skin as well as in tumors. In addition the HF-diet enhanced the expression of proinflammatory cytokines, including tumor necrosis factor-α (P < 0.01), interleukin (IL)-1β (P < 0.01) and IL-6 (P < 0.05) in the UVB-exposed skin as well as in tumors. Western blot analysis revealed that HF-diet enhanced the levels of epidermal cell proliferation, phosphatidylinositol 3-kinase and phosphorylation of Akt at Ser{sup 473} in UVB-exposed skin and skin tumors. Collectively, these data demonstrate that the regular consumption of an HF-diet increases the risk of photocarcinogenesis in mice and that this is associated with enhanced expression of inflammatory mediators in the UVB-exposed skin and tumors. - Highlights: • Consumption of high-fat diet increases UVB-induced skin tumor development in mice. • Intake of high-fat diet stimulates progression of UV-induced papilloma to carcinoma. • Intake of high-fat diet enhances inflammation in UV-exposed skin • Regular

  18. Occurrence of mutations in the epidermal growth factor receptor gene in X-ray-induced rat lung tumors

    International Nuclear Information System (INIS)

    Epidermal growth factor receptor (EGFR) gene alterations have been found in human lung cancers. However, there is no information on the factors inducing EGFR mutations. In rodents, K-ras mutations are frequently found in many lung carcinogenesis models, but hitherto, Egfr mutations have not been reported. Their presence was therefore investigated in representative lung carcinogenesis models with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosobis(2-hydroxypropyl)amine (BHP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MelQx) and ethyl carbamate (urethane), as well as X-ray irradiation. With the chemical carcinogenesis models, no mutations were detected in Egfr, which is in clear contrast to the high rates observed in either codon 12 or 61 of K-ras (21/23 of the lung tumors induced with NNK, 4/5 with MelQx, 1/4 with urethane and 7/18 with BHP). However, in the X-ray-induced lung tumors, Egfr mutations with amino acid substitution were observed in exons 18 and 21 (4/12, 33%), but no activating mutation of K-ras was detected. In addition, one and four silent mutations were identified in K-ras (exon 1) and Egfr (exons 18, 20 and 21), respectively. Most mutations in both Egfr and K-ras were G/C→A/T transitions (7/8, 88% and 31/34, 91%, respectively). Although, the mutational patterns in equivalent human lesions were not completely coincident, this first report of Egfr mutations in an experimental lung tumor model suggests that X-rays or other factors producing oxygen radicals could cause EGFR mutations in some proportion of lung cancers in humans. (author)

  19. Oncogene amplification detected by in situ hybridization in radiation induced rat skin tumors. [C-myc:a3

    Energy Technology Data Exchange (ETDEWEB)

    Yi Jin.

    1991-02-01

    Oncogene activation may play an important role in radiation induced carcinogenesis. C-myc oncogene amplification was detected by in situ hybridization in radiation-induced rat skin tumors, including squamous and basal cell carcinomas. In situ hybridization was performed with a biotinylated human c-myc third exon probe, visualized with an avidin-biotinylated alkaline phosphate detection system. No c-myc oncogene amplification was detected in normal rat skin at very early times after exposure to ionizing radiation, which is consistent with the view that c-myc amplification is more likely to be related to carcinogenesis than to normal cell proliferation. The incorporation of tritiated thymidine into the DNA of rat skin cells showed that the proliferation of epidermal cells reached a peak on the seventh day after exposure to ionizing radiation and then decreased. No connection between the proliferation of epidermal cell and c-myc oncogene amplification in normal or irradiated rat skin was found. The results indicated that c-myc amplification as measured by in situ hybridization was correlated with the Southern bolt results, but only some of the cancer cells were amplified. The c-myc positive cells were distributed randomly within regions of the tumor and exhibited a more uniform nuclear structure in comparison to the more vacuolated c-myc negative cells. No c-myc signal was detected in unirradiated normal skin or in irradiated skin cells near the tumors. C-myc amplification appears to be cell or cell cycle specific within radiation-induced carcinomas. 28 refs., 3 figs., 3 tabs.

  20. Heart tumors specifically induced in young avian embryos by the v-myc oncogene.

    OpenAIRE

    Saule, S; Mérigaud, J P; Al-Moustafa, A E; Ferré, F; Rong, P M; Amouyel, P; Quatannens, B; Stéhelin, D; Dieterlen-Lièvre, F

    1987-01-01

    To determine if expression of the v-myc oncogene had any effect during ontogeny, we injected avian myelocytomatosis virus strain MC29 into avian embryos at various stages of development. The injection of MC29 at embryonic day 2 (E2) or 3 (E3) caused, about 10 days later, rhabdomyosarcomas of the heart and, in some cases, skin muscle hypertrophy. When the injection was performed at E4 or E5, the number of heart tumors declined, whereas the number of skin muscle tumors increased significantly. ...

  1. STAT3 as a target for inducing apoptosis in solid and hematological tumors

    Institute of Scientific and Technical Information of China (English)

    Khandaker Al Zaid Siddiquee; James Turkson

    2008-01-01

    Studies in the past few years have provided compelling evidence for the critical role of aberrant Signal Transducer and Activator of Transcription 3 (STAT3) in malignant transformation and tumorigenesis. Thus, it is now generally accepted that STAT3 is one of the critical players in human cancer formation and represents a valid target for novel anticancer drug design. This review focuses on aberrant STAT3 and its role in promoting tumor cell survival and supporting the malignant phenotype. A brief evaluation of the current strategies targeting STAT3 for the development of novel anticancer agents against human tumors harboring constitutively active STAT3 will also be presented.

  2. Two modes of c-myb activation in virus-induced mouse myeloid tumors.

    OpenAIRE

    1986-01-01

    Two modes of disruption of the protooncogene c-myb by viral insertional mutagenesis in mouse myeloid tumor cells are described. The first mode was found in six tumors in which a Moloney murine leukemia virus component had inserted in the same transcriptional orientation upstream of the 5'-most exon with v-myb homology (vE1). cDNA sequence data indicate the presence of a truncated c-myb mRNA that is initiated in the upstream 5' long terminal repeat of the integrated provirus and processed via ...

  3. Modification of the Tumor Microenvironment in KRAS or c-MYC-Induced Ovarian Cancer-Associated Peritonitis

    Science.gov (United States)

    Kawana, Kei; Adachi, Katsuyuki; Kawata, Akira; Ogishima, Juri; Nakamura, Hiroe; Fujimoto, Asaha; Sato, Masakazu; Inoue, Tomoko; Nishida, Haruka; Furuya, Hitomi; Tomio, Kensuke; Arimoto, Takahide; Koga, Kaori; Wada-Hiraike, Osamu; Oda, Katsutoshi; Nagamatsu, Takeshi; Kiyono, Tohru; Osuga, Yutaka; Fujii, Tomoyuki

    2016-01-01

    The most common properties of oncogenes are cell proliferation and the prevention of apoptosis in malignant cells, which, as a consequence, induce tumor formation and dissemination. However, the effects of oncogenes on the tumor microenvironment (TME) have not yet been examined in detail. The accumulation of ascites accompanied by chronic inflammation and elevated concentrations of VEGF is a hallmark of the progression of ovarian cancer. We herein demonstrated the mechanisms by which oncogenes contribute to modulating the ovarian cancer microenvironment. c-MYC and KRAS were transduced into the mouse ovarian cancer cell line ID8. ID8, ID8-c-MYC, or ID8-KRAS cells were then injected into the peritoneal cavities of C57/BL6 mice and the production of ascites was assessed. ID8-c-MYC and ID8-KRAS both markedly accelerated ovarian cancer progression in vivo, whereas no significant differences were observed in proliferative activity in vitro. ID8-KRAS in particular induced the production of ascites, which accumulated between approximately two to three weeks after the injection, more rapidly than ID8 and ID8-c-MYC (between nine and ten weeks and between six and seven weeks, respectively). VEGF concentrations in ascites significantly increased in c-MYC-induced ovarian cancer, whereas the concentrations of inflammatory cytokines in ascites were significantly high in KRAS-induced ovarian cancer and were accompanied by an increased number of neutrophils in ascites. A cytokine array revealed that KRAS markedly induced the expression of granulocyte macrophage colony-stimulating factor (GM-CSF) in ID8 cells. These results suggest that oncogenes promote cancer progression by modulating the TME in favor of cancer progression. PMID:27483433

  4. alpha-Galactosylceramide can act as a nasal vaccine adjuvant inducing protective immune responses against viral infection and tumor.

    Science.gov (United States)

    Ko, Sung-Youl; Ko, Hyun-Jeong; Chang, Woo-Sung; Park, Se-Ho; Kweon, Mi-Na; Kang, Chang-Yuil

    2005-09-01

    alpha-Galactosylceramide (alpha-GalCer) is a ligand of invariant Valpha14+ NKT cells and is presented by CD1d molecule on APC. NKT cells produce a large amount of Th1 and Th2 cytokines in response to alpha-GalCer-presented APC. In this study, we assessed whether alpha-GalCer could act as an effective nasal vaccine adjuvant for mucosal vaccine that would be capable of inducing systemic as well as mucosal immune responses. When alpha-GalCer was administered with OVA via the intranasal route to C57BL/6 and BALB/c mice, significant OVA-specific mucosal secretory IgA, systemic IgG, and CTL responses were induced with mixed Th1 and Th2 cytokine profiles seen in both strains of mice. Interestingly, as BALB/c mice were intranasally immunized with PR8 hemagglutinin Ag isolated from influenza virus A/PR/8/34 together with alpha-GalCer, significant protection was afforded against influenza viral infection. When alpha-GalCer was coimmunized with a replication-deficient live adenovirus to BALB/c mice, it significantly induced both humoral and cellular immune responses. In addition, intranasal administration of OVA with alpha-GalCer showed complete protection against EG7 tumor challenge in C57BL/6. The adjuvant effects induced by intranasal coadministration with alpha-GalCer were blocked in CD1d-/- mice, indicating that the immune responses were exclusively mediated by CD1d molecule on APC. Most interestingly, intranasally coadministered alpha-GalCer activated naive T cells and triggered them to differentiate into functional effector T cells when CFSE-labeled OT-1 cells were adoptively transferred into syngeneic mice. Overall, our results are the first to show that alpha-GalCer can act as a nasal vaccine adjuvant inducing protective immune responses against viral infections and tumors. PMID:16116223

  5. Pathomorphology of laser-induced interstitial tumor thermotherapy for the liver; Pathomorphologie der Laser-induzierten interstitiellen Tumor-Thermotherapie an der Leber

    Energy Technology Data Exchange (ETDEWEB)

    Filler, T.J.; Peuker, E.T. [Inst. fuer Anatomie, Univ. Muenster (Germany); Bremer, C. [Center for Molecular Imaging Research, Massachusetts General Hospital, Boston, MA (United States); Bankert, J.; Kreft, G. [Inst. fuer klinische Radiologie, Univ. Muenster (Germany); Reimer, P. [Zentralinst. fuer Bildgebende Diagnostik, Staedtisches Klinikum Karlsruhe (Germany)

    2001-02-01

    The aim of this study was to analyse pathomorphological findings after treatment with laser induced tumor thermotherapy (LITT) on liver tissue and to correlate the results with magnetic resonance imaging. LITT was performed ex vivo and in vivo using a Neodym-YAG-Laser. Lesions were monitored by MR-thermometry ex vivo and by contrast-enhanced MRI in vivo. After LITT the lesions were examined macroscopically, histologically and electronmicrosopically. LITT-induced tissue damage was qualitatively evaluated, classified, and quantified by means of digital image analysis. Four different zones of tissue damage were identified within the lesions. Adjacent to the applicator the tissue was completely ablated while more peripheral lesions exhibited only sublethal cell damages seen by EM. In vivo the pattern of tissue injury followed the lobular architecture of the liver tissue. Ultrastructural examination revealed only in areas of minor tissue injury intact sinusoidal patterns. MRI overestimated the diameter of the core zone of complete tissue ablation both ex vivo and to a lesser extent in vivo. (orig.) [German] Ziel der Untersuchungen war die Darstellung pathomorphologischer Befunde nach LITT (Laser-induzierte interstitielle Tumor-Thermotherapie) an Lebergewebe und deren Korrelate in der Kernspintomographie. Die LITT wurde ex- und in vivo unter Verwendung eines Neodym-YAG-Lasers durchgefuehrt. Die LITT-bedingten Laesionen wurden ex vivo mittels kontinuierlichem MR-Thermomonitoring und in vivo mittels KM-MRT untersucht. Nach Beendigung mit LITT wurden die Praeparate vermessen und histologisch sowie elektronenmikroskopisch untersucht. Die Veraenderungen wurden qualitativ erfasst, klassifiziert und mittels digitaler Bildanalyse quantifiziert. Die Laesionen konnten in 4 Schaedigungszonen eingeteilt werden. Zentral fand sich eine komplette Ablation, in der Uebergangszone ultrastrukturell fassbare subletale Zellschaedigungen. In vivo hielt sich die Ausdehnung an die lobulaere

  6. Serological relationship of tumor necrosis factor-inducing exoantigens of Plasmodium falciparum and Plasmodium vivax.

    OpenAIRE

    Bate, C A; Taverne, J.; N.D. Karunaweera; Mendis, K N; D. Kwiatkowski(Institute of Applied Informatics, University of Technology, Cracow Poland); Playfair, J H

    1992-01-01

    Exoantigens of Plasmodium vivax-parasitized erythrocytes stimulated macrophages to secrete tumor necrosis factor, and antisera raised against the exoantigens inhibited this secretion. The antisera also inhibited the activity of Plasmodium falciparum and Plasmodium yoelii exoantigens, and conversely, antisera against the latter cross-reacted with the exoantigens of P. vivax.

  7. Interleukin-8 and Tumor Necrosis Factor Alpha Production in Human Epidermal Keratinocytes Induced by Trichophyton mentagrophytes

    OpenAIRE

    Nakamura, Yuka; KANO, Rui; Hasegawa, Atsuhiko; Watanabe, Shinichi

    2002-01-01

    Production of interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α) was confirmed by enzyme-linked immunosorbent assay in a medium where human epidermal keratinocytes were cocultured with Trichophyton mentagrophytes for 1 to 12 h. IL-8 and TNF-α mRNAs were also detected in the keratinocytes cocultured with T. mentagrophytes.

  8. First report of Spirocerca sp. in Denmark – a tumor-inducing parasite in carnivores

    DEFF Research Database (Denmark)

    Al-Sabi, Mohammad Nafi Solaiman; Hansen, Mette Sif; Larsen, Gitte;

    2014-01-01

    During routine health surveillance of wild carnivores in Denmark, several tumors, measuring up to 3.0 x 4.5 x 2.5 cm, were detected in the stomach and the omentum of an autopsied red fox (Vulpes vulpes). The fox was hunted in the Hanstholm Nature Reserve, which is 230 km from the closest mainland...

  9. Deletion of tumor progression locus 2 attenuates alcohol induced hepatic inflammation

    Science.gov (United States)

    BACKGROUND: The pathogenesis of alcoholic liver disease (ALD) involves the interaction of several inflammatory signaling pathways. Tumor progression locus 2 (TPL2), also known as Cancer Osaka Thyroid (COT) and MAP3K8, is a serine threonine kinase that functions as a critical regulator of inflammator...

  10. The antiinflammatory drug sulfasalazine inhibits tumor necrosis factor alpha expression in macrophages by inducing apoptosis

    NARCIS (Netherlands)

    Rodenburg, R.J.T.; Ganga, A.; Lent, P.L.E.M. van; Putte, L.B.A. van de; Venrooij, W.J. van

    2000-01-01

    Objective. Sulfasalazine (SSZ) is a commonly used drug in the treatment of inflammatory diseases such as rheumatoid arthritis and Crohn's disease. In both diseases, the proinflammatory cytokine tumor necrosis factor α (TNFα) plays a prominent role. In these studies, we investigated the mechanism by

  11. Mo polyoxometalate nanoparticles inhibit tumor growth and vascular endothelial growth factor induced angiogenesis

    International Nuclear Information System (INIS)

    Tumor growth depends on angiogenesis, which can furnish the oxygen and nutrients that proliferate tumor cells. Thus, blocking angiogenesis can be an effective strategy to inhibit tumor growth. In this work, three typical nanoparticles based on polyoxometalates (POMs) have been prepared; we investigated their capability as antitumor and anti-angiogenesis agents. We found that Mo POM nanoparticles, especially complex 3, inhibited the growth of human hepatocellular liver carcinoma cells (HepG2) through cellular reactive oxygen species levels’ elevation and mitochondrial membrane potential damage. Complex 3 also suppressed the proliferation, migration, and tube formation of endothelial cells in vitro and chicken chorioallantoic membrane development ex vivo. Furthermore, western blot analysis of cell signaling molecules indicated that Mo POMs blocked the vascular endothelial growth factor receptor 2-mediated ERK1/2 and AKT signaling pathways in endothelial cells. Using transmission electron microscopy, we demonstrated their cellular uptake and localization within the cytoplasm of HepG2 cells. These results indicate that, owing to the extraordinary physical and chemical properties, Mo POM nanoparticles can significantly inhibit tumor growth and angiogenesis, which makes them potential drug candidates in anticancer and anti-angiogenesis therapies. (paper)

  12. Mo polyoxometalate nanoparticles inhibit tumor growth and vascular endothelial growth factor induced angiogenesis

    Science.gov (United States)

    Zheng, Wenjing; Yang, Licong; Liu, Ying; Qin, Xiuying; Zhou, Yanhui; Zhou, Yunshan; Liu, Jie

    2014-06-01

    Tumor growth depends on angiogenesis, which can furnish the oxygen and nutrients that proliferate tumor cells. Thus, blocking angiogenesis can be an effective strategy to inhibit tumor growth. In this work, three typical nanoparticles based on polyoxometalates (POMs) have been prepared; we investigated their capability as antitumor and anti-angiogenesis agents. We found that Mo POM nanoparticles, especially complex 3, inhibited the growth of human hepatocellular liver carcinoma cells (HepG2) through cellular reactive oxygen species levels’ elevation and mitochondrial membrane potential damage. Complex 3 also suppressed the proliferation, migration, and tube formation of endothelial cells in vitro and chicken chorioallantoic membrane development ex vivo. Furthermore, western blot analysis of cell signaling molecules indicated that Mo POMs blocked the vascular endothelial growth factor receptor 2-mediated ERK1/2 and AKT signaling pathways in endothelial cells. Using transmission electron microscopy, we demonstrated their cellular uptake and localization within the cytoplasm of HepG2 cells. These results indicate that, owing to the extraordinary physical and chemical properties, Mo POM nanoparticles can significantly inhibit tumor growth and angiogenesis, which makes them potential drug candidates in anticancer and anti-angiogenesis therapies.

  13. Acute phase response induced following tumor treatment by photodynamic therapy: relevance for the therapy outcome

    Science.gov (United States)

    Korbelik, Mladen; Merchant, Soroush; Stott, Brandon; Cecic, Ivana; Payne, Peter; Sun, Jinghai

    2006-02-01

    Acute phase response is an effector process orchestrated by the innate immune system for the optimal mobilization of the resources of the organism distant from the local insult site needed in the execution of a host-protecting reaction. Our research has shown that mice bearing tumors treated by photodynamic therapy (PDT) exhibit the three major hallmarks of acute phase response: release of acute phase reactants, neutrophilia, and pituitary/adrenal axis activation. Of particular interest in this study were acute phase proteins that have a pivotal role in the clearance of dead cells, since the occurrence of this process in PDT-treated tumors emerges as a critical event in the course of PDT-associated host response. It is shown that this type of acute phase reactants, including complement proteins (C3, C5, C9, mannose-binding lectin, and ficolin A) and related pentraxins (serum amyloid P component and PTX3), are upregulated following tumor PDT and accumulate in the targeted lesions. Based on the recently accumulated experimental evidence it is definitely established that the acute phase response is manifested in the hosts bearing PDT-treated tumors and it is becoming clear that this effector process is an important element of PDT-associated host response bearing in impact on the eventual outcome of this therapy.

  14. Ultrastructure of auxin-induced tumors of the coleorhiza-epiblast of wheat. [Indolacetic acid

    Energy Technology Data Exchange (ETDEWEB)

    Walne, P.L. (Univ. of Tennessee, Knoxville); Haber, A.H.; Triplett, L.L.

    1975-01-01

    When wheat is germinated in high concentrations of certain auxins, the coleorhiza-epiblast grows in an excessive and disorganized manner and resembles a callus. Wheat was germinated in 10/sup -3/ M indoleacetic acid or in water. There was greater net synthesis of DNA, RNA, and protein in the tumor tissue than in control tissue. Control and tumor tissue was fixed for electron microscopy 1, 2, 3, and 4 days after sowing. In contrast to the controls, many more lipoidal bodies appeared in 1-day-old, auxin-treated tissue and thereafter diminished in number. In 2- and 3-day-old tumor tissue, small membraneous fragments were prominent but disappeared in older tissue. With time, the following changes became progressively more pronounced: cytoplasmic vacuolation, appearance of myelin figures, polyribosome configurations and extensive profiles of rough endoplasmic reticulum, and sloughing of cytoplasmic contents into and accumulation of electron-dense material in vacuoles. Possible factors in susceptibility of certain tissues to tumor formation are discussed.

  15. Analysis of radiation-induced small intestinal tumors in APCMin/+mice

    International Nuclear Information System (INIS)

    Effect of radiation on intestinal tumorigenesis was studied using APCMin/+ mouse, a hetero-knockout strain with highly tumorigenic sensitivity due to the lack of tumor suppressing adenomatous polyposis coli (APC) gene (the causing gene of human familial polyposis) (Min: multiple intestinal neoplasia). Offspring crossed by male APCMin/+ and female wild type c57BL/6N mice were used for experiments. Those offspring at the age of 2 weeks were irradiated by 2 Gy of 60Co-gamma ray at 1.22 Gy/min with the irradiator RE-1082 and were maintained thereafter for 9 and 19 weeks, when they were sacrificed for physical, hematological and histological examinations. No significant radiation-related changes were observed in wild type mice. In comparison with non-irradiated APCMin/+ mice, followings were observed with significance in irradiated animals: the peripheral hemoglobin value was decreased; spleen weight was increased; number of tumors present in small intestine increased to 2-fold; and a colorectal tumor as big as >2 mm diameter was observed in one mouse. Thus radiation promoted the intestinal tumor formation in APCMin/+ mice. (T.T.)

  16. Mesenchymal Stem Cells Promote Pancreatic Tumor Growth by Inducing Alternative Polarization of Macrophages

    Directory of Open Access Journals (Sweden)

    Esha Mathew

    2016-03-01

    Significance: Targeting the stroma is emerging as a new paradigm in pancreatic cancer; however, efforts to that effect are hampered by our limited understanding of the nature and function of stromal components. Here, we uncover previously unappreciated heterogeneity within the stroma and identify interactions among stromal components that promote tumor growth and could be targeted therapeutically.

  17. Delay-induced state transition and resonance in periodically driven tumor model with immune surveillance

    Science.gov (United States)

    Yang, Tao; Han, Qinglin; Zeng, Chunhua; Wang, Hua; Fu, Yunchang; Zhang, Chun

    2014-06-01

    The phenomenon of stochastic resonance (SR) in a tumor growth model under the presence of immune surveillance is investigated. Time delay and cross-correlation between multiplicative and additive noises are considered in the system. The signal-to-noise ratio (SNR) is calculated when periodic signal is introduced multiplicatively. Our results show that: (i) the time delay can accelerate the transition from the state of stable tumor to that of extinction, however the correlation between two noises can accelerate the transition from the state of extinction to that of stable tumor; (ii) the time delay and correlation between two noises can lead to a transition between SR and double SR in the curve of SNR as a function of additive noise intensity, however for the curve of SNR as a function of multiplicative noise intensity, the time delay can cause the SR phenomenon to disappear, and the cross-correlation between two noises can lead to a transition from SR to stochastic reverse-resonance. Finally, we compare the SR phenomenon for the multiplicative periodic signal with that for additive periodic signal in the tumor growth model with immune surveillance.

  18. Bleomycin-Induced Flagellate Erythema in a Patient Diagnosed with Ovarian Yolk Sac Tumor.

    Science.gov (United States)

    Boussios, Stergios; Moschetta, Michele; McLachlan, Jennifer; Banerjee, Susana

    2015-01-01

    Flagellate linear hyperpigmentation can rarely be caused by the chemotherapy agent, bleomycin. Herein, we describe the case of a 20-year-old woman treated with bleomycin for an ovarian yolk sac tumor and review the prominent features of this form of dermatitis. PMID:26798532

  19. Bleomycin-Induced Flagellate Erythema in a Patient Diagnosed with Ovarian Yolk Sac Tumor

    OpenAIRE

    Stergios Boussios; Michele Moschetta; Jennifer McLachlan; Susana Banerjee

    2015-01-01

    Flagellate linear hyperpigmentation can rarely be caused by the chemotherapy agent, bleomycin. Herein, we describe the case of a 20-year-old woman treated with bleomycin for an ovarian yolk sac tumor and review the prominent features of this form of dermatitis.

  20. Bleomycin-Induced Flagellate Erythema in a Patient Diagnosed with Ovarian Yolk Sac Tumor

    Directory of Open Access Journals (Sweden)

    Stergios Boussios

    2015-01-01

    Full Text Available Flagellate linear hyperpigmentation can rarely be caused by the chemotherapy agent, bleomycin. Herein, we describe the case of a 20-year-old woman treated with bleomycin for an ovarian yolk sac tumor and review the prominent features of this form of dermatitis.

  1. Proapoptotic RYBP interacts with FANK1 and induces tumor cell apoptosis through the AP-1 signaling pathway.

    Science.gov (United States)

    Ma, Wen; Zhang, Xuan; Li, Meng; Ma, Xiaoli; Huang, Bingren; Chen, Hong; Chen, Deng

    2016-08-01

    Ring1 and YY1 Binding Protein (RYBP) induces tumor-specific cell apoptosis, but the underlying molecular mechanism has not been fully understood. Here we conducted a yeast two hybrid screen and identified FANK1 (Fibronectin type III and ankyrin repeat domains 1) as a novel RYBP-interacting protein. This interaction was confirmed by coimmunoprecipitation, GST pulldown and immunofluorescence assays. We mapped that the FNIII domain at the N-terminal of FANK1 binds to the Serine/Threonine-rich region at the C-terminal of RYBP. Further studies showed that overexpression of RYBP stabilized, whereas knockdown of RYBP by its specific shRNAs reduced, the expression of FANK1. Mechanistic studies revealed that RYBP inhibited the proteasome degradation of polyubiquitinated FANK1, thus prolonging the half-life of FANK1 protein. Functional studies indicated that RYBP activates FANK1-mediated activator protein 1 (AP-1) signaling pathway which contributes to tumor cell apoptosis. Taken together, our current study uncovered a new mechanism which RYBP utilizes to exert its pro-apoptotic activity in human tumor cells. PMID:27060496

  2. Targeting Hypoxia-Inducible Factor 1α in a New Orthotopic Model of Glioblastoma Recapitulating the Hypoxic Tumor Microenvironment.

    Science.gov (United States)

    Nigim, Fares; Cavanaugh, Jill; Patel, Anoop P; Curry, William T; Esaki, Shin-ichi; Kasper, Ekkehard M; Chi, Andrew S; Louis, David N; Martuza, Robert L; Rabkin, Samuel D; Wakimoto, Hiroaki

    2015-07-01

    Tissue hypoxia and necrosis represent pathophysiologic and histologic hallmarks of glioblastoma (GBM). Although hypoxia inducible factor 1α (HIF-1α) plays crucial roles in the malignant phenotypes of GBM, developing HIF-1α-targeted agents has been hampered by the lack of a suitable preclinical model that recapitulates the complex biology of clinical GBM. We present a new GBM model, MGG123, which was established from a recurrent human GBM. Orthotopic xenografting of stem-like MGG123 cells reproducibly generated lethal tumors that were characterized by foci of palisading necrosis, hypervascularity, and robust stem cell marker expression. Perinecrotic neoplastic cells distinctively express HIF-1α and are proliferative in both xenografts and the patient tissue. The xenografts contain scattered hypoxic foci that were consistently greater than 50 μm distant from blood vessels, indicating intratumoral heterogeneity of oxygenation. Hypoxia enhanced HIF-1α expression in cultured MGG123 cells, which was abrogated by the HIF-1α inhibitors digoxin or ouabain. In vivo, treatment of orthotopic MGG123 xenografts with digoxin decreased HIF-1α expression, vascular endothelial growth factor mRNA levels, and CD34-positive vasculature within the tumors, and extended survival of mice bearing the aggressive MGG123 GBM. This preclinical tumor model faithfully recapitulates the GBM-relevant hypoxic microenvironment and stemness and is a suitable platform for studying disease biology and developing hypoxia-targeted agents. PMID:26083570

  3. Constitutive active/androstane receptor, peroxisome proliferator-activated receptor α, and cytotoxicity are involved in oxadiazon-induced liver tumor development in mice.

    Science.gov (United States)

    Kuwata, Kazunori; Inoue, Kaoru; Ichimura, Ryohei; Takahashi, Miwa; Kodama, Yukio; Yoshida, Midori

    2016-02-01

    Oxadiazon (OX) is a protoporphyrinogen oxidase-inhibiting herbicide that induces porphyria and liver tumors in rodents. Although porphyria is generally considered to be a risk factor for liver tumor development, the mechanisms through which OX mediates tumor development are unclear. Therefore, in this study, we investigated the mechanisms of tumor development by focusing on constitutive active/androstane receptor (CAR), which is essential for the development of tumors in response to several chemicals. After 1, 4, or 13 weeks of dietary treatment with 1000 ppm OX, hepatic Cyp2b10 expression was induced in wild-type (WT) mice. However, this effect was blocked in CAR-knockout (CARKO) mice. Hepatic Cyp4a10 expression, indicative of peroxisome proliferator-activated receptor α (PPARα) activation, and cytotoxic changes in hepatocytes were also observed in both groups of mice. After initiation by diethylnitrosamine, 26-week treatment with OX resulted in an increase in proliferative lesions, including foci and adenomas, in both genotypes, and the incidence and multiplicity of proliferative lesions in CARKO mice were higher than those in control mice but lower than those in WT mice. These results suggested that CAR, PPARα activation, and cytotoxicity were involved in the development of liver tumors. Moreover, porphyrin was not apparently involved in OX-induced tumor development. PMID:26710982

  4. Enhanced tumor cell killing following BNCT with hyperosmotic mannitol-induced blood-brain barrier disruption and intracarotid injection of boronophenylalanine

    International Nuclear Information System (INIS)

    The delivery of boronophenylalanine (BPA) by means of intracarotid injection combined with opening the blood-brain barrier (BBB) have been shown significantly enhanced the tumor boron concentration and the survival time of glioma-bearing rats. However, no direct evidence demonstrates whether this treatment protocol can enhance the cell killing of tumor cells or infiltrating tumor cells and the magnitude of enhanced cell killing. The purpose of the present study was to determine if the tumor cell killing of boron neutron capture therapy could be enhanced by hyperosmotic mannitol-induced BBB disruption using BPA-Fr as the capture agent. F98 glioma-bearing rats were injected intravenously or intracarotidly with BPA at doses of 500 mg/kg body weight (b.w.) and with or without mannitol-induced hyperosmotic BBB disruption. The rats were irradiated with an epithermal neutron beam at the reactor of National Tsing-Hua University (THOR). After neutron beam irradiation, the rats were euthanized and the ipsilateral brains containing intracerebral F98 glioma were removed to perform in vivo/in vitro soft agar clonogenic assay. The results demonstrate BNCT with optimizing the delivery of BPA by means of intracarotid injection combined with opening the BBB by infusing a hyperosmotic solution of mannitol significantly enhanced the cell killing of tumor cells and infiltrating tumor cells, the tumor boron concentration and the boron ratio of tumor to normal brain tissues. (author)

  5. Activation of nuclear TR3 (NR4A1) by a diindolylmethane analog induces apoptosis and proapoptotic genes in pancreatic cancer cells and tumors

    OpenAIRE

    Yoon, Kyungsil; Lee, Syng-Ook; Cho, Sung-Dae; Kim, Kyounghyun; Khan, Shaheen; Safe, Stephen

    2011-01-01

    NR4A1 (Nur77, TR3) is overexpressed in pancreatic tumors and activation of TR3 by 1,1-bis(3′-indolyl)-1-(p-methoxyphenyl)methane (DIM-C-pPhOCH3) inhibits cell and tumor growth and induces apoptosis. Microarray analysis demonstrates that in L3.6pL pancreatic cancer cells DIM-C-pPhOCH3 induces genes associated with metabolism, homeostasis, signal transduction, transcription, stress, transport, immune responses, growth inhibition and apoptosis. Among the most highly induced growth inhibitory and...

  6. Laser-induced thermotherapy of lung metastases and primary lung tumors; Laserinduzierte Thermotherapie von Lungenmetastasen und primaeren Lungentumoren

    Energy Technology Data Exchange (ETDEWEB)

    Vogl, T.J. (Institut fuer Diagnostische und Interventionelle Radiologie, Klinikum der J.-W.-Goethe-Universitaet Frankfurt; Institut fuer Diagnostische und Interventionelle Radiologie, Klinikum der J.-W.-Goethe-Universitaet, Theodor-Stern-Kai 7, 60590, Frankfurt); Fieguth, H.G. (Klinik fuer Thorax-, Herz- und thorakale Gefaesschirurgie, Klinikum der J.-W.-Goethe-Universitaet Frankfurt); Eichler, K.; Straub, R.; Lehnert, T.; Zangos, S.; Mack, M. (Institut fuer Diagnostische und Interventionelle Radiologie, Klinikum der J.-W.-Goethe-Universitaet Frankfurt)

    2004-07-01

    We present laser-induced thermotherapy (LITT) of primary and secondary lung tumors analysing indications and technical concepts. Thirty patients with lung metastases of different primary tumors (n=24) as well as localized lung tumors (n=6) were prospectively treated in 41 sessions using laser-induced thermotherapy (LITT). An MR-compatible puncture system was used with direct puncture technique. The puncture was performed via CT guidance in care vision technique. Eight patients were thermoablated using MR tomographical monitoring, 22 patients using CT monitoring. Local therapy effects, tumor control rate, side effects, complications, and survival were evaluated. In 74% of cases (28/38 lesions) of 24 patients with lung metastases and in all cases of the 6 patients with lung carcinoma a complete local ablation could be achieved. The complication rate (pneumothorax) was 9,8%. One patient with bronchial carcinoma had to be thoracotomized and resected. 93% of the patients are still alive. Percutaneous LITT of lung tumors permits a complete ablation of lung metastases and lung carcinomas with a low complication rate. Indications for the procedure were defined for patients with no more than 5 metastases up to 3 cm in size. (orig.) [German] Wir stellen nachfolgend die Ergebnisse der laserinduzierten Thermotherapie (LITT) primaerer und sekundaerer Lungentumoren vor und analysieren die Indikationsstellung und die Interventionstechnik. Dreissig Patienten mit Lungenmetastasen unterschiedlicher Primaertumoren (n=24) sowie lokalisierten Bronchialkarzinomen (n=6) wurden prospektiv in 41 Sitzungen mittels MR-gesteuerter LITT therapiert. Zum Einsatz kam ein MR-kompatibles Punktionssystem in direkter Punktionstechnik; die Punktion erfolgte jeweils unter CT-Steuerung in Care-vision-Technik. Acht Patienten wurden mittels MR-tomographischem Monitoring thermoablatiert, 22 Patienten mittels CT-Monitoring. Evaluiert wurden die lokalen Therapieeffekte, Tumorkontrollrate, und die Frage von

  7. MRI of radiation-induced tumors of the head and neck in post-radiation nasopharyngeal carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Abrigo, Jill M.; King, Ann D.; Wong, Jeffrey K.T.; Ahuja, Anil T. [The Chinese University of Hong Kong, Prince of Wales Hospital, Department of Diagnostic Radiology and Organ Imaging, Faculty of Medicine, Hong Kong S.A.R. (China); Leung, Sing Fai [The Chinese University of Hong Kong, Prince of Wales Hospital, Department of Clinical Oncology, Faculty of Medicine, Hong Kong S.A.R. (China); Vlantis, Alexander C.; Tong, Michael C.F. [The Chinese University of Hong Kong, Prince of Wales Hospital, Department of Otolaryngology and Head and Neck Surgery, Faculty of Medicine, Hong Kong S.A.R. (China); Tse, Gary M.K. [The Chinese University of Hong Kong, Prince of Wales Hospital, Department of Anatomical and Cellular Pathology, Faculty of Medicine, Hong Kong S.A.R. (China)

    2009-05-15

    The aim of this study was to document the sites and MRI features of radiation-induced tumors (RITs) in the head and neck following treatment for nasopharyngeal carcinoma (NPC). The MRI examinations and clinical records of 20 patients with 21 RITs were reviewed retrospectively. RITs developed 3-30 years after radiotherapy and included eleven squamous cell carcinomas, six sarcomas, two neuroendocrine carcinomas, one mucoepidermoid carcinoma and one meningioma. RITs arose in the maxillary region (9), oro/hypopharynx and oral cavity (5), external auditory canal (4), nasopharynx and sphenoid sinus (2) and brain (1). Radiation-induced carcinoma and sarcoma had MRI features that were useful to distinguish them from recurrent NPC. To improve early detection of RITs, the check areas on an MRI of a patient with previous NPC treated by radiation should always include the maxillary region, tongue, and external auditory canal/temporal bone. (orig.)

  8. MRI of radiation-induced tumors of the head and neck in post-radiation nasopharyngeal carcinoma

    International Nuclear Information System (INIS)

    The aim of this study was to document the sites and MRI features of radiation-induced tumors (RITs) in the head and neck following treatment for nasopharyngeal carcinoma (NPC). The MRI examinations and clinical records of 20 patients with 21 RITs were reviewed retrospectively. RITs developed 3-30 years after radiotherapy and included eleven squamous cell carcinomas, six sarcomas, two neuroendocrine carcinomas, one mucoepidermoid carcinoma and one meningioma. RITs arose in the maxillary region (9), oro/hypopharynx and oral cavity (5), external auditory canal (4), nasopharynx and sphenoid sinus (2) and brain (1). Radiation-induced carcinoma and sarcoma had MRI features that were useful to distinguish them from recurrent NPC. To improve early detection of RITs, the check areas on an MRI of a patient with previous NPC treated by radiation should always include the maxillary region, tongue, and external auditory canal/temporal bone. (orig.)

  9. New Mechanism of Bone Cancer Pain: Tumor Tissue-Derived Endogenous Formaldehyde Induced Bone Cancer Pain via TRPV1 Activation.

    Science.gov (United States)

    Wan, You

    2016-01-01

    In recent years, our serial investigations focused on the role of cancer cells-derived endogenous formaldehyde in bone cancer pain. We found that cancer cells produced formaldehyde through demethylation process by serine hydroxymethyltransferase (SHMT1 and SHMT2) and lysine-specific histone demethylase 1 (LSD1). When the cancer cells metastasized into bone marrow, the elevated endogenous formaldehyde induced bone cancer pain through activation on the transient receptor potential vanilloid subfamily member 1 (TRPV1) in the peripheral nerve fibers. More interestingly, TRPV1 expressions in the peripheral fibers were upregulated by the local insulin-like growth factor I (IGF-I) produced by the activated osteoblasts. In conclusion, tumor tissue-derived endogenous formaldehyde induced bone cancer pain via TRPV1 activation. PMID:26900062

  10. Loss of Cdh1 and Trp53 in the uterus induces chronic inflammation with modification of tumor microenvironment.

    Science.gov (United States)

    Stodden, G R; Lindberg, M E; King, M L; Paquet, M; MacLean, J A; Mann, J L; DeMayo, F J; Lydon, J P; Hayashi, K

    2015-05-01

    Type II endometrial carcinomas (ECs) are estrogen independent, poorly differentiated tumors that behave in an aggressive manner. As TP53 mutation and CDH1 inactivation occur in 80% of human endometrial type II carcinomas, we hypothesized that mouse uteri lacking both Trp53 and Cdh1 would exhibit a phenotype indicative of neoplastic transformation. Mice with conditional ablation of Cdh1 and Trp53 (Cdh1(d/d)Trp53(d/d)) clearly demonstrate architectural features characteristic of type II ECs, including focal areas of papillary differentiation, protruding cytoplasm into the lumen (hobnailing) and severe nuclear atypia at 6 months of age. Further, Cdh1(d/d)Trp53(d/d) tumors in 12-month-old mice were highly aggressive, and metastasized to nearby and distant organs within the peritoneal cavity, such as abdominal lymph nodes, mesentery and peri-intestinal adipose tissues, demonstrating that tumorigenesis in this model proceeds through the universally recognized morphological intermediates associated with type II endometrial neoplasia. We also observed abundant cell proliferation and complex angiogenesis in the uteri of Cdh1(d/d)Trp53(d/d) mice. Our microarray analysis found that most of the genes differentially regulated in the uteri of Cdh1(d/d)Trp53(d/d) mice were involved in inflammatory responses. CD163 and Arg1, markers for tumor-associated macrophages, were also detected and increased in the uteri of Cdh1(d/d)Trp53(d/d) mice, suggesting that an inflammatory tumor microenvironment with immune cell recruitment is augmenting tumor development in Cdh1(d/d)Trp53(d/d) uteri. Further, inflammatory mediators secreted from CDH1-negative, TP53 mutant endometrial cancer cells induced normal macrophages to express inflammatory-related genes through activation of nuclear factor-κB signaling. These results indicate that absence of CDH1 and TP53 in endometrial cells initiates chronic inflammation, promotes tumor microenvironment development following the recruitment of macrophages

  11. Pharmacological inhibition of radiation induced in vitro tumor cell/endothelium cell interactions and in vivo metastasis processes

    International Nuclear Information System (INIS)

    Exposure of endothelial cells with ionizing radiation (IR) or treatment with inflammatory cytokines (e. g. TNFα) induces a Rho-GTPase and NF-κB dependent activation of the expression of various cell adhesion molecules, including E-selectin. E-selectin mediates the adhesion of tumor cells (TC) to endothelial cells and is probably involved in the extravasation step of circulating tumor cells. HMG-CoA reductase inhibitors (e. g. lovastatin) inhibit the function of Rho-GTPases and thus are anticipated to attenuate Rho-regulated cell-cell-adhesion as well. This study focuses on the influence of IR and TNFα on the expression of endothelial- and/or tumor cell-specific pro-adhesive factors and whether these effects are influenced by lovastatin. To this end, the effect of IR and TNFα on cell-cell-interactions between human colon carcinoma cells (HT29) and human umbilical vein endothelial cells (HUVEC) was investigated using an ELISA-based cell adhesion-assay. Moreover, the influence of pre-treatment with lovastatin and other types of inhibitors on HUVEC-HT29 adhesion was monitored. Additionally, we investigated the effect of lovastatin on mRNA expression level of different cell adhesion molecules, metastatic factors and DNA-repair genes upon radiation exposure by qRT-PCR. To scrutinize the in vivo relevance of the data obtained, we investigated the effect of total body irradiation (TBI) on the mRNA expression of pro-adhesive factors in BALB/c mice. To analyze tumor cell extravasation, tumor cells were injected into the lateral tail vein of immundeficient mice, followed by total body irradiation (TBI, 4 Gy). After four weeks a large increase of lung metastases was monitored, which could be blocked by preatreatment of the mice with lovastatin, the Rac1-specific small-molecule inhibitor NSC23766 as well as the sLex-mimetic glycyrrhizin. Summarizing, we provide evidence, that irradiation promotes upregulation of different cell adhesion molecules in vitro and stimulates

  12. Cell Free DNA of Tumor Origin Induces a 'Metastatic' Expression Profile in HT-29 Cancer Cell Line.

    Directory of Open Access Journals (Sweden)

    István Fűri

    Full Text Available Epithelial cells in malignant conditions release DNA into the extracellular compartment. Cell free DNA of tumor origin may act as a ligand of DNA sensing mechanisms and mediate changes in epithelial-stromal interactions.To evaluate and compare the potential autocrine and paracrine regulatory effect of normal and malignant epithelial cell-related DNA on TLR9 and STING mediated pathways in HT-29 human colorectal adenocarcinoma cells and normal fibroblasts.DNA isolated from normal and tumorous colonic epithelia of fresh frozen surgically removed tissue samples was used for 24 and 6 hour treatment of HT-29 colon carcinoma and HDF-α fibroblast cells. Whole genome mRNA expression analysis and qRT-PCR was performed for the elements/members of TLR9 signaling pathway. Immunocytochemistry was performed for epithelial markers (i.e. CK20 and E-cadherin, DNA methyltransferase 3a (DNMT3a and NFκB (for treated HDFα cells.Administration of tumor derived DNA on HT29 cells resulted in significant (p<0.05 mRNA level alteration in 118 genes (logFc≥1, p≤0.05, including overexpression of metallothionein genes (i.e. MT1H, MT1X, MT1P2, MT2A, metastasis-associated genes (i.e. TACSTD2, MACC1, MALAT1, tumor biomarker (CEACAM5, metabolic genes (i.e. INSIG1, LIPG, messenger molecule genes (i.e. DAPP, CREB3L2. Increased protein levels of CK20, E-cadherin, and DNMT3a was observed after tumor DNA treatment in HT-29 cells. Healthy DNA treatment affected mRNA expression of 613 genes (logFc≥1, p≤0.05, including increased expression of key adaptor molecules of TLR9 pathway (e.g. MYD88, IRAK2, NFκB, IL8, IL-1β, STING pathway (ADAR, IRF7, CXCL10, CASP1 and the FGF2 gene.DNA from tumorous colon epithelium, but not from the normal epithelial cells acts as a pro-metastatic factor to HT-29 cells through the overexpression of pro-metastatic genes through TLR9/MYD88 independent pathway. In contrast, DNA derived from healthy colonic epithelium induced TLR9 and STING signaling

  13. p53-related apoptosis resistance and tumor suppression activity in UVB-induced premature senescent human skin fibroblasts.

    Science.gov (United States)

    Chen, Wenqi; Kang, Jian; Xia, Jiping; Li, Yanhua; Yang, Bo; Chen, Bin; Sun, Weiling; Song, Xiuzu; Xiang, Wenzhong; Wang, Xiaoyong; Wang, Fei; Wan, Yinsheng; Bi, Zhigang

    2008-05-01

    Chronic exposure to solar UV irradiation leads to photoaging, immunosuppression, and ultimately carcinogenesis. Cellular senescence is thought to play an important role in tumor suppression and apoptosis resistance. However, the relationships among stress-induced premature senescence (SIPS), tumorigenesis and apoptosis induced by UVB remain unknown. We developed a model of UVB-induced premature senescence in human skin fibroblasts (HSFs). After five repeated subcytotoxic UVB exposures at a dose of 10 mJ/cm2, the following biomarkers of senescence were markedly present: senescence-associated beta-galactosidase (SA beta-gal) activity, growth arrest, and the overexpression of senescence-associated genes. Firstly, there was an increase in the proportion of cells positive for SA beta-gal activity. Secondly, there was a loss of replicative potential as assessed by MTT assay. FACS analysis showed that UVB-stressed HSFs were blocked mostly in the G1 phase of the cell cycle, and replicative senescence, and protein expression of p53, p21(WAF-1) and p16(INK-4a) increased significantly. Thirdly, the mRNA levels of three senescence-associated genes, fibronectin, osteonectin and SM22, also increased. A real time PCR array to investigate the mRNA expression of p53-related genes involved in growth arrest, apoptosis and tumorigenesis indicated that p53, p21, p19, Hdm2, and Bax were up-regulated, and bcl, HIF-1alpha and VEGF were down-regulated. Collectively, our data suggest that UVB-induced SIPS plays an important role in p53-related apoptosis resistance and tumor suppression activity. PMID:18425358

  14. Cisplatin-induced renal toxicity via tumor necrosis factor-α, interleukin 6, tumor suppressor P53, DNA damage, xanthine oxidase, histological changes, oxidative stress and nitric oxide in rats: protective effect of ginseng.

    Science.gov (United States)

    Yousef, Mokhtar I; Hussien, Hend M

    2015-04-01

    Cisplatin is an effective chemotherapeutic agent successfully used in the treatment of a wide range of solid tumors, while its usage is limited due to its nephrotoxicity. The present study was undertaken to examine the effectiveness of ginseng to ameliorate the renal nephrotoxicity, damage in kidney genomic DNA, tumor necrosis factor-α, interleukin 6, tumor suppressor P53, histological changes and oxidative stress induced by cisplatin in rats. Cisplatin caused renal damage, including DNA fragmentation, upregulates gene expression of tumor suppressor protein p53 and tumor necrosis factor-α and IL-6. Cisplatin increased the levels of kidney TBARS, xanthine oxidase, nitric oxide, serum urea and creatinine. Cisplatin decreased the activities of antioxidant enzymes (GST, GPX, CAT and SOD), ATPase and the levels of GSH. A microscopic examination showed that cisplatin caused kidney damage including vacuolization, severe necrosis and degenerative changes. Ginseng co-treatment with cisplatin reduced its renal damage, oxidative stress, DNA fragmentation and induced DNA repair processes. Also, ginseng diminished p53 activation and improved renal cell apoptosis and nephrotoxicity. It can be concluded that, the protective effects of ginseng against cisplatin induced-renal damage was associated with the attenuation of oxidative stress and the preservation of antioxidant enzymes. PMID:25640527

  15. Dehydroleucodine inhibits tumor growth in a preclinical melanoma model by inducing cell cycle arrest, senescence and apoptosis.

    Science.gov (United States)

    Costantino, Valeria V; Lobos-Gonzalez, Lorena; Ibañez, Jorge; Fernandez, Dario; Cuello-Carrión, F Darío; Valenzuela, Manuel A; Barbieri, Manuel A; Semino, Silvana N; Jahn, Graciela A; Quest, Andrew F G; Lopez, Luis A

    2016-03-01

    Malignant melanoma represents the fastest growing public health risk of all cancer types worldwide. Several strategies and anti-cancer drugs have been used in an effort to improve treatments, but the development of resistance to anti-neoplastic drugs remains the major cause of chemotherapy failure in melanomas. Previously, we showed that the sesquiterpene lactone, dehydroleucodine (DhL), promotes the accumulation of DNA damage markers, such as H2AX and 53BP1, in human tumor cells. Also DhL was shown to trigger either cell senescence or apoptosis in a concentration-dependent manner in HeLa and MCF7 cells. Here, we evaluated the effects of DhL on B16F0 mouse melanoma cells in vitro and in a pre-clinical melanoma model. DhL inhibited the proliferation of B16F0 cells by inducing senescence or apoptosis in a concentration-dependent manner. Also, DhL reduced the expression of the cell cycle proteins cyclin D1 and B1 and the inhibitor of apoptosis protein, survivin. In melanomas generated by subcutaneous injection of B16F0 cells into C57/BL6 mice, the treatment with 20 mg DhL /Kg/day in preventive, simultaneous and therapeutic protocols reduced tumor volumes by 70%, 60% and 50%, respectively. DhL treatments reduced the number of proliferating, while increasing the number of senescent and apoptotic tumor cells. To estimate the long-term effects of DhL, a mathematical model was applied to fit experimental data. Extrapolation beyond experimental time points revealed that DhL administration following preventive and therapeutic protocols is predicted to be more effective than simultaneous treatments with DhL in restricting tumor growth. PMID:26718258

  16. Tumor protein 53-induced nuclear protein 1 (TP53INP1 enhances p53 function and represses tumorigenesis

    Directory of Open Access Journals (Sweden)

    Jeyran eShahbazi

    2013-05-01

    Full Text Available Tumor protein 53-induced nuclear protein 1 (TP53INP1 is a stress-induced p53 target gene whose expression is modulated by transcription factors such as p53, p73 and E2F1. TP53INP1 gene encodes two isoforms of TP53INP1 proteins, TP53INP1α and TP53INP1β, both of which appear to be key elements in p53 function. When associated with homeodomain-interacting protein kinase-2 (HIPK2, TP53INP1 phosphorylates p53 protein at Serine 46, enhances p53 protein stability and its transcriptional activity, leading to transcriptional activation of p53 target genes such as p21, PIG-3 and MDM2, cell growth arrest and apoptosis upon DNA damage stress. The anti-proliferative and pro-apoptotic activities of TP53INP1 indicate that TP53INP1 has an important role in cellular homeostasis and DNA damage response. Deficiency in TP53INP1 expression results in increased tumorigenesis; while TP53INP1 expression is repressed during early stages of cancer by factors such as miR-155. This review aims to summarize the roles of TP53INP1 in blocking tumor progression through p53-dependant and p53-independent pathways, as well as the elements which repress TP53INP1 expression, hence highlighting its potential as a therapeutic target in cancer treatment.

  17. YThe BigH3 Tumor Suppressor Gene in Radiation-Induced Malignant Transformation of Human Bronchial Epithelial Cells

    Science.gov (United States)

    Zhao, Y.; Shao, G.; Piao, C.; Hei, T.

    Carcinogenesis is a multi-stage process with sequences of genetic events governing the phenotypic expression of a series of transformation steps leading to the development of metastatic cancer Previous studies from this laboratory have identified a 7 fold down- regulation of the novel tumor suppressor Big-h3 among radiation induced tumorigenic BEP2D cells Furthermore ectopic re-expression of this gene suppresses tumorigenic phenotype and promotes the sensitivity of these tumor cells to etoposide-induced apoptosis To extend these studies using a genomically more stable bronchial cell line we ectopically expresses the catalytic subunit of telomerase hTERT in primary human small airway epithelial SAE cells and generated several clonal cell lines that have been continuously in culture for more than 250 population doublings and are considered immortal Comparably-treated control SAE cells infected with only the viral vector senesced after less than 10 population doublings The immortalized clones demonstrated anchorage dependent growth and are non-tumorigenic in nude mice These cells show no alteration in the p53 gene but a decrease in p16 expression Exponentially growing SAEh cells were exposed to graded doses of 1 GeV nucleon of 56 Fe ions accelerated at the Brookhaven National Laboratory Irradiated cells underwent gradual phenotypic alterations after extensive in vitro cultivation Transformed cells developed through a series of successive steps before becoming anchorage independent in semisolid medium These findings indicate

  18. Simulation of tumor induced angiogenesis using an analytical adaptive modeling including dynamic sprouting and blood flow modeling.

    Science.gov (United States)

    Naghavi, Nadia; Hosseini, Farideh S; Sardarabadi, Mohammad; Kalani, Hadi

    2016-09-01

    In this paper, an adaptive model for tumor induced angiogenesis is developed that integrates generation and diffusion of a growth factor originated from hypoxic cells, adaptive sprouting from a parent vessel, blood flow and structural adaptation. The proposed adaptive sprout spacing model (ASS) determines position, time and number of sprouts which are activated from a parent vessel and also the developed vascular network is modified by a novel sprout branching prediction algorithm. This algorithm couples local vascular endothelial growth factor (VEGF) concentrations, stresses due to the blood flow and stochastic branching to the structural reactions of each vessel segment in response to mechanical and biochemical stimuli. The results provide predictions for the time-dependent development of the network structure, including the position and diameters of each segment and the resulting distributions of blood flow and VEGF. Considering time delays between sprout progressions and number of sprouts activated at different time durations provides information about micro-vessel density in the network. Resulting insights could be useful for motivating experimental investigations of vascular pattern in tumor induced angiogenesis and development of therapies targeting angiogenesis. PMID:27179697

  19. Estrogen-induced nongenomic calcium signaling inhibits lipopolysaccharide-stimulated tumor necrosis factor α production in macrophages.

    Directory of Open Access Journals (Sweden)

    Limin Liu

    Full Text Available Estrogen is traditionally thought to exert genomic actions through members of the nuclear receptor family. Here, we investigated the rapid nongenomic effects of 17β-estradiol (E2 on tumor necrosis factor α (TNF-α production following lipopolysaccharide (LPS stimulation in mouse bone marrow-derived macrophages (BMMs. We found that LPS induced TNF-α production in BMMs via phosphorylation of p38 mitogen-activated protein kinase (MAPK. E2 itself did not affect the MAPK pathway, although it attenuated LPS-induced TNF-α production through suppression of p38 MAPK activation. Recently, G protein-coupled receptor 30 (GPR30 was suggested to be a membrane estrogen receptor (mER that can mediate nongenomic estradiol signaling. We found that BMMs expressed both intracellular estrogen receptors (iER and mER GPR30. The specific GPR30 antagonist G-15 significantly blocked effects of estradiol on LPS-induced TNF-α production, whereas an iER antagonist did not. Moreover, E2 induced a rapid rise in intracellular free Ca(2+ that was due to the influx of extracellular Ca(2+ and was not inhibited by an iER antagonist or silencing of iER. Ca(2+ influx was also induced by an impermeable E2 conjugated to BSA (E2-BSA, which has been used to investigate the nongenomic effects of estrogen. Consequently, Ca(2+, a pivotal factor in E2-stimulated nongenomic action, was identified as the key mediator. The inhibitory effects of E2 on LPS-induced TNF-α production and p38 MAPK phosphorylation were dependent on E2-triggered Ca(2+ influx because BAPTA, an intracellular Ca(2+ chelator, prevented these effects. Taken together, these data indicate that E2 can down-regulate LPS-induced TNF-α production via blockade of p38 MAPK phosphorylation through the mER-mediated nongenomic Ca(2+ signaling pathway in BMMs.

  20. Glycyrrhizin Protects against Acetaminophen-Induced Acute Liver Injury via Alleviating Tumor Necrosis Factor α-Mediated Apoptosis.

    Science.gov (United States)

    Yan, Tingting; Wang, Hong; Zhao, Min; Yagai, Tomoki; Chai, Yingying; Krausz, Kristopher W; Xie, Cen; Cheng, Xuefang; Zhang, Jun; Che, Yuan; Li, Feiyan; Wu, Yuzheng; Brocker, Chad N; Gonzalez, Frank J; Wang, Guangji; Hao, Haiping

    2016-05-01

    Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure in Western countries. Glycyrrhizin (GL), a potent hepatoprotective constituent extracted from the traditional Chinese medicine liquorice, has potential clinical use in treating APAP-induced liver failure. The present study determined the hepatoprotective effects and underlying mechanisms of action of GL and its active metabolite glycyrrhetinic acid (GA). Various administration routes and pharmacokinetics-pharmacodynamics analyses were used to differentiate the effects of GL and GA on APAP toxicity in mice. Mice deficient in cytochrome P450 2E1 enzyme (CYP2E1) or receptor interacting protein 3 (RIPK3) and their relative wild-type littermates were subjected to histologic and biochemical analyses to determine the potential mechanisms. Hepatocyte death mediated by tumor necrosis factorα(TNFα)/caspase was analyzed by use of human liver-derived LO2 cells. The pharmacokinetics-pharmacodynamics analysis using various administration routes revealed that GL but not GA potently attenuated APAP-induced liver injury. The protective effect of GL was found only with intraperitoneal and intravenous administration and not with gastric administration. CYP2E1-mediated metabolic activation and RIPK3-mediated necroptosis were unrelated to GL's protective effect. However, GL inhibited hepatocyte apoptosis via interference with TNFα-induced apoptotic hepatocyte death. These results demonstrate that GL rapidly attenuates APAP-induced liver injury by directly inhibiting TNFα-induced hepatocyte apoptosis. The protective effect against APAP-induced liver toxicity by GL in mice suggests the therapeutic potential of GL for the treatment of APAP overdose. PMID:26965985

  1. Formation of multicellular tumor spheroids induced by cyclic RGD-peptides and use for anticancer drug testing in vitro.

    Science.gov (United States)

    Akasov, Roman; Zaytseva-Zotova, Daria; Burov, Sergey; Leko, Maria; Dontenwill, Monique; Chiper, Manuela; Vandamme, Thierry; Markvicheva, Elena

    2016-06-15

    Development of novel anticancer formulations is a priority challenge in biomedicine. However, in vitro models based on monolayer cultures (2D) which are currently used for cytotoxicity tests leave much to be desired. More and more attention is focusing on 3D in vitro systems which can better mimic solid tumors. The aim of the study was to develop a novel one-step highly reproducible technique for multicellular tumor spheroid (MTS) formation using synthetic cyclic RGD-peptides, and to demonstrate availability of the spheroids as 3D in vitro model for antitumor drug testing. Cell self-assembly effect induced by addition of both linear and cyclic RGD-peptides directly to monolayer cultures was studied for 12 cell lines of various origins, including tumor cells (e.i. U-87 MG, MCF-7, M-3, HCT-116) and normal cells, in particular L-929, BNL.CL2, HepG2. Cyclo-RGDfK and its modification with triphenylphosphonium cation (TPP), namely cyclo-RGDfK(TPP) in a range of 10-100μM were found to induce spheroid formation. The obtained spheroids were unimodal with mean sizes in a range of 60-120μm depending on cell line and serum content in culture medium. The spheroids were used as 3D in vitro model, in order to evaluate cytotoxicity effects of antitumor drugs (doxorubicin, curcumin, temozolomide). The developed technique could be proposed as a promising tool for in vitro test of novel antitumor drugs. PMID:27107900

  2. Multiwalled carbon nanotubes intratracheally instilled into the rat lung induce development of pleural malignant mesothelioma and lung tumors.

    Science.gov (United States)

    Suzui, Masumi; Futakuchi, Mitsuru; Fukamachi, Katsumi; Numano, Takamasa; Abdelgied, Mohamed; Takahashi, Satoru; Ohnishi, Makoto; Omori, Toyonori; Tsuruoka, Shuji; Hirose, Akihiko; Kanno, Jun; Sakamoto, Yoshimitsu; Alexander, David B; Alexander, William T; Jiegou, Xu; Tsuda, Hiroyuki

    2016-07-01

    Multiwalled carbon nanotubes (MWCNT) have a fibrous structure and physical properties similar to asbestos and have been shown to induce malignant mesothelioma of the peritoneum after injection into the scrotum or peritoneal cavity in rats and mice. For human cancer risk assessment, however, data after administration of MWCNT via the airway, the exposure route that is most relevant to humans, is required. The present study was undertaken to investigate the carcinogenicity of MWCNT-N (NIKKISO) after administration to the rat lung. MWCNT-N was fractionated by passing it through a sieve with a pore size of 25 μm. The average lengths of the MWCNT were 4.2 μm before filtration and 2.6 μm in the flow-through fraction; the length of the retained MWCNT could not be determined. For the present study, 10-week-old F344/Crj male rats were divided into five groups: no treatment, vehicle control, MWCNT-N before filtration, MWCNT-N flow-through and MWCNT-N retained groups. Administration was by the trans-tracheal intrapulmonary spraying (TIPS) method. Rats were administered a total of 1 mg/rat during the initial 2 weeks of the experiment and then observed up to 109 weeks. The incidences of malignant mesothelioma and lung tumors (bronchiolo-alveolar adenomas and carcinomas) were 6/38 and 14/38, respectively, in the three groups administered MWCNT and 0/28 and 0/28, respectively, in the control groups. All malignant mesotheliomas were localized in the pericardial pleural cavity. The sieve fractions did not have a significant effect on tumor incidence. In conclusion, administration of MWCNT to the lung in the rat induces malignant mesothelioma and lung tumors. PMID:27098557

  3. Direct therapeutic applications of calcium electroporation to effectively induce tumor necrosis

    DEFF Research Database (Denmark)

    Frandsen, Stine Krog; Gissel, Hanne; Hojman, Pernille;

    2012-01-01

    Electroporation of cells with short, high-voltage pulses causes a transient permeabilization of cell membranes that permits passage of otherwise nonpermeating ions and molecules. In this study, we illustrate how electroporation with isotonic calcium can achieve highly effective cancer cell kill in......, decreased production of ATP due to effects on the mitochondria, as well as loss of ATP through the permeabilized cell membrane. Taken together, our findings offer a preclinical proof of concept for the use of electroporation to load cancer cells with calcium as an efficient anticancer treatment....... Electroporation equipment is already used clinically to enhance the delivery of chemotherapy to superficial tumors, with trials on internal tumors in progress, enabling the introduction of calcium electroporation to clinical use. Moreover, the safety profile, availability, and low cost of calcium facilitate...

  4. Cinnamon extract induces tumor cell death through inhibition of NFκB and AP1

    OpenAIRE

    Lee Sung; Im Chang-Rok; Ko Byoung; Jeon Won; Ryu Jae-Ha; Sahoo Anupama; Lee Choong-Gu; So Jae-Seon; Hwang Ji-Sun; Kwon Ho-Keun; Park Zee; Im Sin-Hyeog

    2010-01-01

    Abstract Background Cinnamomum cassia bark is the outer skin of an evergreen tall tree belonging to the family Lauraceae containing several active components such as essential oils (cinnamic aldehyde and cinnamyl aldehyde), tannin, mucus and carbohydrate. They have various biological functions including anti-oxidant, anti-microbial, anti-inflammation, anti-diabetic and anti-tumor activity. Previously, we have reported that anti-cancer effect of cinnamon extracts is associated with modulation ...

  5. Grhl3 induces human epithelial tumor cell migration and invasion via downregulation of E-cadherin.

    Science.gov (United States)

    Zhao, Pan; Guo, Sijia; Tu, Zhenzhen; Di, Lijun; Zha, Xiaojun; Zhou, Haisheng; Zhang, Xuejun

    2016-03-01

    Grainyhead genes are involved in wound healing and developmental neural tube closure. Metastasis is a multistep process during which cancer cells disseminate from the site of primary tumors and establish secondary tumors in distant organs. The adhesion protein E-cadherin plays an essential role in metastasis. In light of the high degree of similarity between the epithelial-mesenchymal transition (EMT) occurring in wound-healing processes and the EMT occurring during the acquisition of invasiveness in skin or breast cancer, we investigated the role of the Grainyhead genes in cancer invasion. Here, we show that there is an inverse relationship between Grainyhead-like 3 (Grhl3) and E-cadherin expression in some epithelial tumor cell lines. Overexpression of Grhl3 in the E-cadherin-positive epithelial tumor cell line, characterized by less invasiveness, generated a transcriptional blockage of the E-cadherin gene and promoted cell migration and cell invasion. Conversely, Grhl3 depletion inhibited cell migration and cell invasion and was associated with a gain of E-cadherin expression. To further explore the mechanism by which Grhl3 regulated E-cadherin expression, an E-cadherin promoter report analysis was performed and results showed that Grhl3 repressed E-cadherin gene expression by directly or indirectly binding to the E-boxes present in the proximal E-cadherin promoter. Taken together, our findings define a major role for Grhl3 in the induction of migration and invasion by the downregulation of E-cadherin in cancer cells. PMID:26837418

  6. Complement C1q Activates Tumor Suppressor WWOX to Induce Apoptosis in Prostate Cancer Cells

    OpenAIRE

    Hong, Qunying; Sze, Chun-I; Lin, Sing-Ru; Lee, Ming-Hui; He, Ruei-Yu; Schultz, Lori; Chang, Jean-Yun; Chen, Shean-Jen; Boackle, Robert J; Hsu, Li-Jin; Chang, Nan-Shan

    2009-01-01

    Background Tissue exudates contain low levels of serum complement proteins, and their regulatory effects on prostate cancer progression are largely unknown. We examined specific serum complement components in coordinating the activation of tumor suppressors p53 and WWOX (also named FOR or WOX1) and kinases ERK, JNK1 and STAT3 in human prostate DU145 cells. Methodology/Principal Findings DU145 cells were cultured overnight in 1% normal human serum, or in human serum depleted of an indicated co...

  7. The non glycanated endocan polypeptide slows tumor growth by inducing stromal inflammatory reaction

    OpenAIRE

    Yassine, Hanane; De Freitas Caires, Nathalie; Depontieu, Florence; Scherpereel, Arnaud; Awad, Ali,; Tsicopoulos, Anne; Leboeuf, Christophe; Janin, Anne; Duez, Catherine; Grigoriu, Bogdan,; Lassalle, Philippe

    2014-01-01

    Endocan expression is increasingly studied in various human cancers. Experimental evidence showed that human endocan, through its glycan chain, is implicated in various processes of tumor growth. We functionally characterize mouse endocan which is also a chondroitin sulfate proteoglycan but much less glycanated than human endocan. Distant domains from the O-glycanation site, located within exons 1 and 2 determine the glycanation pattern of endocan. In opposite to the human homologue, overexpr...

  8. Importance of maintenance therapy in C225-induced enhancement of tumor control by fractionated radiation

    International Nuclear Information System (INIS)

    Purpose: C225 strongly enhances tumor radioresponse when given concurrently with radiotherapy. We investigated whether additional therapeutic benefit could be achieved by continuing maintenance treatment with C225 after the completion of fractionated radiotherapy. Methods and Materials: A431 xenografts were treated with local irradiation or combined with C225 by two different schedules: (1) 6 h before the first dose of irradiation and at 3-day intervals for a total of 3 doses during the 7-day fractionated radiotherapy, or (2) 6 doses of C225 given both during radiotherapy and continuing for 3 additional doses after radiotherapy. Tumor cure was assessed by the radiation dose yielding local tumor control in 50% of animals (TCD50), and time to recurrence was also determined. Results: Both treatment schedules increased radiocurability as evidenced by reductions in TCD50, but the effect was greater when C225 was given both during and after radiotherapy. C225 reduced the TCD50 of 83.1 (73.2-124.8) Gy by radiation only to 46.2 (39.1-57.5) Gy when given during radiotherapy and to 30.8 (22.2-38.0) Gy when given during and after radiotherapy. Dose modification factors were 1.8 when C225 was given during radiotherapy and 2.7 when given both during and after radiotherapy. C225 was also effective in delaying the onset of tumor recurrences, and was more effective when given as both concurrent and maintenance therapy. Conclusions: Data showed that C225 strongly enhanced the curative effect of fractionated radiation, and its effect was greater if administration was extended beyond the end of radiotherapy. This important finding may influence future designs of clinical trials combining anti-EGFR (anti-epidermal growth factor receptor) agents with radiotherapy

  9. Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1

    OpenAIRE

    Ruud, Johan; Nilsson, Anna; Engström Ruud, Linda; Wang, Wenhua; Nilsberth, Camilla; Iresjo, Britt-Marie; Lundholm, Kent; Engblom, David; Blomqvist, Anders

    2013-01-01

    It is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the anorexia–cachexia syndrome, in malignant cancer. However, the identity of the PGs and the PG producing cyclooxygenase (COX) species responsible for cancer anorexia–cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the anorexia...

  10. Butein Induces Apoptosis and Inhibits Prostate Tumor Growth In Vitro and In Vivo

    OpenAIRE

    Khan, Naghma; Adhami, Vaqar M.; Afaq, Farrukh; Mukhtar, Hasan

    2012-01-01

    Aim: Prostate cancer (PCa) is one of the most common cancers in men in the United States with similar trends worldwide. For several reasons, it is an ideal candidate disease for intervention with dietary botanical antioxidants. Indeed, many botanical antioxidants are showing promise for chemoprevention of PCa. Here, we determined the effect of an antioxidant butein (3,4,2′,4′-tetrahydroxychalone) on cell growth, apoptosis, and signaling pathways in human PCa cells in-vitro and on tumor growth...

  11. KLF10, transforming growth factor-β-inducible early gene 1, acts as a tumor suppressor

    International Nuclear Information System (INIS)

    Highlights: ► KLF10−/− mice exhibited accelerated papilloma development after DMBA/TPA treatment. ► KLF10−/− keratinocytes showed increased proliferation and apoptosis. ► KLF10−/− MEFs yielded more colonies than wild-type one with H-Ras transfection. ► KLF10 dose-dependently activated p21WAF1/CIP1 transcription. ► KLF10 is a tumor suppressor and that it targets p21WAF1/CIP1 transcription. -- Abstract: Krüppel-like factor 10 (KLF10) has been suggested to be a putative tumor suppressor. In the present study, we generated KLF10 deficient mice to explore this hypothesis in vivo. KLF10 deficient mice exhibited increased predisposition to skin tumorigenesis and markedly accelerated papilloma development after DMBA/TPA treatment. On the other hand, KLF10 deficient keratinocytes showed increased proliferation and apoptosis. In colony formation assays after oncogenic H-Ras transfection, KLF10 deficient mouse embryonic fibroblasts (MEFs) yielded more colonies than wild-type MEFs. Furthermore, KLF10 dose-dependently activated p21WAF1/CIP1 transcription, which was independent of p53 and Sp1 binding sites in p21WAF1/CIP1 promoter. This study demonstrates that KLF10 is a tumor suppressor and that it targets p21WAF1/CIP1 transcription.

  12. Somatostatin receptor-1 induces cell cycle arrest and inhibits tumor growth in pancreatic cancer.

    Science.gov (United States)

    Li, Min; Wang, Xiaochi; Li, Wei; Li, Fei; Yang, Hui; Wang, Hao; Brunicardi, F Charles; Chen, Changyi; Yao, Qizhi; Fisher, William E

    2008-11-01

    Functional somatostatin receptors (SSTR) are lost in human pancreatic cancer. Transfection of SSTR-1 inhibited pancreatic cancer cell proliferation in vitro. We hypothesize that stable transfection of SSTR-1 may inhibit pancreatic cancer growth in vivo possibly through cell cycle arrest. In this study, we examined the expression of SSTR-1 mRNA in human pancreatic cancer tissue specimens, and investigated the effect of SSTR-1 overexpression on cell proliferation, cell cycle, and tumor growth in a subcutaneous nude mouse model. We found that SSTR-1 mRNA was downregulated in the majority of pancreatic cancer tissue specimens. Transfection of SSTR-1 caused cell cycle arrest at the G(0)/G(1) growth phase, with a corresponding decline of cells in the S (mitotic) phase. The overexpression of SSTR-1 significantly inhibited subcutaneous tumor size by 71% and 43% (n = 5, P < 0.05, Student's t-test), and inhibited tumor weight by 69% and 47% (n = 5, P < 0.05, Student's t-test), in Panc-SSTR-1 and MIA-SSTR-1 groups, respectively, indicating the potent inhibitory effect of SSTR-1 on pancreatic cancer growth. Our data demonstrate that overexpression of SSTR-1 significantly inhibits pancreatic cancer growth possibly through cell cycle arrest. This study suggests that gene therapy with SSTR-1 may be a potential adjuvant treatment for pancreatic cancer. PMID:18823376

  13. Sulindac Induces Apoptosis and Inhibits Tumor Growth In Vivo in Head and Neck Squamous Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Mark A. Scheper

    2007-03-01

    Full Text Available Sulindac has antineoplastic effects on various cancer cell lines; consequently, we assessed sulindac's effects on laryngeal squamous cell carcinoma (SCC cells in vitro and in vivo. In vitro, SCC (HEP-2 cells treated with various cyclooxygenase inhibitors or transfected with constitutively active signal transducer and activator of transcription 3 (Stat3 or survivin vectors were analyzed using Western blot analysis, annexin V assay, and cell proliferation assay. In parallel, nude mice injected subcutaneously with HEP-2 cells were either treated intraperitoneally with sulindac or left untreated, and analyzed for tumor weight, survivin expression, and tyrosine-phosphorylated Stat3 expression. In vitro studies confirmed the selective antiproliferative and proapoptotic effects of sulindac, which also downregulated Stat3 and survivin protein expression. Stat3 or survivin forced expression partially rescued the antiproliferative effects of sulindac. In vivo studies showed significant repression of HEP-2 xenograft growth in sulindactreated mice versus controls, with near-complete resolution at 10 days. Additionally, tumor specimens treated with sulindac showed downregulation of phosphorylated tyrosine-705 Stat3 and survivin expression. Taken together, our data suggest, for the first time, a specific inhibitory effect of sulindac on tumor growth and survivin expression in laryngeal cancer, both in vitro and in vivo, in a Stat3-dependent manner, suggesting a novel therapeutic approach to head and neck cancer.

  14. KLF10, transforming growth factor-{beta}-inducible early gene 1, acts as a tumor suppressor

    Energy Technology Data Exchange (ETDEWEB)

    Song, Ki-Duk [Center for Agricultural Biomaterials, Seoul National University, Seoul 151-921 (Korea, Republic of); Laboratory of Protein Engineering and Comparative Immunology, School of Agricultural Biotechnology, Seoul National University, Seoul 151-921 (Korea, Republic of); Kim, Duk-Jung [The Institute of Hankook Life Science, 7-9 Myungryun-dong, Jongno-gu, Seoul 110-521 (Korea, Republic of); Lee, Jong Eun [Department of Anatomy, College of Medicine, Yonsei University, Seoul 120-752 (Korea, Republic of); Yun, Cheol-Heui [Center for Agricultural Biomaterials, Seoul National University, Seoul 151-921 (Korea, Republic of); Laboratory of Protein Engineering and Comparative Immunology, School of Agricultural Biotechnology, Seoul National University, Seoul 151-921 (Korea, Republic of); Lee, Woon Kyu, E-mail: wklee@inha.ac.kr [Laboratory of Developmental Genetics, School of Medicine, Inha University, Incheon 400-712 (Korea, Republic of); Brain Korea 21 Center for Advanced Medical Education, School of Medicine, Inha University, Incheon 400-712 (Korea, Republic of)

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer KLF10{sup -/-} mice exhibited accelerated papilloma development after DMBA/TPA treatment. Black-Right-Pointing-Pointer KLF10{sup -/-} keratinocytes showed increased prolifer