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Sample records for lung cells beas-2b

  1. Role of reactive oxygen species in arsenic-induced transformation of human lung bronchial epithelial (BEAS-2B) cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Zhuo, E-mail: zhuo.zhang@uky.edu [Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536 (United States); Pratheeshkumar, Poyil; Budhraja, Amit; Son, Young-Ok [Center for Research on Environmental Diseases, University of Kentucky, Lexington, KY 40536 (United States); Kim, Donghern [Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536 (United States); Shi, Xianglin [Center for Research on Environmental Diseases, University of Kentucky, Lexington, KY 40536 (United States)

    2015-01-09

    Highlights: • Short term exposure of cells to arsenic causes ROS generation. • Chronical exposure of cells to arsenic causes malignant cell transformation. • Inhibition of ROS generation reduces cell transformation by arsenic. • Arsenic-transformed cells exhibit reduced capacity of generating ROS. • Arsenic-transformed cells exhibit increased levels of antioxidants. - Abstract: Arsenic is an environmental carcinogen, its mechanisms of carcinogenesis remain to be investigated. Reactive oxygen species (ROS) are considered to be important. A previous study (Carpenter et al., 2011) has measured ROS level in human lung bronchial epithelial (BEAS-2B) cells and arsenic-transformed BEAS-2B cells and found that ROS levels were higher in transformed cells than that in parent normal cells. Based on these observations, the authors concluded that cell transformation induced by arsenic is mediated by increased cellular levels of ROS. This conclusion is problematic because this study only measured the basal ROS levels in transformed and parent cells and did not investigate the role of ROS in the process of arsenic-induced cell transformation. The levels of ROS in arsenic-transformed cells represent the result and not the cause of cell transformation. Thus question concerning whether ROS are important in arsenic-induced cell transformation remains to be answered. In the present study, we used expressions of catalase (antioxidant against H{sub 2}O{sub 2}) and superoxide dismutase 2 (SOD2, antioxidant against O{sub 2}{sup ·−}) to decrease ROS level and investigated their role in the process of arsenic-induced cell transformation. Our results show that inhibition of ROS by antioxidant enzymes decreased arsenic-induced cell transformation, demonstrating that ROS are important in this process. We have also shown that in arsenic-transformed cells, ROS generation was lower and levels of antioxidants are higher than those in parent cells, in a disagreement with the previous

  2. Role of reactive oxygen species in arsenic-induced transformation of human lung bronchial epithelial (BEAS-2B) cells

    International Nuclear Information System (INIS)

    Zhang, Zhuo; Pratheeshkumar, Poyil; Budhraja, Amit; Son, Young-Ok; Kim, Donghern; Shi, Xianglin

    2015-01-01

    Highlights: • Short term exposure of cells to arsenic causes ROS generation. • Chronical exposure of cells to arsenic causes malignant cell transformation. • Inhibition of ROS generation reduces cell transformation by arsenic. • Arsenic-transformed cells exhibit reduced capacity of generating ROS. • Arsenic-transformed cells exhibit increased levels of antioxidants. - Abstract: Arsenic is an environmental carcinogen, its mechanisms of carcinogenesis remain to be investigated. Reactive oxygen species (ROS) are considered to be important. A previous study (Carpenter et al., 2011) has measured ROS level in human lung bronchial epithelial (BEAS-2B) cells and arsenic-transformed BEAS-2B cells and found that ROS levels were higher in transformed cells than that in parent normal cells. Based on these observations, the authors concluded that cell transformation induced by arsenic is mediated by increased cellular levels of ROS. This conclusion is problematic because this study only measured the basal ROS levels in transformed and parent cells and did not investigate the role of ROS in the process of arsenic-induced cell transformation. The levels of ROS in arsenic-transformed cells represent the result and not the cause of cell transformation. Thus question concerning whether ROS are important in arsenic-induced cell transformation remains to be answered. In the present study, we used expressions of catalase (antioxidant against H 2 O 2 ) and superoxide dismutase 2 (SOD2, antioxidant against O 2 ·− ) to decrease ROS level and investigated their role in the process of arsenic-induced cell transformation. Our results show that inhibition of ROS by antioxidant enzymes decreased arsenic-induced cell transformation, demonstrating that ROS are important in this process. We have also shown that in arsenic-transformed cells, ROS generation was lower and levels of antioxidants are higher than those in parent cells, in a disagreement with the previous report. The

  3. Overexpression of microRNA miR-30a or miR-191 in A549 lung cancer or BEAS-2B normal lung cell lines does not alter phenotype.

    Directory of Open Access Journals (Sweden)

    Santosh Kumar Patnaik

    Full Text Available BACKGROUND: MicroRNAs (miRNAs are small, noncoding RNAs (ribonucleic acids that regulate translation. Several miRNAs have been shown to be altered in whole cancer tissue compared to normal tissue when quantified by microarray. Based on previous such evidence of differential expression, we chose to study the functional significance of miRNAs miR-30a and -191 alterations in human lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: The functional significance of miRNAs miR-30a and -191 was studied by creating stable transfectants of the lung adenocarcinoma cell line A549 and the immortalized bronchial epithelial cell line BEAS-2B with modest overexpression of miR-30a or -191 using a lentiviral system. When compared to the corresponding controls, both cell lines overexpressing miR-30a or -191 do not demonstrate any significant changes in cell cycle distribution, cell proliferation, adherent colony formation, soft agar colony formation, xenograft formation in a subcutaneous SCID mouse model, and drug sensitivity to doxorubicin and cisplatin. There is a modest increase in cell migration in cell lines overexpressing miR-30a compared to their controls. CONCLUSIONS/SIGNIFICANCE: Overexpression of miR-30a or -191 does not lead to an alteration in cell cycle, proliferation, xenograft formation, and chemosensitivity of A549 and BEAS-2B cell lines. Using microarray data from whole tumors to select specific miRNAs for functional study may be a suboptimal strategy.

  4. Oxidative stress induced by cerium oxide nanoparticles in cultured BEAS-2B cells

    International Nuclear Information System (INIS)

    Park, Eun-Jung; Choi, Jinhee; Park, Young-Kwon; Park, Kwangsik

    2008-01-01

    Cerium oxide nanoparticles of different sizes (15, 25, 30, 45 nm) were prepared by the supercritical synthesis method, and cytotoxicity was evaluated using cultured human lung epithelial cells (BEAS-2B). Exposure of the cultured cells to nanoparticles (5, 10, 20, 40 μg/ml) led to cell death, ROS increase, GSH decrease, and the inductions of oxidative stress-related genes such as heme oxygenase-1, catalase, glutathione S-transferase, and thioredoxin reductase. The increased ROS by cerium oxide nanoparticles triggered the activation of cytosolic caspase-3 and chromatin condensation, which means that cerium oxide nanoparticles exert cytotoxicity by an apoptotic process. Uptake of the nanoparticles to the cultured cells was also tested. It was observed that cerium oxide nanoparticles penetrated into the cytoplasm and located in the peri-region of the nucleus as aggregated particles, which may induce the direct interaction between nanoparticles and cellular molecules to cause adverse cellular responses

  5. Culture medium type affects endocytosis of multi-walled carbon nanotubes in BEAS-2B cells and subsequent biological response.

    Science.gov (United States)

    Haniu, Hisao; Saito, Naoto; Matsuda, Yoshikazu; Tsukahara, Tamotsu; Maruyama, Kayo; Usui, Yuki; Aoki, Kaoru; Takanashi, Seiji; Kobayashi, Shinsuke; Nomura, Hiroki; Okamoto, Masanori; Shimizu, Masayuki; Kato, Hiroyuki

    2013-09-01

    We examined the cytotoxicity of multi-walled carbon nanotubes (MWCNTs) and the resulting cytokine secretion in BEAS-2B cells or normal human bronchial epithelial cells (HBEpCs) in two types of culture media (Ham's F12 containing 10% FBS [Ham's F12] and serum-free growth medium [SFGM]). Cellular uptake of MWCNT was observed by fluorescent microscopy and analyzed using flow cytometry. Moreover, we evaluated whether MWCNT uptake was suppressed by 2 types of endocytosis inhibitors. We found that BEAS-2B cells cultured in Ham's F12 and HBEpCs cultured in SFGM showed similar biological responses, but BEAS-2B cells cultured in SFGM did not internalize MWCNTs, and the 50% inhibitory concentration value, i.e., the cytotoxicity, was increased by more than 10-fold. MWCNT uptake was suppressed by a clathrin-mediated endocytosis inhibitor and a caveolae-mediated endocytosis inhibitor in BEAS-2B cells cultured in Ham's F12 and HBEpCs cultured in SFGM. In conclusion, we suggest that BEAS-2B cells cultured in a medium containing serum should be used for the safety evaluation of nanomaterials as a model of normal human bronchial epithelial cells. However, the culture medium composition may affect the proteins that are expressed on the cytoplasmic membrane, which may influence the biological response to MWCNTs. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  6. A Cross-Talk Between NFAT and NF-κB Pathways is Crucial for Nickel-Induced COX-2 Expression in Beas-2B Cells

    Science.gov (United States)

    Cai, T.; Li, X.; Ding, J.; Luo, W.; Li, J.; Huang, C.

    2013-01-01

    Cyclooxygenase-2 (COX-2) is a critical enzyme implicated in chronic inflammation-associated cancer development. Our studies have shown that the exposure of Beas-2B cells, a human bronchial epithelial cell line, to lung carcinogenic nickel compounds results in increased COX-2 expression. However, the signaling pathways leading to nickel-induced COX-2 expression are not well understood. In the current study, we found that the exposure of Beas-2B cells to nickel compounds resulted in the activation of both nuclear factor of activated T cell (NFAT) and nuclear factor-κB (NF-κB). The expression of COX-2 induced upon nickel exposure was inhibited by either a NFAT pharmacological inhibitor or the knockdown of NFAT3 by specific siRNA. We further found that the activation of NFAT and NF-κB was dependent on each other. Since our previous studies have shown that NF-κB activation is critical for nickel-induced COX-2 expression in Beas-2B cells exposed to nickel compounds under same experimental condition, we anticipate that there might be a cross-talk between the activation of NFAT and NF-κB for the COX-2 induction due to nickel exposure in Beas-2B cells. Furthermore, we showed that the scavenging of reactive oxygen species (ROS) by introduction of mitochondrial catalase inhibited the activation of both NFAT and NF-κB, and the induction of COX-2 due to nickel exposure. Taken together, our results defining the evidence showing a key role of the cross-talk between NFAT and NF-κB pathways in regulating nickel-induced COX-2 expression, further provide insight into the understanding of the molecular mechanisms linking nickel exposure to its lung carcinogenic effects. PMID:21486220

  7. MiR-146a regulates PM1 -induced inflammation via NF-κB signaling pathway in BEAS-2B cells.

    Science.gov (United States)

    Liu, Limin; Wan, Chong; Zhang, Wei; Guan, Longfei; Tian, Guoxiong; Zhang, Fang; Ding, Wenjun

    2018-04-18

    Exposure to particulate matter (PM) leads to kinds of cardiopulmonary diseases, such as asthma, COPD, arrhythmias, lung cancer, etc., which are related to PM-induced inflammation. We have found that PM 2.5 (aerodynamics diameter <2.5 µm) exposure induces inflammatory response both in vivo and in vitro. Since the toxicity of PM is tightly associated with its size and components, PM 1 (aerodynamics diameter <1.0 µm) is supposed to be more toxic than PM 2.5 . However, the mechanism of PM 1 -induced inflammation is not clear. Recently, emerging evidences prove that microRNAs play a vital role in regulating inflammation. Therefore, we studied the regulation of miR-146a in PM 1 -induced inflammation in human lung bronchial epithelial BEAS-2B cells. The results show that PM 1 induces the increase of IL-6 and IL-8 in BEAS-2B cells and up-regulates the miR-146a expression by activating NF-κB signaling pathway. Overexpressed miR-146a prevents the nuclear translocation of p65 through inhibiting the IRAK1/TRAF6 expression, and downregulates the expression of IL-6 and IL-8. Taken together, these results demonstrate that miR-146a can negatively feedback regulate PM 1 -induced inflammation via NF-κB signaling pathway in BEAS-2B cells. © 2018 Wiley Periodicals, Inc.

  8. The crosstalk between α-irradiated Beas-2B cells and its bystander U937 cells through MAPK and NF-κB signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Jiamei; Yuan, Dexiao; Xiao, Linlin; Tu, Wenzhi; Dong, Chen; Liu, Weili; Shao, Chunlin, E-mail: clshao@shmu.edu.cn

    2016-01-15

    Highlights: • α-irradiated Beas-2B cells induced bystander effects in macrophage U937 cells. • The neighboring macrophages enhanced the damage of α-irradiated Beas-2B cells. • MAPK and NF-κB pathways were activated in U937 cells after cell co-culture. • NF-κB and MAPK pathways participated in the bilateral bystander responses. - Abstract: Although accumulated evidence suggests that α-particle irradiation induced bystander effect may relevant to lung injury and cancer risk assessment, the exact mechanisms are not yet elucidated. In the present study, a cell co-culture system was used to investigate the interaction between α-particle irradiated human bronchial epithelial cells (Beas-2B) and its bystander macrophage U937 cells. It was found that the cell co-culture amplified the detrimental effects of α-irradiation including cell viability decrease and apoptosis promotion on both irradiated cells and bystander cells in a feedback loop which was closely relevant to the activation of MAPK and NF-κB pathways in the bystander U937 cells. When these two pathways in U937 cells were disturbed by special pharmacological inhibitors before cell co-culture, it was found that a NF-κB inhibitor of BAY 11-7082 further enhanced the proliferation inhibition and apoptosis induction in bystander U937 cells, but MAPK inhibitors of SP600125 and SB203580 protected cells from viability loss and apoptosis and U0126 presented more beneficial effect on cell protection. For α-irradiated epithelial cells, the activation of NF-κB and MAPK pathways in U937 cells participated in detrimental cellular responses since the above inhibitors could largely attenuate cell viability loss and apoptosis of irradiated cells. Our results demonstrated that there are bilateral bystander responses between irradiated lung epithelial cells and macrophages through MAPK and NF-κB signaling pathways, which accounts for the enhancement of α-irradiation induced damage.

  9. The crosstalk between α-irradiated Beas-2B cells and its bystander U937 cells through MAPK and NF-κB signaling pathways

    International Nuclear Information System (INIS)

    Fu, Jiamei; Yuan, Dexiao; Xiao, Linlin; Tu, Wenzhi; Dong, Chen; Liu, Weili; Shao, Chunlin

    2016-01-01

    Highlights: • α-irradiated Beas-2B cells induced bystander effects in macrophage U937 cells. • The neighboring macrophages enhanced the damage of α-irradiated Beas-2B cells. • MAPK and NF-κB pathways were activated in U937 cells after cell co-culture. • NF-κB and MAPK pathways participated in the bilateral bystander responses. - Abstract: Although accumulated evidence suggests that α-particle irradiation induced bystander effect may relevant to lung injury and cancer risk assessment, the exact mechanisms are not yet elucidated. In the present study, a cell co-culture system was used to investigate the interaction between α-particle irradiated human bronchial epithelial cells (Beas-2B) and its bystander macrophage U937 cells. It was found that the cell co-culture amplified the detrimental effects of α-irradiation including cell viability decrease and apoptosis promotion on both irradiated cells and bystander cells in a feedback loop which was closely relevant to the activation of MAPK and NF-κB pathways in the bystander U937 cells. When these two pathways in U937 cells were disturbed by special pharmacological inhibitors before cell co-culture, it was found that a NF-κB inhibitor of BAY 11-7082 further enhanced the proliferation inhibition and apoptosis induction in bystander U937 cells, but MAPK inhibitors of SP600125 and SB203580 protected cells from viability loss and apoptosis and U0126 presented more beneficial effect on cell protection. For α-irradiated epithelial cells, the activation of NF-κB and MAPK pathways in U937 cells participated in detrimental cellular responses since the above inhibitors could largely attenuate cell viability loss and apoptosis of irradiated cells. Our results demonstrated that there are bilateral bystander responses between irradiated lung epithelial cells and macrophages through MAPK and NF-κB signaling pathways, which accounts for the enhancement of α-irradiation induced damage.

  10. Use of human bronchial epithelial cells (BEAS-2B) to study immunological markers resulting from exposure to PM2.5 organic extract from Puerto Rico

    International Nuclear Information System (INIS)

    Fuentes-Mattei, Enrique; Rivera, Evasomary; Gioda, Adriana; Sanchez-Rivera, Diana; Roman-Velazquez, Felix R.; Jimenez-Velez, Braulio D.

    2010-01-01

    Fine particulate air pollutants, mainly their organic fraction, have been demonstrated to be associated with cardiovascular and respiratory health problems. Puerto Rico has been reported to have the highest prevalence of pulmonary diseases (e.g., asthma) in the United States. The aim of this study was to assess, for the first time, the immunological response of human bronchial epithelial cells (BEAS-2B) to organic extracts isolated from airborne particulate matter (PM 2.5 ) in Puerto Rico. Organic extracts from PM 2.5 collected throughout an 8-month period (2000-2001) were pooled (composite) in order to perform chemical analysis and biological activity testing. BEAS-2B cells were exposed to PM 2.5 organic extract to assess cytotoxicity, levels of cytokines and relative gene expression of MHC-II, hPXR and CYP3A5. Our findings show that organic PM 2.5 consist of toxic as well as bioactive components that can regulate the secretion of cytokines in BEAS-2B, which could modulate inflammatory response in the lung. Trace element analyses confirmed the presence of metals in organic extracts highlighting the relative high abundance of Cu and Zn in polar organic extracts. Polar organic extracts exhibited dose-dependant toxicity and were found to significantly induce the release of interleukin 6 (IL-6), IL-1β and IL-7 while significantly inhibiting the secretion of IL-8, G-CSF and MCP-1. Moreover, MHC-II transcriptional activity was up-regulated after 24 h of exposure, whereas PXR and CYP3A5 were down-regulated. This research provides a new insight into the effects of PM 2.5 organic fractions on specific effectors and their possible role in the development of respiratory inflammatory diseases in Puerto Rico.

  11. Signaling factors and pathways of α-particle irradiation induced bilateral bystander responses between Beas-2B and U937 cells

    International Nuclear Information System (INIS)

    Fu, Jiamei; Wang, Juan; Wang, Xiangdong; Wang, Ping; Xu, Jinping; Zhou, Cuiping; Bai, Yang; Shao, Chunlin

    2016-01-01

    Highlights: • Radiation damage of Beas-2B cells was enhanced by macrophage-mediated bilateral bystander responses. • Expressions of TNF-α and IL-8 in the α-irradiated Beas-2B cells were dependent on ERK and p38 pathways. • The neighboring U937 cells further increased the generation of TNF-α and IL-8 in the α-irradiated Beas-2B cells. • NF-κB dependent upregulation of TNF-α and IL-8 was induced in the bystander U937 cells. - Abstract: Although radiation induced bystander effects (RIBE) have been investigated for decades for their potential health risk, the underlying gene regulation is still largely unclear, especially the roles of immune system and inflammatory response in RIBE. In the present study, macrophage U937 cells and epithelial Beas-2B cells were co-cultured to disclose the cascades of bystander signaling factors and intercellular communications. After α-particle irradiation, both ERK and p38 pathways were activated in Beas-2B cells and were associated with the autocrine and paracrine signaling of TNF-α and IL-8, resulting in direct damage to the irradiated cells. Similar upregulation of TNF-α and IL-8 was induced in the bystander U937 cells after co-culture with α-irradiated Beas-2B cells. This upregulation was dependent on the activation of NF-κB pathway and was responsible for the enhanced damage of α-irradiated Beas-2B cells. Interestingly, the increased expressions of TNF-α and IL-8 mRNAs in the bystander U937 cells were clearly relayed on the activated ERK and p38 pathways in the irradiated Beas-2B cells, and the upregulation of TNF-α and IL-8 mRNAs in co-cultured Beas-2B cells was also partly due to the activated NF-κB pathway in the bystander U937 cells. With the pretreatment of U0126 (MEK1/2 inhibitor), SB203580 (p38 inhibitor) or BAY 11-7082 (NF-κB inhibitor), the aggravated damage in the α-irradiated Beas-2B cells could be largely alleviated. Our results disclosed novel signaling cascades of macrophage-mediated bilateral

  12. Signaling factors and pathways of α-particle irradiation induced bilateral bystander responses between Beas-2B and U937 cells

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Jiamei; Wang, Juan; Wang, Xiangdong; Wang, Ping; Xu, Jinping; Zhou, Cuiping; Bai, Yang; Shao, Chunlin, E-mail: clshao@shmu.edu.cn

    2016-07-15

    Highlights: • Radiation damage of Beas-2B cells was enhanced by macrophage-mediated bilateral bystander responses. • Expressions of TNF-α and IL-8 in the α-irradiated Beas-2B cells were dependent on ERK and p38 pathways. • The neighboring U937 cells further increased the generation of TNF-α and IL-8 in the α-irradiated Beas-2B cells. • NF-κB dependent upregulation of TNF-α and IL-8 was induced in the bystander U937 cells. - Abstract: Although radiation induced bystander effects (RIBE) have been investigated for decades for their potential health risk, the underlying gene regulation is still largely unclear, especially the roles of immune system and inflammatory response in RIBE. In the present study, macrophage U937 cells and epithelial Beas-2B cells were co-cultured to disclose the cascades of bystander signaling factors and intercellular communications. After α-particle irradiation, both ERK and p38 pathways were activated in Beas-2B cells and were associated with the autocrine and paracrine signaling of TNF-α and IL-8, resulting in direct damage to the irradiated cells. Similar upregulation of TNF-α and IL-8 was induced in the bystander U937 cells after co-culture with α-irradiated Beas-2B cells. This upregulation was dependent on the activation of NF-κB pathway and was responsible for the enhanced damage of α-irradiated Beas-2B cells. Interestingly, the increased expressions of TNF-α and IL-8 mRNAs in the bystander U937 cells were clearly relayed on the activated ERK and p38 pathways in the irradiated Beas-2B cells, and the upregulation of TNF-α and IL-8 mRNAs in co-cultured Beas-2B cells was also partly due to the activated NF-κB pathway in the bystander U937 cells. With the pretreatment of U0126 (MEK1/2 inhibitor), SB203580 (p38 inhibitor) or BAY 11-7082 (NF-κB inhibitor), the aggravated damage in the α-irradiated Beas-2B cells could be largely alleviated. Our results disclosed novel signaling cascades of macrophage-mediated bilateral

  13. Identification of PM{sub 10} characteristics involved in cellular responses in human bronchial epithelial cells (Beas-2B)

    Energy Technology Data Exchange (ETDEWEB)

    Van Den Heuvel, Rosette, E-mail: rosette.vandenheuvel@vito.be [Flemish Institute for Technological Research (VITO), Environmental Risk and Health Unit, Boeretang 200, 2400 Mol (Belgium); Den Hond, Elly, E-mail: elly.denhond@wiv-isp.be [Flemish Institute for Technological Research (VITO), Environmental Risk and Health Unit, Boeretang 200, 2400 Mol (Belgium); Govarts, Eva, E-mail: eva.govarts@vito.be [Flemish Institute for Technological Research (VITO), Environmental Risk and Health Unit, Boeretang 200, 2400 Mol (Belgium); Colles, Ann, E-mail: ann.colles@vito.be [Flemish Institute for Technological Research (VITO), Environmental Risk and Health Unit, Boeretang 200, 2400 Mol (Belgium); Koppen, Gudrun, E-mail: gudrun.koppen@vito.be [Flemish Institute for Technological Research (VITO), Environmental Risk and Health Unit, Boeretang 200, 2400 Mol (Belgium); Staelens, Jeroen, E-mail: j.staelens@vmm.be [Flanders Environment Agency (VMM), Unit Air, Kronenburgstraat 45, 2000 Antwerp (Belgium); Mampaey, Maja, E-mail: maja.mampaey@lne.vlaanderen.be [LNE (Environment, Nature and Energy Department), Flemish Government, Koning Albert II-laan 20, 1000 Brussels (Belgium); Janssen, Nicole, E-mail: nicole.janssen@rivm.nl [National Institute for Public Health and the Environment (RIVM), P.O. Box, 2720 BA, Bilthoven (Netherlands); Schoeters, Greet, E-mail: greet.schoeters@vito.be [Flemish Institute for Technological Research (VITO), Environmental Risk and Health Unit, Boeretang 200, 2400 Mol (Belgium); University of Antwerp, Department of Biomedical Sciences, 2000 Antwerp (Belgium)

    2016-08-15

    Notwithstanding evidence is present that physicochemical characteristics of ambient particles attribute to adverse health effects, there is still some lack of understanding in this complex relationship. At this moment it is not clear which properties (such as particle size, chemical composition) or sources of the particles are most relevant for health effects. This study investigates the in vitro toxicity of PM{sub 10} in relation to PM chemical composition, black carbon (BC), endotoxin content and oxidative potential (OP). In 2013–2014 PM{sub 10} was sampled (24 h sampling, 108 sampling days) in ambient air at three sites in Flanders (Belgium) with different pollution characteristics: an urban traffic site (Borgerhout), an industrial area (Zelzate) and a rural background location (Houtem). To characterize the toxic potential of PM{sub 10}, airway epithelial cells (Beas-2B cells) have been exposed to particles in vitro. Different endpoints were studied including cell damage and death (cell viability) using the Neutral red Uptake assay, the production of pro-inflammatory molecules by interleukin 8 (IL-8) induction and DNA-damaging activity using the FPG-modified Comet assay. The endotoxin levels in the collected samples were analysed and the capacity of PM{sub 10} particles to produce reactive oxygen species (OP) was evaluated by electron paramagnetic resonance (EPR) spectroscopy. Chemical characteristics of PM{sub 10} (BC, As, Cd, Cr, Cu, Mn, Ni, Pb, Zn) and meteorological conditions were recorded on the sampling days. PM{sub 10} particles exhibited dose-dependent cytotoxicity in Beas-2B cells and were found to significantly induce the release of IL-8 in samples from the three locations. Oxidatively damaged DNA was observed in exposed Beas-2B cells. Endotoxin levels above the detection limit were detected in half of the samples. OP was measurable in all samples. Associations between PM{sub 10} characteristics and biological effects of PM{sub 10} were assessed by

  14. p52-Bcl3 complex promotes cyclin D1 expression in BEAS-2B cells in response to low concentration arsenite

    International Nuclear Information System (INIS)

    Wang, Feng; Shi, Yongli; Yadav, Santosh; Wang, He

    2010-01-01

    Arsenic is a well-recognized human carcinogen that causes a number of malignant diseases, including lung cancer. Previous studies have indicated that cyclin D1 is frequently over-expressed in many cancer types. It is also known that arsenite exposure enhances cyclin D1 expression, which involves NF-κB activation. However, the mechanism between cyclin D1 and the NF-κB pathway has not been well studied. This study was designed to characterize the underlying mechanism of induced cell growth and cyclin D1 expression in response to low concentration sodium arsenic (NaAsO 2 ) exposure through the NF-κB pathway. Cultured human bronchial epithelial cells, BEAS-2B, were exposed to low concentration sodium arsenite for the indicated durations, and cytotoxicity, gene expression, and protein activity were assessed. To profile the canonical and non-canonical NF-κB pathways involved in cell growth and cyclin D1 expression induced by low concentration arsenite, the NF-κB-specific inhibitor-phenethyl caffeate (CAPE) and NF-κB2 mRNA target sequences were used, and cyclin D1 expression in BEAS-2B cells was assessed. Our results demonstrated that exposure to low concentration arsenite enhanced BEAS-2B cells growth and cyclin D1 mRNA and protein expression. Activation and nuclear localization of p52 and Bcl3 in response to low concentration arsenite indicated that the non-canonical NF-κB pathway was involved in arsenite-induced cyclin D1 expression. Moreover, we further demonstrated that p52/Bcl3 complex formation enhanced cyclin D1 expression through the cyclin D1 gene promoter via its κB site. The up-regulation of cyclin D1 mediated by the p52-Bcl3 complex in response to low concentration arsenite might be important in assessing the health risk of low concentration arsenite and understanding the mechanisms of the harmful effects of arsenite.

  15. Biological responses according to the shape and size of carbon nanotubes in BEAS-2B and MESO-1 cells

    Directory of Open Access Journals (Sweden)

    Haniu H

    2014-04-01

    Full Text Available Hisao Haniu,1,2 Naoto Saito,2,3 Yoshikazu Matsuda,4 Tamotsu Tsukahara,5 Yuki Usui,1,6,7 Kayo Maruyama,2,3 Seiji Takanashi,1 Kaoru Aoki,1 Shinsuke Kobayashi,1 Hiroki Nomura,1 Manabu Tanaka,1 Masanori Okamoto,1 Hiroyuki Kato1 1Department of Orthopaedic Surgery, Shinshu University School of Medicine, Nagano, Japan; 2Insutitute for Biomedical Sciences, Shinshu University, Nagano, Japan; 3Department of Applied Physical Therapy, Shinshu University School of Health Sciences, Nagano, Japan; 4Clinical Pharmacology Educational Center, Nihon Pharmaceutical University, Saitama, Japan; 5Department of Hematology and Immunology, Kanazawa Medical University, Ishikawa, Japan; 6Research Center for Exotic Nanocarbons, Shinshu University, Nagano, Japan; 7Aizawa Hospital, Sports Medicine Center, Nagano, Japan Abstract: This study aimed to investigate the influence of the shape and size of multi-walled carbon nanotubes (MWCNTs and cup-stacked carbon nanotubes (CSCNTs on biological responses in vitro. Three types of MWCNTs – VGCF®-X, VGCF®-S, and VGCF® (vapor grown carbon fibers; with diameters of 15, 80, and 150 nm, respectively – and three CSCNTs of different lengths (CS-L, 20–80 µm; CS-S, 0.5–20 µm; and CS-M, of intermediate length were tested. Human bronchial epithelial (BEAS-2B and malignant pleural mesothelioma cells were exposed to the CNTs (1–50 µg/mL, and cell viability, permeability, uptake, total reactive oxygen species/superoxide production, and intracellular acidity were measured. CSCNTs were less toxic than MWCNTs in both cell types over a 24-hour exposure period. The cytotoxicity of endocytosed MWCNTs varied according to cell type/size, while that of CSCNTs depended on tube length irrespective of cell type. CNT diameter and length influenced cell aggregation and injury extent. Intracellular acidity increased independently of lysosomal activity along with the number of vacuoles in BEAS-2B cells exposed for 24 hours to either CNT

  16. The crosstalk between α-irradiated Beas-2B cells and its bystander U937 cells through MAPK and NF-κB signaling pathways.

    Science.gov (United States)

    Fu, Jiamei; Yuan, Dexiao; Xiao, Linlin; Tu, Wenzhi; Dong, Chen; Liu, Weili; Shao, Chunlin

    2016-01-01

    Although accumulated evidence suggests that α-particle irradiation induced bystander effect may relevant to lung injury and cancer risk assessment, the exact mechanisms are not yet elucidated. In the present study, a cell co-culture system was used to investigate the interaction between α-particle irradiated human bronchial epithelial cells (Beas-2B) and its bystander macrophage U937 cells. It was found that the cell co-culture amplified the detrimental effects of α-irradiation including cell viability decrease and apoptosis promotion on both irradiated cells and bystander cells in a feedback loop which was closely relevant to the activation of MAPK and NF-κB pathways in the bystander U937 cells. When these two pathways in U937 cells were disturbed by special pharmacological inhibitors before cell co-culture, it was found that a NF-κB inhibitor of BAY 11-7082 further enhanced the proliferation inhibition and apoptosis induction in bystander U937 cells, but MAPK inhibitors of SP600125 and SB203580 protected cells from viability loss and apoptosis and U0126 presented more beneficial effect on cell protection. For α-irradiated epithelial cells, the activation of NF-κB and MAPK pathways in U937 cells participated in detrimental cellular responses since the above inhibitors could largely attenuate cell viability loss and apoptosis of irradiated cells. Our results demonstrated that there are bilateral bystander responses between irradiated lung epithelial cells and macrophages through MAPK and NF-κB signaling pathways, which accounts for the enhancement of α-irradiation induced damage. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Primary study on the lesions and specific proteins in BEAS-2B cells induced with the 2009 A (H1N1) influenza virus.

    Science.gov (United States)

    Fang, Shisong; Zhang, Kaining; Wang, Ting; Wang, Xin; Lu, Xing; Peng, Bo; Wu, Weihua; Zhang, Ran; Chen, Shiju; Zhang, Renli; Xue, Hong; Yu, Muhua; Cheng, Jinquan

    2014-12-01

    In order to investigate the lesions and proteins with differential expression in cells infected with the 2009 A (H1N1) virus and to determine the specific proteins involved in cell damage, the present study has been performed. BEAS-2B cells were infected with the 2009 A (H1N1) influenza virus or the seasonal H1N1 influenza virus for 12, 24, 48, and 72 h, and cell cycle and apoptosis were analyzed with flow cytometry. Total cellular proteins were extracted and underwent two-dimensional gel electrophoresis. The differentially expressed proteins underwent mass spectrometry for identification. The results showed that after 12 h, cells infected with the virus strain sourced from severe cases had the highest apoptosis rate (P cells infected with the virus strain sourced from fatal cases and severe cases had the highest apoptosis rate (P cells infected with virus strains from fatal cases and ordinary cases had the highest apoptosis rate (P cell cycle arrest mainly at the G0/G1 phase. Eighteen differentially expressed proteins were identified, including galectin-1, cofilin-1, protein DJ-1, proteasome subunit α type-5, macrophage migration inhibitory factor, translationally controlled tumor protein, profilin 1, and interferon α-2. Galectin-1 was specifically observed in BEAS-2B infected with 2009 A (H1N1) influenza viruses, and cofilin-1 was specifically observed in BEAS-2B cells in the late stage of 2009 A (H1N1) influenza virus infection. In conclusion, differential effects of the 2009 A (H1N1) influenza virus and seasonal H1N1 influenza virus were identified on the cell cycle and apoptosis, and galectin-1 may play a role in cell apoptosis induced by 2009 A (H1N1) influenza virus.

  18. Toxicological Impact of Air Pollution Particulate Matter PM 2.5 Collected under Urban Industrial or Rural Influence Occurrence of Oxidative Stress and Inflammatory Reaction in BEAS 2B Human Bronchial Epithelial Cells Corrected Version

    International Nuclear Information System (INIS)

    Dergham, M.; Billet, S; Verdin, A.; Courcot, D.; Cazier, F.; Pirouz, Sh.; Garcon, G.

    2011-01-01

    Exposure to air pollution Particulate Matter (PM) is one of the risk factors involved in the high incidence of respiratory and cardio-vascular diseases. In this work, to integrate inter-seasonal and inter-site variations, fine particle (PM2.5) samples have been collected in spring-summer 2008) and autumn 2008-winter 2009, in Dunkerque (France) under urban or industrial influence, and in Rubrouck (France), under rural influence. Attention was paid to characterize their physico-chemical characteristics, and to determine their ability to induce oxidative stress and inflammatory response in a human bronchial epithelial cell model (BEAS-2B cell line). Physico-chemical characterization of the six PM samples showed their heterogeneities and complexities depending upon their respective natural and/or anthropogenic emission sources. Lung cytotoxicity of these air pollution PM2.5 samples, as shown in BEAS-2B cells, might rely on the induction of oxidative stress conditions and particularly on the excessive inflammatory response. (author)

  19. Cadmium induces carcinogenesis in BEAS-2B cells through ROS-dependent activation of PI3K/AKT/GSK-3β/β-catenin signaling

    Energy Technology Data Exchange (ETDEWEB)

    Son, Young-Ok; Wang, Lei; Poyil, Pratheeshkumar; Budhraja, Amit; Hitron, J. Andrew; Zhang, Zhuo [Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY (United States); Lee, Jeong-Chae [Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY (United States); School of Dentistry and Institute of Oral Biosciences (BK21 program), Research Center of Bioactive Materials, Chonbuk National University, Jeonju 561-756 (Korea, Republic of); Shi, Xianglin, E-mail: xshi5@email.uky.edu [Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY (United States)

    2012-10-15

    Cadmium has been widely used in industry and is known to be carcinogenic to humans. Although it is widely accepted that chronic exposure to cadmium increases the incidence of cancer, the mechanisms underlying cadmium-induced carcinogenesis are unclear. The main aim of this study was to investigate the role of reactive oxygen species (ROS) in cadmium-induced carcinogenesis and the signal transduction pathways involved. Chronic exposure of human bronchial epithelial BEAS-2B cells to cadmium induced cell transformation, as evidenced by anchorage-independent growth in soft agar and clonogenic assays. Chronic cadmium treatment also increased the potential of these cells to invade and migrate. Injection of cadmium-stimulated cells into nude mice resulted in the formation of tumors. In contrast, the cadmium-mediated increases in colony formation, cell invasion and migration were prevented by transfection with catalase, superoxide dismutase-1 (SOD1), or SOD2. In particular, chronic cadmium exposure led to activation of signaling cascades involving PI3K, AKT, GSK-3β, and β-catenin and transfection with each of the above antioxidant enzymes markedly inhibited cadmium-mediated activation of these signaling proteins. Inhibitors specific for AKT or β-catenin almost completely suppressed the cadmium-mediated increase in total and active β-catenin proteins and colony formation. Moreover, there was a marked induction of AKT, GSK-3β, β-catenin, and carcinogenic markers in tumor tissues formed in mice after injection with cadmium-stimulated cells. Collectively, our findings suggest a direct involvement of ROS in cadmium-induced carcinogenesis and implicate a role of AKT/GSK-3β/β-catenin signaling in this process. -- Highlights: ► Chronic exposure to cadmium induces carcinogenic properties in BEAS-2B cells. ► ROS involved in cadmium-induced tumorigenicity of BEAS-2B cells. ► Cadmium activates ROS-dependent AKT/GSK-3β/β-catenin-mediated signaling. ► ROS

  20. Nicotinamide N-Methyltransferase Suppression Participates in Nickel-Induced Histone H3 Lysine9 Dimethylation in BEAS-2B Cells

    Directory of Open Access Journals (Sweden)

    Qian Li

    2017-04-01

    Full Text Available Background: Nickel compounds are well-established human carcinogens with weak mutagenic activity. Histone methylation has been proposed to play an important role in nickel-induced carcinogenesis. Nicotinamide N-methyltransferase (NNMT decreases histone methylation in several cancer cells by altering the cellular ratio of S-adenosylmethionine (SAM to S-adenosylhomocysteine (SAH. However, the role of NNMT in nickel-induced histone methylation remains unclear. Methods: BEAS-2B cells were exposed to different concentrations of nickel chloride (NiCl2 for 72 h or 200 μM NiCl2 for different time periods. Histone H3 on lysine 9 (H3K9 mono-, di-, and trimethylation and NNMT protein levels were measured by western blot analysis. Expressions of NNMT mRNA and the H3k9me2-associated genes, mitogen-activated protein kinase 3 (MAP2K3 and dickkopf1 (DKK1, were determined by qPCR analysis. The cellular ratio of nicotinamide adenine dinucleotide (NAD+ to reduced NAD (NADH and SAM/SAH ratio were determined. Results: Exposure of BEAS-2B cells to nickel increased H3K9 dimethylation (H3K9me2, suppressed the expressions of H3K9me2-associated genes (MAP2K3 and DKK1, and induced NNMT repression at both the protein and mRNA levels. Furthermore, over-expression of NNMT inhibited nickel-induced H3K9me2 and altered the cellular SAM/SAH ratio. Additionally, the NADH oxidant phenazine methosulfate (PMS not only reversed the nickel-induced reduction in NAD+/NADH but also inhibited the increase in H3K9me2. Conclusions: These findings indicate that the repression of NNMT may underlie nickel-induced H3K9 dimethylation by altering the cellular SAM/SAH ratio.

  1. Nicotine Component of Cigarette Smoke Extract (CSE) Decreases the Cytotoxicity of CSE in BEAS-2B Cells Stably Expressing Human Cytochrome P450 2A13.

    Science.gov (United States)

    Ji, Minghui; Zhang, Yudong; Li, Na; Wang, Chao; Xia, Rong; Zhang, Zhan; Wang, Shou-Lin

    2017-10-13

    Cytochrome P450 2A13 (CYP2A13), an extrahepatic enzyme mainly expressed in the human respiratory system, has been reported to mediate the metabolism and toxicity of cigarette smoke. We previously found that nicotine inhibited 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism by CYP2A13, but its influence on other components of cigarette smoke remains unclear. The nicotine component of cigarette smoke extract (CSE) was separated, purified, and identified using high-performance liquid chromatography (HPLC) and ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), splitting CSE into a nicotine section (CSE-N) and nicotine-free section (CSE-O). Cell viability and apoptosis by Cell Counting Kit-8 (CCK-8) and flow cytometry assays were conducted on immortalized human bronchial epithelial (BEAS-2B) cells stably expressing CYP2A13 (B-2A13) or vector (B-V), respectively. Interestingly, CSE and CSE-O were toxic to BEAS-2B cells whereas CSE-N showed less cytotoxicity. CSE-O was more toxic to B-2A13 cells than to B-V cells (IC 50 of 2.49% vs. 7.06%), which was flatted by 8-methoxypsoralen (8-MOP), a CYP inhibitor. CSE-O rather than CSE or CSE-N increased apoptosis of B-2A13 cells rather than B-V cells. Accordingly, compared to CSE-N and CSE, CSE-O significantly changed the expression of three pairs of pro- and anti-apoptotic proteins, Bcl-2 Associated X Protein/B cell lymphoma-2 (Bax/Bcl-2), Cleaved Poly (Adenosine Diphosphate-Ribose) Polymerase/Poly (Adenosine Diphosphate-Ribose) Polymerase (C-PARP/PARP), and C-caspase-3/caspase-3, in B-2A13 cells. In addition, recombination of CSE-N and CSE-O (CSE-O/N) showed similar cytotoxicity and apoptosis to the original CSE. These results demonstrate that the nicotine component decreases the metabolic activation of CYP2A13 to CSE and aids in understanding the critical role of CYP2A13 in human respiratory diseases caused by cigarette smoking.

  2. Proteomic Responses of BEAS-2B Cells to Nontoxic and Toxic Chromium: Protein Indicators of Cytotoxicity Conversion

    Science.gov (United States)

    Hexavalent chromium (Cr (VI)) is an environmental human carcinogen which primarily targets lungs. Among a variety of toxic mechanisms, disruption of biological pathways via translational and post-translational modifications represents a key mechanism through which Cr (VI) induces...

  3. PI3K-delta mediates double-stranded RNA-induced upregulation of B7-H1 in BEAS-2B airway epithelial cells

    International Nuclear Information System (INIS)

    Kan-o, Keiko; Matsumoto, Koichiro; Asai-Tajiri, Yukari; Fukuyama, Satoru; Hamano, Saaka; Seki, Nanae; Nakanishi, Yoichi; Inoue, Hiromasa

    2013-01-01

    Highlights: •Double-stranded RNA upregulates B7-H1 on BEAS-2B airway epithelial cells. •The upregulation of B7-H1 is attenuated by inhibition of PI3Kδ isoform. •PI3Kδ-mediated upregulation of B7-H1 is independent of NF-κB activation. •Inhibition of PI3Kδ may prevent persistent viral infection induced by B7-H1. -- Abstract: Airway viral infection disturbs the health-related quality of life. B7-H1 (also known as PD-L1) is a coinhibitory molecule associated with the escape of viruses from the mucosal immunity, leading to persistent infection. Most respiratory viruses generate double-stranded (ds) RNA during replication. The stimulation of cultured airway epithelial cells with an analog of viral dsRNA, polyinosinic-polycytidylic acid (poly IC) upregulates the expression of B7-H1 via activation of the nuclear factor κB(NF-κB). The mechanism of upregulation was investigated in association with phosphatidylinositol 3-kinases (PI3Ks). Poly IC-induced upregulation of B7-H1 was profoundly suppressed by a pan-PI3K inhibitor and partially by an inhibitor or a small interfering (si)RNA for PI3Kδ in BEAS-2B cells. Similar results were observed in the respiratory syncytial virus-infected cells. The expression of p110δ was detected by Western blot and suppressed by pretreatment with PI3Kδ siRNA. The activation of PI3Kδ is typically induced by oxidative stress. The generation of reactive oxygen species was increased by poly IC. Poly IC-induced upregulation of B7-H1 was attenuated by N-acetyl-L-cysteine, an antioxidant, or by oxypurinol, an inhibitor of xanthine oxidase. Poly IC-induced activation of NF-κB was suppressed by a pan-PI3K inhibitor but not by a PI3Kδ inhibitor. These results suggest that PI3Kδ mediates dsRNA-induced upregulation of B7-H1 without affecting the activation of NF-κB

  4. Downregulation of B-cell lymphoma/leukemia-2 by overexpressed microRNA 34a enhanced titanium dioxide nanoparticle-induced autophagy in BEAS-2B cells

    Science.gov (United States)

    Bai, Wenlin; Chen, Yujiao; Sun, Pengling; Gao, Ai

    2016-01-01

    Titanium dioxide (TiO2) nanoparticles (TNPs) are manufactured worldwide for a wide range of applications and the toxic effect of TNPs on biological systems is gaining attention. Autophagy is recognized as an emerging toxicity mechanism triggered by nanomaterials. MicroRNA 34a (miR34a) acts as a tumor suppressor gene by targeting many oncogenes, but how it affects autophagy induced by TNPs is not completely understood. Here, we observed the activation of TNP-induced autophagy through monodansylcadaverine staining and LC3-I/LC3-II conversion. Meanwhile, the transmission electron microscope ultrastructural analysis showed typical morphological characteristics in autophagy process. We detected the expression of miR34a and B-cell lymphoma/leukemia-2 (Bcl-2). In addition, the underlying mechanism of TNP-induced autophagy was performed using overexpression of miR34a by lentivirus vector transfection. Results showed that TNPs induced autophagy generation evidently. Typical morphological changes in the process of autophagy were observed by the transmission electron microscope ultrastructural analysis and LC3-I/LC3-II conversion increased significantly in TNP-treated cells. Meanwhile, TNPs induced the downregulation of miR34a and increased the expression of Bcl-2. Furthermore, overexpressed miR34a decreased the expression of Bcl-2 both in messenger RNA and protein level, following which the level of autophagy and cell death rate increased after the transfected cells were incubated with TNPs for 24 hours. These findings provide the first evidence that overexpressed miR34a enhanced TNP-induced autophagy and cell death through targeted downregulation of Bcl-2 in BEAS-2B cells. PMID:27226226

  5. DNA damage and DNA damage response in human bronchial epithelial BEAS-2B cells following exposure to 2-nitrobenzanthrone and 3-nitrobenzanthrone: role in apoptosis.

    Science.gov (United States)

    Oya, Elisabeth; Ovrevik, Johan; Arlt, Volker M; Nagy, Eszter; Phillips, David H; Holme, Jørn A

    2011-11-01

    Nitro-polycyclic aromatic hydrocarbons (nitro-PAHs) are mutagenic and carcinogenic environmental pollutants found in diesel exhaust and on urban air pollution particles. In the present study, human bronchial epithelial BEAS-2B cells were exposed to 2-nitrobenzanthrone (2-NBA) and 3-nitrobenzanthrone (3-NBA). DNA damage responses were compared to those observed after exposure to 1-nitropyrene (1-NP) and benzo[a]pyrene (B[a]P). Examination by microscopy revealed that 3-NBA was the most potent toxic compound while weaker responses were observed with 1-NP and B[a]P. Most interestingly, 2-NBA did not induce cell death or any other stress-related responses. 3-NBA induced a typical apoptotic cell death judged by nuclear condensation and little plasma membrane damage as well as cleavage of caspase 3 and poly-(ADP-ribose) polymerase (PARP). Exposure to 3-NBA resulted in an accumulation of cells in S-phase, and further analysis by Western blotting, immunocytochemistry and flow cytometry revealed that 3-NBA induced a DNA damage response characterized by phosphorylation of ATM (ataxia-telangiectasia mutated), checkpoint kinase (Chk) 2/Chk1, H2AX and p53. The p53 inhibitor pifithrin-α inhibited 3-NBA-induced apoptosis while small effects were seen using pifithrin-μ, suggesting that 3-NBA-induced cell death is a result of transcriptional activation of p53. In conclusion, 3-NBA is a potent inducer of apoptosis, which seemed to be triggered by the DNA damage response. Furthermore, a change of the nitro-group to the second position (i.e. 2-NBA) dramatically changed the cellular reactivity of the compound.

  6. Cellular Interactions and Biological Responses to Titanium Dioxide Nanoparticles in HepG2 and BEAS-2B Cells: Role of Cell Culture Media

    Science.gov (United States)

    ABSTRACT We have shown previously that the composition of the biological medium used in vitro can affect the cellular interaction and biological response of titanium dioxide nanoparticles (nano-TiO2) in human lung epithelial cells. However, it is unclear if these effects are co...

  7. Proinflammatory effects of diesel exhaust particles from moderate blend concentrations of 1st and 2nd generation biodiesel in BEAS-2B bronchial epithelial cells-The FuelHealth project.

    Science.gov (United States)

    Skuland, Tonje S; Refsnes, Magne; Magnusson, Pål; Oczkowski, Michał; Gromadzka-Ostrowska, Joanna; Kruszewski, Marcin; Mruk, Remigiusz; Myhre, Oddvar; Lankoff, Anna; Øvrevik, Johan

    2017-06-01

    Biodiesel fuel fuels are introduced at an increasing extent as a more carbon-neutral alternative to reduce CO 2 -emissions, compared to conventional diesel fuel. In the present study we have investigated the impact of increasing the use of 1st generation fatty acid methyl ester (FAME) biodiesel from current 7% blend (B7) to 20% blend (B20), or by increasing the biodiesel content by adding 2nd generation hydrotreated vegetable oil (HVO) based biodiesel (SHB; Synthetic Hydrocarbon Biofuel) on toxicity of diesel exhaust particles (DEP) in an in vitro system. Human bronchial epithelial BEAS-2B cells were exposed for 4 and 20h to DEP from B7, B20 and SHB at different concentrations, and examined for effects on gene expression of interleukin 6 (IL-6), CXCL8 (IL-8), CYP1A1 and heme oxygenase-1 (HO-1). The results show that both B20 and SHB were more potent inducers of IL-6 expression compared to B7. Only B20 induced statistically significant increases in CXCL8 expression. By comparison the rank order of potency to induce CYP1A1 was SHB>B7>B20. No statistically significant difference were observed form HO-1 expression, suggesting that the differences in cytokine responses were not due to oxidative stress. The results show that even moderate increases in biodiesel blends, from 7% to 20%, may increase the proinflammatory potential of emitted DEP in BEAS-2B cells. This effect was observed for both addition of 1st generation FAME and 2nd generation HVO biodiesel. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Arsenic promotes centrosome abnormalities and cell colony formation in p53 compromised human lung cells

    International Nuclear Information System (INIS)

    Liao Weiting; Lin Pinpin; Cheng, T.-S.; Yu, H.-S.; Chang, Louis W.

    2007-01-01

    Epidemiological evidence indicated that residents, especially cigarette smokers, in arseniasis areas had significantly higher lung cancer risk than those living in non-arseniasis areas. Thus, an interaction between arsenic and cigarette smoking in lung carcinogenesis was suspected. p53 dysfunction or mutation in lung epithelial cells was frequently observed in cigarette smokers. Our present study was to explore the differential effects by arsenic on H1355 cells (human lung adenocarcinoma cell line with mutation in p53), BEAS-2B (immortalized lung epithelial cell with functional p53) and pifithrin-α-treated BEAS-2B cells (p53-inhibited cells). These cells were treated with different doses of sodium arsenite (0, 0.1, 1, 5 and 10 μM) for 48 h. A greater reduction in cell viability was observed in the BEAS-2B cells vs. p53 compromised cells (H1355 or p53-inhibited BEAS-2B). Similar observation was also made on 7-day cell survival (growth) study. TUNEL analysis confirmed that there was indeed a significantly reduced arsenite-induced apoptosis found in p53-compromised cells. Centrosomal abnormality has been attributed to eventual chromosomal missegregation, aneuploidy and tumorigenesis. In our present study, reduced p21 and Gadd45a expressions and increased centrosomal abnormality (atopic and multiple centrosomes) were observed in both arsenite-treated H1355 and p53-inhibited BEAS-2B cells as compared with similarly treated BEAS-2B cells. Increased anchorage-independent growth (colony formation) of BEAS-2B cells co-treated with pifithrin-α and 5 μM sodium arsenite was also observed in soft agar. Our present investigation demonstrated that arsenic would act specifically on p53 compromised cells (either with p53 dysfunction or inhibited) to induce centrosomal abnormality and colony formation. These findings provided strong evidence on the carcinogenic promotional role of arsenic, especially under the condition of p53 dysfunction

  9. Comparative Analysis of Toxic Responses of Organic Extracts from Diesel and Selected Alternative Fuels Engine Emissions in Human Lung BEAS-2B Cells

    Czech Academy of Sciences Publication Activity Database

    Líbalová, Helena; Rössner ml., Pavel; Vrbová, Kristýna; Brzicová, Táňa; Sikorová, Jitka; Vojtíšek-Lom, M.; Beránek, V.; Kléma, J.; Cigánek, M.; Neča, J.; Pěnčíková, K.; Machala, M.; Topinka, Jan

    2016-01-01

    Roč. 17, č. 11 (2016), s. 1833 E-ISSN 1422-0067 R&D Projects: GA ČR(CZ) GA13-01438S; GA MŠk(CZ) LO1508; GA MŠk(CZ) LM2015073 Institutional support: RVO:68378041 Keywords : diesel * alternative fuel s * diesel exhaust particles Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 3.226, year: 2016

  10. Selective ATP-Binding Cassette Subfamily C Gene Expression and Proinflammatory Mediators Released by BEAS-2B after PM2.5, Budesonide, and Cotreated Exposures

    Directory of Open Access Journals (Sweden)

    Jarline Encarnación-Medina

    2017-01-01

    Full Text Available ATP-binding cassette subfamily C (ABCC genes code for phase III metabolism proteins that translocate xenobiotic (e.g., particulate matter 2.5 (PM2.5 and drug metabolites outside the cells. IL-6 secretion is related with the activation of the ABCC transporters. This study assesses ABCC1–4 gene expression changes and proinflammatory cytokine (IL-6, IL-8 release in human bronchial epithelial cells (BEAS-2B exposed to PM2.5 organic extract, budesonide (BUD, used to control inflammation in asthmatic patients, and a cotreatment (Co-T: PM2.5 and BUD. A real-time PCR assay shows that ABCC1 was upregulated in BEAS-2B exposed after 6 and 7 hr to PM2.5 extract or BUD but downregulated after 6 hr of the Co-T. ABCC3 was downregulated after 6 hr of BUD and upregulated after 6 hr of the Co-T exposures. ABCC4 was upregulated after 5 hr of PM2.5 extract, BUD, and the Co-T exposures. The cytokine assay revealed an increase in IL-6 release by BEAS-2B exposed after 5 hr to PM2.5 extract, BUD, and the Co-T. At 7 hr, the Co-T decreases IL-6 release and IL-8 at 6 hr. In conclusion, the cotreatment showed an opposite effect on exposed BEAS-2B as compared with BUD. The results suggest an interference of the BUD therapeutic potential by PM2.5.

  11. Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Pratheeshkumar, Poyil; Son, Young-Ok; Divya, Sasidharan Padmaja; Roy, Ram Vinod; Hitron, John Andrew; Wang, Lei [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Kim, Donghern; Dai, Jin [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Asha, Padmaja [National Centre for Aquatic Animal Health, Cochin University of Science and Technology, Cochin (India); Zhang, Zhuo [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Wang, Yitao [State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau (China); Shi, Xianglin, E-mail: xshi5@email.uky.edu [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States)

    2014-12-01

    Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5 μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis. - Highlights: • Luteolin inhibited Cr(VI)-induced oxidative stress. • Luteolin inhibited chronic Cr(VI)-induced malignant transformation.

  12. Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways

    International Nuclear Information System (INIS)

    Pratheeshkumar, Poyil; Son, Young-Ok; Divya, Sasidharan Padmaja; Roy, Ram Vinod; Hitron, John Andrew; Wang, Lei; Kim, Donghern; Dai, Jin; Asha, Padmaja; Zhang, Zhuo; Wang, Yitao; Shi, Xianglin

    2014-01-01

    Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5 μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis. - Highlights: • Luteolin inhibited Cr(VI)-induced oxidative stress. • Luteolin inhibited chronic Cr(VI)-induced malignant transformation.

  13. The Phosphodiesterase 4 Inhibitor Roflumilast Protects against Cigarette Smoke Extract-Induced Mitophagy-Dependent Cell Death in Epithelial Cells.

    Science.gov (United States)

    Kyung, Sun Young; Kim, Yu Jin; Son, Eun Suk; Jeong, Sung Hwan; Park, Jeong Woong

    2018-04-01

    Recent studies show that mitophagy, the autophagy-dependent turnover of mitochondria, mediates pulmonary epithelial cell death in response to cigarette smoke extract (CSE) exposure and contributes to the development of emphysema in vivo during chronic cigarette smoke (CS) exposure, although the underlying mechanisms remain unclear. In this study, we investigated the role of mitophagy in the regulation of CSE-exposed lung bronchial epithelial cell (Beas-2B) death. We also investigated the role of a phosphodiesterase 4 inhibitor, roflumilast, in CSE-induced mitophagy-dependent cell death. Our results demonstrated that CSE induces mitophagy in Beas-2B cells through mitochondrial dysfunction and increased the expression levels of the mitophagy regulator protein, PTEN-induced putative kinase-1 (PINK1), and the mitochondrial fission protein, dynamin-1-like protein (DRP1). CSE-induced epithelial cell death was significantly increased in Beas-2B cells exposed to CSE but was decreased by small interfering RNA-dependent knockdown of DRP1. Treatment with roflumilast in Beas-2B cells inhibited CSE-induced mitochondrial dysfunction and mitophagy by inhibiting the expression of phospho-DRP1 and -PINK1. Roflumilast protected against cell death and increased cell viability, as determined by the lactate dehydrogenase release test and the MTT assay, respectively, in Beas-2B cells exposed to CSE. These findings suggest that roflumilast plays a protective role in CS-induced mitophagy-dependent cell death. Copyright©2018. The Korean Academy of Tuberculosis and Respiratory Diseases.

  14. Differences in gene expression and cytokine production by crystalline vs. amorphous silica in human lung epithelial cells

    Directory of Open Access Journals (Sweden)

    Perkins Timothy N

    2012-02-01

    Full Text Available Abstract Background Exposure to respirable crystalline silica particles, as opposed to amorphous silica, is associated with lung inflammation, pulmonary fibrosis (silicosis, and potentially with lung cancer. We used Affymetrix/GeneSifter microarray analysis to determine whether gene expression profiles differed in a human bronchial epithelial cell line (BEAS 2B exposed to cristobalite vs. amorphous silica particles at non-toxic and equal surface areas (75 and 150 × 106μm2/cm2. Bio-Plex analysis was also used to determine profiles of secreted cytokines and chemokines in response to both particles. Finally, primary human bronchial epithelial cells (NHBE were used to comparatively assess silica particle-induced alterations in gene expression. Results Microarray analysis at 24 hours in BEAS 2B revealed 333 and 631 significant alterations in gene expression induced by cristobalite at low (75 and high (150 × 106μm2/cm2 amounts, respectively (p 6μm2/cm2 induced 108 significant gene changes. Bio-Plex analysis of 27 human cytokines and chemokines revealed 9 secreted mediators (p FOS, ATF3, IL6 and IL8 early and over time (2, 4, 8, and 24 h. Patterns of gene expression in NHBE cells were similar overall to BEAS 2B cells. At 75 × 106μm2/cm2, there were 339 significant alterations in gene expression induced by cristobalite and 42 by amorphous silica. Comparison of genes in response to cristobalite (75 × 106μm2/cm2 revealed 60 common, significant gene alterations in NHBE and BEAS 2B cells. Conclusions Cristobalite silica, as compared to synthetic amorphous silica particles at equal surface area concentrations, had comparable effects on the viability of human bronchial epithelial cells. However, effects on gene expression, as well as secretion of cytokines and chemokines, drastically differed, as the crystalline silica induced more intense responses. Our studies indicate that toxicological testing of particulates by surveying viability and

  15. Wnt5a Is Associated with Cigarette Smoke-Related Lung Carcinogenesis via Protein Kinase C

    OpenAIRE

    Whang, Young Mi; Jo, Ukhyun; Sung, Jae Sook; Ju, Hyun Jung; Kim, Hyun Kyung; Park, Kyong Hwa; Lee, Jong Won; Koh, In Song; Kim, Yeul Hong

    2013-01-01

    Wnt5a is overexpressed during the progression of human non-small cell lung cancer. However, the roles of Wnt5a during smoking-related lung carcinogenesis have not been clearly elucidated. We investigated the associations between Wnt5a and the early development of cigarette smoke related lung cancer using human bronchial epithelial (HBE) cells (NHBE, BEAS-2B, 1799, 1198 and 1170I) at different malignant stages established by exposure to cigarette smoke condensate (CSC). Abnormal up-regulation ...

  16. Effects of bile acids on human airway epithelial cells: implications for aerodigestive diseases

    Directory of Open Access Journals (Sweden)

    Adil Aldhahrani

    2017-03-01

    Full Text Available Gastro-oesophageal reflux and aspiration have been associated with chronic and end-stage lung disease and with allograft injury following lung transplantation. This raises the possibility that bile acids may cause lung injury by damaging airway epithelium. The aim of this study was to investigate the effect of bile acid challenge using the immortalised human bronchial epithelial cell line (BEAS-2B. The immortalised human bronchial epithelial cell line (BEAS-2B was cultured. A 48-h challenge evaluated the effect of individual primary and secondary bile acids. Post-challenge concentrations of interleukin (IL-8, IL-6 and granulocyte−macrophage colony-stimulating factor were measured using commercial ELISA kits. The viability of the BEAS-2B cells was measured using CellTiter-Blue and MTT assays. Lithocholic acid, deoxycholic acid, chenodeoxycholic acid and cholic acid were successfully used to stimulate cultured BEAS-2B cells at different concentrations. A concentration of lithocholic acid above 10 μmol·L−1 causes cell death, whereas deoxycholic acid, chenodeoxycholic acid and cholic acid above 30 μmol·L−1 was required for cell death. Challenge with bile acids at physiological levels also led to a significant increase in the release of IL-8 and IL6 from BEAS-2B. Aspiration of bile acids could potentially cause cell damage, cell death and inflammation in vivo. This is relevant to an integrated gastrointestinal and lung physiological paradigm of chronic lung disease, where reflux and aspiration are described in both chronic lung diseases and allograft injury.

  17. Xianyu decoction attenuates the inflammatory response of human lung bronchial epithelial cell.

    Science.gov (United States)

    Yu, Chenyi; Xiang, Qiangwei; Zhang, Hailin

    2018-06-01

    Xianyu decoction (XD), a Chinese experience recipe, shows inhibitory effects on lung cancer. However, the potential functions of XD on pneumonia were unknown. This study aimed to investigate the effect of XD on inflammatory response of childhood pneumonia. Human lung bronchial epithelial cell line BEAS-2B was cultured in different doses of LPS with or without XD treatment. The expression of miR-15a and IKBKB were altered by transfection assay. RT-PCR and western blot were used to evaluate the effects of XD and miR-15a mimic/inhibitor on the expression levels of miR-15a, IKBKB, p65 and IκBα. ELISA was used to determine the levels of CRP, IL-6 and IL-8. High expression of miR-15a was observed in serum and cell model of pneumonia. miR-15a promoted the expression of inflammatory cytokines IL-6, IL-8, CRP and IKBKB in vitro. XD treatment downregulated the level of miR-15a in pneumonia children. In addition, XD reduced the expression of inflammatory cytokines and the phosphorylation levels of p65 and IκBα by inhibition of miR-15a and IKBKB expression in LPS-stimulated BEAS-2B cells. XD downregulated the level of miR-15a in serum of pneumonia children. Additionally, XD inhibited inflammatory response in LPS-stimulated BEAS-2B cells possibly by blocking IKBKB/NF-κB signal pathway which was regulated by miR-15a. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  18. Proteome Profiling of BEAS-2B Cells Treated with Titanium Dioxide Reveals Potential Toxicity of and Detoxification Pathways for Nanomaterial

    Science.gov (United States)

    Oxidative stress is known to play important roles in nanomaterial-induced toxicities. However, the proteins and signaling pathways associated with nanomaterial-mediated oxidative stress and toxicity are largely unknown. To identify oxidative stress-responding toxicity pathways an...

  19. Proteome Profiling Reveals Potential Toxicity and Detoxification Pathways Following Exposure of BEAS-2B Cells to Engineered Nanoparticle Titanium Dioxide

    Science.gov (United States)

    Identification of toxicity pathways linked to chemical -exposure is critical for a better understanding of biological effects of the exposure, toxic mechanisms, and for enhancement of the prediction of chemical toxicity and adverse health outcomes. To identify toxicity pathways a...

  20. Proteome Profiling Reveals Potential Toxicity and Detoxification Pathways Following Exposure of BEAS-2B Cells to Engineered Titanium Dioxide Nanoparticles

    Science.gov (United States)

    Oxidative stress is known to play important roles in engineered nanomaterial induced cellular toxicity. However, the proteins and signaling pathways associated with the engineered nanomaterial mediated oxidative stress and toxicity are largely unknown. To identify these toxicity ...

  1. Inflammatory Response and Barrier Dysfunction by Different e-Cigarette Flavoring Chemicals Identified by Gas Chromatography-Mass Spectrometry in e-Liquids and e-Vapors on Human Lung Epithelial Cells and Fibroblasts.

    Science.gov (United States)

    Gerloff, Janice; Sundar, Isaac K; Freter, Robert; Sekera, Emily R; Friedman, Alan E; Robinson, Risa; Pagano, Todd; Rahman, Irfan

    2017-03-01

    Recent studies suggest that electronic cigarette (e-cig) flavors can be harmful to lung tissue by imposing oxidative stress and inflammatory responses. The potential inflammatory response by lung epithelial cells and fibroblasts exposed to e-cig flavoring chemicals in addition to other risk-anticipated flavor enhancers inhaled by e-cig users is not known. The goal of this study was to evaluate the release of the proinflammatory cytokine (interleukin-8 [IL-8]) and epithelial barrier function in response to different e-cig flavoring chemicals identified in various e-cig e-liquid flavorings and vapors by chemical characterization using gas chromatography-mass spectrometry analysis. Flavorings, such as acetoin (butter), diacetyl, pentanedione, maltol (malt), ortho-vanillin (vanilla), coumarin, and cinnamaldehyde in comparison with tumor necrosis factor alpha (TNFα), were used in this study. Human bronchial epithelial cells (Beas2B), human mucoepidermoid carcinoma epithelial cells (H292), and human lung fibroblasts (HFL-1) were treated with each flavoring chemical for 24 hours. The cells and conditioned media were then collected and analyzed for toxicity (viability %), lung epithelial barrier function, and proinflammatory cytokine IL-8 release. Cell viability was not significantly affected by any of the flavoring chemicals tested at a concentration of 10 μM to 1 mM. Acetoin and diacetyl treatment induced IL-8 release in Beas2B cells. Acetoin- and pentanedione-treated HFL-1 cells produced a differential, but significant response for IL-8 release compared to controls and TNFα. Flavorings, such as ortho-vanillin and maltol, induced IL-8 release in Beas2B cells, but not in H292 cells. Of all the flavoring chemicals tested, acetoin and maltol were more potent inducers of IL-8 release than TNFα in Beas2B and HFL-1 cells. Flavoring chemicals rapidly impaired epithelial barrier function in human bronchial epithelial cells (16-HBE) as measured by electric cell surface

  2. Gene expression analysis uncovers novel Hedgehog interacting protein (HHIP) effects in human bronchial epithelial cells

    Science.gov (United States)

    Zhou, Xiaobo; Qiu, Weiliang; Sathirapongsasuti, J. Fah.; Cho, Michael H.; Mancini, John D.; Lao, Taotao; Thibault, Derek M.; Litonjua, Gus; Bakke, Per S.; Gulsvik, Amund; Lomas, David A.; Beaty, Terri H.; Hersh, Craig P.; Anderson, Christopher; Geigenmuller, Ute; Raby, Benjamin A.; Rennard, Stephen I.; Perrella, Mark A.; Choi, Augustine M.K.; Quackenbush, John; Silverman, Edwin K.

    2013-01-01

    Hedgehog Interacting Protein (HHIP) was implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS). However, it remains unclear how HHIP contributes to COPD pathogenesis. To identify genes regulated by HHIP, we performed gene expression microarray analysis in a human bronchial epithelial cell line (Beas-2B) stably infected with HHIP shRNAs. HHIP silencing led to differential expression of 296 genes; enrichment for variants nominally associated with COPD was found. Eighteen of the differentially expressed genes were validated by real-time PCR in Beas-2B cells. Seven of 11 validated genes tested in human COPD and control lung tissues demonstrated significant gene expression differences. Functional annotation indicated enrichment for extracellular matrix and cell growth genes. Network modeling demonstrated that the extracellular matrix and cell proliferation genes influenced by HHIP tended to be interconnected. Thus, we identified potential HHIP targets in human bronchial epithelial cells that may contribute to COPD pathogenesis. PMID:23459001

  3. 4-Methoxyestradiol-induced oxidative injuries in human lung epithelial cells

    International Nuclear Information System (INIS)

    Cheng Yahsin; Chang, Louis W.; Cheng Lichuan; Tsai, M.-H.; Lin Pinpin

    2007-01-01

    Epidemiological studies indicated that people exposed to dioxins were prone to the development of lung diseases including lung cancer. Animal studies demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increased liver tumors and promoted lung metaplasia in females. Metabolic changes in 17β-estradiol (E 2 ) resulted from an interaction between TCDD and E 2 could be associated with gender difference. Previously, we reported that methoxylestradiols (MeOE 2 ), especially 4-MeOE 2 , accumulated in human lung cells (BEAS-2B) co-treated with TCDD and E 2 . In the present study, we demonstrate unique accumulation of 4-MeOE 2 , as a result of TCDD/E 2 interaction and revealed its bioactivity in human lung epithelial cell line (H1355). 4-Methoxyestradiol treatment significantly decreased cell growth and increased mitotic index. Elevation of ROS and SOD activity, with a concomitant decrease in the intracellular GSH/GSSG ratio, was also detected in 4-MeOE 2 -treated cells. Quantitative comet assay showed increased oxidative DNA damage in the 4-MeOE 2 -treated H1355 cells, which could be significantly reduced by the anti-oxidant N-acetylcysteine (NAC). However, inhibition of cell growth and increase in mitotic arrest induced by 4-MeOE 2 were unaffected by NAC. We concluded that 4-MeOE 2 accumulation resulting from TCDD and E 2 interaction would contribute to the higher vulnerability on lung pathogenesis in females when exposed to TCDD

  4. Inhibition of lung cancer cells A549 and H460 by curcuminoid extracts and nanoemulsions prepared from Curcuma longa Linnaeus.

    Science.gov (United States)

    Chang, Hong-Bin; Chen, Bing-Huei

    2015-01-01

    The objectives of this study were to explore the inhibition mechanism of lung cancer cells A549 and H460 by curcuminoid extracts and nanoemulsions prepared from Curcuma longa Linnaeus. In addition, human bronchus epithelial cell line BEAS-2B (normal cell) was selected for comparison. A high-performance liquid chromatography (HPLC) method was developed to separate and quantify the various curcuminoids in C. longa extract, including curcumin (1,714.5 μg/mL), demethoxycurcumin (1,147.4 μg/mL), and bisdemethoxycurcumin (190.2 μg/mL). A high-stability nanoemulsion composed of Tween 80, water, and curcuminoid extract was prepared, with mean particle size being 12.6 nm. The cell cycle was retarded at G2/M for both the curcuminoid extract and nanoemulsion treatments; however, the inhibition pathway may be different. H460 cells were more susceptible to apoptosis than A549 cells for both curcuminoid extract and nanoemulsion treatments. Growth of BEAS-2B remained unaffected for both the curcuminoid extract and nanoemulsion treatments, with a concentration range from 1 to 4 μg/mL. Also, the activities of caspase-3, caspase-8, and caspase-9 followed a dose-dependent increase for both A549 and H460 cells for both the treatments, accompanied by a dose-dependent increase in cytochrome C expression and a dose-dependent decrease in CDK1 expression. Interestingly, a dose-dependent increase in cyclin B expression was shown for A549 cells for both the treatments, while a reversed trend was found for H460 cells. Both mitochondria and death receptor pathways may be responsible for apoptosis of both A549 and H460 cells.

  5. Inhibitory effects of Piper betle on production of allergic mediators by bone marrow-derived mast cells and lung epithelial cells.

    Science.gov (United States)

    Wirotesangthong, Mali; Inagaki, Naoki; Tanaka, Hiroyuki; Thanakijcharoenpath, Witchuda; Nagai, Hiroichi

    2008-03-01

    The leaves of the Piper betle Linn. (Piperaceae) are used in traditional medicine and possess anti-oxidant, anti-bacterial, anti-fungal, anti-diabetic and radioprotective activities. However, little is known about their anti-allergic activity. Therefore, the effects of P. betle ethanolic extract (PE) on the production of histamine and granulocyte macrophage-colony-stimulating factor (GM-CSF) by murine bone marrow mast cells (BMMCs) and on the secretion of eotaxin and IL-8 by the human lung epithelial cell line, BEAS-2B, were investigated in vitro. PE significantly decreased histamine and GM-CSF produced by an IgE-mediated hypersensitive reaction, and inhibited eotaxin and IL-8 secretion in a TNF-alpha and IL-4-induced allergic reaction. The results suggest that P. betle may offer a new therapeutic approach for the control of allergic diseases through inhibition of production of allergic mediators.

  6. Lung fibroblasts may play an important role in clearing apoptotic bodies of bronchial epithelial cells generated by exposure to PHMG-P-containing solution.

    Science.gov (United States)

    Park, Eun-Jung; Park, Sung-Jin; Kim, Sanghwa; Lee, Kyuhong; Chang, Jaerak

    2018-04-01

    Polyhexamethylene guanidine (PHMG) has been widely used in the industry owing to its excellent biocidal, anti-corrosive, and anti-biofouling properties. In Korea, consumers exposed to PHMG-phosphate (PHMG-P)-containing humidifier disinfectant have begun to suffer from fibrotic lung injury-related symptoms for unknown reasons. However, no appropriate treatment has yet been found because the detail toxic mechanism has not been identified. Herein, we first studied the toxic mechanism of PHMG-P-containing solution using human normal bronchial epithelial cells (BEAS-2B cells). When exposed for 24 h, PHMG-P-containing solution rapidly decreased cell viability from around 6 h after exposure and significantly increased of the phosphatidylserine exposure and the LDH release. At 6 h of exposure, the material contained in the solution was found to be bound to the cell membrane and the inner wall of vacuoles, and damaged the cell membrane and organelles. In addition, a significant increase of IFN-γ was observed among cytokines, the expression of apoptosis-, autophagy-, and membrane and DNA damage-related proteins was also enhanced. Meanwhile, the level of intracellular ROS and the secretion of IL-8 and CXCL-1, which are chemokines for professional phagocytes, decreased. Thus, we treated dead BEAS-2B cells to lung fibroblasts (HFL-1), non-professional phagocytes, and then we observed that the dead cells rapidly attached to HFL-1 cells and were taken up. Additionally, increased secretion of IL-8 and CXCL-1 was observed in the cells. Based on these results, we suggest that pulmonary exposure to PHMG-P induces apoptosis of bronchial epithelial cells and lung fibroblasts might play an important role in the clearance of the apoptotic debris. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Del-1 overexpression potentiates lung cancer cell proliferation and invasion

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Seung-Hwan; Kim, Dong-Young; Jing, Feifeng; Kim, Hyesoon [Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Yun, Chae-Ok [Department of Bioengineering, College of Engineering, Hanyang University, Seoul (Korea, Republic of); Han, Deok-Jong [Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Choi, Eun Young, E-mail: choieun@ulsan.ac.kr [Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2015-12-04

    Developmental endothelial locus-1 (Del-1) is an endogenous anti-inflammatory molecule that is highly expressed in the lung and the brain and limits leukocyte migration to these tissues. We previously reported that the expression of Del-1 is positively regulated by p53 in lung endothelial cells. Although several reports have implicated the altered expression of Del-1 gene in cancer patients, little is known about its role in tumor cells. We here investigated the effect of Del-1 on the features of human lung carcinoma cells. Del-1 mRNA was found to be significantly decreased in the human lung adenocarcinoma cell lines A549 (containing wild type of p53), H1299 (null for p53) and EKVX (mutant p53), compared to in human normal lung epithelial BEAS-2B cells and MRC-5 fibroblasts. The decrease of Del-1 expression was dependent on the p53 activity in the cell lines, but not on the expression of p53. Neither treatment with recombinant human Del-1 protein nor the introduction of adenovirus expressing Del-1 altered the expression of the apoptosis regulators BAX, PUMA and Bcl-2. Unexpectedly, the adenovirus-mediated overexpression of Del-1 gene into the lung carcinoma cell lines promoted proliferation and invasion of the lung carcinoma cells, as revealed by BrdU incorporation and transwell invasion assays, respectively. In addition, overexpression of the Del-1 gene enhanced features of epithelial–mesenchymal transition (EMT), such as increasing vimentin while decreasing E-cadherin in A549 cells, and increases in the level of Slug, an EMT-associated transcription regulator. Our findings demonstrated for the first time that there are deleterious effects of high levels of Del-1 in lung carcinoma cells, and suggest that Del-1 may be used as a diagnostic or prognostic marker for cancer progression, and as a novel therapeutic target for lung carcinoma. - Highlights: • Developmental Endothelial Locus-1 (Del-1) expression is downregulated in human lung cancer cells.

  8. Del-1 overexpression potentiates lung cancer cell proliferation and invasion

    International Nuclear Information System (INIS)

    Lee, Seung-Hwan; Kim, Dong-Young; Jing, Feifeng; Kim, Hyesoon; Yun, Chae-Ok; Han, Deok-Jong; Choi, Eun Young

    2015-01-01

    Developmental endothelial locus-1 (Del-1) is an endogenous anti-inflammatory molecule that is highly expressed in the lung and the brain and limits leukocyte migration to these tissues. We previously reported that the expression of Del-1 is positively regulated by p53 in lung endothelial cells. Although several reports have implicated the altered expression of Del-1 gene in cancer patients, little is known about its role in tumor cells. We here investigated the effect of Del-1 on the features of human lung carcinoma cells. Del-1 mRNA was found to be significantly decreased in the human lung adenocarcinoma cell lines A549 (containing wild type of p53), H1299 (null for p53) and EKVX (mutant p53), compared to in human normal lung epithelial BEAS-2B cells and MRC-5 fibroblasts. The decrease of Del-1 expression was dependent on the p53 activity in the cell lines, but not on the expression of p53. Neither treatment with recombinant human Del-1 protein nor the introduction of adenovirus expressing Del-1 altered the expression of the apoptosis regulators BAX, PUMA and Bcl-2. Unexpectedly, the adenovirus-mediated overexpression of Del-1 gene into the lung carcinoma cell lines promoted proliferation and invasion of the lung carcinoma cells, as revealed by BrdU incorporation and transwell invasion assays, respectively. In addition, overexpression of the Del-1 gene enhanced features of epithelial–mesenchymal transition (EMT), such as increasing vimentin while decreasing E-cadherin in A549 cells, and increases in the level of Slug, an EMT-associated transcription regulator. Our findings demonstrated for the first time that there are deleterious effects of high levels of Del-1 in lung carcinoma cells, and suggest that Del-1 may be used as a diagnostic or prognostic marker for cancer progression, and as a novel therapeutic target for lung carcinoma. - Highlights: • Developmental Endothelial Locus-1 (Del-1) expression is downregulated in human lung cancer cells.

  9. Graphene-induced apoptosis in lung epithelial cells through EGFR

    Science.gov (United States)

    Tsai, Shih-Ming; Bangalore, Preeti; Chen, Eric Y.; Lu, David; Chiu, Meng-Hsuen; Suh, Andrew; Gehring, Matthew; Cangco, John P.; Garcia, Santiago G.; Chin, Wei-Chun

    2017-07-01

    Expanding interest in nanotechnology applied to electronic and biomedical fields has led to fast-growing development of various nanomaterials. Graphene is a single-atom thick, two-dimensional sheet of hexagonally arranged carbon atoms with unique physical and chemical properties. Recently, graphene has been used in many studies on electronics, photonics, composite materials, energy generation and storage, sensors, and biomedicine. However, the current health risk assessment for graphene has been relatively limited and inconclusive. This study evaluated the toxicity effects of graphene on the airway epithelial cell line BEAS-2B, which represents the first barrier of the human body to interact with airborne graphene particles. Our result showed that graphene can induce the cellular Ca2+ by phospholipase C (PLC) associated pathway by activating epidermal growth factor receptor (EGFR). Subsequently, inositol 1,4,5-triphosphate (IP3) receptors activate the release of Ca2+ from the endoplasmic reticulum (ER) Ca2+ stores. Those Ca2+ signals further trigger the calcium-regulated apoptosis in the cell. Furthermore, the stimulation can cause EGFR upregulation, which have been demonstrated to associate with diseases such as lung cancer, chronic obstructive pulmonary disease (COPD), and cardiovascular diseases. This study highlights the additional health risk considering that it can function as a contributing factor for other respiratory diseases.

  10. Andrographolide protects against cigarette smoke-induced oxidative lung injury via augmentation of Nrf2 activity

    Science.gov (United States)

    Guan, SP; Tee, W; Ng, DSW; Chan, TK; Peh, HY; Ho, WE; Cheng, C; Mak, JC; Wong, WSF

    2013-01-01

    Background and Purpose Cigarette smoke is a major cause for chronic obstructive pulmonary disease (COPD). Andrographolide is an active biomolecule isolated from the plant Andrographis paniculata. Andrographolide has been shown to activate nuclear factor erythroid-2-related factor 2 (Nrf2), a redox-sensitive antioxidant transcription factor. As Nrf2 activity is reduced in COPD, we hypothesize that andrographolide may have therapeutic value for COPD. Experimental Approach Andrographolide was given i.p. to BALB/c mice daily 2 h before 4% cigarette smoke exposure for 1 h over five consecutive days. Bronchoalveolar lavage fluid and lungs were collected for analyses of cytokines, oxidative damage markers and antioxidant activities. BEAS-2B bronchial epithelial cells were exposed to cigarette smoke extract (CSE) and used to study the antioxidant mechanism of action of andrographolide. Key Results Andrographolide suppressed cigarette smoke-induced increases in lavage fluid cell counts; levels of IL-1β, MCP-1, IP-10 and KC; and levels of oxidative biomarkers 8-isoprostane, 8-OHdG and 3-nitrotyrosine in a dose-dependent manner. Andrographolide promoted inductions of glutathione peroxidase (GPx) and glutathione reductase (GR) activities in lungs from cigarette smoke-exposed mice. In BEAS-2B cells, andrographolide markedly increased nuclear Nrf2 accumulation, promoted binding to antioxidant response element (ARE) and total cellular glutathione level in response to CSE. Andrographolide up-regulated ARE-regulated gene targets including glutamate-cysteine ligase catalytic (GCLC) subunit, GCL modifier (GCLM) subunit, GPx, GR and heme oxygenase-1 in BEAS-2B cells in response to CSE. Conclusions Andrographolide possesses antioxidative properties against cigarette smoke-induced lung injury probably via augmentation of Nrf2 activity and may have therapeutic potential for treating COPD. PMID:23146110

  11. Induction of molecular endpoints by reactive oxygen species in human lung cells predicted by physical chemical properties of engineered nanoparticles

    Science.gov (United States)

    A series of six titanium dioxide and two cerium oxide engineered nanomaterials were assessed for their ability to induce cytotoxicity, reactive oxygen species (ROS), and various types of DNA and protein damage in human respiratory BEAS-2B cells exposed in vitro for 72 hours at se...

  12. Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells

    International Nuclear Information System (INIS)

    Stueckle, Todd A.; Lu, Yongju; Davis, Mary E.; Wang, Liying; Jiang, Bing-Hua; Holaskova, Ida; Schafer, Rosana; Barnett, John B.; Rojanasakul, Yon

    2012-01-01

    Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a 6 month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction. Carcinogenic initiation via reactive oxygen species and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-κB, MAPK and NCOR1 signaling disrupted PPARα/δ-mediated lipid homeostasis. A ‘pro-cancer’ gene signaling network identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1α, Akt, MAPK, and NF-κB signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment. Highlights: ► Chronic As 2 O 3

  13. Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Stueckle, Todd A., E-mail: tstueckle@hsc.wvu.edu [Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506 (United States); Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505 (United States); Lu, Yongju, E-mail: yongju6@hotmail.com [Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506 (United States); Davis, Mary E., E-mail: mdavis@wvu.edu [Department of Physiology, West Virginia University, Morgantown, WV 26506 (United States); Wang, Liying, E-mail: lmw6@cdc.gov [Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505 (United States); Jiang, Bing-Hua, E-mail: bhjiang@jefferson.edu [Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107 (United States); Holaskova, Ida, E-mail: iholaskova@hsc.wvu.edu [Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506 (United States); Schafer, Rosana, E-mail: rschafer@hsc.wvu.edu [Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506 (United States); Barnett, John B., E-mail: jbarnett@hsc.wvu.edu [Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506 (United States); Rojanasakul, Yon, E-mail: yrojan@hsc.wvu.edu [Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506 (United States)

    2012-06-01

    Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a 6 month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction. Carcinogenic initiation via reactive oxygen species and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-κB, MAPK and NCOR1 signaling disrupted PPARα/δ-mediated lipid homeostasis. A ‘pro-cancer’ gene signaling network identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1α, Akt, MAPK, and NF-κB signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment. Highlights: ► Chronic As{sub 2}O

  14. Nanodiamond internalization in cells and the cell uptake mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Perevedentseva, E. [National Dong Hwa University, Department of Physics (China); Hong, S.-F.; Huang, K.-J. [National Dong Hwa University, Department of Life Sciences (China); Chiang, I.-T.; Lee, C.-Y. [National Dong Hwa University, Department of Physics (China); Tseng, Y.-T. [National Dong Hwa University, Department of Life Sciences (China); Cheng, C.-L., E-mail: clcheng@mail.ndhu.edu.tw [National Dong Hwa University, Department of Physics (China)

    2013-08-15

    Cell type-dependent penetration of nanodiamond in living cells is one of the important factors for using nanodiamond as cellular markers/labels, for drug delivery as well as for other biomedical applications. In this work, internalization of 100 nm nanodiamonds by A549 lung human adenocarcinoma cell, Beas-2b non-tumorigenic human bronchial epithelial cell, and HFL-1 fibroblast-like human fetal lung cell is studied and compared. The penetration of nanodiamond into the cells was observed using confocal fluorescence imaging and Raman imaging methods. Visualization of the nanodiamond in cells allows comparison of the internalization for diamond nanoparticles in cancer A549 cell, non-cancer HFL-1, and Beas-2b cells. The dose-dependent and time-dependent behavior of nanodiamond uptake is observed in both cancer as well as non-cancer cells. The mechanism of nanodiamond uptake by cancer and non-cancer cells is analyzed by blocking different pathways. The uptake of nanodiamond in both cancer and non-cancer cells was found predominantly via clathrin-dependent endocytosis. In spite of observed similarity in the uptake mechanism for cancer and non-cancer cells, the nanodiamond uptake for cancer cell quantitatively exceeds the uptake for non-cancer cells, for the studied cell lines. The observed difference in internalization of nanodiamond by cancer and non-cancer cells is discussed.

  15. Nanodiamond internalization in cells and the cell uptake mechanism

    International Nuclear Information System (INIS)

    Perevedentseva, E.; Hong, S.-F.; Huang, K.-J.; Chiang, I.-T.; Lee, C.-Y.; Tseng, Y.-T.; Cheng, C.-L.

    2013-01-01

    Cell type-dependent penetration of nanodiamond in living cells is one of the important factors for using nanodiamond as cellular markers/labels, for drug delivery as well as for other biomedical applications. In this work, internalization of 100 nm nanodiamonds by A549 lung human adenocarcinoma cell, Beas-2b non-tumorigenic human bronchial epithelial cell, and HFL-1 fibroblast-like human fetal lung cell is studied and compared. The penetration of nanodiamond into the cells was observed using confocal fluorescence imaging and Raman imaging methods. Visualization of the nanodiamond in cells allows comparison of the internalization for diamond nanoparticles in cancer A549 cell, non-cancer HFL-1, and Beas-2b cells. The dose-dependent and time-dependent behavior of nanodiamond uptake is observed in both cancer as well as non-cancer cells. The mechanism of nanodiamond uptake by cancer and non-cancer cells is analyzed by blocking different pathways. The uptake of nanodiamond in both cancer and non-cancer cells was found predominantly via clathrin-dependent endocytosis. In spite of observed similarity in the uptake mechanism for cancer and non-cancer cells, the nanodiamond uptake for cancer cell quantitatively exceeds the uptake for non-cancer cells, for the studied cell lines. The observed difference in internalization of nanodiamond by cancer and non-cancer cells is discussed

  16. Lung cancer - small cell

    Science.gov (United States)

    Cancer - lung - small cell; Small cell lung cancer; SCLC ... About 15% of all lung cancer cases are SCLC. Small cell lung cancer is slightly more common in men than women. Almost all cases of SCLC are ...

  17. Inhibition of lung cancer cells A549 and H460 by curcuminoid extracts and nanoemulsions prepared from Curcuma longa Linnaeus

    Directory of Open Access Journals (Sweden)

    Chang HB

    2015-08-01

    Full Text Available Hong-Bin Chang,1 Bing-Huei Chen1,21Department of Food Science, 2Graduate Institute of Medicine, Fu Jen Catholic University, Taipei, TaiwanAbstract: The objectives of this study were to explore the inhibition mechanism of lung cancer cells A549 and H460 by curcuminoid extracts and nanoemulsions prepared from Curcuma longa Linnaeus. In addition, human bronchus epithelial cell line BEAS-2B (normal cell was selected for comparison. A high-performance liquid chromatography (HPLC method was developed to separate and quantify the various curcuminoids in C. longa extract, including curcumin (1,714.5 µg/mL, demethoxycurcumin (1,147.4 µg/mL, and bisdemethoxycurcumin (190.2 µg/mL. A high-stability nanoemulsion composed of Tween 80, water, and curcuminoid extract was prepared, with mean particle size being 12.6 nm. The cell cycle was retarded at G2/M for both the curcuminoid extract and nanoemulsion treatments; however, the inhibition pathway may be different. H460 cells were more susceptible to apoptosis than A549 cells for both curcuminoid extract and nanoemulsion treatments. Growth of BEAS-2B remained unaffected for both the curcuminoid extract and nanoemulsion treatments, with a concentration range from 1 to 4 µg/mL. Also, the activities of caspase-3, caspase-8, and caspase-9 followed a dose-dependent increase for both A549 and H460 cells for both the treatments, accompanied by a dose-dependent increase in cytochrome C expression and a dose-dependent decrease in CDK1 expression. Interestingly, a dose-dependent increase in cyclin B expression was shown for A549 cells for both the treatments, while a reversed trend was found for H460 cells. Both mitochondria and death receptor pathways may be responsible for apoptosis of both A549 and H460 cells.Keywords: curcuminoid extract, curcuminoid nanoemulsion, Curcuma longa Linnaeus, lung cancer cell, cell cycle, apoptosis mechanism

  18. Transcriptional response to organic compounds from diverse gasoline and biogasoline fuel emissions in human lung cells.

    Science.gov (United States)

    Libalova, Helena; Rossner, Pavel; Vrbova, Kristyna; Brzicova, Tana; Sikorova, Jitka; Vojtisek-Lom, Michal; Beranek, Vit; Klema, Jiri; Ciganek, Miroslav; Neca, Jiri; Machala, Miroslav; Topinka, Jan

    2018-04-01

    Modern vehicles equipped with Gasoline Direct Injection (GDI) engine have emerged as an important source of particulate emissions potentially harmful to human health. We collected and characterized gasoline exhaust particles (GEPs) produced by neat gasoline fuel (E0) and its blends with 15% ethanol (E15), 25% n-butanol (n-But25) and 25% isobutanol (i-But25). To study the toxic effects of organic compounds extracted from GEPs, we analyzed gene expression profiles in human lung BEAS-2B cells. Despite the lowest GEP mass, n-But25 extract contained the highest concentration of polycyclic aromatic hydrocarbons (PAHs), while i-But25 extract the lowest. Gene expression analysis identified activation of the DNA damage response and other subsequent events (cell cycle arrest, modulation of extracellular matrix, cell adhesion, inhibition of cholesterol biosynthesis) following 4 h exposure to all GEP extracts. The i-But25 extract induced the most distinctive gene expression pattern particularly after 24 h exposure. Whereas E0, E15 and n-But25 extract treatments resulted in persistent stress signaling including DNA damage response, MAPK signaling, oxidative stress, metabolism of PAHs or pro-inflammatory response, i-But25 induced changes related to the metabolism of the cellular nutrients required for cell recovery. Our results indicate that i-But25 extract possessed the weakest genotoxic potency possibly due to the low PAH content. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

  19. SATB2 expression increased anchorage-independent growth and cell migration in human bronchial epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Feng; Jordan, Ashley; Kluz, Thomas [Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987 (United States); Shen, Steven [Center for Health Informatics and Bioinformatics, New York University Langone Medical Center, New York, NY 10016 (United States); Sun, Hong; Cartularo, Laura A. [Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987 (United States); Costa, Max, E-mail: Max.Costa@nyumc.org [Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987 (United States)

    2016-02-15

    The special AT-rich sequence-binding protein 2 (SATB2) is a protein that binds to the nuclear matrix attachment region of the cell and regulates gene expression by altering chromatin structure. In our previous study, we reported that SATB2 gene expression was induced in human bronchial epithelial BEAS-2B cells transformed by arsenic, chromium, nickel and vanadium. In this study, we show that ectopic expression of SATB2 in the normal human bronchial epithelial cell-line BEAS-2B increased anchorage-independent growth and cell migration, meanwhile, shRNA-mediated knockdown of SATB2 significantly decreased anchorage-independent growth in Ni transformed BEAS-2B cells. RNA sequencing analyses of SATB2 regulated genes revealed the enrichment of those involved in cytoskeleton, cell adhesion and cell-movement pathways. Our evidence supports the hypothesis that SATB2 plays an important role in BEAS-2B cell transformation. - Highlights: • We performed SATB2 overexpression in the BEAS-2B cell line. • We performed SATB2 knockdown in a Ni transformed BEAS-2B cell line. • SATB2 induced anchorage-independent growth and increased cell migration. • SATB2 knockdown significantly decreased anchorage-independent growth. • We identified alterations in gene involved in cytoskeleton, cell adhesion.

  20. SATB2 expression increased anchorage-independent growth and cell migration in human bronchial epithelial cells

    International Nuclear Information System (INIS)

    Wu, Feng; Jordan, Ashley; Kluz, Thomas; Shen, Steven; Sun, Hong; Cartularo, Laura A.; Costa, Max

    2016-01-01

    The special AT-rich sequence-binding protein 2 (SATB2) is a protein that binds to the nuclear matrix attachment region of the cell and regulates gene expression by altering chromatin structure. In our previous study, we reported that SATB2 gene expression was induced in human bronchial epithelial BEAS-2B cells transformed by arsenic, chromium, nickel and vanadium. In this study, we show that ectopic expression of SATB2 in the normal human bronchial epithelial cell-line BEAS-2B increased anchorage-independent growth and cell migration, meanwhile, shRNA-mediated knockdown of SATB2 significantly decreased anchorage-independent growth in Ni transformed BEAS-2B cells. RNA sequencing analyses of SATB2 regulated genes revealed the enrichment of those involved in cytoskeleton, cell adhesion and cell-movement pathways. Our evidence supports the hypothesis that SATB2 plays an important role in BEAS-2B cell transformation. - Highlights: • We performed SATB2 overexpression in the BEAS-2B cell line. • We performed SATB2 knockdown in a Ni transformed BEAS-2B cell line. • SATB2 induced anchorage-independent growth and increased cell migration. • SATB2 knockdown significantly decreased anchorage-independent growth. • We identified alterations in gene involved in cytoskeleton, cell adhesion.

  1. Exposure of Human Lung Cells to Tobacco Smoke Condensate Inhibits the Nucleotide Excision Repair Pathway.

    Directory of Open Access Journals (Sweden)

    Nathaniel Holcomb

    Full Text Available Exposure to tobacco smoke is the number one risk factor for lung cancer. Although the DNA damaging properties of tobacco smoke have been well documented, relatively few studies have examined its effect on DNA repair pathways. This is especially true for the nucleotide excision repair (NER pathway which recognizes and removes many structurally diverse DNA lesions, including those introduced by chemical carcinogens present in tobacco smoke. The aim of the present study was to investigate the effect of tobacco smoke on NER in human lung cells. We studied the effect of cigarette smoke condensate (CSC, a surrogate for tobacco smoke, on the NER pathway in two different human lung cell lines; IMR-90 lung fibroblasts and BEAS-2B bronchial epithelial cells. To measure NER, we employed a slot-blot assay to quantify the introduction and removal of UV light-induced 6-4 photoproducts and cyclobutane pyrimidine dimers. We find a dose-dependent inhibition of 6-4 photoproduct repair in both cell lines treated with CSC. Additionally, the impact of CSC on the abundance of various NER proteins and their respective RNAs was investigated. The abundance of XPC protein, which is required for functional NER, is significantly reduced by treatment with CSC while the abundance of XPA protein, also required for NER, is unaffected. Both XPC and XPA RNA levels are modestly reduced by CSC treatment. Finally, treatment of cells with MG-132 abrogates the reduction in the abundance of XPC protein produced by treatment with CSC, suggesting that CSC enhances proteasome-dependent turnover of the protein that is mediated by ubiquitination. Together, these findings indicate that tobacco smoke can inhibit the same DNA repair pathway that is also essential for the removal of some of the carcinogenic DNA damage introduced by smoke itself, increasing the DNA damage burden of cells exposed to tobacco smoke.

  2. Highly purified, multi-wall carbon nanotubes induce light-chain 3B expression in human lung cells

    International Nuclear Information System (INIS)

    Tsukahara, Tamotsu; Matsuda, Yoshikazu; Usui, Yuki; Haniu, Hisao

    2013-01-01

    Highlights: •HTT2800-treated BEAS-2B cells induced LC3B in a time-dependent manner. •HTT2800-treated BEAS-2B cells showed decreased cell proliferation that was both time- and dose-dependent. •Addition of 3-MA, LC3B-II protein and mRNA levels were significantly decreased. •3-MA and E64-d + pepstatin A, but not brefeldin A, provided protection against HTT2800-induced cell death. •These results suggest that HTT2800 predominantly causes autophagy rather than apoptotic cell death in BEAS-2B cells. -- Abstract: Bronchial epithelial cells are targets of inhalation and play a critical role in the maintenance of mucosal integrity as mechanical barriers against various particles. Our previous result suggest that vapor-grown carbon fiber, HTT2800, which is one of the most highly purified multi-wall carbon nanotubes (MWCNT) showed cellular uptake of the carbon nanotube, increased cell death, enhanced DNA damage, and induced cytokine release. Increasing evidence suggests that autophagy may critically influence vital cellular processes such as apoptosis, cell proliferation and inflammation and thereby may play a critical role in pulmonary diseases. Autophagy was recently recognized as a critical cell death pathway, and autophagosome accumulation has been found to be associated with the exposure of various nanoparticles. In this study, the authors focus on the autophagic responses of HTT2800 exposure. The HTT2800-exposed cells induced LC3B expression and induced cell growth inhibition

  3. Highly purified, multi-wall carbon nanotubes induce light-chain 3B expression in human lung cells

    Energy Technology Data Exchange (ETDEWEB)

    Tsukahara, Tamotsu, E-mail: ttamotsu@kanazawa-med.ac.jp [Department of Hematology and Immunology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Matsuda, Yoshikazu [Clinical Pharmacology Educational Center, Nihon Pharmaceutical University, Ina-machi, Saitama 362-0806 (Japan); Usui, Yuki [Research Center for Exotic Nanocarbons, Shinshu University, 4-17-1 Wakasato, Nagano-shi, Nagano 380-8553 (Japan); Haniu, Hisao [Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621 (Japan)

    2013-10-18

    Highlights: •HTT2800-treated BEAS-2B cells induced LC3B in a time-dependent manner. •HTT2800-treated BEAS-2B cells showed decreased cell proliferation that was both time- and dose-dependent. •Addition of 3-MA, LC3B-II protein and mRNA levels were significantly decreased. •3-MA and E64-d + pepstatin A, but not brefeldin A, provided protection against HTT2800-induced cell death. •These results suggest that HTT2800 predominantly causes autophagy rather than apoptotic cell death in BEAS-2B cells. -- Abstract: Bronchial epithelial cells are targets of inhalation and play a critical role in the maintenance of mucosal integrity as mechanical barriers against various particles. Our previous result suggest that vapor-grown carbon fiber, HTT2800, which is one of the most highly purified multi-wall carbon nanotubes (MWCNT) showed cellular uptake of the carbon nanotube, increased cell death, enhanced DNA damage, and induced cytokine release. Increasing evidence suggests that autophagy may critically influence vital cellular processes such as apoptosis, cell proliferation and inflammation and thereby may play a critical role in pulmonary diseases. Autophagy was recently recognized as a critical cell death pathway, and autophagosome accumulation has been found to be associated with the exposure of various nanoparticles. In this study, the authors focus on the autophagic responses of HTT2800 exposure. The HTT2800-exposed cells induced LC3B expression and induced cell growth inhibition.

  4. Alteration of canonical and non-canonical WNT-signaling by crystalline silica in human lung epithelial cells

    International Nuclear Information System (INIS)

    Perkins, Timothy N.; Dentener, Mieke A.; Stassen, Frank R.; Rohde, Gernot G.; Mossman, Brooke T.; Wouters, Emiel F.M.; Reynaert, Niki L.

    2016-01-01

    Growth and development of the mature lung is a complex process orchestrated by a number of intricate developmental signaling pathways. Wingless-type MMTV-integration site (WNT) signaling plays critical roles in controlling branching morphogenesis cell differentiation, and formation of the conducting and respiratory airways. In addition, WNT pathways are often re-activated in mature lungs during repair and regeneration. WNT- signaling has been elucidated as a crucial contributor to the development of idiopathic pulmonary fibrosis as well as other hyper-proliferative lung diseases. Silicosis, a detrimental occupational lung disease caused by excessive inhalation of crystalline silica dust, is hallmarked by repeated cycles of damaging inflammation, epithelial hyperplasia, and formation of dense, hyalinized nodules of whorled collagen. However, mechanisms of epithelial cell hyperplasia and matrix deposition are not well understood, as most research efforts have focused on the pronounced inflammatory response. Microarray data from our previous studies has revealed a number of WNT-signaling and WNT-target genes altered by crystalline silica in human lung epithelial cells. In the present study, we utilize pathway analysis to designate connections between genes altered by silica in WNT-signaling networks. Furthermore, we confirm microarray findings by QRT-PCR and demonstrate both activation of canonical (β-catenin) and down-regulation of non-canonical (WNT5A) signaling in immortalized (BEAS-2B) and primary (PBEC) human bronchial epithelial cells. These findings suggest that WNT-signaling and cross-talk with other pathways (e.g. Notch), may contribute to proliferative, fibrogenic and inflammatory responses to silica in lung epithelial cells. - Highlights: • Pathway analysis reveals silica-induced WNT-signaling in lung epithelial cells. • Silica-induced canonical WNT-signaling is mediated by autocrine/paracrine signals. • Crystalline silica decreases non-canonical WNT

  5. Alteration of canonical and non-canonical WNT-signaling by crystalline silica in human lung epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Perkins, Timothy N.; Dentener, Mieke A. [Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands); Stassen, Frank R. [Department of Medical Microbiology, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands); Rohde, Gernot G. [Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands); Mossman, Brooke T. [Department of Pathology, University of Vermont College of Medicine, Burlington, VT (United States); Wouters, Emiel F.M. [Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands); Reynaert, Niki L., E-mail: n.reynaert@maastrichtuniversity.nl [Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands)

    2016-06-15

    Growth and development of the mature lung is a complex process orchestrated by a number of intricate developmental signaling pathways. Wingless-type MMTV-integration site (WNT) signaling plays critical roles in controlling branching morphogenesis cell differentiation, and formation of the conducting and respiratory airways. In addition, WNT pathways are often re-activated in mature lungs during repair and regeneration. WNT- signaling has been elucidated as a crucial contributor to the development of idiopathic pulmonary fibrosis as well as other hyper-proliferative lung diseases. Silicosis, a detrimental occupational lung disease caused by excessive inhalation of crystalline silica dust, is hallmarked by repeated cycles of damaging inflammation, epithelial hyperplasia, and formation of dense, hyalinized nodules of whorled collagen. However, mechanisms of epithelial cell hyperplasia and matrix deposition are not well understood, as most research efforts have focused on the pronounced inflammatory response. Microarray data from our previous studies has revealed a number of WNT-signaling and WNT-target genes altered by crystalline silica in human lung epithelial cells. In the present study, we utilize pathway analysis to designate connections between genes altered by silica in WNT-signaling networks. Furthermore, we confirm microarray findings by QRT-PCR and demonstrate both activation of canonical (β-catenin) and down-regulation of non-canonical (WNT5A) signaling in immortalized (BEAS-2B) and primary (PBEC) human bronchial epithelial cells. These findings suggest that WNT-signaling and cross-talk with other pathways (e.g. Notch), may contribute to proliferative, fibrogenic and inflammatory responses to silica in lung epithelial cells. - Highlights: • Pathway analysis reveals silica-induced WNT-signaling in lung epithelial cells. • Silica-induced canonical WNT-signaling is mediated by autocrine/paracrine signals. • Crystalline silica decreases non-canonical WNT

  6. Selective and Irreversible Induction of Necroptotic Cell Death in Lung Tumorspheres by Short-Term Exposure to Verapamil in Combination with Sorafenib

    Directory of Open Access Journals (Sweden)

    Juan Sebastian Yakisich

    2017-01-01

    Full Text Available The presence of highly resistant cancer cells and the toxicity to normal cells are key factors that limit chemotherapy. Here, we used two models of highly resistant lung cancer cells: (1 adherent cells growing under prolonged periods of serum starvation (PPSS and (2 cells growing as floating tumorspheres (FTs to evaluate the effect of Verapamil (VP in combination with Sorafenib (SF. Compared to cells growing under routine culture conditions (RCCs, PPPS cells or FTs were highly sensitive to short-term exposure (24 h to VP 100 μM + SF 5 μM (VP100 + SF5. Recovery experiments exposing cells to VP100 + SF5 for 24 h followed by incubation in drug-free media for 48 h demonstrated that while PPSS as well as FT cells were unable to recover, cancer cells and the noncancerous cell line Beas-2B growing under RCCs were less sensitive and were also able to recover significantly. VP100 + SF5 induced significant changes in the expression of protein associated with apoptosis, autophagy, and to a lesser extent necroptosis. Coincubation experiments with z-VAD-FMK, necrostatin 1, or chloroquine showed evidence that necroptosis played a central role. Our data demonstrates that highly resistant cancer cells can be selectively eliminated by VP + SF and that necroptosis plays a central role.

  7. Low-solubility particles and a Trojan-horse type mechanism of toxicity: the case of cobalt oxide on human lung cells

    International Nuclear Information System (INIS)

    Ortega, Richard; Roudeau, Stephane; Perrin, Laura; Carmona, Asuncion; Bresson, Carole; Darolles, Carine; Aloin, Valerie; Malard, Veronique; Gautier, Celine; Janin, Myriam; Floriani, Magali

    2014-01-01

    The mechanisms of toxicity of metal oxide particles towards lung cells are far from being understood. In particular, the relative contribution of intracellular particulate versus solubilized fractions is rarely considered as it is very challenging to assess, especially for low-solubility particles such as cobalt oxide (Co_3O_4). This study was possible owing to two highly sensitive, independent, analytical techniques, based on single-cell analysis, using ion beam microanalysis, and on bulk analysis of cell lysates, using mass spectrometry. Our study shows that cobalt oxide particles, of very low solubility in the culture medium, are readily incorporated by BEAS-2B human lung cells through endocytosis via the clathrin-dependent pathway. They are partially solubilized at low pH within lysosomes, leading to cobalt ions release. Solubilized cobalt was detected within the cytoplasm and the nucleus. As expected from these low-solubility particles, the intracellular solubilized cobalt content is small compared with the intracellular particulate cobalt content, in the parts-per-thousand range or below. However, we were able to demonstrate that this minute fraction of intracellular solubilized cobalt is responsible for the overall toxicity. Cobalt oxide particles are readily internalized by pulmonary cells via the endo-lysosomal pathway and can lead, through a Trojan-horse mechanism, to intracellular release of toxic metal ions over long periods of time, involving specific toxicity. (authors)

  8. Gene expression profiles in asbestos-exposed epithelial and mesothelial lung cell lines

    Directory of Open Access Journals (Sweden)

    Kaski Samuel

    2007-03-01

    Full Text Available Abstract Background Asbestos has been shown to cause chromosomal damage and DNA aberrations. Exposure to asbestos causes many lung diseases e.g. asbestosis, malignant mesothelioma, and lung cancer, but the disease-related processes are still largely unknown. We exposed the human cell lines A549, Beas-2B and Met5A to crocidolite asbestos and determined time-dependent gene expression profiles by using Affymetrix arrays. The hybridization data was analyzed by using an algorithm specifically designed for clustering of short time series expression data. A canonical correlation analysis was applied to identify correlations between the cell lines, and a Gene Ontology analysis method for the identification of enriched, differentially expressed biological processes. Results We recognized a large number of previously known as well as new potential asbestos-associated genes and biological processes, and identified chromosomal regions enriched with genes potentially contributing to common responses to asbestos in these cell lines. These include genes such as the thioredoxin domain containing gene (TXNDC and the potential tumor suppressor, BCL2/adenovirus E1B 19kD-interacting protein gene (BNIP3L, GO-terms such as "positive regulation of I-kappaB kinase/NF-kappaB cascade" and "positive regulation of transcription, DNA-dependent", and chromosomal regions such as 2p22, 9p13, and 14q21. We present the complete data sets as Additional files. Conclusion This study identifies several interesting targets for further investigation in relation to asbestos-associated diseases.

  9. Camptosorus sibiricus rupr aqueous extract prevents lung tumorigenesis via dual effects against ROS and DNA damage.

    Science.gov (United States)

    He, Shugui; Ou, Rilan; Wang, Wensheng; Ji, Liyan; Gao, Hui; Zhu, Yuanfeng; Liu, Xiaomin; Zheng, Hongming; Liu, Zhongqiu; Wu, Peng; Lu, Linlin

    2018-06-28

    Camptosorus sibiricus Rupr (CSR) is a widely used herbal medicine with antivasculitis, antitrauma, and antitumor effects. However, the effect of CSR aqueous extract on B[a]P-initiated tumorigenesis and the underlying mechanism remain unclear. Moreover, the compounds in CSR aqueous extract need to be identified and structurally characterized. We aim to investigate the chemopreventive effect of CSR and the underlying molecular mechanism. A B[a]P-stimulated normal cell model (BEAS.2B) and lung adenocarcinoma animal model were established on A/J mice. In B[a]P-treated BEAS.2B cells, the protective effects of CSR aqueous extract on B[a]P-induced DNA damage and ROS production were evaluated through flow cytometry, Western blot, real-time quantitative PCR, single-cell gel electrophoresis, and immunofluorescence. Moreover, a model of B[a]P-initiated lung adenocarcinoma was established on A/J mice to determine the chemopreventive effect of CSR in vivo. The underlying mechanism was analyzed via immunohistochemistry and microscopy. Furthermore, the new compounds in CSR aqueous extract were isolated and structurally characterized using IR, HR-ESI-MS, and 1D and 2D NMR spectroscopy. CSR effectively suppressed ROS production by re-activating Nrf2-mediated reductases HO-1 and NQO-1. Simultaneously, CSR attenuated the DNA damage of BEAS.2B cells in the presence of B[a]P. Moreover, CSR at 1.5 and 3 g/kg significantly suppressed tumorigenesis with tumor inhibition ratios of 36.65% and 65.80%, respectively. The tumor volume, tumor size, and multiplicity of B[a]P-induced lung adenocarcinoma were effectively decreased by CSR in vivo. After extracting and identifying the compounds in CSR aqueous extract, three new triterpene saponins were isolated and characterized structurally. CSR aqueous extract prevents lung tumorigenesis by exerting dual effects against ROS and DNA damage, suggesting that CSR is a novel and effective agent for B[a]P-induced carcinogenesis. Moreover, by isolating

  10. LINE-1 couples EMT programming with acquisition of oncogenic phenotypes in human bronchial epithelial cells.

    Science.gov (United States)

    Reyes-Reyes, Elsa M; Aispuro, Ivan; Tavera-Garcia, Marco A; Field, Matthew; Moore, Sara; Ramos, Irma; Ramos, Kenneth S

    2017-11-28

    Although several lines of evidence have established the central role of epithelial-to-mesenchymal-transition (EMT) in malignant progression of non-small cell lung cancers (NSCLCs), the molecular events connecting EMT to malignancy remain poorly understood. This study presents evidence that Long Interspersed Nuclear Element-1 (LINE-1) retrotransposon couples EMT programming with malignancy in human bronchial epithelial cells (BEAS-2B). This conclusion is supported by studies showing that: 1) activation of EMT programming by TGF-β1 increases LINE-1 mRNAs and protein; 2) the lung carcinogen benzo(a)pyrene coregulates TGF-β1 and LINE-1 mRNAs, with LINE-1 positioned downstream of TGF-β1 signaling; and, 3) forced expression of LINE-1 in BEAS-2B cells recapitulates EMT programming and induces malignant phenotypes and tumorigenesis in vivo . These findings identify a TGFβ1-LINE-1 axis as a critical effector pathway that can be targeted for the development of precision therapies during malignant progression of intractable NSCLCs.

  11. Cadmium induces cytotoxicity in human bronchial epithelial cells through upregulation of eIF5A1 and NF-kappaB

    Energy Technology Data Exchange (ETDEWEB)

    Chen, De-Ju; Xu, Yan-Ming; Du, Ji-Ying [Laboratory of Cancer Biology and Epigenetics, Shantou University Medical College, Shantou, Guangdong 515041 (China); Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041 (China); Huang, Dong-Yang [Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041 (China); Lau, Andy T.Y., E-mail: andytylau@stu.edu.cn [Laboratory of Cancer Biology and Epigenetics, Shantou University Medical College, Shantou, Guangdong 515041 (China); Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041 (China)

    2014-02-28

    Highlights: • Normal human bronchial epithelial cells (BEAS-2B) were dosed with cadmium (Cd). • A low level (2 μM) of Cd treatment for 36 h elicited negligible cytotoxicity. • High levels (20 or 30 μM) of Cd treatment for 36 h induced cell death. • High levels of Cd can upregulate the protein levels of eIF5A1 and NF-κB p65. • We suggest that eIF5A1 level is possibly modulated by NF-κB. - Abstract: Cadmium (Cd) and Cd compounds are widely-distributed in the environment and well-known carcinogens. Here, we report that in CdCl{sub 2}-exposed human bronchial epithelial cells (BEAS-2B), the level of p53 is dramatically decreased in a time- and dose-dependent manner, suggesting that the observed Cd-induced cytotoxicity is not likely due to the pro-apoptotic function of p53. Therefore, this prompted us to further study the responsive pro-apoptotic factors by proteomic approaches. Interestingly, we identified that high levels (20 or 30 μM) of Cd can significantly upregulate the protein levels of eukaryotic translation initiation factor 5A1 (eIF5A1) and redox-sensitive transcription factor NF-κB p65. Moreover, there is an enhanced NF-κB nuclear translocation as well as chromatin-binding in Cd-treated BEAS-2B cells. We also show that small interfering RNA-specific knockdown of eIF5A1 in Cd-exposed cells attenuated the Cd cytotoxicity, indicating the potential role of eIF5A1 in Cd cytotoxicity. As eIF5A1 is reported to be related with cell apoptosis but little is known about its transcriptional control, we hypothesize that NF-κB might likely modulate eIF5A1 gene expression. Notably, by bioinformatic analysis, several potential NF-κB binding sites on the upstream promoter region of eIF5A1 gene can be found. Subsequent chromatin immunoprecipitation assay revealed that indeed there is enhanced NF-κB binding on eIF5A1 promoter region of Cd-treated BEAS-2B cells. Taken together, our findings suggest for the first time a regulatory mechanism for the pro

  12. Proteomic analysis of secreted proteins by human bronchial epithelial cells in response to cadmium toxicity.

    Science.gov (United States)

    Chen, De-Ju; Xu, Yan-Ming; Zheng, Wei; Huang, Dong-Yang; Wong, Wing-Yan; Tai, William Chi-Shing; Cho, Yong-Yeon; Lau, Andy T Y

    2015-09-01

    For years, many studies have been conducted to investigate the intracellular response of cells challenged with toxic metal(s), yet, the corresponding secretome responses, especially in human lung cells, are largely unexplored. Here, we provide a secretome analysis of human bronchial epithelial cells (BEAS-2B) treated with cadmium chloride (CdCl2 ), with the aim of identifying secreted proteins in response to Cd toxicity. Proteins from control and spent media were separated by two-dimensional electrophoresis and visualized by silver staining. Differentially-secreted proteins were identified by MALDI-TOF-MS analysis and database searching. We characterized, for the first time, the extracellular proteome changes of BEAS-2B dosed with Cd. Our results unveiled that Cd treatment led to the marked upregulation of molecular chaperones, antioxidant enzymes, enzymes associated with glutathione metabolic process, proteins involved in cellular energy metabolism, as well as tumor-suppressors. Pretreatment of cells with the thiol antioxidant glutathione before Cd treatment effectively abrogated the secretion of these proteins and prevented cell death. Taken together, our results demonstrate that Cd causes oxidative stress-induced cytotoxicity; and the differentially-secreted protein signatures could be considered as targets for potential use as extracellular biomarkers upon Cd exposure. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Hexavalent chromium, a lung carcinogen, confers resistance to thermal stress and interferes with heat shock protein expression in human bronchial epithelial cells.

    Science.gov (United States)

    Abreu, Patrícia L; Cunha-Oliveira, Teresa; Ferreira, Leonardo M R; Urbano, Ana M

    2018-03-16

    Exposure to hexavalent chromium [Cr(VI)], a lung carcinogen, triggers several types of cellular stresses, namely oxidative, genotoxic and proteotoxic stresses. Given the evolutionary character of carcinogenesis, it is tempting to speculate that cells that survive the stresses produced by this carcinogen become more resistant to subsequent stresses, namely those encountered during neoplastic transformation. To test this hypothesis, we determined whether pre-incubation with Cr(VI) increased the resistance of human bronchial epithelial cells (BEAS-2B cells) to the antiproliferative action of acute thermal shock, used here as a model for stress. In line with the proposed hypothesis, it was observed that, at mildly cytotoxic concentrations, Cr(VI) attenuated the antiproliferative effects of both cold and heat shock. Mechanistically, Cr(VI) interfered with the expression of two components of the stress response pathway: heat shock proteins Hsp72 and Hsp90α. Specifically, Cr(VI) significantly depleted the mRNA levels of the former and the protein levels of the latter. Significantly, these two proteins are members of heat shock protein (Hsp) families (Hsp70 and Hsp90, respectively) that have been implicated in carcinogenesis. Thus, our results confirm and extend previous studies showing the capacity of Cr(VI) to interfere with the expression of stress response components.

  14. Cellular cytotoxic response induced by highly purified multi-wall carbon nanotube in human lung cells.

    Science.gov (United States)

    Tsukahara, Tamotsu; Haniu, Hisao

    2011-06-01

    Carbon nanotubes, a promising nanomaterial with unique characteristics, have applications in a variety of fields. The cytotoxic effects of carbon nanotubes are partially due to the induction of oxidative stress; however, the detailed mechanisms of nanotube cytotoxicity and their interaction with cells remain unclear. In this study, the authors focus on the acute toxicity of vapor-grown carbon fiber, HTT2800, which is one of the most highly purified multi-wall carbon nanotubes (MWCNT) by high-temperature thermal treatment. The authors exposed human bronchial epithelial cells (BEAS-2B) to HTT2800 and measured the cellular uptake, mitochondrial function, cellular LDH release, apoptotic signaling, reactive oxygen species (ROS) generation and pro-inflammatory cytokine release. The HTT2800-exposed cells showed cellular uptake of the carbon nanotube, increased cell death, enhanced DNA damage, and induced cytokine release. However, the exposed cells showed no obvious intracellular ROS generation. These cellular and molecular findings suggest that HTT2800 could cause a potentially adverse inflammatory response in BEAS-2B cells.

  15. Diatom-derived polyunsaturated aldehydes activate cell death in human cancer cell lines but not normal cells.

    Directory of Open Access Journals (Sweden)

    Clementina Sansone

    Full Text Available Diatoms are an important class of unicellular algae that produce bioactive polyunsaturated aldehydes (PUAs that induce abortions or malformations in the offspring of invertebrates exposed to them during gestation. Here we compare the effects of the PUAs 2-trans,4-trans-decadienal (DD, 2-trans,4-trans-octadienal (OD and 2-trans,4-trans-heptadienal (HD on the adenocarcinoma cell lines lung A549 and colon COLO 205, and the normal lung/brunch epithelial BEAS-2B cell line. Using the viability MTT/Trypan blue assays, we show that PUAs have a toxic effect on both A549 and COLO 205 tumor cells but not BEAS-2B normal cells. DD was the strongest of the three PUAs tested, at all time-intervals considered, but HD was as strong as DD after 48 h. OD was the least active of the three PUAs. The effect of the three PUAs was somewhat stronger for A549 cells. We therefore studied the death signaling pathway activated in A549 showing that cells treated with DD activated Tumor Necrosis Factor Receptor 1 (TNFR1 and Fas Associated Death Domain (FADD leading to necroptosis via caspase-3 without activating the survival pathway Receptor-Interacting Protein (RIP. The TNFR1/FADD/caspase pathway was also observed with OD, but only after 48 h. This was the only PUA that activated RIP, consistent with the finding that OD causes less damage to the cell compared to DD and HD. In contrast, cells treated with HD activated the Fas/FADD/caspase pathway. This is the first report that PUAs activate an extrinsic apoptotic machinery in contrast to other anticancer drugs that promote an intrinsic death pathway, without affecting the viability of normal cells from the same tissue type. These findings have interesting implications also from the ecological viewpoint considering that HD is one of the most common PUAs produced by diatoms.

  16. Cytotoxic and genotoxic responses of human lung cells to combustion smoke particles of Miscanthus straw, softwood and beech wood chips

    Science.gov (United States)

    Arif, Ali Talib; Maschowski, Christoph; Garra, Patxi; Garcia-Käufer, Manuel; Petithory, Tatiana; Trouvé, Gwenaëlle; Dieterlen, Alain; Mersch-Sundermann, Volker; Khanaqa, Polla; Nazarenko, Irina; Gminski, Richard; Gieré, Reto

    2017-08-01

    Inhalation of particulate matter (PM) from residential biomass combustion is epidemiologically associated with cardiovascular and pulmonary diseases. This study investigates PM0.4-1 emissions from combustion of commercial Miscanthus straw (MS), softwood chips (SWC) and beech wood chips (BWC) in a domestic-scale boiler (40 kW). The PM0.4-1 emitted during combustion of the MS, SWC and BWC were characterized by ICP-MS/OES, XRD, SEM, TEM, and DLS. Cytotoxicity and genotoxicity in human alveolar epithelial A549 and human bronchial epithelial BEAS-2B cells were assessed by the WST-1 assay and the DNA-Alkaline Unwinding Assay (DAUA). PM0.4-1 uptake/translocation in cells was investigated with a new method developed using a confocal reflection microscope. SWC and BWC had a inherently higher residual water content than MS. The PM0.4-1 emitted during combustion of SWC and BWC exhibited higher levels of Polycyclic Aromatic Hydrocarbons (PAHs), a greater variety of mineral species and a higher heavy metal content than PM0.4-1 from MS combustion. Exposure to PM0.4-1 from combustion of SWC and BWC induced cytotoxic and genotoxic effects in human alveolar and bronchial cells, whereby the strongest effect was observed for BWC and was comparable to that caused by diesel PM (SRM 2 975), In contrast, PM0.4-1 from MS combustion did not induce cellular responses in the studied lung cells. A high PAH content in PM emissions seems to be a reliable chemical marker of both combustion efficiency and particle toxicity. Residual biomass water content strongly affects particulate emissions and their toxic potential. Therefore, to minimize the harmful effects of fine PM on health, improvement of combustion efficiency (aiming to reduce the presence of incomplete combustion products bound to PM) and application of fly ash capture technology, as well as use of novel biomass fuels like Miscanthus straw is recommended.

  17. A novel synthetic analog of militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells

    International Nuclear Information System (INIS)

    Yoon, Deok Hyo; Lim, Mi-Hee; Lee, Yu Ran; Sung, Gi-Ho; Lee, Tae-Ho; Jeon, Byeong Hwa; Cho, Jae Youl; Song, Won O.; Park, Haeil; Choi, Sunga; Kim, Tae Woong

    2013-01-01

    A synthetic Militarin analog-1[(2R,3R,4R,5R)-1,6-bis(4-(2,4,4-trimethylpentan-2-yl)phenoxy) hexane-2,3,4,5-tetraol] is a novel derivative of constituents from Cordyceps militaris, which has been used to treat a variety of chronic diseases including inflammation, diabetes, hyperglycemia and cancers. Here, we report for the first time the synthesis of Militarin analog-1 (MA-1) and the apoptotic mechanism of MA-1 against human lung cancer cell lines. Treatment with MA-1 significantly inhibited the viability of 3 human lung cancer cell lines. The inhibition of viability and growth in MA-1-treated A549 cells with an IC 50 of 5 μM were mediated through apoptosis induction, as demonstrated by an increase in DNA fragmentation, sub-G 0 /G 1 -DNA fraction, nuclear condensation, and phosphatidylserine exposure. The apoptotic cell death caused mitochondrial membrane permeabilization through regulation of expression of the Bcl-2 family proteins, leading to cytochrome c release in a time-dependent manner. Subsequently, the final stage of apoptosis, activation of caspase-9/-3 and cleavage of poly (ADP ribose) polymerase, was induced. Furthermore, A549 lung cancer cells were more responsive to MA-1 than a bronchial epithelial cell line (BEAS-2B), involving the rapid generation of reactive oxygen species (ROS), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activation. The pharmacological inhibition of ROS generation and JNK/p38 MAPK exhibited attenuated DNA fragmentation in MA-1-induced apoptosis. Oral administration of MA-1 also retarded growth of A549 orthotopic xenografts. In conclusion, the present study indicates that the new synthetic derivative MA-1 triggers mitochondrial apoptosis through ROS generation and regulation of MAPKs and may be a potent therapeutic agent against human lung cancer. - Highlights: • We report a novel synthesized derivative, militarin analog-1 (MA-1). • MA-1-induced cancer cell death was triggered by the ROS

  18. A novel synthetic analog of militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Deok Hyo; Lim, Mi-Hee [Department of Biochemistry, Kangwon National University, Chuncheon 200-701 (Korea, Republic of); Lee, Yu Ran [Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-747 (Korea, Republic of); Sung, Gi-Ho [Mushroom Research Division, National Institute of Horticultural and Herbal Science, Rural Development Administration, Suwon 404-707 (Korea, Republic of); Lee, Tae-Ho [R and D Center, Dong-A Pharmaceutical Co, Ltd, Yongin 446-905 (Korea, Republic of); Jeon, Byeong Hwa [Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-747 (Korea, Republic of); Cho, Jae Youl [Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746 (Korea, Republic of); Song, Won O. [Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824 (United States); Park, Haeil [College of Pharmacy, Kangwon National University, Chuncheon 200-701 (Korea, Republic of); Choi, Sunga, E-mail: sachoi@cnu.ac.kr [Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-747 (Korea, Republic of); Kim, Tae Woong, E-mail: tawkim@kangwon.ac.kr [Department of Biochemistry, Kangwon National University, Chuncheon 200-701 (Korea, Republic of)

    2013-12-15

    A synthetic Militarin analog-1[(2R,3R,4R,5R)-1,6-bis(4-(2,4,4-trimethylpentan-2-yl)phenoxy) hexane-2,3,4,5-tetraol] is a novel derivative of constituents from Cordyceps militaris, which has been used to treat a variety of chronic diseases including inflammation, diabetes, hyperglycemia and cancers. Here, we report for the first time the synthesis of Militarin analog-1 (MA-1) and the apoptotic mechanism of MA-1 against human lung cancer cell lines. Treatment with MA-1 significantly inhibited the viability of 3 human lung cancer cell lines. The inhibition of viability and growth in MA-1-treated A549 cells with an IC{sub 50} of 5 μM were mediated through apoptosis induction, as demonstrated by an increase in DNA fragmentation, sub-G{sub 0}/G{sub 1}-DNA fraction, nuclear condensation, and phosphatidylserine exposure. The apoptotic cell death caused mitochondrial membrane permeabilization through regulation of expression of the Bcl-2 family proteins, leading to cytochrome c release in a time-dependent manner. Subsequently, the final stage of apoptosis, activation of caspase-9/-3 and cleavage of poly (ADP ribose) polymerase, was induced. Furthermore, A549 lung cancer cells were more responsive to MA-1 than a bronchial epithelial cell line (BEAS-2B), involving the rapid generation of reactive oxygen species (ROS), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activation. The pharmacological inhibition of ROS generation and JNK/p38 MAPK exhibited attenuated DNA fragmentation in MA-1-induced apoptosis. Oral administration of MA-1 also retarded growth of A549 orthotopic xenografts. In conclusion, the present study indicates that the new synthetic derivative MA-1 triggers mitochondrial apoptosis through ROS generation and regulation of MAPKs and may be a potent therapeutic agent against human lung cancer. - Highlights: • We report a novel synthesized derivative, militarin analog-1 (MA-1). • MA-1-induced cancer cell death was triggered by

  19. Synthesis and optimization of novel allylated mono-carbonyl analogs of curcumin (MACs) act as potent anti-inflammatory agents against LPS-induced acute lung injury (ALI) in rats.

    Science.gov (United States)

    Zhu, Heping; Xu, Tingting; Qiu, Chenyu; Wu, Beibei; Zhang, Yali; Chen, Lingfeng; Xia, Qinqin; Li, Chenglong; Zhou, Bin; Liu, Zhiguo; Liang, Guang

    2016-10-04

    A series of novel symmetric and asymmetric allylated mono-carbonyl analogs of curcumin (MACs) were synthesized using an appropriate synthetic route and evaluated experimentally thru the LPS-induced expression of TNF-α and IL-6. Most of the obtained compounds exhibited improved water solubility as a hydrochloride salt compared to lead molecule 8f. The most active compound 7a was effective in reducing the Wet/Dry ratio in the lungs and protein concentration in bronchoalveolar lavage fluid. Meanwhile, 7a also inhibited mRNA expression of several inflammatory cytokines, including TNF-α, IL-6, IL-1β, and VCAM-1, in Beas-2B cells after Lipopolysaccharide (LPS) challenge. These results suggest that 7a could be therapeutically beneficial for use as an anti-inflammatory agent in the clinical treatment of acute lung injury (ALI). Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  20. Aryl hydrocarbon receptor-dependent up-regulation of the heterodimeric amino acid transporter LAT1 (SLC7A5)/CD98hc (SLC3A2) by diesel exhaust particle extract in human bronchial epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Le Vee, Marc; Jouan, Elodie; Lecureur, Valérie [Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes (France); Fardel, Olivier, E-mail: olivier.fardel@univ-rennes1.fr [Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes (France); Pôle Biologie, Centre Hospitalier Universitaire, 2 rue Henri Le Guilloux, 35033 Rennes (France)

    2016-01-01

    The heterodimeric L-type amino acid transporter (LAT) 1/CD98hc is overexpressed in lung cancers with a poor prognosis factor. Factors that contribute to LAT1/CD98hc overexpression in lung cells remain however to be determined, but the implication of atmospheric pollution can be suspected. The present study was therefore designed to analyze the effects of diesel exhaust particle (DEP) extract (DEPe) on LAT1/CD98hc expression in bronchial epithelial BEAS-2B cells. Exposure to DEPe up-regulated LAT1 and CD98hc mRNA levels in a concentration-dependent manner, with DEPe EC{sub 50} values (around 0.2 μg/mL) relevant to environmental situations. DEPe concomitantly induced LAT1/CD98hc protein expression and LAT1-mediated leucine accumulation in BEAS-2B cells. Inhibition of the aryl hydrocarbon receptor (AhR) pathway through the use of a chemical AhR antagonist or the siRNA-mediated silencing of AhR expression was next found to prevent DEPe-mediated induction of LAT1/CD98hc, indicating that this regulation depends on AhR, known to be activated by major chemical DEP components like polycyclic aromatic hydrocarbons. DEPe exposure was finally shown to induce mRNA expression and activity of matrix metalloproteinase (MMP)-2 in BEAS-2B cells, in a CD98hc/focal adhesion kinase (FAK)/extracellular regulated kinase (ERK) manner, thus suggesting that DEPe-mediated induction of CD98hc triggers activation of the integrin/FAK/ERK signaling pathway known to be involved in MMP-2 regulation. Taken together, these data demonstrate that exposure to DEPe induces functional overexpression of the amino acid transporter LAT1/CD98hc in lung cells. Such a regulation may participate to pulmonary carcinogenic effects of DEPs, owing to the well-documented contribution of LAT1 and CD98hc to cancer development. - Highlights: • The amino acid transporter LAT1/CD98hc is up-regulated in DEPe-treated lung cells. • The aryl hydrocarbon receptor is involved in DEPe-triggered induction of LAT1/CD98hc.

  1. Streptococcus pneumoniae-Induced Oxidative Stress in Lung Epithelial Cells Depends on Pneumococcal Autolysis and Is Reversible by Resveratrol.

    Science.gov (United States)

    Zahlten, Janine; Kim, Ye-Ji; Doehn, Jan-Moritz; Pribyl, Thomas; Hocke, Andreas C; García, Pedro; Hammerschmidt, Sven; Suttorp, Norbert; Hippenstiel, Stefan; Hübner, Ralf-Harto

    2015-06-01

    Streptococcus pneumoniae is the most common cause of community-acquired pneumonia worldwide. During pneumococcal pneumonia, the human airway epithelium is exposed to large amounts of H2O2 as a product of host and pathogen oxidative metabolism. Airway cells are known to be highly vulnerable to oxidant damage, but the pathophysiology of oxidative stress induced by S. pneumoniae and the role of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant systems of the host are not well characterized. For gluthation/gluthathion disulfide analysis BEAS-2B cells, primary broncho-epithelial cells (pBEC), explanted human lung tissue and mouse lungs were infected with different S. pneumoniae strains (D39, A66, R6x, H2O2/pneumolysin/LytA- deficient mutants of R6x). Cell death was proven by LDH assay and cell viability by IL-8 ELISA. The translocation of Nrf2 and the expression of catalase were shown via Western blot. The binding of Nrf2 at the catalase promoter was analyzed by ChIP. We observed a significant induction of oxidative stress induced by S. pneumoniae in vivo, ex vivo, and in vitro. Upon stimulation, the oxidant-responsive transcription factor Nrf2 was activated, and catalase was upregulated via Nrf2. The pneumococci-induced oxidative stress was independent of S. pneumoniae-derived H2O2 and pneumolysin but depended on the pneumococcal autolysin LytA. The Nrf2 inducer resveratrol, as opposed to catalase, reversed oxidative stress in lung epithelial cells. These observations indicate a H2O2-independent induction of oxidative stress in lung epithelial cells via the release of bacterial factors of S. pneumoniae. Resveratrol might be an option for prevention of acute lung injury and inflammatory responses observed in pneumococcal pneumonia. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  2. Inhalation treatment of primary lung cancer using liposomal curcumin dry powder inhalers

    Directory of Open Access Journals (Sweden)

    Tongtong Zhang

    2018-05-01

    Full Text Available Lung cancer is the leading cause of cancer-related deaths. Traditional chemotherapy causes serious toxicity due to the wide bodily distribution of these drugs. Curcumin is a potential anticancer agent but its low water solubility, poor bioavailability and rapid metabolism significantly limits clinical applications. Here we developed a liposomal curcumin dry powder inhaler (LCD for inhalation treatment of primary lung cancer. LCDs were obtained from curcumin liposomes after freeze-drying. The LCDs had a mass mean aerodynamic diameter of 5.81 μm and a fine particle fraction of 46.71%, suitable for pulmonary delivery. The uptake of curcumin liposomes by human lung cancer A549 cells was markedly greater and faster than that of free curcumin. The high cytotoxicity on A549 cells and the low cytotoxicity of curcumin liposomes on normal human bronchial BEAS-2B epithelial cells yielded a high selection index partly due to increased cell apoptosis. Curcumin powders, LCDs and gemcitabine were directly sprayed into the lungs of rats with lung cancer through the trachea. LCDs showed higher anticancer effects than the other two medications with regard to pathology and the expression of many cancer-related markers including VEGF, malondialdehyde, TNF-α, caspase-3 and BCL-2. LCDs are a promising medication for inhalation treatment of lung cancer with high therapeutic efficiency. Key words: Curcumin, Dry powder inhaler, Liposome, Primary lung cancer, Pulmonary delivery

  3. Anti-oxidative and inflammatory responses induced by fly ash particles and carbon black in lung epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Diabate, Silvia; Plaumann, Diana; Uebel, Caroline; Weiss, Carsten [Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Eggenstein-Leopoldshafen (Germany); Bergfeldt, Britta [Karlsruhe Institute of Technology, Institute of Technical Chemistry, Eggenstein-Leopoldshafen (Germany)

    2011-12-15

    Combustion-derived nanoparticles as constituents of ambient particulate matter have been shown to induce adverse health effects due to inhalation. However, the components inducing these effects as well as the biological mechanisms are still not fully understood. The fine fraction of fly ash particles collected from the electrostatic precipitator of a municipal solid waste incinerator was taken as an example for real particles with complex composition released into the atmosphere to study the mechanism of early biological responses of BEAS-2B human lung epithelial cells. The studies include the effects of the water-soluble and -insoluble fractions of the fly ash and the well-studied carbon black nanoparticles were used as a reference. Fly ash induced reactive oxygen species (ROS) and increased the total cellular glutathione (tGSH) content. Carbon black also induced ROS generation; however, in contrast to the fly ash, it decreased the intracellular tGSH. The fly ash-induced oxidative stress was correlated with induction of the anti-oxidant enzyme heme oxygenase-1 and increase of the redox-sensitive transcription factor Nrf2. Carbon black was not able to induce HO-1. ROS generation, tGSH increase and HO-1 induction were only induced by the insoluble fraction of the fly ash, not by the water-soluble fraction. ROS generation and HO-1 induction were markedly inhibited by pre-incubation of the cells with the anti-oxidant N-acetyl cysteine which confirmed the involvement of oxidative stress. Both effects were also reduced by the metal chelator deferoxamine indicating a contribution of bioavailable transition metals. In summary, both fly ash and carbon black induce ROS but only fly ash induced an increase of intracellular tGSH and HO-1 production. Bioavailable transition metals in the solid water-insoluble matrix of the fly ash mostly contribute to the effects. (orig.)

  4. Anti-lung cancer effects of novel ginsenoside 25-OCH(3)-PPD.

    Science.gov (United States)

    Wang, Wei; Rayburn, Elizabeth R; Hang, Jie; Zhao, Yuqing; Wang, Hui; Zhang, Ruiwen

    2009-09-01

    20(S)-25-methoxyl-dammarane-3beta, 12beta, 20-triol (25-OCH(3)-PPD), a newly identified natural product from Panax notoginseng, exhibits activity against a variety of cancer cells. Herein, we report the effects of this compound on human A549, H358, and H838 lung cancer cells, and compare these effects with a control lung epithelial cell line, BEAS-2B. 25-OCH(3)-PPD decreased survival, inhibited proliferation, and induced apoptosis and G1 cell cycle arrest in the lung cancer cell lines. The P. notoginseng compound also decreased the levels of proteins associated with cell proliferation and cell survival. Moreover, 25-OCH(3)-PPD inhibited the growth of A549 lung cancer xenograft tumors. 25-OCH(3)-PPD demonstrated low toxicity to non-cancer cells, and no observable toxicity was seen when the compound was administered to animals. In conclusion, our preclinical data indicate that 25-OCH(3)-PPD is a potential therapeutic agent in vitro and in vivo, and further preclinical and clinical development of this agent for lung cancer is warranted.

  5. Intersections of lung progenitor cells, lung disease and lung cancer.

    Science.gov (United States)

    Kim, Carla F

    2017-06-30

    The use of stem cell biology approaches to study adult lung progenitor cells and lung cancer has brought a variety of new techniques to the field of lung biology and has elucidated new pathways that may be therapeutic targets in lung cancer. Recent results have begun to identify the ways in which different cell populations interact to regulate progenitor activity, and this has implications for the interventions that are possible in cancer and in a variety of lung diseases. Today's better understanding of the mechanisms that regulate lung progenitor cell self-renewal and differentiation, including understanding how multiple epigenetic factors affect lung injury repair, holds the promise for future better treatments for lung cancer and for optimising the response to therapy in lung cancer. Working between platforms in sophisticated organoid culture techniques, genetically engineered mouse models of injury and cancer, and human cell lines and specimens, lung progenitor cell studies can begin with basic biology, progress to translational research and finally lead to the beginnings of clinical trials. Copyright ©ERS 2017.

  6. Intersections of lung progenitor cells, lung disease and lung cancer

    Directory of Open Access Journals (Sweden)

    Carla F. Kim

    2017-06-01

    Full Text Available The use of stem cell biology approaches to study adult lung progenitor cells and lung cancer has brought a variety of new techniques to the field of lung biology and has elucidated new pathways that may be therapeutic targets in lung cancer. Recent results have begun to identify the ways in which different cell populations interact to regulate progenitor activity, and this has implications for the interventions that are possible in cancer and in a variety of lung diseases. Today's better understanding of the mechanisms that regulate lung progenitor cell self-renewal and differentiation, including understanding how multiple epigenetic factors affect lung injury repair, holds the promise for future better treatments for lung cancer and for optimising the response to therapy in lung cancer. Working between platforms in sophisticated organoid culture techniques, genetically engineered mouse models of injury and cancer, and human cell lines and specimens, lung progenitor cell studies can begin with basic biology, progress to translational research and finally lead to the beginnings of clinical trials.

  7. Electrical characterization of single cells using polysilicon wire ion sensor in an isolation window.

    Science.gov (United States)

    Wu, You-Lin; Hsu, Po-Yen; Hsu, Chung-Ping; Wang, Chih-Cheng; Lee, Li-Wen; Lin, Jing-Jenn

    2011-10-01

    A polysilicon wire (PSW) sensor can detect the H(+) ion density (pH value) of the medium coated on its surface, and different cells produce different extracellular acidification and hence different H(+) ion densities. Based on this, we used a PSW sensor in combination with a mold-cast polydimethylsiloxane (PDMS) isolation window to detect the adhesion, apoptosis and extracellular acidification of single normal cells and single cancer cells. Single living human normal cells WI38, MRC5, and BEAS-2B as well as non-small-cell lung cancer (NSCLC) cells A549, H1299, and CH27 were cultivated separately inside the isolation window. The current flowing through the PSW channel was measured. From the PSW channel current change as a function of time, we determined the cell adhesion time by observing the time required for the current change to saturate, since a stable extracellular ion density was established after the cells were completely adhered to the PSW surface. The apoptosis of cells can also be determined when the channel current change drops to zero. We found that all the NSCLC cells had a higher channel current change and hence a lower pH value than the normal cells anytime after they were seeded. The corresponding average pH values were 5.86 for A549, 6.00 for H1299, 6.20 for CH27, 6.90 for BEAS-2B, 6.96for MRC5, and 7.02 for WI38, respectively, after the cells were completely adhered to the PSW surface. Our results show that NSCLC cells have a stronger cell-substrate adhesion and a higher extracellular acidification rate than normal cells.

  8. Lung cancer - non-small cell

    Science.gov (United States)

    Cancer - lung - non-small cell; Non-small cell lung cancer; NSCLC; Adenocarcinoma - lung; Squamous cell carcinoma - lung ... Research shows that smoking marijuana may help cancer cells grow. But there is no direct link between ...

  9. Cobalt chloride speciation, mechanisms of cytotoxicity on human pulmonary cells, and synergistic toxicity with zinc

    International Nuclear Information System (INIS)

    Bresson, Carole; Darolles, Carine; Sage, Nicole; Malard, Veronique; Carmona, Asuncion; Roudeau, Stephane; Ortega, Richard; Gautier, Celine; Ansoborlo, Eric

    2013-01-01

    Cobalt is used in numerous industrial sectors, leading to occupational diseases, particularly by inhalation. Cobalt-associated mechanisms of toxicity are far from being understood and information that could improve knowledge in this area is required. We investigated the impact of a soluble cobalt compound, CoCl 2 .6H 2 O, on the BEAS-2B lung epithelial cell line, as well as its impact on metal homeostasis. Cobalt speciation in different culture media, in particular soluble and precipitated cobalt species, was investigated via theoretical and analytical approaches. The cytotoxic effects of cobalt on the cells were assessed. Upon exposure of BEAS-2B cells to cobalt, intracellular accumulation of cobalt and zinc was demonstrated using direct in situ microchemical analysis based on ion micro-beam techniques and analysis after cell lysis by inductively coupled plasma mass spectrometry (ICP-MS). Microchemical imaging revealed that cobalt was rather homogeneously distributed in the nucleus and in the cytoplasm whereas zinc was more abundant in the nucleus. The modulation of zinc homeostasis led to the evaluation of the effect of combined cobalt and zinc exposure. In this case, a clear synergistic increase in toxicity was observed as well as a substantial increase in zinc content within cells. Western blots performed under the same co-exposure conditions revealed a decrease in ZnT1 expression, suggesting that cobalt could inhibit zinc release through the modulation of ZnT1. Overall, this study highlights the potential hazard to lung function, of combined exposure to cobalt and zinc. (authors)

  10. Cobalt chloride speciation, mechanisms of cytotoxicity on human pulmonary cells, and synergistic toxicity with zinc

    International Nuclear Information System (INIS)

    Bresson, Carole; Darolles, Carine; Sage, Nicole; Malard, Veronique; Carmona, Asuncion; Roudeau, Stephane; Ortega, Richard; Gautier, Celine; Ansoborlo, Eric

    2013-01-01

    Complete text of publication follows: Cobalt is used in numerous industrial sectors, leading to occupational diseases, particularly by inhalation. Cobalt-associated mechanisms of toxicity are far from being understood and information that could improve knowledge in this area is required. We investigated the impact of a soluble cobalt compound, CoCl 2 , on the BEAS-2B lung epithelial cell line, as well as its impact on metal homeostasis. Cobalt speciation in different culture media, in particular soluble and precipitated cobalt species, was investigated via theoretical and analytical approaches. The cytotoxic effects of cobalt on the cells were assessed. Upon exposure of BEAS-2B cells to cobalt, intracellular accumulation of cobalt and zinc was demonstrated using direct in situ microchemical analysis based on ion micro-beam techniques and analysis after cell lysis by inductively coupled plasma mass spectrometry (ICP-MS). Microchemical imaging revealed that cobalt was rather homogeneously distributed in the nucleus and in the cytoplasm whereas zinc was more abundant in the nucleus. The modulation of zinc homeostasis led to the evaluation of the effect of combined cobalt and zinc exposure. In this case, a clear synergistic increase in toxicity was observed as well as a substantial increase in zinc content within cells. Western blots performed under the same co-exposure conditions revealed a decrease in ZnT1 expression, suggesting that cobalt could inhibit zinc release through the modulation of ZnT1. Overall, this study highlights the potential hazard to lung function, of combined exposure to cobalt and zinc

  11. Nicotine signals through muscle-type and neuronal nicotinic acetylcholine receptors in both human bronchial epithelial cells and airway fibroblasts

    Directory of Open Access Journals (Sweden)

    Luketich James D

    2004-12-01

    Full Text Available Abstract Background Non-neuronal cells, including those derived from lung, are reported to express nicotinic acetylcholine receptors (nAChR. We examined nAChR subunit expression in short-term cultures of human airway cells derived from a series of never smokers, ex-smokers, and active smokers. Methods and Results At the mRNA level, human bronchial epithelial (HBE cells and airway fibroblasts expressed a range of nAChR subunits. In multiple cultures of both cell types, mRNA was detected for subunits that constitute functional muscle-type and neuronal-type pentomeric receptors. Two immortalized cell lines derived from HBE cells also expressed muscle-type and neuronal-type nAChR subunits. Airway fibroblasts expressed mRNA for three muscle-type subunits (α1, δ, and ε significantly more often than HBE cells. Immunoblotting of HBE cell and airway fibroblast extracts confirmed that mRNA for many nAChR subunits is translated into detectable levels of protein, and evidence of glycosylation of nAChRs was observed. Some minor differences in nAChR expression were found based on smoking status in fibroblasts or HBE cells. Nicotine triggered calcium influx in the immortalized HBE cell line BEAS2B, which was blocked by α-bungarotoxin and to a lesser extent by hexamethonium. Activation of PKC and MAPK p38, but not MAPK p42/44, was observed in BEAS2B cells exposed to nicotine. In contrast, nicotine could activate p42/44 in airway fibroblasts within five minutes of exposure. Conclusions These results suggest that muscle-type and neuronal-type nAChRs are functional in airway fibroblasts and HBE cells, that prior tobacco exposure does not appear to be an important variable in nAChR expression, and that distinct signaling pathways are observed in response to nicotine.

  12. Comparison between micro- and nanosized copper oxide and water soluble copper chloride: interrelationship between intracellular copper concentrations, oxidative stress and DNA damage response in human lung cells.

    Science.gov (United States)

    Strauch, Bettina Maria; Niemand, Rebecca Katharina; Winkelbeiner, Nicola Lisa; Hartwig, Andrea

    2017-08-01

    Nano- and microscale copper oxide particles (CuO NP, CuO MP) are applied for manifold purposes, enhancing exposure and thus the potential risk of adverse health effects. Based on the pronounced in vitro cytotoxicity of CuO NP, systematic investigations on the mode of action are required. Therefore, the impact of CuO NP, CuO MP and CuCl 2 on the DNA damage response on transcriptional level was investigated by quantitative gene expression profiling via high-throughput RT-qPCR. Cytotoxicity, copper uptake and the impact on the oxidative stress response, cell cycle regulation and apoptosis were further analysed on the functional level. Cytotoxicity of CuO NP was more pronounced when compared to CuO MP and CuCl 2 in human bronchial epithelial BEAS-2B cells. Uptake studies revealed an intracellular copper overload in the soluble fractions of both cytoplasm and nucleus, reaching up to millimolar concentrations in case of CuO NP and considerably lower levels in case of CuO MP and CuCl 2 . Moreover, CuCl 2 caused copper accumulation in the nucleus only at cytotoxic concentrations. Gene expression analysis in BEAS-2B and A549 cells revealed a strong induction of uptake-related metallothionein genes, oxidative stress-sensitive and pro-inflammatory genes, anti-oxidative defense-associated genes as well as those coding for the cell cycle inhibitor p21 and the pro-apoptotic Noxa and DR5. While DNA damage inducible genes were activated, genes coding for distinct DNA repair factors were down-regulated. Modulation of gene expression was most pronounced in case of CuO NP as compared to CuO MP and CuCl 2 and more distinct in BEAS-2B cells. GSH depletion and activation of Nrf2 in HeLa S3 cells confirmed oxidative stress induction, mainly restricted to CuO NP. Also, cell cycle arrest and apoptosis induction were most distinct for CuO NP. The high cytotoxicity and marked impact on gene expression by CuO NP can be ascribed to the strong intracellular copper ion release, with subsequent

  13. Multiplexed quantitative high content screening reveals that cigarette smoke condensate induces changes in cell structure and function through alterations in cell signaling pathways in human bronchial cells

    International Nuclear Information System (INIS)

    Carter, Charleata A.; Hamm, Jonathan T.

    2009-01-01

    Human bronchial cells are one of the first cell types exposed to environmental toxins. Toxins often activate nuclear factor-κB (NF-κB) and protein kinase C (PKC). We evaluated the hypothesis that cigarette smoke condensate (CSC), the particulate fraction of cigarette smoke, activates PKC-α and NF-κB, and concomitantly disrupts the F-actin cytoskeleton, induces apoptosis and alters cell function in BEAS-2B human bronchial epithelial cells. Compared to controls, exposure of BEAS-2B cells to doses of 30 μg/ml CSC significantly activated PKC-α, while CSC doses above 20 μg/ml CSC significantly activated NF-κB. As NF-κB was activated, cell number decreased. CSC treatment of BEAS-2B cells induced a decrease in cell size and an increase in cell surface extensions including filopodia and lamellipodia. CSC treatment of BEAS-2B cells induced F-actin rearrangement such that stress fibers were no longer prominent at the cell periphery and throughout the cells, but relocalized to perinuclear regions. Concurrently, CSC induced an increase in the focal adhesion protein vinculin at the cell periphery. CSC doses above 30 μg/ml induced a significant increase in apoptosis in BEAS-2B cells evidenced by an increase in activated caspase 3, an increase in mitochondrial mass and a decrease in mitochondrial membrane potential. As caspase 3 increased, cell number decreased. CSC doses above 30 μg/ml also induced significant concurrent changes in cell function including decreased cell spreading and motility. CSC initiates a signaling cascade in human bronchial epithelial cells involving PKC-α, NF-κB and caspase 3, and consequently decreases cell spreading and motility. These CSC-induced alterations in cell structure likely prevent cells from performing their normal function thereby contributing to smoke-induced diseases.

  14. Airborne urban particles (Milan winter-PM2.5) cause mitotic arrest and cell death: Effects on DNA, mitochondria, AhR binding and spindle organization

    Energy Technology Data Exchange (ETDEWEB)

    Gualtieri, Maurizio [Applied Cell Biology and Particles Effects, Department of Environmental Science, University Milano-Bicocca, Piazza della Scienza 1, 20126 Milano (Italy); Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo (Norway); Ovrevik, Johan [Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo (Norway); Mollerup, Steen [Section for Toxicology, National Institute of Occupational Health, N-0033 Oslo (Norway); Asare, Nana [Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo (Norway); Longhin, Eleonora [Applied Cell Biology and Particles Effects, Department of Environmental Science, University Milano-Bicocca, Piazza della Scienza 1, 20126 Milano (Italy); Dahlman, Hans-Jorgen [Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo (Norway); Camatini, Marina [Applied Cell Biology and Particles Effects, Department of Environmental Science, University Milano-Bicocca, Piazza della Scienza 1, 20126 Milano (Italy); Centre Research POLARIS, Department of Environmental Science, University Milano-Bicocca, Piazza della Scienza 1, 20126 Milano (Italy); Holme, Jorn A., E-mail: jorn.holme@fhi.no [Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo (Norway)

    2011-08-01

    Highlights: {yields} PM2.5 induces mitotic arrest in BEAS-2B cells. {yields} PM2.5 induces DNA damage and activates DNA damage response. {yields} AhR regulated genes (Cyp1A1, Cyp1B1 and AhRR) are upregulated after PM exposure. {yields} Mitotic spindle assembly is perturbed in PM exposed cells. - Abstract: Airborne particulate matter (PM) is considered to be an important contributor to lung diseases. In the present study we report that Milan winter-PM2.5 inhibited proliferation in human bronchial epithelial cells (BEAS-2B) by inducing mitotic arrest. The cell cycle arrest was followed by an increase in mitotic-apoptotic cells, mitotic slippage and finally an increase in 'classical' apoptotic cells. Exposure to winter-PM10 induced only a slight effect which may be due to the presence of PM2.5 in this fraction while pure combustion particles failed to disturb mitosis. Fewer cells expressing the mitosis marker phospho-histone H3 compared to cells with condensed chromosomes, suggest that PM2.5 induced premature mitosis. PM2.5 was internalized into the cells and often localized in laminar organelles, although particles without apparent plasma membrane covering were also seen. In PM-containing cells mitochondria and lysosomes were often damaged, and in mitotic cells fragmented chromosomes often appeared. PM2.5 induced DNA strands breaks and triggered a DNA-damage response characterized by increased phosphorylation of ATM, Chk2 and H2AX; as well as induced a marked increase in expression of the aryl hydrocarbon receptor (AhR)-regulated genes, CYP1A1, CYP1B1 and AhRR. Furthermore, some disturbance of the organization of microtubules was indicated. It is hypothesized that the induced mitotic arrest and following cell death was due to a premature chromosome condensation caused by a combination of DNA, mitochondrial and spindle damage.

  15. General Information about Small Cell Lung Cancer

    Science.gov (United States)

    ... Lung Cancer Prevention Lung Cancer Screening Research Small Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Small Cell Lung Cancer Go to Health Professional Version Key Points Small ...

  16. Stages of Small Cell Lung Cancer

    Science.gov (United States)

    ... Lung Cancer Prevention Lung Cancer Screening Research Small Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Small Cell Lung Cancer Go to Health Professional Version Key Points Small ...

  17. Intrinsic and Extrinsic Regulation of PD-L2 Expression in Oncogene-Driven Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Shibahara, Daisuke; Tanaka, Kentaro; Iwama, Eiji; Kubo, Naoki; Ota, Keiichi; Azuma, Koichi; Harada, Taishi; Fujita, Jiro; Nakanishi, Yoichi; Okamoto, Isamu

    2018-03-27

    The interaction of programmed cell death ligand 2 (PD-L2) with programmed cell death 1 is implicated in tumor immune escape. The regulation of PD-L2 expression in tumor cells has remained unclear, however. We here examined intrinsic and extrinsic regulation of PD-L2 expression in NSCLC. PD-L2 expression was evaluated by reverse transcription and real-time polymerase chain reaction analysis and by flow cytometry. BEAS-2B cells stably expressing an activated mutant form of EGFR or the echinoderm microtubule associated protein like 4 (EML4)-ALK receptor tyrosine kinase fusion oncoprotein manifested increased expression of PD-L2 at both the mRNA and protein levels. Furthermore, treatment of NSCLC cell lines that harbor such driver oncogenes with corresponding EGFR or ALK tyrosine kinase inhibitors or depletion of EGFR or ALK by small interfering RNA transfection suppressed expression of PD-L2, demonstrating that activating EGFR mutations or echinoderm microtubule associated protein like 4 gene (EML4)-ALK receptor tyrosine kinase gene (ALK) fusion intrinsically induce PD-L2 expression. We also found that interferon gamma (IFN-γ) extrinsically induced expression of PD-L2 through signal transducer and activator of transcription 1 signaling in NSCLC cells. Oncogene-driven expression of PD-L2 in NSCLC cells was inhibited by knockdown of the transcription factors signal transducer and activator of transcription 3 (STAT3) or c-FOS. IFN-γ also activated STAT3 and c-FOS, suggesting that these proteins may also contribute to the extrinsic induction of PD-L2 expression. Expression of PD-L2 is induced intrinsically by activating EGFR mutations or EML4-ALK fusion and extrinsically by IFN-γ, with STAT3 and c-FOS possibly contributing to both intrinsic and extrinsic pathways. Our results thus provide insight into the complexity of tumor immune escape in NSCLC. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  18. Ethyl Acetate Extract of Scindapsus cf. hederaceus Exerts the Inhibitory Bioactivity on Human Non-Small Cell Lung Cancer Cells through Modulating ER Stress

    Directory of Open Access Journals (Sweden)

    Chon-Kit Chou

    2018-06-01

    Full Text Available Unfolded protein response (UPR is a cytoprotective mechanism that alleviates the protein-folding burden in eukaryotic organisms. Moderate activation of UPR is required for maintaining endoplasmic reticulum (ER homeostasis and profoundly contributes to tumorigenesis. Defects in UPR signaling are implicated in the attenuation of various malignant phenotypes including cell proliferation, migration, and invasion, as well as angiogenesis. This suggests UPR as a promising target in cancer therapy. The pharmacological effects of the plant Scindapsus cf. hederaceus on human cancer cell lines is not understood. In this study, we identified an ethyl acetate extract from Scindapsus cf. hederaceus (SH-EAE, which markedly altered the protein expression of UPR-related genes in human non-small cell lung cancer (NSCLC cells. Treatment with the SH-EAE led to the dose-dependent suppression of colony forming ability of both H1299 and H460 cells, but not markedly in normal bronchial epithelial BEAS-2B cells. SH-EAE treatment also attenuated the migration and invasion ability of H1299 and H460 cells. Moreover, SH-EAE strikingly suppressed the protein expression of two ER stress sensors, including inositol requiring enzyme-1α (IRE-1α and protein kinase R-like ER kinase (PERK, and antagonized the induction of C/EBP homologous protein (CHOP expression by thapsigargin, an ER stress inducer. SH-EAE induced the formation of massive vacuoles which are probably derived from ER. Importantly, SH-EAE impaired the formation of intersegmental vessels (ISV in zebrafish larvae, an index of angiogenesis, but had no apparent effect on the rate of larval development. Together, our findings demonstrate, for the first time, that the ability of SH-EAE specifically targets the two sensors of UPR, with significant anti-proliferation and anti-migration activities as a crude extract in human NSCLC cells. Our finding also indicates potential applications of SH-EAE in preventing UPR

  19. Exosomes from asbestos-exposed cells modulate gene expression in mesothelial cells.

    Science.gov (United States)

    Munson, Phillip; Lam, Ying-Wai; Dragon, Julie; MacPherson, Maximilian; Shukla, Arti

    2018-03-19

    Asbestos exposure is a determinate cause of many diseases, such as mesothelioma, fibrosis, and lung cancer, and poses a major human health hazard. At this time, there are no identified biomarkers to demarcate asbestos exposure before the presentation of disease and symptoms, and there is only limited understanding of the underlying biology that governs asbestos-induced disease. In our study, we used exosomes, 30-140 nm extracellular vesicles, to gain insight into these knowledge gaps. As inhaled asbestos is first encountered by lung epithelial cells and macrophages, we hypothesize that asbestos-exposed cells secrete exosomes with signature proteomic cargo that can alter the gene expression of mesothelial cells, contributing to disease outcomes like mesothelioma. In the present study using lung epithelial cells (BEAS2B) and macrophages (THP-1), we first show that asbestos exposure causes changes in abundance of some proteins in the exosomes secreted from these cells. Furthermore, exposure of human mesothelial cells (HPM3) to these exosomes resulted in gene expression changes related to epithelial-to-mesenchymal transition and other cancer-related genes. This is the first report to indicate that asbestos-exposed cells secrete exosomes with differentially abundant proteins and that those exosomes have a gene-altering effect on mesothelial cells.-Munson, P., Lam, Y.-W., Dragon, J. MacPherson, M., Shukla, A. Exosomes from asbestos-exposed cells modulate gene expression in mesothelial cells.

  20. Potential targets for lung squamous cell carcinoma

    Science.gov (United States)

    Researchers have identified potential therapeutic targets in lung squamous cell carcinoma, the second most common form of lung cancer. The Cancer Genome Atlas (TCGA) Research Network study comprehensively characterized the lung squamous cell carcinoma gen

  1. Malignant human cell transformation of Marcellus Shale gas drilling flow back water

    Energy Technology Data Exchange (ETDEWEB)

    Yao, Yixin [Department of Epidemiology, Shanghai Jiaotong University School of Public Health (China); Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987 (United States); Chen, Tingting [School of Material Science and Engineering, Nanjing University of Science and Technology, Nanjing 210094 (China); Shen, Steven S. [Biochemistry and Molecular Pharmaceutical, New York University School of Medicine (United States); Niu, Yingmei; DesMarais, Thomas L.; Linn, Reka; Saunders, Eric; Fan, Zhihua [Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987 (United States); Lioy, Paul [Robert Wood Johnson Medical School Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States); Kluz, Thomas; Chen, Lung-Chi [Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987 (United States); Wu, Zhuangchun, E-mail: wuzhuangchun@mail.njust.edu.cn [College of Science, Donghua University, Shanghai 201620 (China); Costa, Max, E-mail: max.costa@nyumc.org [Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987 (United States)

    2015-10-01

    The rapid development of high-volume horizontal hydraulic fracturing for mining natural gas from shale has posed potential impacts on human health and biodiversity. The produced flow back waters after hydraulic stimulation are known to carry high levels of saline and total dissolved solids. To understand the toxicity and potential carcinogenic effects of these wastewaters, flow back waters from five Marcellus hydraulic fracturing oil and gas wells were analyzed. The physicochemical nature of these samples was analyzed by inductively coupled plasma mass spectrometry and scanning electron microscopy/energy dispersive X-ray spectroscopy. A cytotoxicity study using colony formation as the endpoint was carried out to define the LC{sub 50} values of test samples using human bronchial epithelial cells (BEAS-2B). The BEAS-2B cell transformation assay was employed to assess the carcinogenic potential of the samples. Barium and strontium were among the most abundant metals in these samples and the same metals were found to be elevated in BEAS-2B cells after long-term treatment. BEAS-2B cells treated for 6 weeks with flow back waters produced colony formation in soft agar that was concentration dependent. In addition, flow back water-transformed BEAS-2B cells show better migration capability when compared to control cells. This study provides information needed to assess the potential health impact of post-hydraulic fracturing flow back waters from Marcellus Shale natural gas mining. - Highlights: • This is the first report of potential cytotoxicity and transforming activity of Marcellus shale gas mining flow back to mammalian cells. • Barium and Strontium were elevated in flow back water exposed cells. • Flow back water malignantly transformed cells and formed tumor in athymic nude mice. • Flow back transformed cells exhibited altered transcriptome with dysregulated cell migration pathway and adherent junction pathway.

  2. Malignant human cell transformation of Marcellus Shale gas drilling flow back water

    International Nuclear Information System (INIS)

    Yao, Yixin; Chen, Tingting; Shen, Steven S.; Niu, Yingmei; DesMarais, Thomas L.; Linn, Reka; Saunders, Eric; Fan, Zhihua; Lioy, Paul; Kluz, Thomas; Chen, Lung-Chi; Wu, Zhuangchun; Costa, Max

    2015-01-01

    The rapid development of high-volume horizontal hydraulic fracturing for mining natural gas from shale has posed potential impacts on human health and biodiversity. The produced flow back waters after hydraulic stimulation are known to carry high levels of saline and total dissolved solids. To understand the toxicity and potential carcinogenic effects of these wastewaters, flow back waters from five Marcellus hydraulic fracturing oil and gas wells were analyzed. The physicochemical nature of these samples was analyzed by inductively coupled plasma mass spectrometry and scanning electron microscopy/energy dispersive X-ray spectroscopy. A cytotoxicity study using colony formation as the endpoint was carried out to define the LC 50 values of test samples using human bronchial epithelial cells (BEAS-2B). The BEAS-2B cell transformation assay was employed to assess the carcinogenic potential of the samples. Barium and strontium were among the most abundant metals in these samples and the same metals were found to be elevated in BEAS-2B cells after long-term treatment. BEAS-2B cells treated for 6 weeks with flow back waters produced colony formation in soft agar that was concentration dependent. In addition, flow back water-transformed BEAS-2B cells show better migration capability when compared to control cells. This study provides information needed to assess the potential health impact of post-hydraulic fracturing flow back waters from Marcellus Shale natural gas mining. - Highlights: • This is the first report of potential cytotoxicity and transforming activity of Marcellus shale gas mining flow back to mammalian cells. • Barium and Strontium were elevated in flow back water exposed cells. • Flow back water malignantly transformed cells and formed tumor in athymic nude mice. • Flow back transformed cells exhibited altered transcriptome with dysregulated cell migration pathway and adherent junction pathway.

  3. Uptake and cytotoxic effects of multi-walled carbon nanotubes in human bronchial epithelial cells

    International Nuclear Information System (INIS)

    Hirano, Seishiro; Fujitani, Yuji; Furuyama, Akiko; Kanno, Sanae

    2010-01-01

    Carbon nanotubes (CNT) are cytotoxic to several cell types. However, the mechanism of CNT toxicity has not been fully studied, and dosimetric analyses of CNT in the cell culture system are lacking. Here, we describe a novel, high throughput method to measure cellular uptake of CNT using turbimetry. BEAS-2B, a human bronchial epithelial cell line, was used to investigate cellular uptake, cytotoxicity, and inflammatory effects of multi-walled CNT (MWCNT). The cytotoxicity of MWCNT was higher than that of crocidolite asbestos in BEAS-2B cells. The IC 50 of MWCNT was 12 μg/ml, whereas that of asbestos (crocidolite) was 678 μg/ml. Over the course of 5 to 8 h, BEAS-2B cells took up 17-18% of the MWCNT when they were added to the culture medium at a concentration of 10 μg/ml. BEAS-2B cells were exposed to 2, 5, or 10 μg/ml of MWCNT, and total RNA was extracted for cytokine cDNA primer array assays. The culture supernatant was collected for cytokine antibody array assays. Cytokines IL-6 and IL-8 increased in a dose dependent manner at both the mRNA and protein levels. Migration inhibitory factor (MIF) also increased in the culture supernatant in response to MWCNT. A phosphokinase array study using lysates from BEAS-2B cells exposed to MWCNT indicated that phosphorylation of p38, ERK1, and HSP27 increased significantly in response to MWCNT. Results from a reporter gene assays using the NF-κB or AP-1 promoter linked to the luciferase gene in transiently transfected CHO-KI cells revealed that NF-κB was activated following MWCNT exposure, while AP-1 was not changed. Collectively, MWCNT activated NF-κB, enhanced phosphorylation of MAP kinase pathway components, and increased production of proinflammatory cytokines in human bronchial epithelial cells.

  4. Wnt5a is associated with cigarette smoke-related lung carcinogenesis via protein kinase C.

    Science.gov (United States)

    Whang, Young Mi; Jo, Ukhyun; Sung, Jae Sook; Ju, Hyun Jung; Kim, Hyun Kyung; Park, Kyong Hwa; Lee, Jong Won; Koh, In Song; Kim, Yeul Hong

    2013-01-01

    Wnt5a is overexpressed during the progression of human non-small cell lung cancer. However, the roles of Wnt5a during smoking-related lung carcinogenesis have not been clearly elucidated. We investigated the associations between Wnt5a and the early development of cigarette smoke related lung cancer using human bronchial epithelial (HBE) cells (NHBE, BEAS-2B, 1799, 1198 and 1170I) at different malignant stages established by exposure to cigarette smoke condensate (CSC). Abnormal up-regulation of Wnt5a mRNA and proteins was detected in CSC-exposed transformed 1198 and tumorigenic 1170I cells as compared with other non-CSC exposed HBE cells. Tumor tissues obtained from smokers showed higher Wnt5a expressions than matched normal tissues. In non-CSC exposed 1799 cells, treatment of recombinant Wnt5a caused the activations of PKC and Akt, and the blockage of Wnt5a and PKC significantly decreased the viabilities of CSC-transformed 1198 cells expressing high levels of Wnt5a. This reduced cell survival rate was associated with increased apoptosis via the down-regulation of Bcl2 and the induction of cleaved poly ADP-ribose polymerase. Moreover, CSC-treated 1799 cells showed induction of Wnt5a expression and enhanced colony-forming capacity. The CSC-induced colony forming efficiency was suppressed by the co-incubation with a PKC inhibitor. In conclusion, these results suggest that cigarette smoke induces Wnt5a-coupled PKC activity during lung carcinogenesis, which causes Akt activity and anti-apoptosis in lung cancer. Therefore, current study provides novel clues for the crucial role of Wnt5a in the smoking-related lung carcinogenesis.

  5. Wnt5a is associated with cigarette smoke-related lung carcinogenesis via protein kinase C.

    Directory of Open Access Journals (Sweden)

    Young Mi Whang

    Full Text Available Wnt5a is overexpressed during the progression of human non-small cell lung cancer. However, the roles of Wnt5a during smoking-related lung carcinogenesis have not been clearly elucidated. We investigated the associations between Wnt5a and the early development of cigarette smoke related lung cancer using human bronchial epithelial (HBE cells (NHBE, BEAS-2B, 1799, 1198 and 1170I at different malignant stages established by exposure to cigarette smoke condensate (CSC. Abnormal up-regulation of Wnt5a mRNA and proteins was detected in CSC-exposed transformed 1198 and tumorigenic 1170I cells as compared with other non-CSC exposed HBE cells. Tumor tissues obtained from smokers showed higher Wnt5a expressions than matched normal tissues. In non-CSC exposed 1799 cells, treatment of recombinant Wnt5a caused the activations of PKC and Akt, and the blockage of Wnt5a and PKC significantly decreased the viabilities of CSC-transformed 1198 cells expressing high levels of Wnt5a. This reduced cell survival rate was associated with increased apoptosis via the down-regulation of Bcl2 and the induction of cleaved poly ADP-ribose polymerase. Moreover, CSC-treated 1799 cells showed induction of Wnt5a expression and enhanced colony-forming capacity. The CSC-induced colony forming efficiency was suppressed by the co-incubation with a PKC inhibitor. In conclusion, these results suggest that cigarette smoke induces Wnt5a-coupled PKC activity during lung carcinogenesis, which causes Akt activity and anti-apoptosis in lung cancer. Therefore, current study provides novel clues for the crucial role of Wnt5a in the smoking-related lung carcinogenesis.

  6. PKC activation induces inflammatory response and cell death in human bronchial epithelial cells.

    Directory of Open Access Journals (Sweden)

    Hyunhee Kim

    Full Text Available A variety of airborne pathogens can induce inflammatory responses in airway epithelial cells, which is a crucial component of host defence. However, excessive inflammatory responses and chronic inflammation also contribute to different diseases of the respiratory system. We hypothesized that the activation of protein kinase C (PKC is one of the essential mechanisms of inflammatory response in airway epithelial cells. In the present study, we stimulated human bronchial lung epithelial (BEAS-2B cells with the phorbol ester Phorbol 12, 13-dibutyrate (PDBu, and examined gene expression profile using microarrays. Microarray analysis suggests that PKC activation induced dramatic changes in gene expression related to multiple cellular functions. The top two interaction networks generated from these changes were centered on NFκB and TNF-α, which are two commonly known pathways for cell death and inflammation. Subsequent tests confirmed the decrease in cell viability and an increase in the production of various cytokines. Interestingly, each of the increased cytokines was differentially regulated at mRNA and/or protein levels by different sub-classes of PKC isozymes. We conclude that pathological cell death and cytokine production in airway epithelial cells in various situations may be mediated through PKC related signaling pathways. These findings suggest that PKCs can be new targets for treatment of lung diseases.

  7. Signalling with retinoids in the human lung: validation of new tools for the expression study of retinoid receptors

    International Nuclear Information System (INIS)

    Poulain, Stéphane; Lacomme, Stéphanie; Battaglia-Hsu, Shyue-Fang; Manoir, Stanislas du; Brochin, Lydia; Vignaud, Jean-Michel; Martinet, Nadine

    2009-01-01

    Retinoid Receptors are involved in development and cell homeostasis. Alterations of their expressions have been observed in lung cancer. However, retinoid chemoprevention trials in populations at risk to develop such tumors have failed. Therefore, the pertinence of new clinical trials using second generation retinoid requires prior better understanding of retinoid signalling. This is our aim when validating extensively research tools, focused on Retinoic Acid Receptor beta, whose major role in lung cancer is documented. Biocomputing was used to assess the genomic organization of RAR beta. Its putative RAR-beta1' promoter features were investigated experimentally. Specific measures realized, with qRT-PCR Syber Green assays and a triplex of Taqman probes, were extensively validated to establish Retinoid Receptors mRNAs reference values for in vivo normal human bronchial cells, lung tumors and cell lines. Finally, a pan-RAR-beta antibody was generated and extensively validated by western-blot and immunoprecipitation. No promoter-like activity was found for RAR-beta1'. RAR-beta2 mRNAs increase signs the normal differentiation of the human bronchial epithelium while a decrease is observed in most lung cancer cell lines. Accordingly, it is also, along with RXR beta, down-regulated in lung tumors. When using nuclear extracts of BEAS-2B and normal lung cells, only the RAR-beta2 long protein isoform was recognized by our antibody. Rigorous samples processing and extensive biocomputing, were the key factors for this study. mRNA reference values and validated tools can now be used to advance researches on retinoid signalling in the lung

  8. Tumour-associated neutrophils and loss of epithelial PTEN can promote corticosteroid-insensitive MMP-9 expression in the chronically inflamed lung microenvironment.

    Science.gov (United States)

    Vannitamby, Amanda; Seow, Huei Jiunn; Anderson, Gary; Vlahos, Ross; Thompson, Michelle; Steinfort, Daniel; Irving, Louis B; Bozinovski, Steven

    2017-12-01

    Matrix metalloproteinase-9 (MMP-9) is increased in a number of pathological lung conditions, where the proteinase contributes to deleterious remodelling of the airways. While both lung cancer and COPD are associated with increased MMP-9 expression, the cellular and molecular drivers of MMP-9 remain unresolved. In this study, MMP-9 transcript measured within the tumour region from patients with non-small-cell lung cancer (NSCLC) and coexisting COPD was found to be uniformly increased relative to adjacent tumour-free tissue. MMP-9 gene expression and immunohistochemistry identified tumour-associated neutrophils, but not macrophages, as a predominant source of this proteinase. In addition, PTEN gene expression was significantly reduced in tumour and there was evidence of epithelial MMP-9 expression. To explore whether PTEN can regulate epithelial MMP-9 expression, a small interfering (si)RNA knockdown strategy was used in Beas-2B bronchial epithelial cells. PTEN knockdown by siRNA selectively increased MMP-9 expression in response to lipopolysaccharide in a corticosteroid-insensitive manner. In summary, tumour-associated neutrophils represent an important source of MMP-9 in NSCLC, and loss of epithelial PTEN may further augment steroid-insensitive expression. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  9. TIPE2 Inhibits the Expression of Asthma-Related Inflammatory Factors in Hyperstretched Bronchial Epithelial Cells Through the Wnt/β-Catenin Pathway.

    Science.gov (United States)

    Sun, Xinrong; Chen, Lu; Yan, Wen

    2017-06-01

    Childhood asthma, an airway inflammatory disease, is a serious threat to the child's quality of life. Recently, TIPE2 expression was reported to be decreased in children with asthma. Therefore, additional studies focusing on TIPE2 might provide an approach for treating childhood asthma. In this study, we found that TIPE2 was poorly expressed in hyperstretched human bronchial epithelial cells (BEAS-2B). TIPE2 overexpression also significantly suppressed the stretch-induced secretion of asthma-related inflammatory factors (TNF-α, TSLP, MMP-9, and VEGF). In contrast, TIPE2 inhibition significantly promoted the secretion of TNF-α, TSLP, MMP-9, and VEGF. Furthermore, overexpression of TIPE2 remarkably inhibited the activation of Wnt/β-catenin in hyperstretched BEAS-2B cells, while siTIPE2 activated Wnt/β-catenin in hyperstretched BEAS-2B cells. Further analysis showed that the Wnt/β-catenin signal inhibitor Dkk-1 could further enhance the TIPE2-induced suppression of Wnt/β-catenin signaling, which also suppressed the siTIPE2-induced secretion of TNF-α, TSLP, MMP-9, and VEGF in hyperstretched BEAS-2B cells. Dkk-1 reversed the effects of siRNA-TIPE2 on Wnt/β-catenin signaling and inflammatory cytokines. In summary, we have exhibited that TIPE2 inhibited the expression of asthma-related inflammatory factors in hyperstretched BEAS-2B cells by suppressing the Wnt/β-catenin signaling pathway. TIPE2 may be involved in airway inflammation during asthma attack, and it may be used as a potential therapeutic target for bronchial epithelial inflammation in childhood asthma.

  10. Involvement of the MAPK and PI3K pathways in chitinase 3-like 1-regulated hyperoxia-induced airway epithelial cell death

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Mi Na; Lee, Kyung Eun; Hong, Jung Yeon; Heo, Won Il; Kim, Kyung Won; Kim, Kyu Earn [Department of Pediatrics and Institute of Allergy, Severance Medical Research Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul (Korea, Republic of); Sohn, Myung Hyun, E-mail: mhsohn@yuhs.ac [Department of Pediatrics and Institute of Allergy, Severance Medical Research Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2012-05-18

    Highlights: Black-Right-Pointing-Pointer Hyperoxia induces apoptosis and chitinase 3-like 1 expression in human airway epithelial cells. Black-Right-Pointing-Pointer Presence of chitinase 3-like 1 affects airway epithelial cell death after hyperoxic exposure. Black-Right-Pointing-Pointer Silencing chitinase 3-like 1 manipulate the phosphorylation of ERK, p38 and Akt. -- Abstract: Background: Exposure to 100% oxygen causes hyperoxic acute lung injury characterized by cell death and injury of alveolar epithelial cells. Recently, the role of chitinase 3-like 1 (CHI3L1), a member of the glycosyl hydrolase 18 family that lacks chitinase activity, in oxidative stress was demonstrated in murine models. High levels of serum CHI3L1 have been associated with various diseases of the lung, such as asthma, chronic obstructive pulmonary disease, and cancer. However, the role of CHI3L1 in human airway epithelial cells undergoing oxidative stress remains unknown. In addition, the signaling pathways associated with CHI3L1 in this process are poorly understood. Purpose: In this study, we demonstrate the role of CHI3L1, along with the MAPK and PI3K signaling pathways, in hyperoxia-exposed airway epithelial cells. Method: The human airway epithelial cell line, BEAS-2B, was exposed to >95% oxygen (hyperoxia) for up to 72 h. Hyperoxia-induced cell death was determined by assessing cell viability, Annexin-V FITC staining, caspase-3 and -7 expression, and electron microscopy. CHI3L1 knockdown and overexpression studies were conducted in BEAS-2B cells to examine the role of CHI3L1 in hyperoxia-induced apoptosis. Activation of the MAPK and PI3K pathways was also investigated to determine the role of these signaling cascades in this process. Results: Hyperoxia exposure increased CHI3L1 expression and apoptosis in a time-dependent manner. CHI3L1 knockdown protected cells from hyperoxia-induced apoptosis. In contrast, CHI3L1 overexpression promoted cell death after hyperoxia exposure. Finally

  11. Evaluation of the health impact of nanoparticles emitted from combustion sources: Comprehensive characterization of the physicochemical properties of nanoparticle emissions from wood combustion compliances, car- and ship diesel-engines as well as investigation of their toxicological effects on human lung cells and macrophages.

    Science.gov (United States)

    Zimmermann, R.; Dittmar, G.; Kanashova, T.; Buters, J.; Öder, S.; Paur, H. R.; Mülhopt, S.; Dilger, M.; Weiss, C.; Harndorf, H.; Stengel, B.; Hirvonen, M. R.; Jokiniemi, J.; Hiller, K.; Sapcariu, S.; Sippula, O.; Streibel, T.; Karg, E.; Weggler, B.; Schnelle-Kreis, J.; Lintelmann, J.; Sklorz, M.; Orasche, J.; Müller, L.; Passig, J.; Gröger, T.; BéruBé, K.; Krebs, T.

    2016-12-01

    Combustion emissions cause health effects. The HICE-Aerosol and Health project team studies the physicochemical properties as well as biological and toxicological effects on lung cells of combustion particle emissions. The chemical composition and physical parameters thoroughly characterized. Human lung cells are exposed to the diluted combustion exhaust fumes at the air-liquid interface (ALI), allowing a realistic lung-cell exposure by simulation of the lung situation. After exposure, cellular responses of the exposed lung cells are studied by multi-omics molecular biological analyses on transcriptomic, proteomic and metabolomic level. Emissions of wood combustion (log wood, pellet heater), ship diesel engines and car gasoline engines are addressed. Special field deployable ALI-exposition systems in a mobile S2-biological laboratory were set up and applied. Human alveolar epithelial cells (A549, BEAS2B and primary cells) as well as murine macrophages were ALI-exposed to diluted emissions. The cellular effects were then comprehensively characterized (viability, cyto-toxicology, multi-omics effects monitoring) and put in context with the chemical and physical aerosol data. The following order of overall cellular response-strength was observed: A relatively mild cellular effect is observed for the diluted wood combustion emissions. Interestingly the effects-strength for log-wood and pellet burner emissions are similar, although PM-concentrations are much higher for the log-wood heater. Similar mild biological effects are observed for the gasoline car emissions. The ship diesel engine emissions induced the most intense biological responses. A surprising result in this context is, that heavy fuel oil (HFO)-emissions showed lower biological effect strengths than the supposedly cleaner diesel fuel emissions (DF). The HFO-emission contain high concentrations of known toxicants (transition metals, polycyclic aromatics). This result was recently confirmed by experiments

  12. Stem cells and repair of lung injuries

    Directory of Open Access Journals (Sweden)

    Randell Scott H

    2004-07-01

    Full Text Available Abstract Fueled by the promise of regenerative medicine, currently there is unprecedented interest in stem cells. Furthermore, there have been revolutionary, but somewhat controversial, advances in our understanding of stem cell biology. Stem cells likely play key roles in the repair of diverse lung injuries. However, due to very low rates of cellular proliferation in vivo in the normal steady state, cellular and architectural complexity of the respiratory tract, and the lack of an intensive research effort, lung stem cells remain poorly understood compared to those in other major organ systems. In the present review, we concisely explore the conceptual framework of stem cell biology and recent advances pertinent to the lungs. We illustrate lung diseases in which manipulation of stem cells may be physiologically significant and highlight the challenges facing stem cell-related therapy in the lung.

  13. NEIL2 protects against oxidative DNA damage induced by sidestream smoke in human cells.

    Directory of Open Access Journals (Sweden)

    Altaf H Sarker

    Full Text Available Secondhand smoke (SHS is a confirmed lung carcinogen that introduces thousands of toxic chemicals into the lungs. SHS contains chemicals that have been implicated in causing oxidative DNA damage in the airway epithelium. Although DNA repair is considered a key defensive mechanism against various environmental attacks, such as cigarette smoking, the associations of individual repair enzymes with susceptibility to lung cancer are largely unknown. This study investigated the role of NEIL2, a DNA glycosylase excising oxidative base lesions, in human lung cells treated with sidestream smoke (SSS, the main component of SHS. To do so, we generated NEIL2 knockdown cells using siRNA-technology and exposed them to SSS-laden medium. Representative SSS chemical compounds in the medium were analyzed by mass spectrometry. An increased production of reactive oxygen species (ROS in SSS-exposed cells was detected through the fluorescent detection and the induction of HIF-1α. The long amplicon-quantitative PCR (LA-QPCR assay detected significant dose-dependent increases of oxidative DNA damage in the HPRT gene of cultured human pulmonary fibroblasts (hPF and BEAS-2B epithelial cells exposed to SSS for 24 h. These data suggest that SSS exposure increased oxidative stress, which could contribute to SSS-mediated toxicity. siRNA knockdown of NEIL2 in hPF and HEK 293 cells exposed to SSS for 24 h resulted in significantly more oxidative DNA damage in HPRT and POLB than in cells with control siRNA. Taken together, our data strongly suggest that decreased repair of oxidative DNA base lesions due to an impaired NEIL2 expression in non-smokers exposed to SSS would lead to accumulation of mutations in genomic DNA of lung cells over time, thus contributing to the onset of SSS-induced lung cancer.

  14. Quercetogetin protects against cigarette smoke extract-induced apoptosis in epithelial cells by inhibiting mitophagy.

    Science.gov (United States)

    Son, Eun Suk; Kim, Se-Hee; Ryter, Stefan W; Yeo, Eui-Ju; Kyung, Sun Young; Kim, Yu Jin; Jeong, Sung Hwan; Lee, Chang Soo; Park, Jeong-Woong

    2018-04-01

    Recent studies demonstrate that the autophagy-dependent turnover of mitochondria (mitophagy) mediates pulmonary epithelial cell death in response to cigarette smoke extract (CSE) exposure, and contributes to emphysema development in vivo during chronic cigarette smoke (CS)-exposure, although the underlying mechanisms remain unclear. Here, we investigated the role of mitophagy in regulating apoptosis in CSE-exposed human lung bronchial epithelial cells. Furthermore, we investigated the potential of the polymethoxylated flavone antioxidant quercetogetin (QUE) to inhibit CSE-induced mitophagy-dependent apoptosis. Our results demonstrate that CSE induces mitophagy in epithelial cells via mitochondrial dysfunction, and causes increased expression levels of the mitophagy-regulator protein PTEN-induced putative kinase-1 (PINK1) and the mitochondrial fission protein dynamin-1-like protein (DRP-1). CSE induced epithelial cell death and increased the expression of the apoptosis-related proteins cleaved caspase-3, -8 and -9. Caspase-3 activity was significantly increased in Beas-2B cells exposed to CSE, and decreased by siRNA-dependent knockdown of DRP-1. Treatment of epithelial cells with QUE inhibited CSE-induced mitochondrial dysfunction and mitophagy by inhibiting phospho (p)-DRP-1 and PINK1 expression. QUE suppressed mitophagy-dependent apoptosis by inhibiting the expression of cleaved caspase-3, -8 and -9 and downregulating caspase activity in human bronchial epithelial cells. These findings suggest that QUE may serve as a potential therapeutic in CS-induced pulmonary diseases. Copyright © 2018 Elsevier Ltd. All rights reserved.

  15. Lung Squamous Cell Carcinoma Stem Cells as Immunotherapy Targets

    Science.gov (United States)

    2017-08-01

    AWARD NUMBER: W81XWH-16-1-0260 TITLE: Lung Squamous Cell Carcinoma Stem Cells as Immunotherapy Targets PRINCIPAL INVESTIGATOR: Carla Kim... Cell Carcinoma Stem Cells as Immunotherapy Targets 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-16-1-0260 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...SUPPLEMENTARY NOTES 14. ABSTRACT Lung squamous cell carcinoma (SCC) is the second most common type of lung cancer, and immunotherapy is a promising new

  16. Mesenchymal Stem Cells Adopt Lung Cell Phenotype in Normal and Radiation-induced Lung Injury Conditions.

    Science.gov (United States)

    Maria, Ola M; Maria, Ahmed M; Ybarra, Norma; Jeyaseelan, Krishinima; Lee, Sangkyu; Perez, Jessica; Shalaby, Mostafa Y; Lehnert, Shirley; Faria, Sergio; Serban, Monica; Seuntjens, Jan; El Naqa, Issam

    2016-04-01

    Lung tissue exposure to ionizing irradiation can invariably occur during the treatment of a variety of cancers leading to increased risk of radiation-induced lung disease (RILD). Mesenchymal stem cells (MSCs) possess the potential to differentiate into epithelial cells. However, cell culture methods of primary type II pneumocytes are slow and cannot provide a sufficient number of cells to regenerate damaged lungs. Moreover, effects of ablative radiation doses on the ability of MSCs to differentiate in vitro into lung cells have not been investigated yet. Therefore, an in vitro coculture system was used, where MSCs were physically separated from dissociated lung tissue obtained from either healthy or high ablative doses of 16 or 20 Gy whole thorax irradiated rats. Around 10±5% and 20±3% of cocultured MSCs demonstrated a change into lung-specific Clara and type II pneumocyte cells when MSCs were cocultured with healthy lung tissue. Interestingly, in cocultures with irradiated lung biopsies, the percentage of MSCs changed into Clara and type II pneumocytes cells increased to 40±7% and 50±6% at 16 Gy irradiation dose and 30±5% and 40±8% at 20 Gy irradiation dose, respectively. These data suggest that MSCs to lung cell differentiation is possible without cell fusion. In addition, 16 and 20 Gy whole thorax irradiation doses that can cause varying levels of RILD, induced different percentages of MSCs to adopt lung cell phenotype compared with healthy lung tissue, providing encouraging outlook for RILD therapeutic intervention for ablative radiotherapy prescriptions.

  17. Nicotine transport in lung and non-lung epithelial cells.

    Science.gov (United States)

    Takano, Mikihisa; Kamei, Hidetaka; Nagahiro, Machi; Kawami, Masashi; Yumoto, Ryoko

    2017-11-01

    Nicotine is rapidly absorbed from the lung alveoli into systemic circulation during cigarette smoking. However, mechanism underlying nicotine transport in alveolar epithelial cells is not well understood to date. In the present study, we characterized nicotine uptake in lung epithelial cell lines A549 and NCI-H441 and in non-lung epithelial cell lines HepG2 and MCF-7. Characteristics of [ 3 H]nicotine uptake was studied using these cell lines. Nicotine uptake in A549 cells occurred in a time- and temperature-dependent manner and showed saturation kinetics, with a Km value of 0.31mM. Treatment with some organic cations such as diphenhydramine and pyrilamine inhibited nicotine uptake, whereas treatment with organic cations such as carnitine and tetraethylammonium did not affect nicotine uptake. Extracellular pH markedly affected nicotine uptake, with high nicotine uptake being observed at high pH up to 11.0. Modulation of intracellular pH with ammonium chloride also affected nicotine uptake. Treatment with valinomycin, a potassium ionophore, did not significantly affect nicotine uptake, indicating that nicotine uptake is an electroneutral process. For comparison, we assessed the characteristics of nicotine uptake in another lung epithelial cell line NCI-H441 and in non-lung epithelial cell lines HepG2 and MCF-7. Interestingly, these cell lines showed similar characteristics of nicotine uptake with respect to pH dependency and inhibition by various organic cations. The present findings suggest that a similar or the same pH-dependent transport system is involved in nicotine uptake in these cell lines. A novel molecular mechanism of nicotine transport is proposed. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Proinflammatory effects and oxidative stress within human bronchial epithelial cells exposed to atmospheric particulate matter (PM2.5 and PM>2.5) collected from Cotonou, Benin

    International Nuclear Information System (INIS)

    Cachon, Boris Fresnel; Firmin, Stéphane; Verdin, Anthony; Ayi-Fanou, Lucie

    2014-01-01

    After particulate matter (PM) collection in Cotonou (Benin), a complete physicochemical characterization of PM 2.5 and PM >2.5 was led. Then, their adverse health effects were evaluated by using in vitro culture of human lung cells. BEAS-2B (bronchial epithelial cells) were intoxicated during short-term exposure at increasing PM concentrations (1.5–96 μg/cm 2 ) to determine global cytotoxicity. Hence, cells were exposed to 3 and 12 μg/cm 2 to investigate the potential biological imbalance generated by PM toxicity. Our findings showed the ability of both PM to induce oxidative stress and to cause inflammatory cytokines/chemokines gene expression and secretion. Furthermore, PM were able to induce gene expression of enzymes involved in the xenobiotic metabolism pathway. Strong correlations between gene expression of metabolizing enzymes, proinflammatory responses and cell cycle alteration were found, as well as between proinflammatory responses and cell viability. Stress oxidant parameters were highly correlated with expression and protein secretion of inflammatory mediators. Highlights: • The aim of this study was to investigate the toxic potential of collected particles. • Toxicological effects were determined by using human bronchial epithelial cells. • Both particles induced oxidative stress, proinflammatory response and cell alterations. • Metabolizing enzymes were linked to proinflammatory responses and cell alterations. • Oxidative stress was highly correlated to the proinflammatory mediators. -- This study evidences the toxic potential of African fine and coarse particulate matters on respiratory epithelial cells

  19. Pulmonary Rehabilitation in Improving Lung Function in Patients With Locally Advanced Non-Small Cell Lung Cancer Undergoing Chemoradiation

    Science.gov (United States)

    2017-04-12

    Cachexia; Fatigue; Pulmonary Complications; Radiation Toxicity; Recurrent Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  20. Different roles of ROS and Nrf2 in Cr(VI)-induced inflammatory responses in normal and Cr(VI)-transformed cells

    Energy Technology Data Exchange (ETDEWEB)

    Roy, Ram Vinod; Pratheeshkumar, Poyil; Son, Yong-Ok; Wang, Lei [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Hitron, John Andrew [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Divya, Sasidharan Padmaja; Zhang, Zhuo [Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Shi, Xianglin, E-mail: xshi5@email.uky.edu [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States)

    2016-09-15

    Hexavalent chromium (Cr(VI)) is classified as a human carcinogen. Cr(VI) has been associated with adenocarcinomas and squamous cell carcinoma of the lung. The present study shows that acute Cr(VI) treatment in human bronchial epithelial cells (BEAS-2B) increased inflammatory responses (TNF-α, COX-2, and NF-кB/p65) and expression of Nrf2. Cr(VI)-induced generation of reactive oxygen species (ROS) are responsible for increased inflammation. Despite the fact that Nrf2 is a master regulator of response to oxidative stress, silencing of Nrf2 in the acute Cr(VI) treatment had no effect on Cr(VI)-induced inflammation. In contrast, in Cr(VI)-transformed (CrT) cells, Nrf2 is constitutively activated. Knock-down of this protein resulted in decreased inflammation, while silencing of SOD2 and CAT had no effect in the expression of these inflammatory proteins. Results obtained from the knock-down of Nrf2 in CrT cells are very different from the results obtained in the acute Cr(VI) treatment. In BEAS-2B cells, knock-down of Nrf2 had no effect in the inflammation levels, while in CrT cells a decrease in the expression of inflammation markers was observed. These results indicate that before transformation, ROS plays a critical role while Nrf2 not in Cr(VI)-induced inflammation, whereas after transformation (CrT cells), Nrf2 is constitutively activated and this protein maintains inflammation while ROS not. Constitutively high levels of Nrf2 in CrT binds to the promoter regions of COX-2 and TNF-α, leading to increased inflammation. Collectively, our results demonstrate that before cell transformation ROS are important in Cr(VI)-induced inflammation and after transformation a constitutively high level of Nrf2 is important. - Highlights: • Cr(VI)-induced ROS increased inflammation, while Nrf2 had no effect. • In the CrT cells knock-down of Nrf2 resulted in decreased inflammation. • Mechanistic differences in regulating Cr(VI)-induced inflammation.

  1. Lung cells support osteosarcoma cell migration and survival.

    Science.gov (United States)

    Yu, Shibing; Fourman, Mitchell Stephen; Mahjoub, Adel; Mandell, Jonathan Brendan; Crasto, Jared Anthony; Greco, Nicholas Giuseppe; Weiss, Kurt Richard

    2017-01-25

    Osteosarcoma (OS) is the most common primary bone tumor, with a propensity to metastasize to the lungs. Five-year survival for metastatic OS is below 30%, and has not improved for several decades despite the introduction of multi-agent chemotherapy. Understanding OS cell migration to the lungs requires an evaluation of the lung microenvironment. Here we utilized an in vitro lung cell and OS cell co-culture model to explore the interactions between OS and lung cells, hypothesizing that lung cells would promote OS cell migration and survival. The impact of a novel anti-OS chemotherapy on OS migration and survival in the lung microenvironment was also examined. Three human OS cell lines (SJSA-1, Saos-2, U-2) and two human lung cell lines (HULEC-5a, MRC-5) were cultured according to American Type Culture Collection recommendations. Human lung cell lines were cultured in growth medium for 72 h to create conditioned media. OS proliferation was evaluated in lung co-culture and conditioned media microenvironment, with a murine fibroblast cell line (NIH-3 T3) in fresh growth medium as controls. Migration and invasion were measured using a real-time cell analysis system. Real-time PCR was utilized to probe for Aldehyde Dehydrogenase (ALDH1) expression. Osteosarcoma cells were also transduced with a lentivirus encoding for GFP to permit morphologic analysis with fluorescence microscopy. The anti-OS efficacy of Disulfiram, an ALDH-inhibitor previously shown to inhibit OS cell proliferation and metastasis in vitro, was evaluated in each microenvironment. Lung-cell conditioned medium promoted osteosarcoma cell migration, with a significantly higher attractive effect on all three osteosarcoma cell lines compared to basic growth medium, 10% serum containing medium, and NIH-3 T3 conditioned medium (p cell conditioned medium induced cell morphologic changes, as demonstrated with GFP-labeled cells. OS cells cultured in lung cell conditioned medium had increased alkaline

  2. PdO Doping Tunes Band-Gap Energy Levels as Well as Oxidative Stress Responses to a Co3O4p-Type Semiconductor in Cells and the Lung

    Science.gov (United States)

    2014-01-01

    We demonstrate through PdO doping that creation of heterojunctions on Co3O4 nanoparticles can quantitatively adjust band-gap and Fermi energy levels to study the impact of metal oxide nanoparticle semiconductor properties on cellular redox homeostasis and hazard potential. Flame spray pyrolysis (FSP) was used to synthesize a nanoparticle library in which the gradual increase in the PdO content (0–8.9%) allowed electron transfer from Co3O4 to PdO to align Fermi energy levels across the heterojunctions. This alignment was accompanied by free hole accumulation at the Co3O4 interface and production of hydroxyl radicals. Interestingly, there was no concomitant superoxide generation, which could reflect the hole dominance of a p-type semiconductor. Although the electron flux across the heterojunctions induced upward band bending, the Ec levels of the doped particles showed energy overlap with the biological redox potential (BRP). This allows electron capture from the redox couples that maintain the BRP from −4.12 to −4.84 eV, causing disruption of cellular redox homeostasis and induction of oxidative stress. PdO/Co3O4 nanoparticles showed significant increases in cytotoxicity at 25, 50, 100, and 200 μg/mL, which was enhanced incrementally by PdO doping in BEAS-2B and RAW 264.7 cells. Oxidative stress presented as a tiered cellular response involving superoxide generation, glutathione depletion, cytokine production, and cytotoxicity in epithelial and macrophage cell lines. A progressive series of acute pro-inflammatory effects could also be seen in the lungs of animals exposed to incremental PdO-doped particles. All considered, generation of a combinatorial PdO/Co3O4 nanoparticle library with incremental heterojunction density allowed us to demonstrate the integrated role of Ev, Ec, and Ef levels in the generation of oxidant injury and inflammation by the p-type semiconductor, Co3O4. PMID:24673286

  3. PdO doping tunes band-gap energy levels as well as oxidative stress responses to a Co₃O₄ p-type semiconductor in cells and the lung.

    Science.gov (United States)

    Zhang, Haiyuan; Pokhrel, Suman; Ji, Zhaoxia; Meng, Huan; Wang, Xiang; Lin, Sijie; Chang, Chong Hyun; Li, Linjiang; Li, Ruibin; Sun, Bingbing; Wang, Meiying; Liao, Yu-Pei; Liu, Rong; Xia, Tian; Mädler, Lutz; Nel, André E

    2014-04-30

    We demonstrate through PdO doping that creation of heterojunctions on Co3O4 nanoparticles can quantitatively adjust band-gap and Fermi energy levels to study the impact of metal oxide nanoparticle semiconductor properties on cellular redox homeostasis and hazard potential. Flame spray pyrolysis (FSP) was used to synthesize a nanoparticle library in which the gradual increase in the PdO content (0-8.9%) allowed electron transfer from Co3O4 to PdO to align Fermi energy levels across the heterojunctions. This alignment was accompanied by free hole accumulation at the Co3O4 interface and production of hydroxyl radicals. Interestingly, there was no concomitant superoxide generation, which could reflect the hole dominance of a p-type semiconductor. Although the electron flux across the heterojunctions induced upward band bending, the E(c) levels of the doped particles showed energy overlap with the biological redox potential (BRP). This allows electron capture from the redox couples that maintain the BRP from -4.12 to -4.84 eV, causing disruption of cellular redox homeostasis and induction of oxidative stress. PdO/Co3O4 nanoparticles showed significant increases in cytotoxicity at 25, 50, 100, and 200 μg/mL, which was enhanced incrementally by PdO doping in BEAS-2B and RAW 264.7 cells. Oxidative stress presented as a tiered cellular response involving superoxide generation, glutathione depletion, cytokine production, and cytotoxicity in epithelial and macrophage cell lines. A progressive series of acute pro-inflammatory effects could also be seen in the lungs of animals exposed to incremental PdO-doped particles. All considered, generation of a combinatorial PdO/Co3O4 nanoparticle library with incremental heterojunction density allowed us to demonstrate the integrated role of E(v), E(c), and E(f) levels in the generation of oxidant injury and inflammation by the p-type semiconductor, Co3O4.

  4. In Vitro Toxicity of Naturally Occurring Silica Nanoparticles in C1 Coal 
in Bronchial Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Guangjian LI

    2012-10-01

    Full Text Available Background and objective China’s Xuan Wei County in Yunnan Province have the world’s highest incidence of lung cancer in nonsmoking women-20 times higher than the rest of China. Previous studies showed, this high lung cancer incidence may be associated with the silica particles embedded in the production combustion from the C1 coal. The aim of this study is to separate the silica particles from production combustion from the C1 bituminous coal in Xuan Wei County of Yunnan Province, and study in vitro toxicity of naturally occurring silica particles on BEAS-2B. Methods ①Separating the silica particles from combustion products of C1 bituminous coal by physical method, observing the morphology by Scanning Electron Microscope, analysis elements by SEM-EDX, observed the single particle morphology by Transmission Electron Microscope, analyed its particle size distribution by Laser particle size analyzer, the surface area of silica particles were determined by BET nitrogen adsorption analysis; ②Cell viability of the experimental group (silica; naturally occurring, control group (silica; industrial produced and crystalline silica was detected by assay used the 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT method, and the reactive oxygen species (ROS, lactate dehydrogenase (LDH were determined after 24 h-72 h exposed to these particles. Results ①The physical method can separate silica particles from production combustion from the C1 bituminous coal, which have different size, and from 30 nm to 120 nm particles accounted for 86.8%, different morphology, irregular surface area and containing trace of aluminum, calcium and iron and other elements; ②Under the same concentration, the experiment group have higher toxicity on BEAS-2B than control groups. Conclusion ①Physical method can separate silica particles from production combustion from the C1 bituminous coal and not change the original morphology and containing trace;

  5. Reactive oxygen species contribute to arsenic-induced EZH2 phosphorylation in human bronchial epithelial cells and lung cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Li, Lingzhi; Qiu, Ping; Chen, Bailing; Lu, Yongju; Wu, Kai; Thakur, Chitra; Chang, Qingshan; Sun, Jiaying; Chen, Fei, E-mail: fchen@wayne.edu

    2014-05-01

    Our previous studies suggested that arsenic is able to induce serine 21 phosphorylation of the EZH2 protein through activation of JNK, STAT3, and Akt signaling pathways in the bronchial epithelial cell line, BEAS-2B. In the present report, we further demonstrated that reactive oxygen species (ROS) were involved in the arsenic-induced protein kinase activation that leads to EZH2 phosphorylation. Several lines of evidence supported this notion. First, the pretreatment of the cells with N-acetyl-L-cysteine (NAC), a potent antioxidant, abolishes arsenic-induced EZH2 phosphorylation along with the inhibition of JNK, STAT3, and Akt. Second, H{sub 2}O{sub 2}, the most important form of ROS in the cells in response to extracellular stress signals, can induce phosphorylation of the EZH2 protein and the activation of JNK, STAT3, and Akt. By ectopic expression of the myc-tagged EZH2, we additionally identified direct interaction and phosphorylation of the EZH2 protein by Akt in response to arsenic and H{sub 2}O{sub 2}. Furthermore, both arsenic and H{sub 2}O{sub 2} were able to induce the translocation of ectopically expressed or endogenous EZH2 from nucleus to cytoplasm. In summary, the data presented in this report indicate that oxidative stress due to ROS generation plays an important role in the arsenic-induced EZH2 phosphorylation. - Highlights:: • Arsenic (As{sup 3+}) induces EZH phosphorylation. • JNK, STAT3, and Akt contribute to EZH2 phosphorylation. • Oxidative stress is involved in As{sup 3+}-induced EZH2 phosphorylation. • As{sup 3+} induces direct interaction of Akt and EZH2. • Phosphorylated EZH2 localized in cytoplasm.

  6. Proteomic Assessment of Biochemical Pathways That Are Critical to Nickel-Induced Toxicity Responses in Human Epithelial Cells

    Science.gov (United States)

    Ge, Yue; Bruno, Maribel; Haykal-Coates, Najwa; Wallace, Kathleen; Andrews, Debora; Swank, Adam; Winnik, Witold; Ross, Jeffrey A.

    2016-01-01

    Understanding the mechanisms underlying toxicity initiated by nickel, a ubiquitous environmental contaminant and known human carcinogen is necessary for proper assessment of its risks to human and environment. Among a variety of toxic mechanisms, disruption of protein responses and protein response-based biochemical pathways represents a key mechanism through which nickel induces cytotoxicity and carcinogenesis. To identify protein responses and biochemical pathways that are critical to nickel-induced toxicity responses, we measured cytotoxicity and changes in expression and phosphorylation status of 14 critical biochemical pathway regulators in human BEAS-2B cells exposed to four concentrations of nickel using an integrated proteomic approach. A subset of the pathway regulators, including interleukin-6, and JNK, were found to be linearly correlated with cell viability, and may function as molecular determinants of cytotoxic responses of BEAS-2B cells to nickel exposures. In addition, 128 differentially expressed proteins were identified by two dimensional electrophoresis (2-DE) and mass spectrometry. Principal component analysis, hierarchical cluster analyses, and ingenuity signaling pathway analysis (IPA) identified putative nickel toxicity pathways. Some of the proteins and pathways identified have not previously been linked to nickel toxicity. Based on the consistent results obtained from both ELISA and 2-DE proteomic analysis, we propose a core signaling pathway regulating cytotoxic responses of human BEAS-2B cells to nickel exposures, which integrates a small set of proteins involved in glycolysis and gluconeogenesis pathways, apoptosis, protein degradation, and stress responses including inflammation and oxidative stress. PMID:27626938

  7. Inhibition of PDGFR by CP-673451 induces apoptosis and increases cisplatin cytotoxicity in NSCLC cells via inhibiting the Nrf2-mediated defense mechanism.

    Science.gov (United States)

    Yang, Yang; Deng, Yanchao; Chen, Xiangcui; Zhang, Jiahao; Chen, Yueming; Li, Huachao; Wu, Qipeng; Yang, Zhicheng; Zhang, Luyong; Liu, Bing

    2018-05-29

    Platelet-derived growth factor receptors (PDGFRs) are abundantly expressed by stromal cells in the non-small cell lung cancer (NSCLC) microenvironment, and in a subset of cancer cells, usually with their overexpression and/or activating mutation. However, the effect of PDGFR inhibition on lung cancer cells themselves has been largely neglected. In this study, we investigated the anticancer activity of CP-673451, a potent and selective inhibitor of PDGFRβ, on NSCLC cell lines (A549 and H358) and the potential mechanism. The results showed that inhibition of PDGFRβ by CP-673451 induced a significant increase in cell apoptosis, accompanied by ROS accumulation. However, CP-673451 exerted less cytotoxicity in normal lung epithelial cell line BEAS-2B cells determined by MTT and apoptosis assay. Elimination of ROS by NAC reversed the CP-673451-induced apoptosis in NSCLC cells. Furthermore, CP-673451 down-regulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) probably through inhibition of PI3K/Akt pathway. Rescue of Nrf2 activity counteracted the effects of CP-673451 on cell apoptosis and ROS accumulation. Silencing PDGFRβ expression by PDGFRβ siRNA exerted similar effects with CP-673451 in A549 cells, and when PDGFRβ was knockdowned by PDGFRβ siRNA, CP-673451 produced no additional effects on cell viability, ROS and GSH production, Nrf2 expression as well as PI3K/Akt pathway activity. Specifically, Nrf2 plays an indispensable role in NSCLC cell sensitivity to platinum-based treatments and we found that combination of CP-673451 and cisplatin produced a synergistic anticancer effect and substantial ROS production in vitro. Therefore, these results clearly demonstrate the effectiveness of inhibition of PDGFRβ against NSCLC cells and strongly suggest that CP-673451 may be a promising adjuvant chemotherapeutic drug. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. Replication of cultured lung epithelial cells

    International Nuclear Information System (INIS)

    Guzowski, D.; Bienkowski, R.

    1986-01-01

    The authors have investigated the conditions necessary to support replication of lung type 2 epithelial cells in culture. Cells were isolated from mature fetal rabbit lungs (29d gestation) and cultured on feeder layers of mitotically inactivated 3T3 fibroblasts. The epithelial nature of the cells was demonstrated by indirect immunofluorescent staining for keratin and by polyacid dichrome stain. Ultrastructural examination during the first week showed that the cells contained myofilaments, microvilli and lamellar bodies (markers for type 2 cells). The following changes were observed after the first week: increase in cell size; loss of lamellar bodies and appearance of multivesicular bodies; increase in rough endoplasmic reticulum and golgi; increase in tonafilaments and well-defined junctions. General cell morphology was good for up to 10 wk. Cells cultured on plastic surface degenerated after 1 wk. Cell replication was assayed by autoradiography of cultures exposed to ( 3 H)-thymidine and by direct cell counts. The cells did not replicate during the first week; however, between 2-10 wk the cells incorporated the label and went through approximately 6 population doublings. They have demonstrated that lung alveolar epithelial cells can replicate in culture if they are maintained on an appropriate substrate. The coincidence of ability to replicate and loss of markers for differentiation may reflect the dichotomy between growth and differentiation commonly observed in developing systems

  9. ADAM28 is expressed by epithelial cells in human normal tissues and protects from C1q-induced cell death.

    Science.gov (United States)

    Miyamae, Yuka; Mochizuki, Satsuki; Shimoda, Masayuki; Ohara, Kentaro; Abe, Hitoshi; Yamashita, Shuji; Kazuno, Saiko; Ohtsuka, Takashi; Ochiai, Hiroki; Kitagawa, Yuko; Okada, Yasunori

    2016-05-01

    ADAM28 (disintegrin and metalloproteinase 28), which was originally reported to be lymphocyte-specific, is over-expressed by carcinoma cells and plays a key role in cell proliferation and progression in human lung and breast carcinomas. We studied ADAM28 expression in human normal tissues and examined its biological function. By using antibodies specific to ADAM28, ADAM28 was immunolocalized mainly to epithelial cells in several tissues, including epididymis, bronchus and stomach, whereas lymphocytes in lymph nodes and spleen were negligibly immunostained. RT-PCR, immunoblotting and ELISA analyses confirmed the expression in these tissues, and low or negligible expression by lymphocytes was found in the lymph node and spleen. C1q was identified as a candidate ADAM28-binding protein from a human lung cDNA library by yeast two-hybrid system, and specific binding was demonstrated by binding assays, immunoprecipitation and surface plasmon resonance. C1q treatment of normal bronchial epithelial BEAS-2B and NHBE cells, both of which showed low-level expression of ADAM28, caused apoptosis through activation of p38 and caspase-3, and cell death with autophagy through accumulation of LC3-II and autophagosomes, respectively. C1q-induced cell death was attenuated by treatment of the cells with antibodies against the C1q receptor gC1qR/p33 or cC1qR/calreticulin. Treatment of C1q with recombinant ADAM28 prior to addition to culture media reduced C1q-induced cell death, and knockdown of ADAM28 using siRNAs increased cell death. These data demonstrate that ADAM28 is expressed by epithelial cells of several normal organs, and suggest that ADAM28 plays a role in cell survival by suppression of C1q-induced cytotoxicity in bronchial epithelial cells. © 2016 Federation of European Biochemical Societies.

  10. Cancer cell-selective, clathrin-mediated endocytosis of aptamer decorated nanoparticles

    Science.gov (United States)

    Engelberg, Shira; Modrejewski, Julia; Walter, Johanna G.; Livney, Yoav D.; Assaraf, Yehuda G.

    2018-01-01

    Lung cancer is the leading cause of cancer mortality worldwide, resulting in 88% deaths of all diagnosed patients. Hence, novel therapeutic modalities are urgently needed. Single-stranded oligonucleotide-based aptamers (APTs) are excellent ligands for tumor cell targeting. However, the molecular mechanisms underlying their internalization into living cells have been poorly studied. Towards the application of APTs for active drug targeting to cancer cells, we herein studied the mechanism underlying S15-APT internalization into human non-small cell lung cancer A549 cells. We thus delineated the mode of entry of a model nanomedical system based on quantum dots (QDs) decorated with S15-APTs as a selective targeting moiety for uptake by A549 cells. These APT-decorated QDs displayed selective binding to, and internalization by target A549 cells, but not by normal human bronchial epithelial BEAS2B, cervical carcinoma (HeLa) and colon adenocarcinoma CaCo-2 cells, hence demonstrating high specificity. Flow cytometric analysis revealed a remarkably low dissociation constant of S15-APTs-decorated QDs to A549 cells (Kd = 13.1 ± 1.6 nM). Through the systematic application of a series of established inhibitors of known mechanisms of endocytosis, we show that the uptake of S15-APTs proceeds via a classical clathrin-dependent receptor-mediated endocytosis. This cancer cell-selective mode of entry could possibly be used in the future to evade plasma membrane-localized multidrug resistance efflux pumps, thereby overcoming an important mechanism of cancer multidrug resistance. PMID:29765515

  11. Current therapy of small cell lung cancer

    DEFF Research Database (Denmark)

    Sorensen, M; Lassen, U; Hansen, H H

    1998-01-01

    This article reviews the most important recent clinical trials on the treatment of small cell lung cancer (SCLC). Two randomized studies addressing the timing of thoracic radiotherapy in limited stage SCLC are discussed. In the smaller of the two studies (n = 103), a survival benefit was associated...

  12. Stem cell treatment for chronic lung diseases.

    Science.gov (United States)

    Tzouvelekis, Argyris; Ntolios, Paschalis; Bouros, Demosthenes

    2013-01-01

    Chronic lung diseases such as idiopathic pulmonary fibrosis and cystic fibrosis or chronic obstructive pulmonary disease and asthma are leading causes of morbidity and mortality worldwide with a considerable human, societal and financial burden. In view of the current disappointing status of available pharmaceutical agents, there is an urgent need for alternative more effective therapeutic approaches that will not only help to relieve patient symptoms but will also affect the natural course of the respective disease. Regenerative medicine represents a promising option with several fruitful therapeutic applications in patients suffering from chronic lung diseases. Nevertheless, despite relative enthusiasm arising from experimental data, application of stem cell therapy in the clinical setting has been severely hampered by several safety concerns arising from the major lack of knowledge on the fate of exogenously administered stem cells within chronically injured lung as well as the mechanisms regulating the activation of resident progenitor cells. On the other hand, salient data arising from few 'brave' pilot investigations of the safety of stem cell treatment in chronic lung diseases seem promising. The main scope of this review article is to summarize the current state of knowledge regarding the application status of stem cell treatment in chronic lung diseases, address important safety and efficacy issues and present future challenges and perspectives. In this review, we argue in favor of large multicenter clinical trials setting realistic goals to assess treatment efficacy. We propose the use of biomarkers that reflect clinically inconspicuous alterations of the disease molecular phenotype before rigid conclusions can be safely drawn. Copyright © 2013 S. Karger AG, Basel.

  13. A case of squamous cell lung cancer after treating with radiation for small cell lung cancer

    International Nuclear Information System (INIS)

    Hayashi, Toshinari; Ide, Hiroshi; Siomi, Katsuhiko; Nakamura, Yukinobu; Tada, Shinya; Kageyama, Hiroshi; Kido, Masamitsu

    1999-01-01

    A 77-year-old man was admitted due to an abnormal shadow on a chest X-ray film in September 1993. Small cell lung cancer was diagnosed by transbronchial lung biopsy of left S 3 . Because of his pulmonary and renal dysfunction, he received only 40 Gy irradiation alone, and the tumor shadow disappeared. After 38 months' observation, a new nodular shadow was detected in the left upper lung field in March 1997. A tumor was found in left B 3 by bronchoscopy, and biopsy revealed squamous cell carcinoma. Because of his advanced age and hypoxia, he has had no active treatment. This was a rare case of small cell lung cancer with long term survival, treated only by radiation, in which a different histologic type of carcinoma appeared in the same radiation field. (author)

  14. Poisson-event-based analysis of cell proliferation.

    Science.gov (United States)

    Summers, Huw D; Wills, John W; Brown, M Rowan; Rees, Paul

    2015-05-01

    A protocol for the assessment of cell proliferation dynamics is presented. This is based on the measurement of cell division events and their subsequent analysis using Poisson probability statistics. Detailed analysis of proliferation dynamics in heterogeneous populations requires single cell resolution within a time series analysis and so is technically demanding to implement. Here, we show that by focusing on the events during which cells undergo division rather than directly on the cells themselves a simplified image acquisition and analysis protocol can be followed, which maintains single cell resolution and reports on the key metrics of cell proliferation. The technique is demonstrated using a microscope with 1.3 μm spatial resolution to track mitotic events within A549 and BEAS-2B cell lines, over a period of up to 48 h. Automated image processing of the bright field images using standard algorithms within the ImageJ software toolkit yielded 87% accurate recording of the manually identified, temporal, and spatial positions of the mitotic event series. Analysis of the statistics of the interevent times (i.e., times between observed mitoses in a field of view) showed that cell division conformed to a nonhomogeneous Poisson process in which the rate of occurrence of mitotic events, λ exponentially increased over time and provided values of the mean inter mitotic time of 21.1 ± 1.2 hours for the A549 cells and 25.0 ± 1.1 h for the BEAS-2B cells. Comparison of the mitotic event series for the BEAS-2B cell line to that predicted by random Poisson statistics indicated that temporal synchronisation of the cell division process was occurring within 70% of the population and that this could be increased to 85% through serum starvation of the cell culture. © 2015 International Society for Advancement of Cytometry.

  15. Cell kinetics and acute lung injury

    International Nuclear Information System (INIS)

    Witschi, H.P.; Whitaker, M.S.

    1987-01-01

    In order to estimate whether acute lung injury is followed by a stereotype pattern of cell proliferation in the lungs, mice were treated with three cytostatic drugs: cyclophosphamide, busulfan, or 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU). The alveolar labeling index was measured following drug administration with a pulse of 3 H-labeled thymidine and autoradiography. In cyclophosphamide treated animals, peak alveolar cell proliferation was seen 5 days after injection of the drug. In animals treated with busulfan or BCNU, proliferation was even more delayed (occurring 2 to 3 wks after administration). In contrast, with oleic acid, the highest alveolar cell labeling was found 2 days after intravenous administration. In animals exposed to a cytostatic drug, proliferation of type II alveolar cells was never a prominent feature; whereas, in animals treated with oleic acid there was an initial burst of type II cell proliferation. It was concluded that the patterns of pulmonary repair vary between chemical designed to interfere with DNA replication as compared to agents which produce acute lung damage such as oleic acid

  16. Airway Basal Cell Heterogeneity and Lung Squamous Cell Carcinoma.

    Science.gov (United States)

    Hynds, Robert E; Janes, Sam M

    2017-09-01

    Basal cells are stem/progenitor cells that maintain airway homeostasis, enact repair following epithelial injury, and are a candidate cell-of-origin for lung squamous cell carcinoma. Heterogeneity of basal cells is recognized in terms of gene expression and differentiation capacity. In this Issue, Pagano and colleagues isolate a subset of immortalized basal cells that are characterized by high motility, suggesting that they might also be heterogeneous in their biophysical properties. Motility-selected cells displayed an increased ability to colonize the lung in vivo The possible implications of these findings are discussed in terms of basal cell heterogeneity, epithelial cell migration, and modeling of metastasis that occurs early in cancer evolution. Cancer Prev Res; 10(9); 491-3. ©2017 AACR See related article by Pagano et al., p. 514 . ©2017 American Association for Cancer Research.

  17. Small cell lung cancer: chemo- and radiotherapy

    International Nuclear Information System (INIS)

    Drings, P.

    1992-01-01

    Small-Cell Lung Cancer - Chemo- and Radiotherapy: Small-cell lung cancer (SCLC) should be regarded as a systematic disease for which systematic therapy, i.e. chemotherapy, is considered as the cornerstone of treatment. Combination chemotherapy consisting of 2 or mostly 3 active drugs, given at an adequate dose, should be used. Thoracic radiation therapy promises both survival and local-regional control benefits to patients though its optimal role remains to be definitively established. The results of treatment have reached a plateau with a remission rate of up to 90% in stage 'limited disease' and 60% in stage 'extensive disease'. But considering long-term results diseasefree survival and cure only seem possible in 5-10% of patients with limited disease. (orig.) [de

  18. Cellular radiosensitivity of small-cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Krarup, M; Poulsen, H S; Spang-Thomsen, M

    1997-01-01

    PURPOSE: The objective of this study was to determine the radiobiological characteristics of a panel of small-cell lung cancer (SCLC) cell lines by use of a clonogenic assay. In addition, we tested whether comparable results could be obtained by employing a growth extrapolation method based...

  19. RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer.

    Science.gov (United States)

    Rao, Shuan; Sigl, Verena; Wimmer, Reiner Alois; Novatchkova, Maria; Jais, Alexander; Wagner, Gabriel; Handschuh, Stephan; Uribesalgo, Iris; Hagelkruys, Astrid; Kozieradzki, Ivona; Tortola, Luigi; Nitsch, Roberto; Cronin, Shane J; Orthofer, Michael; Branstetter, Daniel; Canon, Jude; Rossi, John; D'Arcangelo, Manolo; Botling, Johan; Micke, Patrick; Fleur, Linnea La; Edlund, Karolina; Bergqvist, Michael; Ekman, Simon; Lendl, Thomas; Popper, Helmut; Takayanagi, Hiroshi; Kenner, Lukas; Hirsch, Fred R; Dougall, William; Penninger, Josef M

    2017-10-15

    Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women; however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts. Clonal genetic inactivation of KRas G12D in mouse lung epithelial cells markedly impairs the progression of KRas G12D -driven lung cancer, resulting in a significant survival advantage. Mechanistically, RANK rewires energy homeostasis in human and murine lung cancer cells and promotes expansion of lung cancer stem-like cells, which is blocked by inhibiting mitochondrial respiration. Our data also indicate survival differences in KRas G12D -driven lung cancer between male and female mice, and we show that female sex hormones can promote lung cancer progression via the RANK pathway. These data uncover a direct role for RANK in lung cancer and may explain why female sex hormones accelerate lung cancer development. Inhibition of RANK using the approved drug denosumab may be a therapeutic drug candidate for primary lung cancer. © 2017 Rao et al.; Published by Cold Spring Harbor Laboratory Press.

  20. Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches.

    Science.gov (United States)

    Akram, Khondoker M; Patel, Neil; Spiteri, Monica A; Forsyth, Nicholas R

    2016-01-19

    The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases.

  1. Mast cells in lung of rat

    Directory of Open Access Journals (Sweden)

    I. Ivanova

    2017-09-01

    Full Text Available This paper is a short review of scientific literature on lung mast cells in norm and pathology that shows the current state of this problem. Particular attention is paid to the quantity, location and arrangement of the mast cells. The mast cells are a part of immune system whom origin are myeloid stem cells. They are a kind of white blood cells. Many authors from the 19th century to the present day have traced and described the role of mast cells in the human body, their structure and changes depending on the functional state of the organism. Paul Ehrlich is the first author that described in his doctoral thesis the mast cells as effectors of allergy particularly in the beginning of reaction and in acute phase of the process. Research has continued through out the 20th century and researchers' efforts are primarily focused on clarifying the structure and function of mast cells and identifying their role in pathological responses in the human body. Mast cells are found in all organs, but they predominate in peripheral blood, spleen and bone marrow. There are cells in the rat skin that live for about 12 weeks, and more recent studies have found that proliferation of mature mast cells is caused by various factors.

  2. MET and Small-Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Francesco Gelsomino

    2014-10-01

    Full Text Available Small-cell lung cancer (SCLC is one of the most aggressive lung tumors. The majority of patients with SCLC are diagnosed at an advanced stage. This tumor type is highly sensitive to chemo-radiation treatment, with very high response rates, but invariably relapses. At this time, treatment options are still limited and the prognosis of these patients is poor. A better knowledge of the molecular biology of SCLC allowed us to identify potential druggable targets. Among these, the MET/HGF axis seems to be one of the most aberrant signaling pathways involved in SCLC invasiveness and progression. In this review, we describe briefly all recent literature on the different molecular profiling in SCLC; in particular, we discuss the specific alterations involving c-MET gene and their implications as a potential target in SCLC.

  3. Immune and Inflammatory Cell Composition of Human Lung Cancer Stroma.

    Directory of Open Access Journals (Sweden)

    G-Andre Banat

    Full Text Available Recent studies indicate that the abnormal microenvironment of tumors may play a critical role in carcinogenesis, including lung cancer. We comprehensively assessed the number of stromal cells, especially immune/inflammatory cells, in lung cancer and evaluated their infiltration in cancers of different stages, types and metastatic characteristics potential. Immunohistochemical analysis of lung cancer tissue arrays containing normal and lung cancer sections was performed. This analysis was combined with cyto-/histomorphological assessment and quantification of cells to classify/subclassify tumors accurately and to perform a high throughput analysis of stromal cell composition in different types of lung cancer. In human lung cancer sections we observed a significant elevation/infiltration of total-T lymphocytes (CD3+, cytotoxic-T cells (CD8+, T-helper cells (CD4+, B cells (CD20+, macrophages (CD68+, mast cells (CD117+, mononuclear cells (CD11c+, plasma cells, activated-T cells (MUM1+, B cells, myeloid cells (PD1+ and neutrophilic granulocytes (myeloperoxidase+ compared with healthy donor specimens. We observed all of these immune cell markers in different types of lung cancers including squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma, small cell carcinoma, papillary adenocarcinoma, metastatic adenocarcinoma, and bronchioloalveolar carcinoma. The numbers of all tumor-associated immune cells (except MUM1+ cells in stage III cancer specimens was significantly greater than those in stage I samples. We observed substantial stage-dependent immune cell infiltration in human lung tumors suggesting that the tumor microenvironment plays a critical role during lung carcinogenesis. Strategies for therapeutic interference with lung cancer microenvironment should consider the complexity of its immune cell composition.

  4. Circulating tumor cells in lung cancer.

    Science.gov (United States)

    Young, Rachel; Pailler, Emma; Billiot, Fanny; Drusch, Françoise; Barthelemy, Amélie; Oulhen, Marianne; Besse, Benjamin; Soria, Jean-Charles; Farace, Françoise; Vielh, Philippe

    2012-01-01

    Circulating tumor cells (CTCs) have emerged as potential biomarkers in several cancers such as colon, prostate, and breast carcinomas, with a correlation between CTC number and patient prognosis being established by independent research groups. The detection and enumeration of CTCs, however, is still a developing field, with no universal method of detection suitable for all types of cancer. CTC detection in lung cancer in particular has proven difficult to perform, as CTCs in this type of cancer often present with nonepithelial characteristics. Moreover, as many detection methods rely on the use of epithelial markers to identify CTCs, the loss of these markers during epithelial-to-mesenchymal transition in certain metastatic cancers can render these methods ineffective. The development of personalized medicine has led to an increase in the advancement of molecular characterization of CTCs. The application of techniques such as FISH and RT-PCR to detect EGFR, HER2, and KRAS abnormalities in lung, breast, and colon cancer, for example, could be used to characterize CTCs in real time. The use of CTCs as a 'liquid biopsy' is therefore an exciting possibility providing information on patient prognosis and treatment efficacy. This review summarizes the state of CTC detection today, with particular emphasis on lung cancer, and discusses the future applications of CTCs in helping the clinician to develop new strategies in patient treatment. Copyright © 2012 S. Karger AG, Basel.

  5. Tungsten-induced carcinogenesis in human bronchial epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Laulicht, Freda; Brocato, Jason; Cartularo, Laura; Vaughan, Joshua; Wu, Feng; Kluz, Thomas; Sun, Hong [Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, NY 10987 (United States); Oksuz, Betul Akgol [Genome Technology Center, New York University Langone Medical Center, New York, NY 10016 (United States); Shen, Steven [Center for Health Informatics and Bioinformatics, New York University Langone Medical Center, New York, NY 10016 (United States); Peana, Massimiliano; Medici, Serenella; Zoroddu, Maria Antonietta [Department of Chemistry and Pharmacy, University of Sassari, Sassari (Italy); Costa, Max, E-mail: Max.Costa@nyumc.org [Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, NY 10987 (United States)

    2015-10-01

    Metals such as arsenic, cadmium, beryllium, and nickel are known human carcinogens; however, other transition metals, such as tungsten (W), remain relatively uninvestigated with regard to their potential carcinogenic activity. Tungsten production for industrial and military applications has almost doubled over the past decade and continues to increase. Here, for the first time, we demonstrate tungsten's ability to induce carcinogenic related endpoints including cell transformation, increased migration, xenograft growth in nude mice, and the activation of multiple cancer-related pathways in transformed clones as determined by RNA sequencing. Human bronchial epithelial cell line (Beas-2B) exposed to tungsten developed carcinogenic properties. In a soft agar assay, tungsten-treated cells formed more colonies than controls and the tungsten-transformed clones formed tumors in nude mice. RNA-sequencing data revealed that the tungsten-transformed clones altered the expression of many cancer-associated genes when compared to control clones. Genes involved in lung cancer, leukemia, and general cancer genes were deregulated by tungsten. Taken together, our data show the carcinogenic potential of tungsten. Further tests are needed, including in vivo and human studies, in order to validate tungsten as a carcinogen to humans. - Highlights: • Tungsten (W) induces cell transformation and increases migration in vitro. • W increases xenograft growth in nude mice. • W altered the expression of cancer-related genes such as those involved in leukemia. • Some of the dysregulated leukemia genes include, CD74, CTGF, MST4, and HOXB5. • For the first time, data is presented that demonstrates tungsten's carcinogenic potential.

  6. Advanced sickle cell associated interstitial lung disease presenting ...

    African Journals Online (AJOL)

    Previous studies have reported abnormal pulmonary function and pulmonary hypertension among Nigerians with sickle cell disease, but there is no report of interstitial lung disease among them. We report a Nigerian sickle cell patient who presented with computed tomography proven interstitial lung disease complicated by ...

  7. Mast cells in the human lung at high altitude

    Science.gov (United States)

    Heath, Donald

    1992-12-01

    Mast cell densities in the lung were measured in five native highlanders of La Paz (3600 m) and in one lowlander dying from high-altitude pulmonary oedema (HAPO) at 3440 m. Two of the highlanders were mestizos with normal pulmonary arteries and the others were Aymara Indians with muscular remodelling of their pulmonary vasculature. The aim of the investigation was to determine if accumulation of mast cells in the lung at high altitude (HA) is related to alveolar hypoxia alone, to a combination of hypoxia and muscularization of the pulmonary arterial tree, or to oedema of the lung. The lungs of four lowlanders were used as normoxic controls. The results showed that the mast cell density of the two Mestizos was in the normal range of lowlanders (0.6-8.8 cells/mm2). In the Aymara Indians the mast cell counts were raised (25.6-26.0 cells/mm2). In the lowlander dying from HAPO the mast cell count was greatly raised to 70.1 cells/mm2 lung tissue. The results show that in native highlanders an accumulation of mast cells in the lung is not related to hypoxia alone but to a combination of hypoxia and muscular remodelling of the pulmonary arteries. However, the most potent cause of increased mast cell density in the lung at high altitude appears to be high-altitude pulmonary oedema.

  8. Treatment of stage III non-small cell lung cancer and limited-disease small-cell lung cancer

    NARCIS (Netherlands)

    El Sharouni, S.Y.

    2009-01-01

    This thesis concerns the treatment of stage III non-small cell lung cancer (NSCLC) and limited disease small-cell lung cancer (SCLC). We described a systematic review on the clinical results of radiotherapy, combined or not with chemotherapy, for inoperable NSCLC stage III with the aim to define the

  9. Genotoxicity of short single-wall and multi-wall carbon nanotubes in human bronchial epithelial and mesothelial cells in vitro

    International Nuclear Information System (INIS)

    Lindberg, Hanna K.; Falck, Ghita C.-M.; Singh, Rajinder; Suhonen, Satu; Järventaus, Hilkka; Vanhala, Esa; Catalán, Julia; Farmer, Peter B.; Savolainen, Kai M.; Norppa, Hannu

    2013-01-01

    Although some types of carbon nanotubes (CNTs) have been described to induce mesothelioma in rodents and genotoxic effects in various cell systems, there are few previous studies on the genotoxicity of CNTs in mesothelial cells. Here, we examined in vitro DNA damage induction by short multi-wall CNTs (MWCNTs; 10–30 nm × 1–2 μm) and single-wall CNTs (SWCNTs; >50% SWCNTs, ∼40% other CNTs; 1 dG) DNA adducts. In BEAS 2B cells, we also studied the induction of micronuclei (MN) by the CNTs using the cytokinesis-block method. The cells were exposed to the CNTs (5–200 μg/cm 2 , corresponding to 19–760 μg/ml) for 24 and 48 h in the comet assay and for 48 and 72 h in the MN and M 1 dG assays. Transmission electron microscopy (TEM) showed more MWCNT fibres and SWCNT clusters in BEAS 2B than MeT-5A cells, but no significant differences were seen in intracellular dose expressed as area of SWCNT clusters between TEM sections of the cell lines. In MeT-5A cells, both CNTs caused a dose-dependent induction of DNA damage (% DNA in comet tail) in the 48-h treatment and SWCNTs additionally in the 24-h treatment, with a statistically significant increase at 40 μg/cm 2 of SWCNTs and (after 48 h) 80 μg/cm 2 of both CNTs. SWCNTs also elevated the level of M 1 dG DNA adducts at 1, 5, 10 and 40 μg/cm 2 after the 48-h treatment, but both CNTs decreased M 1 dG adduct level at several doses after the 72-h treatment. In BEAS 2B cells, SWCNTs induced a statistically significant increase in DNA damage at 80 and 120 μg/cm 2 after the 24-h treatment and in M 1 dG adduct level at 5 μg/cm 2 after 48 h and 10 and 40 μg/cm 2 after 72 h; MWCNTs did not affect the level of DNA damage but produced a decrease in M 1 dG adducts in the 72-h treatment. The CNTs did not affect the level of MN. In conclusion, MWCNTs and SWCNTs induced DNA damage in MeT-5A cells but showed a lower (SWCNTs) or no (MWCNTs) effect in BEAS 2B cells, suggesting that MeT-5A cells were more sensitive to the DNA

  10. Effect of primarily cultured human lung cancer-associated fibroblasts on radiosensitivity of lung cancer cells

    International Nuclear Information System (INIS)

    Ji Xiaoqin; Ji Jiang; Chen Yongbing; Shan Fang; Lu Xueguan

    2014-01-01

    Objective: To investigate the effect of human lung cancer-associated fibroblasts (CAF) on the radiosensitivity of lung cancer cells when CAF is placed in direct contact co-culture with lung cancer cells. Methods: Human lung CAF was obtained from fresh human lung adenocarcinoma tissue specimens by primary culture and subculture and was then identified by immunofluorescence staining. The CAF was placed in direct contact co-culture with lung cancer A 549 and H 1299 cells, and the effects of CAF on the radiosensitivity of A 549 and H 1299 cells were evaluated by colony-forming assay. Results: The human lung CAF obtained by adherent culture could stably grow and proliferate, and it had specific expression of α-smooth muscle actin, vimentin, and fibroblast activation protein,but without expression of cytokeratin-18. The plating efficiency (PE, %) of A 549 cells at 0 Gy irradiation was (20.0 ± 3.9)% when cultured alone versus (32.3 ± 5.5)% when co-cultured with CAF (t=3.16, P<0.05), and the PE of H 1299 cells at 0 Gy irradiation was (20.6 ± 3.1)% when cultured alone versus (35.2 ± 2.3)% when co-cultured with CAF (t=6.55, P<0.05). The cell survival rate at 2 Gy irradiation (SF 2 ) of A 549 cells was 0.727 ±0.061 when cultured alone versus 0.782 ± 0.089 when co-cultured with CAF (t=0.88, P>0.05), and the SF 2 of H 1299 cells was 0.692 ±0.065 when cultured alone versus 0.782 ± 0.037 when co-cultured with CAF (t=2.08, P>0.05). The protection enhancement ratios of human lung CAF for A 549 cells and H 1299 cells were 1.29 and 1.25, respectively. Conclusions: Human lung CAF reduces the radiosensitivity of lung cancer cells when placed in direct contact co-culture with them, and the radioprotective effect may be attributed to CAF promoting the proliferation of lung cancer cells. (authors)

  11. Cancer Stem-Like Cells Accumulated in Nickel-Induced Malignant Transformation

    Science.gov (United States)

    Wang, Lei; Fan, Jia; Hitron, John Andrew; Son, Young-Ok; Wise, James T.F.; Roy, Ram Vinod; Kim, Donghern; Dai, Jin; Pratheeshkumar, Poyil; Zhang, Zhuo; Shi, Xianglin

    2016-01-01

    Nickel compounds are known as human carcinogens. Chronic environmental exposure to nickel is a worldwide health concern. Although the mechanisms of nickel-induced carcinogenesis are not well understood, recent studies suggest that stem cells/cancer stem cells are likely important targets. This study examines the role of cancer stem cells in nickel-induced cell transformation. The nontransformed human bronchial epithelial cell line (Beas-2B) was chronically exposed to nickel chloride for 12 months to induce cell transformation. Nickel induced Beas-2B cell transformation, and cancer stem-like cells were enriched in nickel-transformed cell (BNiT) population. The BNiT cancer stem-like cells demonstrated enhanced self-renewal and distinctive differentiation properties. In vivo tumorigenesis studies show that BNiT cancer stem-like cells possess a high tumor-initiating capability. It was also demonstrated that superoxide dismutase 1 was involved in the accumulation of cancer stem-like cells; the regulation of superoxide dismutase 1 expression was different in transformed stem-like cells and nontransformed. Overall, the accumulation of stem-like cells and their enhanced stemness functions contribute to nickel-induced tumorigenesis. Our study provides additional insight into the mechanisms by which metals or other chemicals can induce carcinogenesis. PMID:26962057

  12. Vulnerability of cultured canine lung tumor cells to NK cell-mediated cytolysis

    International Nuclear Information System (INIS)

    Haley, P.J.; Kohr, J.M.; Kelly, G.; Muggenburg, B.A.; Guilmette, B.A.

    1988-01-01

    Five cell lines, designated as canine lung epithelial cell (CLEP), derived from radiation induced canine lung tumors and canine thyroid adeno-carcinoma (CTAC) cells were compared for their susceptibility to NK cell-mediated cytolysis using peripheral blood lymphocytes from normal, healthy Beagle dogs as effector cells. Effector cells and chromium 51 radiolabeled target cells were incubated for 16 h at ratios of 12.5:1, 25:1, 50:1, and 100:1. Increasing cytolysis was observed for all cell lines as the effector-to-target-cell ratios increased from 12.5:1 to 100:1. The percent cytotoxicity was significantly less for all lung tumor cell lines as compared to CTAC at the 100:1 ratio. One lung tumor cell line, CLEP-9, had 85% of the lytic vulnerability of the CTAC cell line and significantly greater susceptibility to NK cell-mediated lysis than all of the other lung tumor cell lines. Susceptibility to NK cell cytolysis did not correlate with in vivo malignant behavior of the original tumor. These data suggest that cultured canine lung tumor cells are susceptible to NK cell cytolytic activity in vitro and that at least one of these cell lines (CLEP-9) is a candidate for substitution of the standard canine NK cell target, CTAC, in NK cell assays. The use of lung tumor cells in NK cell assays may provide greater insight into the control of lung tumors by immune mechanisms. (author)

  13. 1st ESMO Consensus Conference in lung cancer; Lugano 2010: small-cell lung cancer

    DEFF Research Database (Denmark)

    Stahel, R; Thatcher, N; Früh, M

    2011-01-01

    , the expert panel prepared clinically relevant questions concerning five areas as follows: early and locally advanced non-small-cell lung cancer (NSCLC), first-line metastatic NSCLC, second-/third-line NSCLC, NSCLC pathology and molecular testing, and small-cell lung cancer (SCLC) to be addressed through......The 1st ESMO Consensus Conference on lung cancer was held in Lugano, Switzerland on 21st and 22nd May 2010 with the participation of a multidisciplinary panel of leading professionals in pathology and molecular diagnostics and medical, surgical and radiation oncology. Before the conference...

  14. 1st ESMO Consensus Conference in lung cancer; Lugano 2010: small-cell lung cancer

    DEFF Research Database (Denmark)

    Stahel, R; Thatcher, N; Früh, M

    2011-01-01

    The 1st ESMO Consensus Conference on lung cancer was held in Lugano, Switzerland on 21st and 22nd May 2010 with the participation of a multidisciplinary panel of leading professionals in pathology and molecular diagnostics and medical, surgical and radiation oncology. Before the conference......, the expert panel prepared clinically relevant questions concerning five areas as follows: early and locally advanced non-small-cell lung cancer (NSCLC), first-line metastatic NSCLC, second-/third-line NSCLC, NSCLC pathology and molecular testing, and small-cell lung cancer (SCLC) to be addressed through...

  15. Erlotinib in previously treated non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Smrdel, U.; Kovac, V.

    2006-01-01

    Background. Erlotinib is a novel biological anti-tumour agent in the treatment of advanced non small cell lung cancer. It represents the molecularly-targeted therapy which has been studied extensively. Case report. We present a case of a patient who suffered from advanced non-small-cell lung cancer. After the progress of disease following a prior chemotherapy he was treated with erlotinib with remarkable effect which was shown at chest x ray and symptoms were quite reduced. Conclusions. In selected patients with advanced non-small-cell lung cancer Erlotinib improves survival and symptom control as it results in presented case. (author)

  16. Matrine suppresses airway inflammation by downregulating SOCS3 expression via inhibition of NF-κB signaling in airway epithelial cells and asthmatic mice

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Daqing [Department of Respiration, Xi’an Children’s Hospital, Xi’an 710003 (China); Wang, Jing [Department of Neonatology, Xi’an Children’s Hospital, Xi’an 710003 (China); Yang, Niandi [Outpatient Department, School of Aerospace Engineering, Air Force Engineering University, Xi’an 710038 (China); Ma, Haixin, E-mail: drhaixinma@163.com [Department of Quality Control, Xi’an Children’s Hospital, Xi’an 710003 (China)

    2016-08-12

    Matrine has been demonstrated to attenuate allergic airway inflammation. Elevated suppressor of cytokine signaling 3 (SOCS3) was correlated with the severity of asthma. The aim of this study was to investigate the effect of matrine on SOCS3 expression in airway inflammation. In this study, we found that matrine significantly inhibited OVA-induced AHR, inflammatory cell infiltration, goblet cell differentiation, and mucous production in a dose-dependent manner in mice. Matrine also abrogated the level of interleukin (IL)-4 and IL-13, but enhanced interferon (IFN)-γ expression, both in BALF and in lung homogenates. Furthermore, matrine impeded TNF-α-induced the expression of IL-6 and adhesion molecules in airway epithelial cells (BEAS-2B and MLE-12). Additionally, we found that matrine inhibited SOCS3 expression, both in asthmatic mice and TNF-α-stimulated epithelial cells via suppression of the NF-κB signaling pathway by using pcDNA3.1-SOCS3 plasmid, SOCS3 siRNA, or nuclear factor kappa-B (NF-κB) inhibitor PDTC. Conclusions: Matrine suppresses airway inflammation by downregulating SOCS3 expression via inhibition of NF-κB signaling in airway epithelial cells and asthmatic mice. - Highlights: • Matrine attenuates asthmatic symptoms and regulates Th1/Th2 balance in vivo. • Matrine suppresses inflammation responses in vitro. • Matrine decreases SOCS3 expression both in vivo and in vitro. • Matrine inhibits SOCS3 expression by suppressing NF-κB signaling.

  17. β2-Microglobulin participates in development of lung emphysema by inducing lung epithelial cell senescence.

    Science.gov (United States)

    Gao, Na; Wang, Ying; Zheng, Chun-Ming; Gao, Yan-Li; Li, Hui; Li, Yan; Fu, Ting-Ting; Xu, Li-Li; Wang, Wei; Ying, Sun; Huang, Kewu

    2017-05-01

    β 2 -Microglobulin (β 2 M), the light chain of the major histocompatibility complex class I (MHC I), has been identified as a proaging factor and is involved in the pathogenesis of neurodegenerative disorders by driving cognitive and regenerative impairments. However, little attention has focused on the effect of β 2 M in the development of lung emphysema. Here, we found that concentrations of β 2 M in plasma were significantly elevated in patients with lung emphysema than those in normal control subjects (1.89 ± 0.12 vs. 1.42 ± 0.06 mg/l, P lung tissue of emphysema (39.90 ± 1.97 vs. 23.94 ± 2.11%, P lung emphysema through induction of lung epithelial cell senescence and inhibition. Copyright © 2017 the American Physiological Society.

  18. TP53 Mutations in Nonsmall Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Akira Mogi

    2011-01-01

    Full Text Available The tumor suppressor gene TP53 is frequently mutated in human cancers. Abnormality of the TP53 gene is one of the most significant events in lung cancers and plays an important role in the tumorigenesis of lung epithelial cells. Human lung cancers are classified into two major types, small cell lung cancer (SCLC and nonsmall cell lung cancer (NSCLC. The latter accounts for approximately 80% of all primary lung cancers, and the incidence of NSCLC is increasing yearly. Most clinical studies suggest that NSCLC with TP53 alterations carries a worse prognosis and may be relatively more resistant to chemotherapy and radiation. A deep understanding of the role of TP53 in lung carcinogenesis may lead to a more reasonably targeted clinical approach, which should be exploited to enhance the survival rates of patients with lung cancer. This paper will focus on the role of TP53 in the molecular pathogenesis, epidemiology, and therapeutic strategies of TP53 mutation in NSCLC.

  19. Cell Cycle Related Differentiation of Bone Marrow Cells into Lung Cells

    Energy Technology Data Exchange (ETDEWEB)

    Dooner, Mark; Aliotta, Jason M.; Pimental, Jeffrey; Dooner, Gerri J.; Abedi, Mehrdad; Colvin, Gerald; Liu, Qin; Weier, Heinz-Ulli; Dooner, Mark S.; Quesenberry, Peter J.

    2007-12-31

    Green-fluorescent protein (GFP) labeled marrow cells transplanted into lethally irradiated mice can be detected in the lungs of transplanted mice and have been shown to express lung specific proteins while lacking the expression of hematopoietic markers. We have studied marrow cells induced to transit cell cycle by exposure to IL-3, IL-6, IL-11 and steel factor at different times of culture corresponding to different phases of cell cycle. We have found that marrow cells at the G1/S interface have a 3-fold increase in cells which assume a lung phenotype and that this increase is no longer seen in late S/G2. These cells have been characterized as GFP{sup +} CD45{sup -} and GFP{sup +} cytokeratin{sup +}. Thus marrow cells with the capacity to convert into cells with a lung phenotype after transplantation show a reversible increase with cytokine induced cell cycle transit. Previous studies have shown the phenotype of bone marrow stem cells fluctuates reversibly as these cells traverse cell cycle, leading to a continuum model of stem cell regulation. The present studies indicate that marrow stem cell production of nonhematopoietic cells also fluctuates on a continuum.

  20. Kaempferol Inhibits Endoplasmic Reticulum Stress-Associated Mucus Hypersecretion in Airway Epithelial Cells And Ovalbumin-Sensitized Mice.

    Science.gov (United States)

    Park, Sin-Hye; Gong, Ju-Hyun; Choi, Yean-Jung; Kang, Min-Kyung; Kim, Yun-Ho; Kang, Young-Hee

    2015-01-01

    Mucus hypersecretion is an important pathological feature of chronic airway diseases, such as asthma and pulmonary diseases. MUC5AC is a major component of the mucus matrix forming family of mucins in the airways. The initiation of endoplasmic reticulum (ER)-mediated stress responses contributes to the pathogenesis of airway diseases. The present study investigated that ER stress was responsible for airway mucus production and this effect was blocked by the flavonoid kaempferol. Oral administration of ≥10 mg/kg kaempferol suppressed mucus secretion and goblet cell hyperplasia observed in the bronchial airway and lung of BALB/c mice sensitized with ovalbumin (OVA). TGF-β and tunicamycin promoted MUC5AC induction after 72 h in human bronchial airway epithelial BEAS-2B cells, which was dampened by 20 μM kaempferol. Kaempferol inhibited tunicamycin-induced ER stress of airway epithelial cells through disturbing the activation of the ER transmembrane sensor ATF6 and IRE1α. Additionally, this compound demoted the induction of ER chaperones such as GRP78 and HSP70 and the splicing of XBP-1 mRNA by tunicamycin. The in vivo study further revealed that kaempferol attenuated the induction of XBP-1 and IRE1α in epithelial tissues of OVA-challenged mice. TGF-β and tunicamycin induced TRAF2 with JNK activation and such induction was deterred by kaempferol. The inhibition of JNK activation encumbered the XBP-1 mRNA splicing and MUC5AC induction by tunicamycin and TGF-β. These results demonstrate that kaempferol alleviated asthmatic mucus hypersecretion through blocking bronchial epithelial ER stress via the inhibition of IRE1α-TRAF2-JNK activation. Therefore, kaempferol may be a potential therapeutic agent targeting mucus hypersecretion-associated pulmonary diseases.

  1. small cell lung cancer in a Chinese population

    African Journals Online (AJOL)

    clinical significance in patients with non-small cell lung cancer (NSCLC) in Hubei province ... diagnosis, tumor stage, treatment, progression .... Table 4: Association between EGFR mutation, gender and histologic type in 138 NSCLC patients.

  2. Regeneration of the lung: Lung stem cells and the development of lung mimicking devices

    NARCIS (Netherlands)

    Schilders, K.; Eenjes, E.; van Riet, S.; Poot, Andreas A.; Stamatialis, Dimitrios; Truckenmüller, R.K.; Hiemstra, P.; Rottier, R.

    2016-01-01

    Inspired by the increasing burden of lung associated diseases in society and an growing demand to accommodate patients, great efforts by the scientific community produce an increasing stream of data that are focused on delineating the basic principles of lung development and growth, as well as

  3. Adult Lung Spheroid Cells Contain Progenitor Cells and Mediate Regeneration in Rodents With Bleomycin-Induced Pulmonary Fibrosis.

    Science.gov (United States)

    Henry, Eric; Cores, Jhon; Hensley, M Taylor; Anthony, Shirena; Vandergriff, Adam; de Andrade, James B M; Allen, Tyler; Caranasos, Thomas G; Lobo, Leonard J; Cheng, Ke

    2015-11-01

    Lung diseases are devastating conditions and ranked as one of the top five causes of mortality worldwide according to the World Health Organization. Stem cell therapy is a promising strategy for lung regeneration. Previous animal and clinical studies have focused on the use of mesenchymal stem cells (from other parts of the body) for lung regenerative therapies. We report a rapid and robust method to generate therapeutic resident lung progenitors from adult lung tissues. Outgrowth cells from healthy lung tissue explants are self-aggregated into three-dimensional lung spheroids in a suspension culture. Without antigenic sorting, the lung spheroids recapitulate the stem cell niche and contain a natural mixture of lung stem cells and supporting cells. In vitro, lung spheroid cells can be expanded to a large quantity and can form alveoli-like structures and acquire mature lung epithelial phenotypes. In severe combined immunodeficiency mice with bleomycin-induced pulmonary fibrosis, intravenous injection of human lung spheroid cells inhibited apoptosis, fibrosis, and infiltration but promoted angiogenesis. In a syngeneic rat model of pulmonary fibrosis, lung spheroid cells outperformed adipose-derived mesenchymal stem cells in reducing fibrotic thickening and infiltration. Previously, lung spheroid cells (the spheroid model) had only been used to study lung cancer cells. Our data suggest that lung spheroids and lung spheroid cells from healthy lung tissues are excellent sources of regenerative lung cells for therapeutic lung regeneration. The results from the present study will lead to future human clinical trials using lung stem cell therapies to treat various incurable lung diseases, including pulmonary fibrosis. The data presented here also provide fundamental knowledge regarding how injected stem cells mediate lung repair in pulmonary fibrosis. ©AlphaMed Press.

  4. Stem cell therapy: the great promise in lung disease.

    Science.gov (United States)

    Siniscalco, Dario; Sullo, Nikol; Maione, Sabatino; Rossi, Francesco; D'Agostino, Bruno

    2008-06-01

    Lung injuries are leading causes of morbidity and mortality worldwide. Pulmonary diseases such as asthma or chronic obstructive pulmonary disease characterized by loss of lung elasticity, small airway tethers, and luminal obstruction with inflammatory mucoid secretions, or idiopathic pulmonary fibrosis characterized by excessive matrix deposition and destruction of the normal lung architecture, have essentially symptomatic treatments and their management is costly to the health care system.Regeneration of tissue by stem cells from endogenous, exogenous, and even genetically modified cells is a promising novel therapy. The use of adult stem cells to help with lung regeneration and repair could be a newer technology in clinical and regenerative medicine. In fact, different studies have shown that bone marrow progenitor cells contribute to repair and remodeling of lung in animal models of progressive pulmonary hypertension.Therefore, lung stem cell biology may provide novel approaches to therapy and could represent a great promise for the future of molecular medicine. In fact, several diseases can be slowed or even blocked by stem cell transplantation.

  5. Interleukin-17A and Toll-Like Receptor 3 Ligand Poly(I:C Synergistically Induced Neutrophil Chemoattractant Production by Bronchial Epithelial Cells.

    Directory of Open Access Journals (Sweden)

    Hirotaka Matsuzaki

    Full Text Available Chronic inflammatory airway diseases, such as bronchial asthma and chronic obstructive pulmonary disease, are common respiratory disorders worldwide. Exacerbations of these diseases are frequent and worsen patients' respiratory condition and overall health. However, the mechanisms of exacerbation have not been fully elucidated. Recently, it was reported that interleukin (IL-17A might play an important role in neutrophilic inflammation, which is characteristic of such exacerbations, through increased production of neutrophil chemoattractants. Therefore, we hypothesized that IL-17A was involved in the pathogenesis of acute exacerbation, due to viral infection in chronic inflammatory airway diseases. In this study, we assessed chemokine production by bronchial epithelial cells and investigated the underlying mechanisms. Comprehensive chemokine analysis showed that, compared with poly(I:C alone, co-stimulation of BEAS-2B cells with IL-17A and poly(I:C strongly induced production of such neutrophil chemoattractants as CXC chemokine ligand (CXCL8, growth-related oncogene (GRO, and CXCL1. Co-stimulation synergistically induced CXCL8 and CXCL1 mRNA and protein production by BEAS-2B cells and normal human bronchial epithelial cells. Poly(I:C induced chemokine expression by BEAS-2B cells mainly via Toll-like receptor 3/TIR-domain-containing adapter-inducing interferon-β-mediated signals. The co-stimulation with IL-17A and poly(I:C markedly activated the p38 and extracellular-signal-regulated kinase 1/2 pathway, compared with poly(I:C, although there was little change in nuclear factor-κB translocation into the nucleus or the transcriptional activities of nuclear factor-κB and activator protein 1. IL-17A promoted stabilization of CXCL8 mRNA in BEAS-2B cells treated with poly(I:C. In conclusion, IL-17A appears to be involved in the pathogenesis of chronic inflammatory airway disease exacerbation, due to viral infection by promoting release of neutrophil

  6. Lung Injury; Relates to Real-Time Endoscopic Monitoring of Single Cells Respiratory Health in Lung

    Science.gov (United States)

    2017-09-01

    AWARD NUMBER: W81XWH-16-1-0253 TITLE: Lung Injury; Relates to Real- Time Endoscopic Monitoring of Single Cells Respiratory Health in Lung...2017 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 DISTRIBUTION ...STATEMENT: Approved for Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author(s

  7. Radiation sensitivity of human lung cancer cell lines

    International Nuclear Information System (INIS)

    Carmichael, J.; Degraff, W.G.; Gamson, J.; Russo, G.; Mitchell, J.B.; Gazdar, A.F.; Minna, J.D.; Levitt, M.L.

    1989-01-01

    X-Ray survival curves were determined using a panel of 17 human lung cancer cell lines, with emphasis on non-small cell lung cancer (NSCLC). In contrast to classic small cell lung cancer (SCLC) cell lines, NSCLC cell lines were generally less sensitive to radiation as evidenced by higher radiation survival curve extrapolation numbers, surviving fraction values following a 2Gy dose (SF2) and the mean inactivation dose values (D) values. The spectrum of in vitro radiation responses observed was similar to that expected in clinical practice, although mesothelioma was unexpectedly sensitive in vitro. Differences in radiosensitivity were best distinguished by comparison of SF2 values. Some NSCLC lines were relatively sensitive, and in view of this demonstrable variability in radiation sensitivity, the SF2 value may be useful for in vitro predictive assay testing of clinical specimens. (author)

  8. Cellular radiosensitivity of small-cell lung cancer cell lines

    International Nuclear Information System (INIS)

    Krarup, Marianne; Poulsen, Hans Skovgaard; Spang-Thomsen, Mogens

    1997-01-01

    Purpose: The objective of this study was to determine the radiobiological characteristics of a panel of small-cell lung cancer (SCLC) cell lines by use of a clonogenic assay. In addition, we tested whether comparable results could be obtained by employing a growth extrapolation method based on the construction of continuous exponential growth curves. Methods and Materials: Fifteen SCLC cell lines were studied, applying a slightly modified clonogenic assay and a growth extrapolation method. A dose-survival curve was obtained for each experiment and used for calculating several survival parameters. The multitarget single hit model was applied to calculate the cellular radiosensitivity (D 0 ), the capacity for sublethal damage repair (D q ), and the extrapolation number (n). Values for α and β were determined from best-fit curves according to the linear-quadratic model and these values were applied to calculate the surviving fraction after 2-Gy irradiation (SF 2 ). Results: In our investigation, the extrapolation method proved to be inappropriate for the study of in vitro cellular radiosensitivity due to lack of reproducibility. The results obtained by the clonogenic assay showed that the cell lines studied were radiobiologically heterogeneous with no discrete features of the examined parameters including the repair capacity. Conclusion: The results indicate that SCLC tumors per se are not generally candidates for hyperfractionated radiotherapy

  9. Squamous cell lung cancer in a male with pulmonary tuberculosis.

    Science.gov (United States)

    Skowroński, Marcin; Iwanik, Katarzyna; Halicka, Anna; Barinow-Wojewódzki, Aleksander

    2015-01-01

    Lung cancer and pulmonary tuberculosis (TB) are highly prevalent and representing major public health issues. They share common risk factors and clinical manifestations. It is also suggested that TB predicts raised lung cancer risk likely related to chronic inflammation in the lungs. However, it does not seem to influence the clinical course of lung cancer provided that it is properly treated. We present a case report of a 57-year old male with concurrent TB and lung cancer. He was diagnosed with positive sputum smear for acid fast bacilli (AFB) and subsequent culture of Mycobacterium tuberculosis. Besides, his comorbid conditions were chronic hepatitis C virus (HCV) infection and peripheral artery disease (PAD). Later while on anti-tuberculous treatment (ATT) squamous cell lung cancer (SCC) was confirmed with computed tomography (CT) guided biopsy. Due to poor general condition the patient was not fit for either surgery or radical chemo- and radiotherapy. He was transferred to hospice for palliative therapy. We want to emphasize that both TB and lung cancer should be actively sought for in patients with either disorder. In addition, there is no doubt that these patients with lung cancer and with good response to TB treatment should be promptly considered for appropriate anticancer therapy.

  10. Selection of radioresistant cells by vitamin A deficiency in a small cell lung cancer cell line

    International Nuclear Information System (INIS)

    Terasaki, Takeo; Shimosato, Yukio; Wada, Makio; Yokota, Jun; Terada, Masaaki

    1990-01-01

    Radiation sensitivity of a human small cell lung cancer cell line, Lu-134-B cells, cultured in serum-supplemented medium and of cells transferred to and cultured in delipidized serum-supplemented (vitamin A-deficient) medium was studied. The cells cultured in serum-supplemented medium showed the phenotype of classic small cell lung cancer sensitive to radiation, while cells transferred to delipidized serum-supplemented medium showed partial squamous cell differentiation and became resistant to radiation. These results suggest that some small cell lung cancer cells in vitro change their morphology and radiosensitivity depending on the culture conditions. The change in radiosensitivity was reproducible, and was not reversible by culture of the radioresistant cells in delipidized serum-supplemented medium with addition of retinoic acid (vitamin A-sufficient medium) for two months, although squamous cells disappeared. Acquisition of radioresistancy was considered to occur as the result of clonal selective growth in delipidized medium of a minor cell population in the original cell culture, based on a study of chromosome number. It was also found that there was no association of myc-family oncogenes with the changes of radiosensitivity in this cell line. (author)

  11. Integrated quantitative fractal polarimetric analysis of monolayer lung cancer cells

    Science.gov (United States)

    Shrestha, Suman; Zhang, Lin; Quang, Tri; Farrahi, Tannaz; Narayan, Chaya; Deshpande, Aditi; Na, Ying; Blinzler, Adam; Ma, Junyu; Liu, Bo; Giakos, George C.

    2014-05-01

    Digital diagnostic pathology has become one of the most valuable and convenient advancements in technology over the past years. It allows us to acquire, store and analyze pathological information from the images of histological and immunohistochemical glass slides which are scanned to create digital slides. In this study, efficient fractal, wavelet-based polarimetric techniques for histological analysis of monolayer lung cancer cells will be introduced and different monolayer cancer lines will be studied. The outcome of this study indicates that application of fractal, wavelet polarimetric principles towards the analysis of squamous carcinoma and adenocarcinoma cancer cell lines may be proved extremely useful in discriminating among healthy and lung cancer cells as well as differentiating among different lung cancer cells.

  12. Isolation and Characterization of Human Lung Lymphatic Endothelial Cells

    Science.gov (United States)

    Lorusso, Bruno; Falco, Angela; Madeddu, Denise; Frati, Caterina; Cavalli, Stefano; Graiani, Gallia; Gervasi, Andrea; Rinaldi, Laura; Lagrasta, Costanza; Maselli, Davide; Gnetti, Letizia; Silini, Enrico M.; Quaini, Eugenio; Ampollini, Luca; Carbognani, Paolo; Quaini, Federico

    2015-01-01

    Characterization of lymphatic endothelial cells from the respiratory system may be crucial to investigate the role of the lymphatic system in the normal and diseased lung. We describe a simple and inexpensive method to harvest, isolate, and expand lymphatic endothelial cells from the human lung (HL-LECs). Fifty-five samples of healthy lung selected from patients undergoing lobectomy were studied. A two-step purification tool, based on paramagnetic sorting with monoclonal antibodies to CD31 and Podoplanin, was employed to select a pure population of HL-LECs. The purity of HL-LECs was assessed by morphologic criteria, immunocytochemistry, flow cytometry, and functional assays. Interestingly, these cells retain in vitro several receptor tyrosine kinases (RTKs) implicated in cell survival and proliferation. HL-LECs represent a clinically relevant cellular substrate to study lymphatic biology, lymphoangiogenesis, interaction with microbial agents, wound healing, and anticancer therapy. PMID:26137493

  13. Cigarette smoke alters the secretome of lung epithelial cells.

    Science.gov (United States)

    Mossina, Alessandra; Lukas, Christina; Merl-Pham, Juliane; Uhl, Franziska E; Mutze, Kathrin; Schamberger, Andrea; Staab-Weijnitz, Claudia; Jia, Jie; Yildirim, Ali Ö; Königshoff, Melanie; Hauck, Stefanie M; Eickelberg, Oliver; Meiners, Silke

    2017-01-01

    Cigarette smoke is the most relevant risk factor for the development of lung cancer and chronic obstructive pulmonary disease. Many of its more than 4500 chemicals are highly reactive, thereby altering protein structure and function. Here, we used subcellular fractionation coupled to label-free quantitative MS to globally assess alterations in the proteome of different compartments of lung epithelial cells upon exposure to cigarette smoke extract. Proteomic profiling of the human alveolar derived cell line A549 revealed the most pronounced changes within the cellular secretome with preferential downregulation of proteins involved in wound healing and extracellular matrix organization. In particular, secretion of secreted protein acidic and rich in cysteine, a matricellular protein that functions in tissue response to injury, was consistently diminished by cigarette smoke extract in various pulmonary epithelial cell lines and primary cells of human and mouse origin as well as in mouse ex vivo lung tissue cultures. Our study reveals a previously unrecognized acute response of lung epithelial cells to cigarette smoke that includes altered secretion of proteins involved in extracellular matrix organization and wound healing. This may contribute to sustained alterations in tissue remodeling as observed in lung cancer and chronic obstructive pulmonary disease. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Sirolimus and Gold Sodium Thiomalate in Treating Patients With Advanced Squamous Non-Small Cell Lung Cancer

    Science.gov (United States)

    2012-12-13

    Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  15. Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T. [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Aftab, Blake T. [Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Rudin, Charles M. [Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Tran, Phuoc T. [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Hales, Russell K., E-mail: rhales1@jhmi.edu [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States)

    2013-05-01

    Purpose: Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials: We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of Kras{sup G12D}-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results: In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radiosensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions: Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer.

  16. Stem cells in sepsis and acute lung injury.

    Science.gov (United States)

    Cribbs, Sushma K; Matthay, Michael A; Martin, Greg S

    2010-12-01

    Sepsis and acute lung injury continue to be major causes of morbidity and mortality worldwide despite advances in our understanding of pathophysiology and the discovery of new management strategies. Recent investigations show that stem cells may be beneficial as prognostic biomarkers and novel therapeutic strategies in these syndromes. This article reviews the potential use of endogenous adult tissue-derived stem cells in sepsis and acute lung injury as prognostic markers and also as exogenous cell-based therapy. A directed systematic search of the medical literature using PubMed and OVID, with particular emphasis on the time period after 2002, was done to evaluate topics related to 1) the epidemiology and pathophysiology of sepsis and acute lung injury; and 2) the definition, characterization, and potential use of stem cells in these diseases. DATA SYNTHESIS AND FINDINGS: When available, preferential consideration was given to prospective nonrandomized clinical and preclinical studies. Stem cells have shown significant promise in the field of critical care both for 1) prognostic value and 2) treatment strategies. Although several recent studies have identified the potential benefit of stem cells in sepsis and acute lung injury, further investigations are needed to more completely understand stem cells and their potential prognostic and therapeutic value.

  17. Alpinetin inhibits lung cancer progression and elevates sensitization drug-resistant lung cancer cells to cis-diammined dichloridoplatium

    Directory of Open Access Journals (Sweden)

    Wu L

    2015-11-01

    Full Text Available Lin Wu, Wei Yang, Su-ning Zhang, Ji-bin Lu Department of Thoracic Surgery, Sheng Jing Hospital of China Medical University, Shenyang, People’s Republic of China Objective: Alpinetin is a novel flavonoid that has demonstrated potent antitumor activity in previous studies. However, the efficacy and mechanism of alpinetin in treating lung cancer have not been determined. Methods: We evaluated the impact of different doses and durations of alpinetin treatment on the cell proliferation, the apoptosis of lung cancer cells, as well as the drug-resistant lung cancer cells. Results: This study showed that the alpinetin inhibited the cell proliferation, enhanced the apoptosis, and inhibited the PI3K/Akt signaling in lung cancer cells. Moreover, alpinetin significantly increased the sensitivity of drug-resistant lung cancer cells to the chemotherapeutic effect of cis-diammined dichloridoplatium. Taken together, this study demonstrated that alpinetin significantly suppressed the development of human lung cancer possibly by influencing mitochondria and the PI3K/Akt signaling pathway and sensitized drug-resistant lung cancer cells. Conclusion: Alpinetin may be used as a potential compound for combinatorial therapy or as a complement to other chemotherapeutic agents when multiple lines of treatments have failed to reduce lung cancer. Keywords: alpinetin, cell proliferation and apoptosis, drug resistance reversal, PI3K/Akt, lung cancer

  18. 'Dancing eyes, dancing feet syndrome' in small cell lung carcinoma.

    Science.gov (United States)

    Sharma, Chandramohan; Acharya, Mihir; Kumawat, Bansi Lal; Kochar, Abhishek

    2014-04-23

    A 60-year-old man presented with a 25-day history of acute onset instability of gait, tremulousness of limbs and involuntary eye movements. Examination revealed presence of opsoclonus, myoclonus and ataxia, without any loss of motor power in the limbs. Prompt investigations were directed towards identifying an underlying malignancy which is often associated with this type of clinical scenario. CT of the brain was normal and cerebrospinal fluid examination showed lymphocytic pleocytosis. A cavitatory lesion was found in the right lung base on the high-resolution CT of the chest and histopathological examination of this lung mass showed small cell lung carcinoma. The patient was managed symptomatically with levetiracetam and baclofen and referred to oncology department for resection of the lung mass.

  19. Metabolic cooperation between co-cultured lung cancer cells and lung fibroblasts.

    Science.gov (United States)

    Koukourakis, Michael I; Kalamida, Dimitra; Mitrakas, Achilleas G; Liousia, Maria; Pouliliou, Stamatia; Sivridis, Efthimios; Giatromanolaki, Alexandra

    2017-11-01

    Cooperation of cancer cells with stromal cells, such as cancer-associated fibroblasts (CAFs), has been revealed as a mechanism sustaining cancer cell survival and growth. In the current study, we focus on the metabolic interactions of MRC5 lung fibroblasts with lung cancer cells (A549 and H1299) using co-culture experiments and studying changes of the metabolic protein expression profile and of their growth and migration abilities. Using western blotting, confocal microscopy and RT-PCR, we observed that in co-cultures MRC5 respond by upregulating pyruvate dehydrogenase (PDH) and the monocarboxylate transporter MCT1. In contrast, cancer cells increase the expression of glucose transporters (GLUT1), LDH5, PDH kinase and the levels of phosphorylated/inactivated pPDH. H1299 cells growing in the same culture medium with fibroblasts exhibit a 'metastasis-like' phenomenon by forming nests within the fibroblast area. LDH5 and pPDH were drastically upregulated in these nests. The growth rate of both MRC5 and cancer cells increased in co-cultures. Suppression of LDHA or PDK1 in cancer cells abrogates the stimulatory signal from cancer cells to fibroblasts. Incubation of MRC5 fibroblasts with lactate resulted in an increase of LDHB and of PDH expression. Silencing of PDH gene in fibroblasts, or silencing of PDK1 or LDHA gene in tumor cells, impedes cancer cell's migration ability. Overall, a metabolic cooperation between lung cancer cells and fibroblasts has been confirmed in the context of direct Warburg effect, thus the fibroblasts reinforce aerobic metabolism to support the intensified anaerobic glycolytic pathways exploited by cancer cells.

  20. Identification of different subsets of lung cells using Raman microspectroscopy and whole cell nucleus isolation.

    Science.gov (United States)

    Pijanka, Jacek K; Stone, Nicholas; Rutter, Abigail V; Forsyth, Nicholas; Sockalingum, Ganesh D; Yang, Ying; Sulé-Suso, Josep

    2013-09-07

    Raman spectroscopy has been widely used to study its possible clinical application in cancer diagnosis. However, in order to make it into clinical practice, it is important that this technique is able not only to identify cancer cells from their normal counterparts, but also from the array of cells present in human tissues. To this purpose, we used Raman spectroscopy to assess whether this technique was able to differentiate not only between lung cancer cells and lung epithelial cells but also from lung fibroblasts. Furthermore, we studied whether the differences were due to cell lineage (epithelial versus fibroblast) or to different proliferative characteristics of cells, and where in the cell compartment these differences might reside. To answer these questions we studied cell cytoplasm, cell nucleus and isolated whole cell nuclei. Our data suggests that Raman spectroscopy can differentiate between lung cancer, lung epithelial cells and lung fibroblasts. More important, it can also differentiate between 2 cells from the same lineage (fibroblast) but with one of them rendered immortal and with an increased proliferative activity. Finally, it seems that the main spectral differences reside in the cell nucleus and that the study of isolated nuclei strengthens the differences between cells.

  1. Change from lung adenocarcinoma to small cell lung cancer as a mechanism of resistance to afatinib.

    Science.gov (United States)

    Manca, Paolo; Russano, Marco; Pantano, Francesco; Tonini, Giuseppe; Santini, Daniele

    2017-08-29

    We report the case of a patient affected by advanced EGFR mutation-positive lung who experienced resistance to therapy during treatment with Afatinib through the occurrence of a switch of tumor histotype to small cell lung cancer (SCLC) with features of a G3 neuroendocrine carcinoma. Unexpectedly, the switch to SCLC histotype occurred in the only site not responsive to afatinib and subsequently the most responsive to chemotherapy. Our case shows that occurrence of switch to SCLC is a possible mechanism of resistance during treatment with Afatinib.

  2. Inhibition of airway epithelial-to-mesenchymal transition and fibrosis by kaempferol in endotoxin-induced epithelial cells and ovalbumin-sensitized mice.

    Science.gov (United States)

    Gong, Ju-Hyun; Cho, In-Hee; Shin, Daekeun; Han, Seon-Young; Park, Sin-Hye; Kang, Young-Hee

    2014-03-01

    Chronic airway remodeling is characterized by structural changes within the airway wall, including smooth muscle hypertrophy, submucosal fibrosis and epithelial shedding. Epithelial-to-mesenchymal transition (EMT) is a fundamental mechanism of organ fibrosis, which can be induced by TGF-β. In the in vitro study, we investigated whether 1-20 μM kaempferol inhibited lipopolysaccharide (LPS)-induced bronchial EMT in BEAS-2B cells. The in vivo study explored demoting effects of 10-20 mg/kg kaempferol on airway fibrosis in BALB/c mice sensitized with ovalbumin (OVA). LPS induced airway epithelial TGF-β1 signaling that promoted EMT with concurrent loss of E-cadherin and induction of α-smooth muscle actin (α-SMA). Nontoxic kaempferol significantly inhibited TGF-β-induced EMT process through reversing E-cadherin expression and retarding the induction of N-cadherin and α-SMA. Consistently, OVA inhalation resulted in a striking loss of epithelial morphology by displaying myofibroblast appearance, which led to bronchial fibrosis with submucosal accumulation of collagen fibers. Oral administration of kaempferol suppressed collagen deposition, epithelial excrescency and goblet hyperplasia observed in the lung of OVA-challenged mice. The specific inhibition of TGF-β entailed epithelial protease-activated receptor-1 (PAR-1) as with 20 μM kaempferol. The epithelial PAR-1 inhibition by SCH-79797 restored E-cadherin induction and deterred α-SMA induction, indicating that epithelial PAR-1 localization was responsible for resulting in airway EMT. These results demonstrate that dietary kaempferol alleviated fibrotic airway remodeling via bronchial EMT by modulating PAR1 activation. Therefore, kaempferol may be a potential therapeutic agent targeting asthmatic airway constriction.

  3. Cytotoxic effects of air freshener biocides in lung epithelial cells.

    Science.gov (United States)

    Kwon, Jung-Taek; Lee, Mimi; Seo, Gun-Baek; Kim, Hyun-Mi; Shim, Ilseob; Lee, Doo-Hee; Kim, Taksoo; Seo, Jung Kwan; Kim, Pilje; Choi, Kyunghee

    2013-09-01

    This study evaluated the cytotoxicity of mixtures of citral (CTR) and either benzisothiazolinone (BIT, Mix-CTR-BIT) or triclosan (TCS, Mix-CTR-TCS) in human A549 lung epithelial cells. We investigated the effects of various mix ratios of these common air freshener ingredients on cell viability, cell proliferation, reactive oxygen species (ROS) generation, and DNA damage. Mix-CTR-BIT and Mix-CTR-TCS significantly decreased the viability of lung epithelial cells and inhibited cell growth in a dose-dependent manner. In addition, both mixtures increased ROS generation, compared to that observed in control cells. In particular, cell viability, growth, and morphology were affected upon increase in the proportion of BIT or TCS in the mixture. However, comet analysis showed that treatment of cells with Mix-CTR-BIT or Mix-CTR-TCS did not increase DNA damage. Taken together, these data suggested that increasing the content of biocides in air fresheners might induce cytotoxicity, and that screening these compounds using lung epithelial cells may contribute to hazard assessment.

  4. Increased hydrostatic pressure enhances motility of lung cancer cells.

    Science.gov (United States)

    Kao, Yu-Chiu; Lee, Chau-Hwang; Kuo, Po-Ling

    2014-01-01

    Interstitial fluid pressures within most solid tumors are significantly higher than that in the surrounding normal tissues. Therefore, cancer cells must proliferate and migrate under the influence of elevated hydrostatic pressure while a tumor grows. In this study, we developed a pressurized cell culture device and investigated the influence of hydrostatic pressure on the migration speeds of lung cancer cells (CL1-5 and A549). The migration speeds of lung cancer cells were increased by 50-60% under a 20 mmHg hydrostatic pressure. We also observed that the expressions of aquaporin in CL1-5 and A549 cells were increased under the hydrostatic pressure. Our preliminary results indicate that increased hydrostatic pressure plays an important role in tumor metastasis.

  5. From here to there, progenitor cells and stem cells are everywhere in lung vascular remodeling

    Directory of Open Access Journals (Sweden)

    Rebecca L. Heise

    2016-08-01

    Full Text Available The field of stem cell biology, cell therapy and regenerative medicine has expanded almost exponentially in the last decade. Clinical trials are evaluating the potential therapeutic use of stem cells in many adult and pediatric lung diseases with vascular component, such as bronchopulmonary dysplasia (BPD, chronic obstructive pulmonary disease (COPD, idiopathic pulmonary fibrosis (IPF or pulmonary arterial hypertension (PAH. Extensive research activity is exploring lung resident and circulating progenitor cells and their contribution to vascular complications of chronic lung diseases, and researchers hope to use resident or circulating stem/progenitor cells to treat chronic lung diseases and their vascular complications. It is becoming more and more clear that progress in mechanobiology will help to understand the various influences of physical forces and extracellular matrix composition on the phenotype and features of the progenitor cells and stem cells. The current review provides an overview of current concepts in the field.

  6. Radiosensitization of non-small cell lung cancer by kaempferol.

    Science.gov (United States)

    Kuo, Wei-Ting; Tsai, Yuan-Chung; Wu, His-Chin; Ho, Yung-Jen; Chen, Yueh-Sheng; Yao, Chen-Han; Yao, Chun-Hsu

    2015-11-01

    The aim of the present study was to determine whether kaempferol has a radiosensitization potential for lung cancer in vitro and in vivo. The in vitro radio-sensitization activity of kaempferol was elucidated in A-549 lung cancer cells by using an MTT (3-(4 5-dimethylthiazol-2-yl)-25-diphenyl-tetrazolium bromide) assay, cell cycle analysis and clonogenic assay. The in vivo activity was evaluated in the BALB/c nude mouse xenograft model of A-549 cells by hematoxylin and eosin staining and immunohistochemistry, and the tumor volume was recorded. Protein levels of the apoptotic pathway were detected by western blot analysis. Treatment with kaempferol inhibited the growth of A-549 cells through activation of apoptotic pathway. However, the same doses did not affect HFL1 normal lung cell growth. Kaempferol induced G2/M cell cycle arrest and the enhancement of radiation-induced death and clonogenic survival inhibition. The in vivo data showed that kaempferol increased tumor cell apoptosis and killing of radiation. In conclusion, the findings demonstrated that kaempferol increased tumor cell killing by radiation in vitro and in vivo through inhibition of the AKT/PI3K and ERK pathways and activation of the mitochondria apoptosis pathway. The results of the present study provided solid evidence that kaempferol is a safe and potential radiosensitizer.

  7. Reciprocal modulation of mesenchymal stem cells and tumor cells promotes lung cancer metastasis

    Directory of Open Access Journals (Sweden)

    Giulia Fregni

    2018-03-01

    Full Text Available Metastasis is a multi-step process in which direct crosstalk between cancer cells and their microenvironment plays a key role. Here, we assessed the effect of paired tumor-associated and normal lung tissue mesenchymal stem cells (MSCs on the growth and dissemination of primary human lung carcinoma cells isolated from the same patients. We show that the tumor microenvironment modulates MSC gene expression and identify a four-gene MSC signature that is functionally implicated in promoting metastasis. We also demonstrate that tumor-associated MSCs induce the expression of genes associated with an aggressive phenotype in primary lung cancer cells and selectively promote their dissemination rather than local growth. Our observations provide insight into mechanisms by which the stroma promotes lung cancer metastasis. Keywords: Tumor-associated MSCs, lung cancer, metastasis, GREM1, LOXL2, ADAMTS12, ITGA11

  8. Lung cancer

    International Nuclear Information System (INIS)

    Aisner, J.

    1985-01-01

    This book contains 13 chapters. Some of the chapter titles are: The Pathology of Lung Cancer; Radiotherapy for Non-Small-Cell Cancer of the Lung; Chemotherapy for Non-Small-Cell Lung Cancer; Immunotherapy in the Management of Lung Cancer; Preoperative Staging and Surgery for Non-Small-Cell Lung Cancer; and Prognostic Factors in Lung Cancer

  9. Personalizing Therapy in Advanced Non–Small Cell Lung Cancer

    Science.gov (United States)

    Villaruz, Liza C.; Burns, Timothy F.; Ramfidis, Vasilis S.; Socinski, Mark A.

    2016-01-01

    The recognition that non–small cell lung cancer (NSCLC) is not a single disease entity, but rather a collection of distinct molecularly driven neoplasms, has permanently shifted the therapeutic landscape of NSCLC to a personalized approach. This personalization of NSCLC therapy is typified by the dramatic response rates seen in EGFR mutant NSCLC when treated with targeted tyrosine kinase inhibitor therapy and in ALK translocation–driven NSCLC when treated with ALK inhibitors. Targeted therapeutic approaches in NSCLC necessitate consideration of more invasive biopsy techniques aimed at providing sufficient tissue for both histological determination and molecular profiling in all patients with stage IV disease both at the time of diagnosis and at the time of disease progression. Comprehensive genotyping efforts have identified oncogenic drivers in 62% lung adenocarcinomas and an increasing proportion of squamous cell carcinomas of the lung. The identification of these oncogenic drivers and the triage of patients to clinical trials evaluating novel targeted therapeutic approaches will increasingly mold a landscape of personalized lung cancer therapy where each genotype has an associated targeted therapy. This review outlines the state of personalized lung cancer therapy as it pertains to individual NSCLC genotypes. PMID:24258572

  10. [Small-cell lung cancer: epidemiology, diagnostics and therapy].

    Science.gov (United States)

    Pešek, Miloš; Mužík, Jan

    Authors present actual overview of information on diagnostic and therapeutic procedures in small-cell lung cancer (SCLC). This highly aggressive type of lung cancer is diagnosed in 14.8 % of Czech lung cancer patients. Vast majority of those patients (87 %) suffer from advanced and metastatic disease in the time of diagnosis. In this issue are presented prognostic factors, staging diagnostic procedures and therapeutic recommendations. The backbone of actual SCLC treatment is combined chemotherapy and radiotherapy and less frequently, carefully in selected cases, surgical procedures. SCLC should be have as chemosensitive, chemoresistent or chemorefractory disease. Actual cytostatic combinations used in 1st line treatment, different schedules of chemoradiotherapy, drugs used in second line treatment and schedules and timing of prophylactic brain irradiation are presented. In near future, perspectively, there are some promissible data on antitumour immunotherapy based on anti CTLA-4 and anti PD-1/PE-L1 antibodies also in SCLC patients.Key words: cancer immunotherapy - concomitant chemoradiotherapy - chemotherapy - chest radiotherapy - lung resections - prophylactic brain irradiation - small cell lung cancer.

  11. Detection of cytoskeletal proteins in small cell lung carcinoma

    Czech Academy of Sciences Publication Activity Database

    Hložánková, M.; Lukáš, Z.; Viklický, Vladimír

    1999-01-01

    Roč. 18, - (1999), s. 47-49 ISSN 0231-5882 Grant - others:MŠk1(CZ) OE10a/EU1450 Keywords : cytoskeletal proteins * small cell lung carcinoma Subject RIV: EI - Biotechnology ; Bionics Impact factor: 0.400, year: 1999

  12. Anticoagulant drugs increase natural killer cell activity in lung cancer

    Czech Academy of Sciences Publication Activity Database

    Bobek, M.; Boubelík, Michael; Fišerová, Anna; Luptovcová, Martina; Vannucci, Luca; Kacprzak, G.; Kolodzej, J.; Majewski, A.M.; Hoffman, R. M.

    2005-01-01

    Roč. 47, č. 2 (2005), s. 215-223 ISSN 0169-5002 Institutional research plan: CEZ:AV0Z5052915 Keywords : anticoagulant drugs * lung cancer * NK cells Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.172, year: 2005

  13. Tracking the Evolution of Non-Small-Cell Lung Cancer

    DEFF Research Database (Denmark)

    Jamal-Hanjani, Mariam; Wilson, Gareth A.; McGranahan, Nicholas

    2017-01-01

    Background Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine...... as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .)....

  14. Long-term survival in small-cell lung cancer

    DEFF Research Database (Denmark)

    Lassen, U; Osterlind, K; Hansen, M

    1995-01-01

    PURPOSE: To describe in patients with small-cell lung cancer (SCLC) the characteristics of those who survive for > or = 5 years, to identify long-term prognostic factors, to analyze survival data of 5-year survivors, and to study 10-year survival in patients entered before 1981. PATIENTS......, especially tobacco-related cancers and other tobacco-related diseases....

  15. Surgery in limited stage small cell lung cancer

    DEFF Research Database (Denmark)

    Lassen, U; Hansen, H H

    1999-01-01

    The role of surgery in small cell lung cancer (SCLC) is controversial. Surgery has several potential advantages because it may reduce the frequency of local relapses, it does not impede the intensity of chemotherapy, it does not affect the bone marrow, and surgical staging may be of prognostic...

  16. Specifically targeted gene therapy for small-cell lung cancer

    DEFF Research Database (Denmark)

    Christensen, C.L.; Zandi, R.; Gjetting, T.

    2009-01-01

    Small-cell lung cancer (SCLC) is a highly malignant disease with poor prognosis. Hence, there is great demand for new therapies that can replace or supplement the current available treatment regimes. Gene therapy constitutes a promising strategy and relies on the principle of introducing exogenous...

  17. Lung function after allogeneic hematopoietic stem cell transplantation in children

    DEFF Research Database (Denmark)

    Uhlving, Hilde Hylland; Larsen Bang, Cæcilie; Christensen, Ib Jarle

    2013-01-01

    Reduction in pulmonary function (PF) has been reported in up to 85% of pediatric patients during the first year after hematopoietic stem cell transplantation (HSCT). Our understanding of the etiology for this decrease in lung function is, however, sparse. The aim of this study was to describe PF...

  18. ORAL-THERAPY FOR SMALL-CELL LUNG-CANCER

    NARCIS (Netherlands)

    POSTMUS, PE; SMIT, EF

    After a remarkable improvement of the very poor prognosis of small cell lung cancer with very simple therapy such as iv and oral cyclophosphamide the role of oral therapy has become minimal. However, since more than a decade results of combination chemotherapy are at a plateau and it is necessary to

  19. Iris metastasis in small-cell lung carcinoma

    NARCIS (Netherlands)

    Roenhorst, Anke W. J.; van den Bergh, Alphons C. M.; van Putten, John W. G.; Smit, Egbert F.

    2007-01-01

    Small-cell lung cancer (SCLC) is characterized by rapid growth and early metastasis. Despite its sensitivity to cytotoxic treatment, until now treatments have failed to control or cure this disease in most patients. Here, we describe a patient with SCLC in which symptoms caused by iris metastasis

  20. Value of brain computed tomography in small cell lung cancers

    International Nuclear Information System (INIS)

    Fernet, M.; Breau, J.L.; Goldlust, D.; Israel, L.

    1988-01-01

    88 patients with small cell lung cancer were studied. Brain scans were performed first at initial staging and repeated at regular intervals during the survey. The results confirm the limited value of brain scans in the detection of metastases in neurologically asymptomatic patients [fr

  1. Penta- and octa-bromodiphenyl ethers promote proinflammatory protein expression in human bronchial epithelial cells in vitro.

    Science.gov (United States)

    Koike, Eiko; Yanagisawa, Rie; Takigami, Hidetaka; Takano, Hirohisa

    2014-03-01

    Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants in consumer products. Humans can be exposed to PBDEs mainly through the inhalation of air or dust. Thus, PBDEs can affect respiratory and immune systems. In the present study, we investigated whether PBDEs stimulate bronchial epithelial cells. We examined commercial penta-BDE (DE-71), octa-BDE (DE-79), and deca-BDE (DE-83R). Human bronchial epithelial cells (BEAS-2B) were exposed to each PBDE for 24h. Subsequently, the expression of intercellular adhesion molecule-1 (ICAM-1) and proinflammatory cytokines were investigated. DE-71 and DE-79, but not DE-83R, significantly increased the expression of ICAM-1, interleukin-6 (IL-6), and IL-8 in BEAS-2B. Because these remarkable effects were observed with DE-71, we further investigated the underlying intracellular mechanisms. DE-71 promoted epidermal growth factor receptor (EGFR) phosphorylation. Inhibitors of EGFR-selective tyrosine kinase and p38 mitogen-activated protein kinase effectively blocked the increase of IL-6 and IL-8. Furthermore, antagonists of thyroid hormone receptor and aryl hydrocarbon receptor significantly suppressed the increase in IL-6 and/or IL-8 production. In conclusion, penta- and octa-BDE, but not deca-BDE, might promote the expression of proinflammatory proteins in bronchial epithelial cells possibly by activating protein kinases and/or stimulating nuclear receptors related to subsequent activation of transcriptional factors. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Uranium induces oxidative stress in lung epithelial cells

    International Nuclear Information System (INIS)

    Periyakaruppan, Adaikkappan; Kumar, Felix; Sarkar, Shubhashish; Sharma, Chidananda S.; Ramesh, Govindarajan T.

    2007-01-01

    Uranium compounds are widely used in the nuclear fuel cycle, antitank weapons, tank armor, and also as a pigment to color ceramics and glass. Effective management of waste uranium compounds is necessary to prevent exposure to avoid adverse health effects on the population. Health risks associated with uranium exposure includes kidney disease and respiratory disorders. In addition, several published results have shown uranium or depleted uranium causes DNA damage, mutagenicity, cancer and neurological defects. In the current study, uranium toxicity was evaluated in rat lung epithelial cells. The study shows uranium induces significant oxidative stress in rat lung epithelial cells followed by concomitant decrease in the antioxidant potential of the cells. Treatment with uranium to rat lung epithelial cells also decreased cell proliferation after 72 h in culture. The decrease in cell proliferation was attributed to loss of total glutathione and superoxide dismutase in the presence of uranium. Thus the results indicate the ineffectiveness of antioxidant system's response to the oxidative stress induced by uranium in the cells. (orig.)

  3. Mast cell density in isolated monkey lungs on exposure to cigarette smoke.

    OpenAIRE

    Walter, A; Walter, S

    1982-01-01

    The density and percentage of degranulated cells of the mast cell population were studied in the isolated lungs of 25 monkeys (Macaca radiata radiata) before and after acute exposure to cigarette smoke. In each animal one lung was used as the test lung while the other lung was used as its control. In the control lungs the total mean mast cell count was 9.5/mm2 and the proportion of degranulated cells was 9.7%. In the lungs exposed to smoke the total counts were lower (7.3/mm2) and the percent...

  4. Primary mesenchymal stem cells in human transplanted lungs are CD90/CD105 perivascularly located tissue-resident cells

    DEFF Research Database (Denmark)

    Rolandsson, Sara; Andersson Sjöland, Annika; Brune, Jan C

    2014-01-01

    BACKGROUND: Mesenchymal stem cells (MSC) have not only been implicated in the development of lung diseases, but they have also been proposed as a future cell-based therapy for lung diseases. However, the cellular identity of the primary MSC in human lung tissues has not yet been reported. This st......BACKGROUND: Mesenchymal stem cells (MSC) have not only been implicated in the development of lung diseases, but they have also been proposed as a future cell-based therapy for lung diseases. However, the cellular identity of the primary MSC in human lung tissues has not yet been reported...

  5. Paracytosis of Haemophilus influenzae through cell layers of NCI-H292 lung epithelial cells

    NARCIS (Netherlands)

    van Schilfgaarde, M.; van Alphen, L.; Eijk, P.; Everts, V.; Dankert, J.

    1995-01-01

    Haemophilus influenzae penetrates the respiratory epithelium during carriage and invasive disease, including respiratory tract infections. We developed an in vitro model system consisting of lung epithelial NCI-H292 cells on permeable supports to study the passage of H. influenzae through lung

  6. SAMHD1 is down regulated in lung cancer by methylation and inhibits tumor cell proliferation

    International Nuclear Information System (INIS)

    Wang, Jia-lei; Lu, Fan-zhen; Shen, Xiao-Yong; Wu, Yun; Zhao, Li-ting

    2014-01-01

    Highlights: • SAMHD1 expression level is down regulated in lung adenocarcinoma. • The promoter of SAMHD1 is methylated in lung adenocarcinoma. • Over expression of SAMHD1 inhibits the proliferation of lung cancer cells. - Abstract: The function of dNTP hydrolase SAMHD1 as a viral restriction factor to inhibit the replication of several viruses in human immune cells was well established. However, its regulation and function in lung cancer have been elusive. Here, we report that SAMHD1 is down regulated both on protein and mRNA levels in lung adenocarcinoma compared to adjacent normal tissue. We also found that SAMHD1 promoter is highly methylated in lung adenocarcinoma, which may inhibit its gene expression. Furthermore, over expression of the SAMHD1 reduces dNTP level and inhibits the proliferation of lung tumor cells. These results reveal the regulation and function of SAMHD1 in lung cancer, which is important for the proliferation of lung tumor cells

  7. Palliative Care Intervention in Improving Symptom Control and Quality of Life in Patients With Stage II-IV Non-small Cell Lung Cancer and Their Family Caregivers

    Science.gov (United States)

    2017-10-16

    Caregiver; Psychological Impact of Cancer and Its Treatment; Recurrent Non-small Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  8. Gamma Delta T-Cells Regulate Inflammatory Cell Infiltration of the Lung after Trauma-Hemorrhage

    Science.gov (United States)

    2015-06-01

    suggesting a role for this T- cell subset in both innate and acquired immunity (7, 8). Studies have shown that +% T cells are required for both controlled...increased infiltration of both lymphoid and myeloid cells in WT mice after TH-induced ALI. In parallel to +% T cells , myeloid cells (i.e., monocytes...GAMMA DELTA T CELLS REGULATE INFLAMMATORY CELL INFILTRATION OF THE LUNG AFTER TRAUMA-HEMORRHAGE Meenakshi Rani,* Qiong Zhang,* Richard F. Oppeltz

  9. Prostaglandin E2 stimulates normal bronchial epithelial cell growth through induction of c-Jun and PDK1, a kinase implicated in oncogenesis.

    Science.gov (United States)

    Fan, Yu; Wang, Ye; Wang, Ke

    2015-12-18

    Cyclooxygenase-2-derived prostaglandin E2 (PGE2), a bioactive eicosanoid, has been implicated in many biological processes including reproduction, inflammation and tumor growth. We previously showed that PGE2 stimulated lung cancer cell growth and progression through PGE2 receptor EP2/EP4-mediated kinase signaling pathways. However, the role of PGE2 in controlling lung airway epithelial cell phenotype remains unknown. We evaluated the effects of c-Jun and 3-phosphoinositede dependent protein kinase-1 (PDK1) in mediating epithelial cell hyperplasia induced by PGE2. The bronchial epithelial cell lines BEAS-2B and HBEc14-KT were cultured and then treated with PGE2. PDK1 small interfering RNA (siRNA) and a PDK1 inhibitor, an antagonist of the PGE2 receptor subtype EP4 and EP4 siRNA, c-Jun siRNA, and overexpressions of c-Jun and PDK1 have been used to evaluate the effects on cell proliferation. We demonstrated that PGE2 increased normal bronchial epithelial cell proliferation through induction of PDK1, an ankyrin repeat-containing Ser/Thr kinase implicated in the induction of apoptosis and the suppression of tumor growth. PDK1 siRNA and a PDK1 inhibitor blocked the effects of PGE2 on normal cell growth. The PGE2-induced PDK1 expression was blocked by an antagonist of the PGE2 receptor subtype EP4 and by EP4 siRNA. In addition, we showed that induction of PDK1 by PGE2 was associated with induction of the transcription factor, c-Jun protein. Silencing of c-Jun using siRNA and point mutations of c-Jun sites in the PDK1 gene promoter resulted in blockade of PDK1 expression and promoter activity induced by PGE2. In contrast, overexpression of c-Jun induced PDK1 gene promoter activity and expression followed increased cell proliferation. PGE2 increases normal bronchial epithelial cell proliferation through increased PDK1 gene expression that is dependent on EP4 and induction of c-Jun. Therewith, our data suggest a new role of c-Jun and PDK1 in mediating epithelial cell

  10. Lipidomic Profiling of Lung Pleural Effusion Identifies Unique Metabotype for EGFR Mutants in Non-Small Cell Lung Cancer

    OpenAIRE

    Ying Swan Ho; Lian Yee Yip; Nurhidayah Basri; Vivian Su Hui Chong; Chin Chye Teo; Eddy Tan; Kah Ling Lim; Gek San Tan; Xulei Yang; Si Yong Yeo; Mariko Si Yue Koh; Anantham Devanand; Angela Takano; Eng Huat Tan; Daniel Shao Weng Tan

    2016-01-01

    Cytology and histology forms the cornerstone for the diagnosis of non-small cell lung cancer (NSCLC) but obtaining sufficient tumour cells or tissue biopsies for these tests remains a challenge. We investigate the lipidome of lung pleural effusion (PE) for unique metabolic signatures to discriminate benign versus malignant PE and EGFR versus non-EGFR malignant subgroups to identify novel diagnostic markers that is independent of tumour cell availability. Using liquid chromatography mass spect...

  11. Autopsy findings in small cell lung cancer

    International Nuclear Information System (INIS)

    Jereczek, B.; Jassem, J.; Karnicka-Mlodkowska, H.; Badzio, A.; Mos-Antkowiak, R.; Dziadziuszko, R.; Szczepek, B.; Chojak, E.; Lisowska, B.; Malak, K.

    1996-01-01

    The objective of this study was to assess the pattern of autopsy in 174 small lung cancer patients treated between 1971 and 1991 at seven Polish medical centres. Eighty nine autopsied patients were previously treated with different chemotherapy regimens including 32 patients who also received chest irradiation, 74 received only supportive care and for 11 patients the data on treatment were not available. The age range at diagnosis was 28-81 years (median 57); there were 39 females (22%) and 135 males (78%). Seventy two patients had limited disease at the time of diagnosis, 86 - extensive disease and in 16 the disease extent was not determined. The primary tumor and/or metastases in regional lymph nodes were present in 157 autopsies (90%). There was a significant difference in the rate of locoregional disease found at autopsy in patients given chemotherapy and in those who received only supportive care (85% and 100%, respectively; p = 0.01). Chest radiation therapy given in limited as an adjunct to chemotherapy did not decrease the rate of persistent locoregional disease (primary tumor in the chest was found in 92% of irradiated and in 96% of nonirradiated patients). Locoregional tumor deposit only was found in 28 (16%). Distant metastases were distributed in 143 patients (82%) and were found in 25 different locations, most frequently in liver (49%), supra-renal glands (25%), peripheral lymph nodes (21%), kidneys (18%), brain (17%) and pancreas (12%). In 3 patients no tumor foci were found. The number of organs involved varied between 0 and 10 (median 3). The number of involved organs was not dependent on the disease extent at the time of diagnosis and on the type of treatment. (author)

  12. Asymmetric cell division of stem cells in the lung and other systems

    Directory of Open Access Journals (Sweden)

    Mohamed eBerika

    2014-07-01

    Full Text Available New insights have been added to identification, behavior and cellular properties of embryonic and tissue-specific stem cells over the last few years. The modes of stem cell division, asymmetric versus symmetric, are tightly regulated during development and regeneration. The proper choice of a stem cell to divide asymmetrically or symmetrically has great consequences for development and disease because inappropriate asymmetric division disrupts organ morphogenesis, whereas uncontrolled symmetric division induces tumorigenesis. Therefore, understanding the behavior of lung stem cells could identify innovative solutions for restoring normal morphogenesis and/or regeneration of different organs. In this concise review, we describe recent studies in our laboratory about the mode of division of lung epithelial stem cells. We also compare asymmetric cell division in the lung stem cells with other tissues in different organisms.

  13. Miniature Dielectric Barrier Discharge Nonthermal Plasma Induces Apoptosis in Lung Cancer Cells and Inhibits Cell Migration.

    Science.gov (United States)

    Karki, Surya B; Yildirim-Ayan, Eda; Eisenmann, Kathryn M; Ayan, Halim

    2017-01-01

    Traditional cancer treatments like radiotherapy and chemotherapy have drawbacks and are not selective for killing only cancer cells. Nonthermal atmospheric pressure plasmas with dielectric barrier discharge (DBD) can be applied to living cells and tissues and have emerged as novel tools for localized cancer therapy. The purpose of this study was to investigate the different effects caused by miniature DBD (mDBD) plasma to A549 lung cancer cells. In this study, A549 lung cancer cells cultured in 12 well plates were treated with mDBD plasma for specified treatment times to assess the changes in the size of the area of cell detachment, the viability of attached or detached cells, and cell migration. Furthermore, we investigated an innovative mDBD plasma-based therapy for localized treatment of lung cancer cells through apoptotic induction. Our results indicate that plasma treatment for 120 sec causes apoptotic cell death in 35.8% of cells, while mDBD plasma treatment for 60 sec, 30 sec, or 15 sec causes apoptotic cell death in 20.5%, 14.1%, and 6.3% of the cell population, respectively. Additionally, we observed reduced A549 cell migration in response to mDBD plasma treatment. Thus, mDBD plasma system can be a viable platform for localized lung cancer therapy.

  14. Miniature Dielectric Barrier Discharge Nonthermal Plasma Induces Apoptosis in Lung Cancer Cells and Inhibits Cell Migration

    Directory of Open Access Journals (Sweden)

    Surya B. Karki

    2017-01-01

    Full Text Available Traditional cancer treatments like radiotherapy and chemotherapy have drawbacks and are not selective for killing only cancer cells. Nonthermal atmospheric pressure plasmas with dielectric barrier discharge (DBD can be applied to living cells and tissues and have emerged as novel tools for localized cancer therapy. The purpose of this study was to investigate the different effects caused by miniature DBD (mDBD plasma to A549 lung cancer cells. In this study, A549 lung cancer cells cultured in 12 well plates were treated with mDBD plasma for specified treatment times to assess the changes in the size of the area of cell detachment, the viability of attached or detached cells, and cell migration. Furthermore, we investigated an innovative mDBD plasma-based therapy for localized treatment of lung cancer cells through apoptotic induction. Our results indicate that plasma treatment for 120 sec causes apoptotic cell death in 35.8% of cells, while mDBD plasma treatment for 60 sec, 30 sec, or 15 sec causes apoptotic cell death in 20.5%, 14.1%, and 6.3% of the cell population, respectively. Additionally, we observed reduced A549 cell migration in response to mDBD plasma treatment. Thus, mDBD plasma system can be a viable platform for localized lung cancer therapy.

  15. Inhibition of Zoledronic Acid on Cell Proliferation and Invasion of Lung Cancer Cell Line 95D

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    Mingming LI

    2009-03-01

    Full Text Available Background and objective Abnormal proliferation and metastasis is the basic characteristic of malignant tumors. The aim of this work is to explore the effects of zoledronic acid on cell proliferation and invasion in lung cancer cell line 95D. Methods The effect of zoledrnic acid (ZOL on proliferation of lung cancer cell line 95D was detected by MTT. The expression of proliferation and invasion-relation genes and proteins were detected by Western blot, RT-PCR and immunofluorescence. Changes of invasion of lung cancer cell numbers were measured by polycarbonates coated with Matrigel. Results ZOL could inhibit the proliferation of lung cancer cell line 95D in vitro in a time-dependant and a dose-dependant manner. With time extending after ZOL treated, the mRNA expresion of VEGF, MMP9, MMP2 and protein expression of VEGF, MMP9, ERK1/ ERK2 were decreased. The results of Tanswell invasion showed the numbers of invasive cells were significantly reduced in 95D cells treated with ZOL 4 d and 6 d later. Conclusion ZOL could inhibit cell proliferation and invasion of lung cancer cell line 95D.

  16. Melittin exerts an antitumor effect on non‑small cell lung cancer cells.

    Science.gov (United States)

    Zhang, Su-Fang; Chen, Zhe

    2017-09-01

    Lung cancer accounts for a significant percentage of all cancer‑associated mortalities in men and women, with non‑small cell lung cancer being the most frequently occurring type of lung cancer. Melittin is the principal active component of apitoxin (bee venom) that has been reported to exert anti‑chronic inflammatory and anti‑cancer effects. In the present study, the antitumor effect of melittin was evaluated using in vivo and in vitro analyses. The results demonstrated that melittin significantly inhibited the epidermal growth factor‑induced invasion and migration of non‑small cell lung cancer cells. Subcutaneous injection of melittin at doses of 1 and 10 mg/kg significantly suppressed non‑small cell lung cancer tumor growth by 27 and 61%, respectively. In addition, melittin significantly inhibited the secretion of vascular endothelial growth factor (VEGF) in non‑small cell lung cancer cells. Furthermore, melittin decreased the protein expression of VEGF and hypoxia‑inducible factor 1‑α. Therefore, the antitumor activity of melittin may be associated with the anti‑angiogenic actions of inhibiting the VEGF and hypoxia‑inducible factor signaling pathways.

  17. When does the lung die? Kfc, cell viability, and adenine nucleotide changes in the circulation-arrested rat lung.

    Science.gov (United States)

    Jones, D R; Becker, R M; Hoffmann, S C; Lemasters, J J; Egan, T M

    1997-07-01

    Lungs harvested from cadaveric circulation-arrested donors may increase the donor pool for lung transplantation. To determine the degree and time course of ischemia-reperfusion injury, we evaluated the effect of O2 ventilation on capillary permeability [capillary filtration coefficient (Kfc)], cell viability, and total adenine nucleotide (TAN) levels in in situ circulation-arrested rat lungs. Kfc increased with increasing postmortem ischemic time (r = 0.88). Lungs ventilated with O2 1 h postmortem had similar Kfc and wet-to-dry ratios as controls. Nonventilated lungs had threefold (P Kfc at 30 and 60 min postmortem compared with controls. Cell viability decreased in all groups except for 30-min postmortem O2-ventilated lungs. TAN levels decreased with increasing ischemic time, particularly in nonventilated lungs. Loss of adenine nucleotides correlated with increasing Kfc values (r = 0.76). This study indicates that lungs retrieved 1 h postmortem may have normal Kfc with preharvest O2 ventilation. The relationship between Kfc and TAN suggests that vascular permeability may be related to lung TAN levels.

  18. Approach for oligometastasis in non-small cell lung cancer.

    Science.gov (United States)

    Suzuki, Hidemi; Yoshino, Ichiro

    2016-04-01

    Non-small cell lung cancer (NSCLC) harboring a limited number of distant metastases, referred to as the oligometastatic state, has been indicated for surgery for the past several decades. However, whether the strategy of surgical treatment results in a survival benefit for such patients remains controversial. Experientially, however, thoracic surgeons often encounter long-term survivors among surgically resected oligometastatic NSCLC patients. In this article, the current situation of surgical approach and potential future perspective for oligometastatic NSCLC are reviewed.

  19. Evaluation of pentavalent Tc-99m DMSA scintigraphy in small cell and nonsmall cell lung cancers

    International Nuclear Information System (INIS)

    Atasever, T.; Guendogdu, C.; Vural, G.; Kapucu, L.Oe.; Karalezli, A.; Uenlue, M.

    1997-01-01

    Aim: The purpose of this study was to evaluate the clinical usefulness of Tc-99m (V) DMSA in patients suspected of lung cancer and determine whether this agent may have value in differentiation between small cell (SCLC) and non-small cell (NSCLC) lung carcinoma. Methods: Thirty-six patients with clinical and radiological suspicion of primary lung carcinoma were injected 450-600 MBq of Tc-99m (V) DMSA intravenously. Whole body and planar anterior, posterior thorax images were obtained 4-5 h after injection of the radioactive complex. Results: Histopathological results confirmed 23 NSCLC, 10 SCLC and 1 metastatic lung carcinoma and 2 lung abscess. Nineteen of the 23 (82%) NSCLC and all of the 10 (100%) SCLC cases showed Tc-99m (V) DMSA uptake. Single metastatic lung cancer also accumulated radiotracer. Lung abscess did not show uptake. Lesion/Nonlesion (L/N) ratio of SCLC (1.59±0.32) and NSCLC (1.43±0.19) tumour types did not show statistical difference (p>0.05). Tc-99m (V) DMSA whole body imaging also showed bone metastases. Conclusion: Tc-99m (V) DMSA is a noninvasive and cheap imaging method to detect malignant lung cancers and their bone metastases but, differentiation of SCLC and NSCLC is not possible. (orig.) [de

  20. Preferential elevation of Prx I and Trx expression in lung cancer cells following hypoxia and in human lung cancer tissues.

    Science.gov (United States)

    Kim, H J; Chae, H Z; Kim, Y J; Kim, Y H; Hwangs, T S; Park, E M; Park, Y M

    2003-10-01

    Transient/chronic microenvironmental hypoxia that exists within a majority of solid tumors has been suggested to have a profound influence on tumor growth and therapeutic outcome. Since the functions of novel antioxidant proteins, peroxiredoxin I (Prx I) and II, have been implicated in regulating cell proliferation, differentiation, and apoptosis, it was of our special interest to probe a possible role of Prx I and II in the context of hypoxic tumor microenvironment. Since both Prx I and II use thioredoxin (Trx) as an electron donor and Trx is a substrate for thioredoxin reductase (TrxR), we investigated the regulation of Trx and TrxR as well as Prx expression following hypoxia. Here we show a dynamic change of glutathione homeostasis in lung cancer A549 cells and an up-regulation of Prx I and Trx following hypoxia. Western blot analysis of 10 human lung cancer and paired normal lung tissues also revealed an elevated expression of Prx I and Trx proteins in lung cancer tissues. Immunohistochemical analysis of the lung cancer tissues confirmed an augmented Prx I and Trx expression in cancer cells with respect to the parenchymal cells in adjacent normal lung tissue. Based on these results, we suggest that the redox changes in lung tumor microenvironment could have acted as a trigger for the up-regulation of Prx I and Trx in lung cancer cells. Although the clinical significance of our finding awaits more rigorous future study, preferential augmentation of the Prx I and Trx in lung cancer cells may well represent an attempt of cancer cells to manipulate a dynamic redox change in tumor microenvironment in a manner that is beneficial for their proliferation and malignant progression.

  1. Toona Sinensis Extracts Induced Cell Cycle Arrest and Apoptosis in the Human Lung Large Cell Carcinoma

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    Cheng-Yuan Wang

    2010-02-01

    Full Text Available Toona sinensis extracts have been shown to exhibit anti-cancer effects in human ovarian cancer cell lines, human promyelocytic leukemia cells and human lung adenocarcinoma. Its safety has also been confirmed in animal studies. However, its anti-cancer properties in human lung large cell carcinoma have not been studied. Here, we used a powder obtained by freeze-drying the super-natant of centrifuged crude extract from Toona sinensis leaves (TSL-1 to treat the human lung carcinoma cell line H661. Cell viability was evaluated by the 3-(4-,5-dimethylthiazol-2-yl-2,5-diphenyl tetrazolium bromide assay. Flow cytometry analysis revealed that TSL-1 blocked H661 cell cycle progression. Western blot analysis showed decreased expression of cell cycle proteins that promote cell cycle progression, including cyclin-dependent kinase 4 and cyclin D1, and increased the expression of proteins that inhibit cell cycle progression, including p27. Furthermore, flow cytometry analysis showed that TSL-1 induced H661 cell apoptosis. Western blot analysis showed that TSL-1 reduced the expression of the anti-apoptotic protein B-cell lymphoma 2, and degraded the DNA repair protein, poly(ADP-ribose polymerase. TSL-1 shows potential as a novel therapeutic agent or for use as an adjuvant for treating human lung large cell carcinoma.

  2. Exosomes derived from mesenchymal non-small cell lung cancer cells promote chemoresistance.

    Science.gov (United States)

    Lobb, Richard J; van Amerongen, Rosa; Wiegmans, Adrian; Ham, Sunyoung; Larsen, Jill E; Möller, Andreas

    2017-08-01

    Non-small cell lung cancer (NSCLC) is the most common lung cancer type and the most common cause of mortality in lung cancer patients. NSCLC is often associated with resistance to chemotherapeutics and together with rapid metastatic spread, results in limited treatment options and poor patient survival. NSCLCs are heterogeneous, and consist of epithelial and mesenchymal NSCLC cells. Mesenchymal NSCLC cells are thought to be responsible for the chemoresistance phenotype, but if and how this phenotype can be transferred to other NSCLC cells is currently not known. We hypothesised that small extracellular vesicles, exosomes, secreted by mesenchymal NSCLC cells could potentially transfer the chemoresistance phenotype to surrounding epithelial NSCLC cells. To explore this possibility, we used a unique human bronchial epithelial cell (HBEC) model in which the parental cells were transformed from an epithelial to mesenchymal phenotype by introducing oncogenic alterations common in NSCLC. We found that exosomes derived from the oncogenically transformed, mesenchymal HBECs could transfer chemoresistance to the parental, epithelial HBECs and increase ZEB1 mRNA, a master EMT transcription factor, in the recipient cells. Additionally, we demonstrate that exosomes from mesenchymal, but not epithelial HBECs contain the ZEB1 mRNA, thereby providing a potential mechanism for the induction of a mesenchymal phenotype in recipient cells. Together, this work demonstrates for the first time that exosomes derived from mesenchymal, oncogenically transformed lung cells can transfer chemoresistance and mesenchymal phenotypes to recipient cells, likely via the transfer of ZEB1 mRNA in exosomes. © 2017 UICC.

  3. The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells

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    Roberto Gomez-Casal

    2015-05-01

    Full Text Available The molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibitor, was evaluated in human lung adenocarcinoma (AC cells for its ability to potentiate the effects of IR treatment in both in vitro and in vivo. The cytotoxic effects of ganetespib included; G2/M cell cycle arrest, inhibition of DNA repair, apoptosis induction, and promotion of senescence. All of these antitumor effects were both concentration- and time-dependent. Both pretreatment and post-radiation treatment with ganetespib at low nanomolar concentrations induced radiosensitization in lung AC cells in vitro. Ganetespib may impart radiosensitization through multiple mechanisms: such as down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and promotion of cellular senescence. In vivo, ganetespib reduced growth of T2821 tumor xenografts in mice and sensitized tumors to IR. Tumor irradiation led to dramatic upregulation of β-catenin expression in tumor tissues, an effect that was mitigated in T2821 xenografts when ganetespib was combined with IR treatments. These data highlight the promise of combining ganetespib with IR therapies in the treatment of AC lung tumors.

  4. Definitive Radiotherapy of Non-Small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Lee, Jong Young; Park, Kyung Ran

    1995-01-01

    Purpose : The effect of dose escalation of up to 6500 cGy on local control and survival was investigated in locally advanced non-small cell lung cancer. Materials and Methods : Ninety eight patients with biopsy-proven unresectable non-small cell lung cancer without distant metastases or medically inoperable patients with lower-stage were treated with definitive radiotherapy alone. Group A were treated by thoracic irradiation, 6000 cGy or less in total tumor dose with daily fractions of 180 to 200 cGy: and group B was treated with 6500 cGy of same daily fractions. Results : The actuarial overall survival rate for the entire group was 54% at 1 year, 26.6% at 2 years and 16.4% at 3 years with a median survival time of 13 months. Statistically significant prognostic factors that affect survival rate were stage and N-stage. However, no improvement in local control and survival has been seen with higher dose radiotherapy(group B). Conclusion : Dose escalation of up to 6500 cGy was no effect on local control and survival rate. To increase the survival rate of non-small cell lung cancer hyperfractionated radiotherapy or concurrent chemoradiotherapy should be considered

  5. Lichen Secondary Metabolite, Physciosporin, Inhibits Lung Cancer Cell Motility

    Science.gov (United States)

    Yang, Yi; Park, So-Yeon; Nguyen, Thanh Thi; Yu, Young Hyun; Nguyen, Tru Van; Sun, Eun Gene; Udeni, Jayalal; Jeong, Min-Hye; Pereira, Iris; Moon, Cheol; Ha, Hyung-Ho; Kim, Kyung Keun; Hur, Jae-Seoun; Kim, Hangun

    2015-01-01

    Lichens produce various unique chemicals that can be used for pharmaceutical purposes. To screen for novel lichen secondary metabolites showing inhibitory activity against lung cancer cell motility, we tested acetone extracts of 13 lichen samples collected in Chile. Physciosporin, isolated from Pseudocyphellaria coriacea (Hook f. & Taylor) D.J. Galloway & P. James, was identified as an effective compound and showed significant inhibitory activity in migration and invasion assays against human lung cancer cells. Physciosporin treatment reduced both protein and mRNA levels of N-cadherin with concomitant decreases in the levels of epithelial-mesenchymal transition markers such as snail and twist. Physciosporin also suppressed KITENIN (KAI1 C-terminal interacting tetraspanin)-mediated AP-1 activity in both the absence and presence of epidermal growth factor stimulation. Quantitative real-time PCR analysis showed that the expression of the metastasis suppressor gene, KAI1, was increased while that of the metastasis enhancer gene, KITENIN, was dramatically decreased by physciosporin. Particularly, the activity of 3’-untranslated region of KITENIN was decreased by physciosporin. Moreover, Cdc42 and Rac1 activities were decreased by physciosporin. These results demonstrated that the lichen secondary metabolite, physciosporin, inhibits lung cancer cell motility through novel mechanisms of action. PMID:26371759

  6. Tumor-Induced CD8+ T-Cell Dysfunction in Lung Cancer Patients

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    Heriberto Prado-Garcia

    2012-01-01

    Full Text Available Lung cancer is the leading cause of cancer deaths worldwide and one of the most common types of cancers. The limited success of chemotherapy and radiotherapy regimes have highlighted the need to develop new therapies like antitumor immunotherapy. CD8+ T-cells represent a major arm of the cell-mediated anti-tumor response and a promising target for developing T-cell-based immunotherapies against lung cancer. Lung tumors, however, have been considered to possess poor immunogenicity; even so, lung tumor-specific CD8+ T-cell clones can be established that possess cytotoxicity against autologous tumor cells. This paper will focus on the alterations induced in CD8+ T-cells by lung cancer. Although memory CD8+ T-cells infiltrate lung tumors, in both tumor-infiltrating lymphocytes (TILs and malignant pleural effusions, these cells are dysfunctional and the effector subset is reduced. We propose that chronic presence of lung tumors induces dysfunctions in CD8+ T-cells and sensitizes them to activation-induced cell death, which may be associated with the poor clinical responses observed in immunotherapeutic trials. Getting a deeper knowledge of the evasion mechanisms lung cancer induce in CD8+ T-cells should lead to further understanding of lung cancer biology, overcome tumor evasion mechanisms, and design improved immunotherapeutic treatments for lung cancer.

  7. Cellular Glycolysis and The Differential Survival of Lung Fibroblast and Lung Carcinoma Cell Lines.

    Science.gov (United States)

    Farah, Ibrahim O

    2016-04-01

    Tumor growth and abnormal cell survival were shown to be associated with a number of cellular metabolic abnormalities revealed by impaired oral glucose tolerance, depressed lipoprotein lipase activity leading to hypertriglyceridemia, and changes in amino acid profile as evidenced by increased plasma free tryptophan levels in patients with breast, lung, colon, stomach, and other cancers from various origins. The above findings seem to relate to or indicate a shift to non-oxidative metabolic pathways in cancer. In contrast to normal cells, cancer cells may lose the ability to utilize aerobic respiration due to either defective mitochondria or hypoxia within the tumor microenvironments. Glucose was shown to be the major energy source in cancer cells where it utilizes aerobic /anaerobic glycolysis with the resultant lactic acid formation. The role of energetic modulations and use of glycolytic inhibitors on cancer/normal cell survival is not clearly established in the literature. We hypothesize that natural intermediates of glycolysis and the citric acid cycle will differentially and negatively impact the cancer phenotype in contrast to their no effects on the normal cell phenotype. Therefore, the purpose of this study was to evaluate six potential glycolytic modulators namely, Pyruvic acid, oxalic acid, Zn acetate, sodium citrate, fructose diphosphate (FDP) and sodium bicarbonate at μM concentrations on growing A549 (lung cancer) and MRC-5 (normal; human lung fibroblast) cell lines with the objective of determining their influence on visual impact, cell metabolic activity, cell viability and end-point cell survival. Exposed and non-exposed cells were tested with phase-contrast micro-scanning, survival/death and metabolic activity trends through MTT-assays, as well as death end-point determinations by testing re-growth on complete media and T4 cellometer counts. Results showed that oxalic acid and Zn acetate both influenced the pH of the medium and resulted in

  8. ABCC4 is required for cell proliferation and tumorigenesis in non-small cell lung cancer

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    Zhao X

    2014-02-01

    Full Text Available Xiaoting Zhao, Yinan Guo, Wentao Yue, Lina Zhang, Meng Gu, Yue Wang Department of Cellular and Molecular Biology, Beijing TB and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, People's Republic of China Background: Multidrug resistance protein 4 (MRP4, also known as ATP-cassette binding protein 4 (ABCC4, is a member of the MRP/ABCC subfamily of ATP-binding cassette transporters, which are capable of pumping a wide variety of drugs out of the cell. However, little is known about the function of ABCC4 in the proliferation of lung cancer cells. Methods: ABCC4 mRNA and protein levels in lung cancer cell lines were measured by real-time polymerase chain reaction and Western blot, respectively. A lentivirus-mediated RNA interference technique was used to inhibit ABCC4 mRNA expression in A549 and 801D cells. The function of ABCC4 in cell growth was investigated by MTS and colony formation assays. The role of ABCC4 in cell cycle progression was evaluated by flow cytometry and Western blot analysis. ABCC4 mRNA levels in 30 pairs of tumors and corresponding matched adjacent normal tissues from non-small cell lung cancer patients were detected by real-time polymerase chain reaction. Results: ABCC4 was highly expressed in lung cancer cell lines. ABCC4 expression was markedly downregulated in A549 and 801D cells using the RNA interference technique. Suppression of ABCC4 expression inhibited cell growth. The percentage of cells in G1 phase was increased when ABCC4 expression was suppressed. Phosphorylation of retinoblastoma protein was weakened, originating in the downregulation of ABCC4. ABCC4 mRNA was highly expressed in lung cancer tissue and lung cancer cell lines. Conclusion: ABCC4 may play an important role in the control of A549 and 801D cell growth. ABCC4 is a potential target for lung cancer therapy. Keywords: ABCC4, cell proliferation, lung cancer, cell cycle

  9. Regulated gene expression in cultured type II cells of adult human lung

    OpenAIRE

    Ballard, Philip L.; Lee, Jae W.; Fang, Xiaohui; Chapin, Cheryl; Allen, Lennell; Segal, Mark R.; Fischer, Horst; Illek, Beate; Gonzales, Linda W.; Kolla, Venkatadri; Matthay, Michael A.

    2010-01-01

    Alveolar type II cells have multiple functions, including surfactant production and fluid clearance, which are critical for lung function. Differentiation of type II cells occurs in cultured fetal lung epithelial cells treated with dexamethasone plus cAMP and isobutylmethylxanthine (DCI) and involves increased expression of 388 genes. In this study, type II cells of human adult lung were isolated at ∼95% purity, and gene expression was determined (Affymetrix) before and after culturing 5 days...

  10. Immune checkpoint inhibitors for nonsmall cell lung cancer treatment

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    Yuh-Min Chen

    2017-01-01

    Full Text Available Immune checkpoint inhibition with blocking antibodies that target cytotoxic T-lymphocyte antigen-4 (CTLA-4 and the programmed cell death protein 1 (PD-1 pathway [PD-1/programmed death-ligand 1 (PD-L1] have demonstrated promise in a variety of malignancies. While ipilimumab has been approved as a CTLA-4 blocking antibody by the US Food and Drug Administration for the treatment of advanced melanoma, it is still not approved for lung cancer treatment. In contrast, nivolumab and pembrolizumab, both PD-1 blocking antibodies, have been approved for second-line treatment of nonsmall cell lung cancer in 2015 because of their high potency and long-lasting effects in some patient subgroups. Other PD-1 and PD-L1 monoclonal antibodies are also in active development phase. Treatment with such immune checkpoint inhibitors is associated with a unique pattern of immune-related adverse events or side effects. Combination approaches involving CTLA-4 and PD-1/PD-L1 blockade or checkpoint inhibitors with chemotherapy or radiotherapy are being investigated to determine whether they may enhance the efficacy of treatment. Despite many challenges ahead, immunotherapy with checkpoint inhibitors has already become a new and important treatment modality for lung cancer in the last decade following the discovery of targeted therapy.

  11. Management of non-small cell lung cancer with oligometastasis.

    Science.gov (United States)

    Villaruz, Liza C; Kubicek, Gregory J; Socinski, Mark A

    2012-08-01

    Patients with oligometastatic Non-Small Cell Lung Cancer (NSCLC) present a potential opportunity for curative therapy; however, the challenge remains the definitive treatment of their localized disease and ablation of their limited overt metastatic sites of disease. In selecting patients with oligometastatic NSCLC for definitive therapy, proper staging through radiographic studies, including PET and brain MRI, and the pathologic staging of the mediastinal lymph nodes and potential sites of metastatic disease, are critical. With that in mind, the available literature suggests that in highly selected patients with solitary metastases to the brain, adrenals and other organs, long term survival may be achieved with combined definitive therapy of both the primary lung tumor and the solitary metastatic site.

  12. Pulmonary stromal cells induce the generation of regulatory DC attenuating T-cell-mediated lung inflammation.

    Science.gov (United States)

    Li, Qian; Guo, Zhenhong; Xu, Xiongfei; Xia, Sheng; Cao, Xuetao

    2008-10-01

    The tissue microenvironment may affect the development and function of immune cells such as DC. Whether and how the pulmonary stromal microenvironment can affect the development and function of lung DC need to be investigated. Regulatory DC (DCreg) can regulate T-cell response. We wondered whether such regulatory DC exist in the lung and what is the effect of the pulmonary stromal microenvironment on the generation of DCreg. Here we demonstrate that murine pulmonary stromal cells can drive immature DC, which are regarded as being widely distributed in the lung, to proliferate and differentiate into a distinct subset of DCreg, which express high levels of CD11b but low levels of MHC class II (I-A), CD11c, secrete high amounts of IL-10, NO and prostaglandin E2 (PGE2) and suppress T-cell proliferation. The natural counterpart of DCreg in the lung with similar phenotype and regulatory function has been identified. Pulmonary stroma-derived TGF-beta is responsible for the differentiation of immature DC to DCreg, and DCreg-derived PGE2 contributes to their suppression of T-cell proliferation. Moreover, DCreg can induce the generation of CD4+CD25+Foxp3+ Treg. Importantly, infusion with DCreg attenuates T-cell-mediated eosinophilic airway inflammation in vivo. Therefore, the pulmonary microenvironment may drive the generation of DCreg, thus contributing to the maintenance of immune homoeostasis and the control of inflammation in the lung.

  13. Lung Adenocarcinomas and Lung Cancer Cell Lines Show Association of MMP-1 Expression With STAT3 Activation

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    Alexander Schütz

    2015-04-01

    Full Text Available Signal transducer and activator of transcription 3 (STAT3 is constitutively activated in the majority of lung cancer. This study aims at defining connections between STAT3 function and the malignant properties of non–small cell lung carcinoma (NSCLC cells. To address possible mechanisms by which STAT3 influences invasiveness, the expression of matrix metalloproteinase-1 (MMP-1 was analyzed and correlated with the STAT3 activity status. Studies on both surgical biopsies and on lung cancer cell lines revealed a coincidence of STAT3 activation and strong expression of MMP-1. MMP-1 and tyrosine-phosphorylated activated STAT3 were found co-localized in cancer tissues, most pronounced in tumor fronts, and in particular in adenocarcinomas. STAT3 activity was constitutive, although to different degrees, in the lung cancer cell lines investigated. Three cell lines (BEN, KNS62, and A549 were identified in which STAT3 activitation was inducible by Interleukin-6 (IL-6. In A549 cells, STAT3 activity enhanced the level of MMP-1 mRNA and stimulated transcription from the MMP-1 promoter in IL-6–stimulated A549 cells. STAT3 specificity of this effect was confirmed by STAT3 knockdown through RNA interference. Our results link aberrant activity of STAT3 in lung cancer cells to malignant tumor progression through up-regulation of expression of invasiveness-associated MMPs.

  14. A Novel Natural Product, KL-21, Inhibits Proliferation and Induces Apoptosis in Chronic Lymphocytic Leukemia Cells

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    Aysun Adan Gökbulut

    2015-06-01

    Full Text Available INTRODUCTION: The aims of this study were to examine the cytotoxic and apoptotic effects of KL-21, a novel plant product (produced by Naturin Natural Products, İzmir, Turkey, on 232B4 chronic lymphocytic leukemia (CLL cells and to determine the cytotoxic effects on healthy BEAS-2B human bronchial epithelial cells. METHODS: The cytotoxic effect of KL-21 was determined by MTT cell proliferation assay. Changes in caspase-3 enzyme activity were measured using the caspase-3 colorimetric assay. Changes in mitochondrial membrane potential were determined using the JC-1 dye-based method. Annexin V-FITC/PI double staining was performed to measure the apoptotic cell population. Effects of KL-21 on cell cycle profiles of CLL cells were investigated by flow cytometry. RESULTS: We detected time- and concentration-dependent increases in the cytotoxic effect of KL-21 on 232B4 CLL cells. However, we also showed that, especially at higher concentrations, KL-21 was less cytotoxic towards BEAS-2B healthy cells than towards CLL cells. Annexin-V/PI double staining results showed that the apoptotic cell population increased in 232B4 cells. Increasing concentrations of KL-21 increased caspase-3 enzyme activity and induced loss of mitochondrial membrane potential. KL-21 administration resulted in small increases in the percentage of the cells in the G0/G1 phase while it decreased the S phase cell population up to 1 mg/mL. At the highest concentration, most of the cells accumulated in the G0/G1 phase. DISCUSSION AND CONCLUSION: KL-21 has a growth-inhibitory effect on 232B4 CLL cells. KL-21 causes apoptosis and cell cycle arrest at G0/G1.

  15. Donor lung derived myeloid and plasmacytoid dendritic cells differentially regulate T cell proliferation and cytokine production

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    Benson Heather L

    2012-03-01

    Full Text Available Abstract Background Direct allorecognition, i.e., donor lung-derived dendritic cells (DCs stimulating recipient-derived T lymphocytes, is believed to be the key mechanism of lung allograft rejection. Myeloid (cDCs and plasmacytoid (pDCs are believed to have differential effects on T cell activation. However, the roles of each DC type on T cell activation and rejection pathology post lung transplantation are unknown. Methods Using transgenic mice and antibody depletion techniques, either or both cell types were depleted in lungs of donor BALB/c mice (H-2d prior to transplanting into C57BL/6 mice (H-2b, followed by an assessment of rejection pathology, and pDC or cDC-induced proliferation and cytokine production in C57BL/6-derived mediastinal lymph node T cells (CD3+. Results Depleting either DC type had modest effect on rejection pathology and T cell proliferation. In contrast, T cells from mice that received grafts depleted of both DCs did not proliferate and this was associated with significantly reduced acute rejection scores compared to all other groups. cDCs were potent inducers of IFNγ, whereas both cDCs and pDCs induced IL-10. Both cell types had variable effects on IL-17A production. Conclusion Collectively, the data show that direct allorecognition by donor lung pDCs and cDCs have differential effects on T cell proliferation and cytokine production. Depletion of both donor lung cDC and pDC could prevent the severity of acute rejection episodes.

  16. Metabolic shift in lung alveolar cell mitochondria following acrolein exposure.

    Science.gov (United States)

    Agarwal, Amit R; Yin, Fei; Cadenas, Enrique

    2013-11-15

    Acrolein, an α,β unsaturated electrophile, is an environmental pollutant released in ambient air from diesel exhausts and cooking oils. This study examines the role of acrolein in altering mitochondrial function and metabolism in lung-specific cells. RLE-6TN, H441, and primary alveolar type II (pAT2) cells were exposed to acrolein for 4 h, and its effect on mitochondrial oxygen consumption rates was studied by XF Extracellular Flux analysis. Low-dose acrolein exposure decreased mitochondrial respiration in a dose-dependent manner because of alteration in the metabolism of glucose in all the three cell types. Acrolein inhibited glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity, leading to decreased substrate availability for mitochondrial respiration in RLE-6TN, H441, and pAT2 cells; the reduced GAPDH activity was compensated in pAT2 cells by an increase in the activity of glucose-6-phosphate dehydrogenase, the regulatory control of the pentose phosphate pathway. The decrease in pyruvate from glucose metabolism resulted in utilization of alternative sources to support mitochondrial energy production: palmitate-BSA complex increased mitochondrial respiration in RLE-6TN and pAT2 cells. The presence of palmitate in alveolar cells for surfactant biosynthesis may prove to be the alternative fuel source for mitochondrial respiration. Accordingly, a decrease in phosphatidylcholine levels and an increase in phospholipase A2 activity were found in the alveolar cells after acrolein exposure. These findings have implications for understanding the decrease in surfactant levels frequently observed in pathophysiological situations with altered lung function following exposure to environmental toxicants.

  17. File list: His.Lng.20.AllAg.Lung_adenocarcinoma_cell_lines [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Lng.20.AllAg.Lung_adenocarcinoma_cell_lines hg19 Histone Lung Lung adenocarcino...ma cell lines SRX1143596,SRX1143597,SRX1143598,SRX1143599 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/His.Lng.20.AllAg.Lung_adenocarcinoma_cell_lines.bed ...

  18. Effects of Src on Proliferation and Invasion of Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Rui ZHENG

    2011-04-01

    Full Text Available Background and objective It has been proven that Src played pivotal roles in carcinogenesis, cancer progression and metastasis. The aim of this study is to explore the roles of Src phosphorylation on lung cancer cells. Methods Western blot and immunoprecipitation was used to detect the expression and phosphorylation of Src in lung cancer cells. MTT and Boyden chamber assay was used to examine the effects of inhibition of Src phosphorylation on proliferation and invasion of lung cancer cells in vitro, respectively. Results pp60src was expressed in all lung cancer cell lines in this study. All 5 non-small cell lung cancer (NSCLC cell lines had increased autophosphorylated tyrosine-418, while nearly no phosphorylated Src in small cell lung cancer SBC5 cell line was detected. The effect of inhibition of Src tyrosine kinase on cell proliferation varied among the lung cancer cell lines. Submicromolar Src tyrosine kinase inhibitor (≤1 μM remarkably suppressed the proliferation of PC-9 and A549 cells in a dose dependent manner (P < 0.05, while the same concentration of Src tyrosine kinase inhibitor had no significant effect on proliferation of H226, PC14PE6 and RERFLCOK cells. Invasiveness of lung cancer cells was significantly suppressed by Src tyrosine kinase in a dose-dependent manner (P < 0.05. Conclusion Phosphorylation of Src, but not over-expression, plays a pivotal role in proliferation and invasion of NSCLC cell lines in vitro.

  19. Development of the Fibulin-3 protein therapeutics of non small cell lung cancer stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, In Gyu; Kim, Kugchan; Jung, Il Lae; Kim, Seo Yeon; Choi, Su Im; Lee, Jae Ha

    2013-09-15

    This study focuses on developing an efficient bioprocess for large-scale production of fibulin-3 using Chinese Hamster Ovary cell expression system and evaluating its therapeutic potential for the treatment of cancer. The specific aims are as follows: Isolation and establishment of CSCs using FACS based on cell surface markers and high ALDH1 activity. Identification and characterization of lung cancer stem cells that acquire features of CSC upon exposure to ionizing radiation. Evaluation of the fibulin-3 effects on the stem traits and signaling pathways required for the generation and maintenance of CSCs. In vivo validation of fivulin-3 for tumor prognosis and therapeutic efficacy against lung cancer using animal model.

  20. Role of free radicals in an adriamycin-resistant human small cell lung cancer cell line

    NARCIS (Netherlands)

    Meijer, C.; Mulder, N H; Timmer-Bosscha, H; Zijlstra, J G; de Vries, E G

    1987-01-01

    In two Adriamycin (Adr) resistant sublines (GLC4-Adr1 and GLC4-Adr2) of a human small cell lung carcinoma cell line, GLC4, cross-resistance for radiation was found. GLC4-Adr1 has an acquired Adr resistance factor of 44 after culturing without Adr for 20 days and GLC4-Adr2, the same subline cultured

  1. Bone marrow-derived fibrocytes promote stem cell-like properties of lung cancer cells.

    Science.gov (United States)

    Saijo, Atsuro; Goto, Hisatsugu; Nakano, Mayuri; Mitsuhashi, Atsushi; Aono, Yoshinori; Hanibuchi, Masaki; Ogawa, Hirohisa; Uehara, Hisanori; Kondo, Kazuya; Nishioka, Yasuhiko

    2018-05-01

    Cancer stem cells (CSCs) represent a minor population that have clonal tumor initiation and self-renewal capacity and are responsible for tumor initiation, metastasis, and therapeutic resistance. CSCs reside in niches, which are composed of diverse types of stromal cells and extracellular matrix components. These stromal cells regulate CSC-like properties by providing secreted factors or by physical contact. Fibrocytes are differentiated from bone marrow-derived CD14 + monocytes and have features of both macrophages and fibroblasts. Accumulating evidence has suggested that stromal fibrocytes might promote cancer progression. However, the role of fibrocytes in the CSC niches has not been revealed. We herein report that human fibrocytes enhanced the CSC-like properties of lung cancer cells through secreted factors, including osteopontin, CC-chemokine ligand 18, and plasminogen activator inhibitor-1. The PIK3K/AKT pathway was critical for fibrocytes to mediate the CSC-like functions of lung cancer cells. In human lung cancer specimens, the number of tumor-infiltrated fibrocytes was correlated with high expression of CSC-associated protein in cancer cells. These results suggest that fibrocytes may be a novel cell population that regulates the CSC-like properties of lung cancer cells in the CSC niches. Copyright © 2018. Published by Elsevier B.V.

  2. Cytochrome P450 2A13 enhances the sensitivity of human bronchial epithelial cells to aflatoxin B1-induced DNA damage

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Xuejiao [Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 818 East Tiangyuan Rd., Nanjing 211166 (China); Jiaojiang District Center for Disease Control and Prevention, 518 Jingdong Rd., Taizhou 318000 (China); Zhang, Zhan; Wang, Xichen; Wang, Yun; Zhang, Xiaoming; Lu, Huiyuan [Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 818 East Tiangyuan Rd., Nanjing 211166 (China); Wang, Shou-Lin, E-mail: wangshl@njmu.edu.cn [Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 818 East Tiangyuan Rd., Nanjing 211166 (China)

    2013-07-15

    Cytochrome P450 2A13 (CYP2A13) mainly expresses in human respiratory system and mediates the metabolic activation of aflatoxin B1 (AFB1). Our previous study suggested that CYP2A13 could increase the cytotoxic and apoptotic effects of AFB1 in immortalized human bronchial epithelial cells (BEAS-2B). However, the role of CYP2A13 in AFB1-induced DNA damage is unclear. Using BEAS-2B cells that stably express CYP2A13 (B-2A13), CYP1A2 (B-1A2), and CYP2A6 (B-2A6), we compared their effects in AFB1-induced DNA adducts, DNA damage, and cell cycle changes. BEAS-2B cells that were transfected with vector (B-vector) were used as a control. The results showed that AFB1 (5–80 nM) dose- and time-dependently induced DNA damage in B-2A13 cells. AFB1 at 10 and 80 nM significantly augmented this effect in B-2A13 and B-1A2 cells, respectively. B-2A6 cells showed no obvious DNA damage, similar to B-vector cells and the vehicle control. Similarly, compared with B-vector, B-1A2 or B-2A6 cells, B-2A13 cells showed more sensitivity in AFB1-induced γH2AX expression, DNA adduct 8-hydroxy-deoxyguanosine formation, and S-phase cell-cycle arrest. Furthermore, AFB1 activated the proteins related to DNA damage responses, such as ATM, ATR, Chk2, p53, BRCA1, and H2AX, rather than the proteins related to DNA repair. These effects could be almost completely inhibited by 100 μM nicotine (a substrate of CYP2A13) or 1 μM 8-methoxypsoralen (8-MOP; an inhibitor of CYP enzyme). Collectively, these findings suggest that CYP2A13 plays an important role in low-concentration AFB1-induced DNA damage, possibly linking environmental airborne AFB1 to genetic injury in human respiratory system. - Highlights: • CYP2A13 plays a critical role in low concentration of AFB1-induced DNA damage. • B-2A13 cells were more sensitive to AFB1 than B-1A2 cells and B-2A6 cells. • AFB1 dose- and time-dependently induced DNA damage in B-2A13 cells • AFB1-induced DNA adducts and damage can be inhibited by nicotine and 8

  3. Cytochrome P450 2A13 enhances the sensitivity of human bronchial epithelial cells to aflatoxin B1-induced DNA damage

    International Nuclear Information System (INIS)

    Yang, Xuejiao; Zhang, Zhan; Wang, Xichen; Wang, Yun; Zhang, Xiaoming; Lu, Huiyuan; Wang, Shou-Lin

    2013-01-01

    Cytochrome P450 2A13 (CYP2A13) mainly expresses in human respiratory system and mediates the metabolic activation of aflatoxin B1 (AFB1). Our previous study suggested that CYP2A13 could increase the cytotoxic and apoptotic effects of AFB1 in immortalized human bronchial epithelial cells (BEAS-2B). However, the role of CYP2A13 in AFB1-induced DNA damage is unclear. Using BEAS-2B cells that stably express CYP2A13 (B-2A13), CYP1A2 (B-1A2), and CYP2A6 (B-2A6), we compared their effects in AFB1-induced DNA adducts, DNA damage, and cell cycle changes. BEAS-2B cells that were transfected with vector (B-vector) were used as a control. The results showed that AFB1 (5–80 nM) dose- and time-dependently induced DNA damage in B-2A13 cells. AFB1 at 10 and 80 nM significantly augmented this effect in B-2A13 and B-1A2 cells, respectively. B-2A6 cells showed no obvious DNA damage, similar to B-vector cells and the vehicle control. Similarly, compared with B-vector, B-1A2 or B-2A6 cells, B-2A13 cells showed more sensitivity in AFB1-induced γH2AX expression, DNA adduct 8-hydroxy-deoxyguanosine formation, and S-phase cell-cycle arrest. Furthermore, AFB1 activated the proteins related to DNA damage responses, such as ATM, ATR, Chk2, p53, BRCA1, and H2AX, rather than the proteins related to DNA repair. These effects could be almost completely inhibited by 100 μM nicotine (a substrate of CYP2A13) or 1 μM 8-methoxypsoralen (8-MOP; an inhibitor of CYP enzyme). Collectively, these findings suggest that CYP2A13 plays an important role in low-concentration AFB1-induced DNA damage, possibly linking environmental airborne AFB1 to genetic injury in human respiratory system. - Highlights: • CYP2A13 plays a critical role in low concentration of AFB1-induced DNA damage. • B-2A13 cells were more sensitive to AFB1 than B-1A2 cells and B-2A6 cells. • AFB1 dose- and time-dependently induced DNA damage in B-2A13 cells • AFB1-induced DNA adducts and damage can be inhibited by nicotine and 8

  4. Inhibition of thromboxane synthase induces lung cancer cell death via increasing the nuclear p27

    International Nuclear Information System (INIS)

    Leung, Kin Chung; Hsin, Michael K.Y.; Chan, Joey S.Y.; Yip, Johnson H.Y.; Li, Mingyue; Leung, Billy C.S.; Mok, Tony S.K.; Warner, Timothy D.; Underwood, Malcolm J.; Chen, George G.

    2009-01-01

    The role of thromboxane in lung carcinogenesis is not clearly known, though thromboxane B2 (TXB 2 ) level is increased and antagonists of thromboxane receptors or TXA2 can induce apoptosis of lung cancer cells. p27, an atypical tumor suppressor, is normally sequestered in the nucleus. The increased nuclear p27 may result in apoptosis of tumor cells. We hypothesize that the inhibition of thromboxane synthase (TXS) induces the death of lung cancer cells and that such inhibition is associated with the nuclear p27 level. Our experiment showed that the inhibition of TXS significantly induced the death or apoptosis in lung cancer cells. The activity of TXS was increased in lung cancer. The nuclear p27 was remarkably reduced in lung cancer tissues. The inhibition of TXS caused the cell death and apoptosis of lung cancer cells, likely via the elevation of the nuclear p27 since the TXS inhibition promoted the nuclear p27 level and the inhibition of p27 by its siRNA recovered the cell death induced by TXS inhibition. Collectively, lung cancer cells produce high levels of TXB 2 but their nuclear p27 is markedly reduced. The inhibition of TXS results in the p27-related induction of cell death in lung cancer cells.

  5. Inhibition of thromboxane synthase induces lung cancer cell death via increasing the nuclear p27

    Energy Technology Data Exchange (ETDEWEB)

    Leung, Kin Chung; Hsin, Michael K.Y.; Chan, Joey S.Y.; Yip, Johnson H.Y.; Li, Mingyue; Leung, Billy C.S. [Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories (Hong Kong); Mok, Tony S.K. [Department of Clinical Oncology, The Chinese University of Hong Kong, Shatin, New Territories (Hong Kong); Warner, Timothy D. [The William Harvey Research Institute, Queen Mary University of London, London (United Kingdom); Underwood, Malcolm J. [Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories (Hong Kong); Chen, George G., E-mail: gchen@cuhk.edu.hk [Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories (Hong Kong)

    2009-10-15

    The role of thromboxane in lung carcinogenesis is not clearly known, though thromboxane B2 (TXB{sub 2}) level is increased and antagonists of thromboxane receptors or TXA2 can induce apoptosis of lung cancer cells. p27, an atypical tumor suppressor, is normally sequestered in the nucleus. The increased nuclear p27 may result in apoptosis of tumor cells. We hypothesize that the inhibition of thromboxane synthase (TXS) induces the death of lung cancer cells and that such inhibition is associated with the nuclear p27 level. Our experiment showed that the inhibition of TXS significantly induced the death or apoptosis in lung cancer cells. The activity of TXS was increased in lung cancer. The nuclear p27 was remarkably reduced in lung cancer tissues. The inhibition of TXS caused the cell death and apoptosis of lung cancer cells, likely via the elevation of the nuclear p27 since the TXS inhibition promoted the nuclear p27 level and the inhibition of p27 by its siRNA recovered the cell death induced by TXS inhibition. Collectively, lung cancer cells produce high levels of TXB{sub 2} but their nuclear p27 is markedly reduced. The inhibition of TXS results in the p27-related induction of cell death in lung cancer cells.

  6. Radiation cell survival and growth delay studies in multicellular spheroids of small-cell lung carcinoma

    International Nuclear Information System (INIS)

    Duchesne, G.M.; Peacock, J.H.

    1987-01-01

    The radiation sensitivity of two small-cell lung carcinoma cell lines growing as multicellular spheroids in static culture was determined using clonogenic cell survival and growth delay as endpoints. Growth delay determination suggested that clonogenic cell kill was less than was obtained by direct assay of cell survival. Recovery from potentially lethal damage was assayed in one line (HC12) but was not demonstrable, and clonogenic cell survival decreased with time in treated spheroids with diameters greater than 300 μm which contained a hypoxic cell population. Microscopic examination of the treated spheroids showed the emergence of an abnormal giant-cell population, and the progressive clonogenic cell loss that occurred after treatment was thought to be due to oxygen and nutrient deprivation of the remaining viable cells by this doomed cell population. Correction of the growth delay measurements for changes in cell size and clonogenic cell population allowed correlation of the growth delay and cell survival data. (author)

  7. Low-Dose Radiation Induces Cell Proliferation in Human Embryonic Lung Fibroblasts but not in Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Xinyue Liang

    2016-01-01

    Full Text Available Hormesis and adaptive responses are 2 important biological effects of low-dose ionizing radiation (LDR. In normal tissue, LDR induces hormesis as evinced by increased cell proliferation; however, whether LDR also increases tumor cell proliferation needs to be investigated. In this study, cell proliferation was assayed by total cell numbers and the Cell Counting Kit 8 assay. Mitogen-activated protein kinases (MAPK/extracellular signal-regulated kinase (ERK and phosphatidylinositol 3′ -kinase(PI3K-Akt (PI3K/AKT phosphorylation were determined by Western blot analysis. Human embryonic lung fibroblast 2BS and lung cancer NCI-H446 cell lines were irradiated with LDR at different doses (20-100 mGy. In response to 20 to 75 mGy X-rays, cell proliferation was significantly increased in 2BS but not in NCI-H446 cells. In 2BS cells, LDR at 20 to 75 mGy also stimulated phosphorylation of MAPK/ERK pathway proteins including ERK, MEK, and Raf and of the PI3K/AKT pathway protein AKT. To test whether ERK1/2 and AKT pathway activation was involved in the stimulation of cell proliferation in 2BS cells, the MAPK/ERK and PI3K/AKT pathways were inhibited using their specific inhibitors, U0126 and LY294002. U0126 decreased the phosphorylation of ERK1/2, and LY294002 decreased the phosphorylation of AKT; each could significantly inhibit LDR-induced 2BS cell proliferation. However, LDR did not stimulate these kinases, and kinase inhibitors also did not affect cell proliferation in the NCI-H446 cells. These results suggest that LDR stimulates cell proliferation via the activation of both MAPK/ERK and PI3K/AKT signaling pathways in 2BS but not in NCI-H446 cells. This finding implies the potential for applying LDR to protect normal tissues from radiotherapy without diminishing the efficacy of tumor therapy.

  8. Arsenite promotes centrosome abnormalities under a p53 compromised status induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

    International Nuclear Information System (INIS)

    Liao, W.-T.; Yu, H.-S.; Lin Pinpin; Chang, Louis W.

    2010-01-01

    Epidemiological evidence indicated that residents, especially cigarette smokers, in arseniasis areas had significantly higher lung cancer risk than those living in non-arseniasis areas. Thus an interaction between arsenite and cigarette smoking in lung carcinogenesis was suspected. In the present study, we investigated the interactions of a tobacco-specific carcinogen 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone (nicotine-derived nitrosamine ketone, NNK) and arsenite on lung cell transformation. BEAS-2B, an immortalized human lung epithelial cell line, was selected to test the centrosomal abnormalities and colony formation by NNK and arsenite. We found that NNK, alone, could enhance BEAS-2B cell growth at 1-5 μM. Under NNK exposure, arsenite was able to increase centrosomal abnormality as compared with NNK or arsenite treatment alone. NNK treatment could also reduce arsenite-induced G2/M cell cycle arrest and apoptosis, these cellular effects were found to be correlated with p53 dysfunction. Increased anchorage-independent growth (colony formation) of BEAS-2B cells cotreated with NNK and arsenite was also observed in soft agar. Our present investigation demonstrated that NNK could provide a p53 compromised status. Arsenite would act specifically on this p53 compromised status to induce centrosomal abnormality and colony formation. These findings provided strong evidence on the carcinogenic promotional role of arsenite under tobacco-specific carcinogen co-exposure.

  9. CD24 negative lung cancer cells, possessing partial cancer stem cell properties, cannot be considered as cancer stem cells.

    Science.gov (United States)

    Xu, Haineng; Mu, Jiasheng; Xiao, Jing; Wu, Xiangsong; Li, Maolan; Liu, Tianrun; Liu, Xinyuan

    2016-01-01

    Cancer stem cells (CSCs) play vital role in lung cancer progression, resistance, metastasis and relapse. Identifying lung CSCs makers for lung CSCs targeting researches are critical for lung cancer therapy. In this study, utilizing previous identified lung CSCs as model, we compared the expression of CD24, CD133 and CD44 between CSCs and non-stem cancer cells. Increased ratio of CD24- cells were found in CSCs. CD24- cells were then sorted by flow cytometry and their proliferative ability, chemo-resistance property and in vivo tumor formation abilities were detected. A549 CD24- cells formed smaller colonies, slower proliferated in comparison to A549 CD24+ cells. Besides, A549 CD24- exhibited stronger resistance to chemotherapy drug. However, A549 CD24- didn't exert any stronger tumor formation ability in vivo, which is the gold standard of CSCs. These results showed that CD24- A549 cells showed some properties of CSCs but not actually CSCs. This study provides evidence that CD24 cannot be considered as lung CSCs marker.

  10. The incorporation of SPECT functional lung imaging into inverse radiotherapy planning for non-small cell lung cancer

    International Nuclear Information System (INIS)

    Christian, Judith A.; Partridge, Mike; Nioutsikou, Elena; Cook, Gary; McNair, Helen A.; Cronin, Bernadette; Courbon, Frederic; Bedford, James L.; Brada, Michael

    2005-01-01

    Background and purpose: Patients with non-small cell lung cancer (NSCLC) often have inhomogeneous lung perfusion. Radiotherapy planning computed tomography (CT) scans have been accurately co-registered with lung perfusion single photon emission computed tomography (SPECT) scans to design radiotherapy treatments which limit dose to healthy 'perfused' lung. Patients and methods: Patients with localised NSCLC had CT and SPECT scans accurately co-registered in the planning system. The SPECT images were used to define a volume of perfused 'functioning' lung (FL). Inverse planning software was used to create 3D-conformal plans, the planning objective being either to minimise the dose to whole lungs (WL) or to minimise the dose to FL. Results: Four plans were created for each of six patients. The mean difference in volume between WL and FL was 1011.7 cm 3 (range 596.2-1581.1 cm 3 ). One patient with bilateral upper lobe perfusion deficits had a 16% reduction in FLV 2 (the percentage volume of functioning lung receiving ≥20 Gy). The remaining patients had inhomogeneous perfusion deficits such that inverse planning was not able to sufficiently optimise beam angles to avoid functioning lung. Conclusion: SPECT perfusion images can be accurately co-registered with radiotherapy planning CT scans and may be helpful in creating treatment plans for patients with large perfusion deficits

  11. Validation of an elastic registration technique to estimate anatomical lung modification in Non-Small-Cell Lung Cancer Tomotherapy

    International Nuclear Information System (INIS)

    Faggiano, Elena; Cattaneo, Giovanni M; Ciavarro, Cristina; Dell'Oca, Italo; Persano, Diego; Calandrino, Riccardo; Rizzo, Giovanna

    2011-01-01

    The study of lung parenchyma anatomical modification is useful to estimate dose discrepancies during the radiation treatment of Non-Small-Cell Lung Cancer (NSCLC) patients. We propose and validate a method, based on free-form deformation and mutual information, to elastically register planning kVCT with daily MVCT images, to estimate lung parenchyma modification during Tomotherapy. We analyzed 15 registrations between the planning kVCT and 3 MVCT images for each of the 5 NSCLC patients. Image registration accuracy was evaluated by visual inspection and, quantitatively, by Correlation Coefficients (CC) and Target Registration Errors (TRE). Finally, a lung volume correspondence analysis was performed to specifically evaluate registration accuracy in lungs. Results showed that elastic registration was always satisfactory, both qualitatively and quantitatively: TRE after elastic registration (average value of 3.6 mm) remained comparable and often smaller than voxel resolution. Lung volume variations were well estimated by elastic registration (average volume and centroid errors of 1.78% and 0.87 mm, respectively). Our results demonstrate that this method is able to estimate lung deformations in thorax MVCT, with an accuracy within 3.6 mm comparable or smaller than the voxel dimension of the kVCT and MVCT images. It could be used to estimate lung parenchyma dose variations in thoracic Tomotherapy

  12. Cyclooxygenase-2 Regulates Th17 Cell Differentiation during Allergic Lung Inflammation

    OpenAIRE

    Li, Hong; Bradbury, J. Alyce; Dackor, Ryan T.; Edin, Matthew L.; Graves, Joan P.; DeGraff, Laura M.; Wang, Ping Ming; Bortner, Carl D.; Maruoka, Shuichiro; Lih, Fred B.; Cook, Donald N.; Tomer, Kenneth B.; Jetten, Anton M.; Zeldin, Darryl C.

    2011-01-01

    Rationale: Th17 cells comprise a distinct lineage of proinflammatory T helper cells that are major contributors to allergic responses. It is unknown whether cyclooxygenase (COX)-derived eicosanoids regulate Th17 cells during allergic lung inflammation.

  13. Radiographic findings of oat cell carcinoma of the lung

    International Nuclear Information System (INIS)

    Park, Y. H.; Yoon, Y.; Kim, S. Y.

    1984-01-01

    Growth of oat cell carcinoma tends to be invasive and extends rapidly through the bronchial lymphatics to the hilus and mediastinum, where bulky mass of tumor develop. Authors have analysed roentgenologic manifestations of 22 cases of histologically proven oat cell carcinoma of the lung seen during the period of 3 years from Jan, 1980 to May. 1983. The results 18 males and 4 females. Incidence was the most common in 7th decade as 45%. 2. Chief complaints are cough, sputum and dyspnea. Metastatic symptoms are hoarseness, SVC syndrome and back pain. 3. The radiographic findings of oat cell carcinoma were as follows. 1) hilar and perihilar mass 73% 2) Mediastinal mass 64% 3) Bronchial obstruction sign 55% 4) Peripheral mass 18% 5) Pleural effusion 18%

  14. Advances of Immunotherapy in Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Jingjing LIU

    2014-06-01

    Full Text Available Small cell lung cancer (SCLC is complex heterogeneous due to unclear biological characteristics in terms of cell origin, pathogenesis and driver genes etc. Diagnosis and treatment of SCLC has been slowly improved and few breakthroughs have been discovered up to now. Therefore new strategies are urgently needed to improve the efficacy of SCLC treatment. Tumor immunotherapy has potential to restore and trigger the immune system to recognize and eliminate tumor cells, notably it has only minimal adverse impact on normal tissue. Cancer vaccine, adoptive immunotherapy, cytokines and checkpoint inhibitors have now been launched for clinical treatment of SCLC. Ipilimumab is the most promising medicine of immunotherapy. Immunotherapy is expected to bring new vision to the treatment of SCLC. And further researches are needed on such problems affecting efficacy of immunotherapy as the heterogeneity of SCLC, the uncertainty of target for immunotherapy, the immune tolerance, etc.

  15. Opioid and nicotine receptors affect growth regulation of human lung cancer cell lines

    International Nuclear Information System (INIS)

    Maneckjee, R.; Minna, J.D.

    1990-01-01

    Using specific radioactively-labeled ligands, the authors find that lung cancer cell lines of diverse histologic types express multiple, high-affinity membrane receptors for μ, δ, and κ opioid agonists and for nicotine and α-bungarotoxin. These receptors are biologically active because cAMP levels decreased in lung cancer cells after opioid and nicotine application. Nicotine at concentrations found in the blood of smokers had no effect on in vitro lung cancer cell growth, whereas μ, δ, and κ opioid agonists at low concentrations inhibited lung cancer growth in vitro. They also found that lung cancer cells expressed various combinations of immunoreactive opioid peptides (β-endorphin, enkephalin, or dynorphin), suggesting the participation of opioids in a negative autocrine loop or tumor-suppressing system. Due to the almost universal exposure of patients with lung cancer to nicotine, they tested whether nicotine affected the response of lung cancer cell growth to opioids and found that nicotine at concentrations of 100-200 nM partially or totally reversed opioid-induced growth inhibition in 9/14 lung cancer cell lines. These in vitro results for lung cancer cells suggest that opioids could function as part of a tumor suppressor system and that nicotine can function to circumvent this system in the pathogenesis of lung cancer

  16. Opioid and nicotine receptors affect growth regulation of human lung cancer cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Maneckjee, R.; Minna, J.D. (National Cancer Institute-Navy Medical Oncology Branch, Bethesda, MD (USA) Uniformed Services Univ. of the Health Sciences, Bethesda, MD (USA))

    1990-05-01

    Using specific radioactively-labeled ligands, the authors find that lung cancer cell lines of diverse histologic types express multiple, high-affinity membrane receptors for {mu}, {delta}, and {kappa} opioid agonists and for nicotine and {alpha}-bungarotoxin. These receptors are biologically active because cAMP levels decreased in lung cancer cells after opioid and nicotine application. Nicotine at concentrations found in the blood of smokers had no effect on in vitro lung cancer cell growth, whereas {mu}, {delta}, and {kappa} opioid agonists at low concentrations inhibited lung cancer growth in vitro. They also found that lung cancer cells expressed various combinations of immunoreactive opioid peptides ({beta}-endorphin, enkephalin, or dynorphin), suggesting the participation of opioids in a negative autocrine loop or tumor-suppressing system. Due to the almost universal exposure of patients with lung cancer to nicotine, they tested whether nicotine affected the response of lung cancer cell growth to opioids and found that nicotine at concentrations of 100-200 nM partially or totally reversed opioid-induced growth inhibition in 9/14 lung cancer cell lines. These in vitro results for lung cancer cells suggest that opioids could function as part of a tumor suppressor system and that nicotine can function to circumvent this system in the pathogenesis of lung cancer.

  17. Early growth of tumour cells in lung tissue

    International Nuclear Information System (INIS)

    Poll, P.H.A.

    1981-01-01

    As the treatment of metastases is a very important problem in human and veterinary medicine (for instance osteosarcoma is notorious for its high deathrate due to this problem), proof was sought for the hypothesis that the doubling time of early metastases is shorter than that of tumor cells of an older age. This is of fundamental importance for the therapeutic problem: is a favourable effect to be expected from a limited dose of radiation on the lungs when metastases are still very small or even invisible. If the hypothesis holds true, it would be justified to treat patients, even though a small group of patients will be treated unnecessarily; clinical experience shows that some patients have not developed metastases without adjuvant treatment. The interest was directed at the very early (1-cell, 2-cell etc.) stages. Obviously these are not detectable in patients and therefore an experimental study with tumourcells in the lungs of mice was devised. The expectation is that the theoretical approach may produce an additional basis for the radiotherapeutic and chemotherapeutic treatment of patients, in whom the tumourload has been diminished by treatment of the primary tumour but where metastases, although frequently not detectable must be expected. (Auth.)

  18. Experimental rat lung tumor model with intrabronchial tumor cell implantation.

    Science.gov (United States)

    Gomes Neto, Antero; Simão, Antônio Felipe Leite; Miranda, Samuel de Paula; Mourão, Lívia Talita Cajaseiras; Bezerra, Nilfácio Prado; Almeida, Paulo Roberto Carvalho de; Ribeiro, Ronaldo de Albuquerque

    2008-01-01

    The objective of this study was to develop a rat lung tumor model for anticancer drug testing. Sixty-two female Wistar rats weighing 208 +/- 20 g were anesthetized intraperitoneally with 2.5% tribromoethanol (1 ml/100 g live weight), tracheotomized and intubated with an ultrafine catheter for inoculation with Walker's tumor cells. In the first step of the experiment, a technique was established for intrabronchial implantation of 10(5) to 5 x 10(5) tumor cells, and the tumor take rate was determined. The second stage consisted of determining tumor volume, correlating findings from high-resolution computed tomography (HRCT) with findings from necropsia and determining time of survival. The tumor take rate was 94.7% for implants with 4 x 10(5) tumor cells, HRCT and necropsia findings matched closely (r=0.953; p<0.0001), the median time of survival was 11 days, and surgical mortality was 4.8%. The present rat lung tumor model was shown to be feasible: the take rate was high, surgical mortality was negligible and the procedure was simple to perform and easily reproduced. HRCT was found to be a highly accurate tool for tumor diagnosis, localization and measurement and may be recommended for monitoring tumor growth in this model.

  19. Cigarette Smoke Decreases the Maturation of Lung Myeloid Dendritic Cells.

    Directory of Open Access Journals (Sweden)

    Elena Arellano-Orden

    Full Text Available Conflicting data exist on the role of pulmonary dendritic cells (DCs and their maturation in patients with chronic obstructive pulmonary disease (COPD. Herein, we investigated whether disease severity and smoking status could affect the distribution and maturation of DCs in lung tissues of patients undergoing elective pneumectomy or lobectomy for suspected primary lung cancer.A total of 75 consecutive patients were included. Spirometry testing was used to identify COPD. Lung parenchyma sections anatomically distant from the primary lesion were examined. We used flow cytometry to identify different DCs subtypes-including BDCA1-positive myeloid DCs (mDCs, BDCA3-positive mDCs, and plasmacytoid DCs (pDCs-and determine their maturation markers (CD40, CD80, CD83, and CD86 in all participants. We also identified follicular DCs (fDCs, Langerhans DCs (LDCs, and pDCs in 42 patients by immunohistochemistry.COPD was diagnosed in 43 patients (16 current smokers and 27 former smokers, whereas the remaining 32 subjects were classified as non-COPD (11 current smokers, 13 former smokers, and 8 never smokers. The number and maturation of DCs did not differ significantly between COPD and non-COPD patients. However, the results of flow cytometry indicated that maturation markers CD40 and CD83 of BDCA1-positive mDCs were significantly decreased in smokers than in non-smokers (P = 0.023 and 0.013, respectively. Immunohistochemistry also revealed a lower number of LDCs in COPD patients than in non-COPD subjects.Cigarette smoke, rather than airflow limitation, is the main determinant of impaired DCs maturation in the lung.

  20. Radio(chemotherapy in locally advanced nonsmall cell lung cancer

    Directory of Open Access Journals (Sweden)

    Markus Glatzer

    2016-03-01

    Full Text Available Definitive radiochemotherapy is the standard treatment for many patients with locally advanced nonsmall cell lung cancer (NSCLC. Treatment outcomes have improved over the last decades. Several treatment regimens have been shown effective and safe. This review summarises the results of significant studies between 1996 and 2015 on concomitant and sequential radiochemotherapy regimens and radiation dose per fraction. Beside therapy regimens, optimised radiotherapy planning is indispensable to improve outcome and minimise radiation-induced toxicity. An insight into the rationale of radiotherapy planning for stage III NSCLC is also provided.

  1. A Novel Model for Squamous Cell Carcinoma of the Lung | Center for Cancer Research

    Science.gov (United States)

    In the U.S. lung cancer remains the most deadly cancer type with less than one in five patients alive five years after diagnosis. The majority of lung cancer deaths are due to tobacco smoke, and the squamous cell carcinoma (SCC) subtype of lung cancer is strongly associated with smoking. Researchers have identified a number of mutations in lung SCC tumors but have failed to

  2. Systemic Chemotherapy for Progression of Brain Metastases in Extensive-Stage Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Nagla Abdel Karim

    2015-01-01

    Full Text Available Lung cancer is the most common cause of cancer related mortality in men and women. Approximately 15% of lung cancers are small cell type. Chemotherapy and radiation are the mainstay treatments. Currently, the standard chemotherapy regimen includes platinum/etoposide. For extensive small cell lung cancer, irinotecan and cisplatin have also been used. Patients with relapsed small cell lung cancer have a very poor prognosis, and the morbidity increases with brain metastases. Approximately 10%–14% of small cell lung cancer patients exhibit brain metastases at the time of diagnosis, which increases to 50%–80% as the disease progresses. Mean survival with brain metastases is reported to be less than six months, thus calling for improved regimens. Here we present a case series of patients treated with irinotecan for progressive brain metastases in small cell lung cancer, which serves as a reminder of the role of systemic chemotherapy in this setting.

  3. Concise review: current status of stem cells and regenerative medicine in lung biology and diseases.

    Science.gov (United States)

    Weiss, Daniel J

    2014-01-01

    Lung diseases remain a significant and devastating cause of morbidity and mortality worldwide. In contrast to many other major diseases, lung diseases notably chronic obstructive pulmonary diseases (COPDs), including both asthma and emphysema, are increasing in prevalence and COPD is expected to become the third leading cause of disease mortality worldwide by 2020. New therapeutic options are desperately needed. A rapidly growing number of investigations of stem cells and cell therapies in lung biology and diseases as well as in ex vivo lung bioengineering have offered exciting new avenues for advancing knowledge of lung biology as well as providing novel potential therapeutic approaches for lung diseases. These initial observations have led to a growing exploration of endothelial progenitor cells and mesenchymal stem (stromal) cells in clinical trials of pulmonary hypertension and COPD with other clinical investigations planned. Ex vivo bioengineering of the trachea, larynx, diaphragm, and the lung itself with both biosynthetic constructs as well as decellularized tissues have been used to explore engineering both airway and vascular systems of the lung. Lung is thus a ripe organ for a variety of cell therapy and regenerative medicine approaches. Current state-of-the-art progress for each of the above areas will be presented as will discussion of current considerations for cell therapy-based clinical trials in lung diseases. © AlphaMed Press.

  4. Effects of Monoclonal Antibody Cetuximab on Proliferation of Non-small Cell Lung Cancer Cell lines

    Directory of Open Access Journals (Sweden)

    Zhen CHEN

    2010-08-01

    Full Text Available Background and objective The epidermal growth factor receptor (EGFR monoclonal antibody cetuximab has been used widely in non-small cell lung cancer patients. The aim of this study is to explore the effect of lung cancer cells (A549, H460, H1299, SPC-A-1 which were treated by cetuximab in vitro. Methods We studied the effects of increasing concentrations of cetuximab (1 nmol/L-625 nmol/L in four human lung cancer cell lines (A549, SPC-A-1, H460, H1229. CCK8 measured the inhibition of cell proliferation in each group. A549, SPC-A-1 were marked by PI and the statuses of apoptosis were observed. Western blot were used to detect the proliferation-related signaling protein and apoptosis-related protein in A549. Results The treatment with cetuximab resulted in the effect on cell proliferation and apoptosis in a time- and dosedependent manner. The expression of activated key enzymes (p-AKT, p-EGFR, p-MAPK in EGFR signaling transduction pathway were down-regulated more obviously. Conclusion Cetuximab is an effective targeted drug in the treatment of lung cancer cell lines, tissues, most likely to contribute to the inhibition of key enzymes in EGFR signaling transduction pathway.

  5. Regulation of nonsmall-cell lung cancer stem cell like cells by neurotransmitters and opioid peptides.

    Science.gov (United States)

    Banerjee, Jheelam; Papu John, Arokya M S; Schuller, Hildegard M

    2015-12-15

    Nonsmall-cell lung cancer (NSCLC) is the leading type of lung cancer and has a poor prognosis. We have shown that chronic stress promoted NSCLC xenografts in mice via stress neurotransmitter-activated cAMP signaling downstream of beta-adrenergic receptors and incidental beta-blocker therapy was reported to improve clinical outcomes in NSCLC patients. These findings suggest that psychological stress promotes NSCLC whereas pharmacologically or psychologically induced decreases in cAMP may inhibit NSCLC. Cancer stem cells are thought to drive the development, progression and resistance to therapy of NSCLC. However, their potential regulation by stress neurotransmitters has not been investigated. In the current study, epinephrine increased the number of cancer stem cell like cells (CSCs) from three NSCLC cell lines in spheroid formation assays while enhancing intracellular cAMP and the stem cell markers sonic hedgehog (SHH), aldehyde dehydrogenase-1 (ALDH-1) and Gli1, effects reversed by GABA or dynorphin B via Gαi -mediated inhibition of cAMP formation. The growth of NSCLC xenografts in a mouse model of stress reduction was significantly reduced as compared with mice maintained under standard conditions. Stress reduction reduced serum levels of corticosterone, norepinephrine and epinephrine while the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and opioid peptides increased. Stress reduction significantly reduced cAMP, VEGF, p-ERK, p-AKT, p-CREB, p-SRc, SHH, ALDH-1 and Gli1 in xenograft tissues whereas cleaved caspase-3 and p53 were induced. We conclude that stress neurotransmitters activate CSCs in NSCLC via multiple cAMP-mediated pathways and that pharmacologically or psychologically induced decreases in cAMP signaling may improve clinical outcomes in NSCLC patients. © 2015 UICC.

  6. Treatment of initially metastatic small-cell lung cancer

    International Nuclear Information System (INIS)

    Kohutek, F.; Bystricky, B.; Tamasova, M.

    2013-01-01

    Lung cancer (LC) is the most common cause of death associated with neoplasms. The incidence of LC in 2007 was 71.3/100,000 men and 18.6/100,000 women in Slovakia. Small-cell lung cancer (SCLC) includes 15 - 18% of all cases. The diagnosis of LC is based on patient's history, physical examination, basic laboratory tests, x-ray imaging and computed tomography (CT) imaging and histology. The material required for histology can be obtained by means of endoscopy or surgery. Ultrasonography (USG) and/or CT of abdomen is commonly performed as a part of staging process, along with CT or MRI of brain. Bone scan is performed in case of suspicion of bone involvement. According to TNM classification, seventh edition, the same classification can be used for SCLC and non-small cell lung cancer (NSCLC). Chemotherapy and radiotherapy are available for treatment of initially metastatic SCLC. First-line chemotherapy regimen should be based on combination of cisplatin or carboplatin with etoposide (PE). Alternatively, CAV regimen (cyclophosphamide, doxorubicin, vincristine) can be used. Newer regimens did not provide benefit when compared to standard regimens. If progression occurs later than 3 months after finishing first-line chemotherapy, the same regimen may be used in second-line chemotherapy. If progression occurs earlier than 3 months after finishing first-line chemotherapy, topotecan-based regimen is an option for second-line line chemotherapy. Despite promising outcomes of amrubicin-based second-line chemotherapy in Japan, amrubicin is not available in countries of E U. Standard therapy schedules do not include radiotherapy targeted on primary tumor and affected lymph-nodes. According to American and European guidelines, prophylactic cranial irradiation is recommended for patients with extensive disease-SCLC with good performance status after achieving complete or partial response to first-line chemotherapy. (author)

  7. Role of Immune Checkpoint Inhibitors in Small Cell Lung Cancer.

    Science.gov (United States)

    Cooper, Maryann R; Alrajhi, Abdullah M; Durand, Cheryl R

    Small cell lung cancer (SCLC) accounts for approximately 13% of all lung cancer diagnoses each year. SCLC is characterized by a rapid doubling time, early metastatic spread, and an unfavorable prognosis overall. Most patients with SCLC will respond to initial treatment; however, the majority will experience a disease recurrence and response to second-line therapies is poor. Immune checkpoint inhibitors may be an option given the success in other diseases. A literature search was conducted using Medline (1946-July week 1, 2017) and Embase (1996-2017 week 28) with the search terms small cell lung cancer combined with nivolumab or ipilimumab or pembrolizumab or atezolizumab or tremelimumab or durvalumab. Five clinical trials, including extended follow-up for 2, that evaluated immune checkpoint inhibitors in limited stage or extensive stage SCLC were included. In 2 phase 2 trials, ipilimumab was added to upfront chemotherapy. In both trials, an improvement in progression-free survival was seen. Toxicity, when combined with a platinum and etoposide, was significant. In a confirmatory phase 3 trial, ipilimumab did not prolong overall survival when added to first-line chemotherapy. Overall, response rates were similar between the placebo and ipilimumab groups. A phase 1/2 trial evaluated nivolumab alone or in combination with ipilimumab in recurrent SCLC. Results revealed that nivolumab monotherapy and the combination of nivolumab and ipilimumab were relatively safe and had antitumor activity. Pembrolizumab has been evaluated in a multicohort, phase 1b trial. Preliminary data showed a durable response in the second-line setting. Given the lack of overall survival data and significant toxicity associated with the combination of ipilimumab with first-line chemotherapy, this treatment is not a reasonable option at this time. Nivolumab alone or in combination with ipilimumab is a valid option for recurrent SCLC.

  8. Topotecan in the treatment of relapsed small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Elisabeth Quoix

    2008-12-01

    Full Text Available Elisabeth QuoixService de Pneumologie, Hôpitaux Universitaires, Strasbourg, FranceAbstract: Small cell lung cancer (SCLC represents about 15% to 20% of all lung cancers. Chemotherapy is the cornerstone of the treatment, cisplatin–etoposide combination being the most used combination as first-line therapy. Despite high initial chemosensitivity, most SCLC patients will experience relapse sooner or later. Unfortunately, second-line chemotherapy does not result in a high response rate like first-line therapy, most patients having developed wide chemoresistance. This chemoresistance is far more important in refractory patients, ie, those who never responded to first-line therapy or who relapsed within 3 months after the end of chemotherapy, than in sensitive patients, ie, those who relapse more than 3 months after the end of chemotherapy. Topotecan, a topoisomerase I inhibitor, is the most studied drug in this second-line setting and has proved its efficacy as a single agent and in combination. A phase III trial comparing oral topotecan to best supportive care (BSC in relapsed SCLC demonstrated a significant survival benefit as well as a better quality of life. Although the usual schedule is 1.5 mg/m2, days 1–5 intravenously, it is not convenient for patients with relapsed SCLC, especially those who are refractory because of their short survival expectation. Oral topotecan is of similar efficacy and much more convenient with limited stay in a treatment unit and has a comparable toxicity profile for these patients with short expected survival. Combination of topotecan with platinum salts or taxanes does not seem to improve further the outcome of the patients and thus single-agent therapy with topotecan is the standard treatment for relapsed SCLC.Keywords: topotecan, small cell lung cancer, chemoresistance

  9. Oligometastatic non-small-cell lung cancer: current treatment strategies

    Directory of Open Access Journals (Sweden)

    Richard PJ

    2016-11-01

    Full Text Available Patrick J Richard, Ramesh Rengan Department of Radiation Oncology, University of Washington, Seattle, WA, USA Abstract: The oligometastatic disease theory was initially described in 1995 by Hellman and Weichselbaum. Since then, much work has been performed to investigate its existence in many solid tumors. This has led to subclassifications of stage IV cancer, which could redefine our treatment approaches and the therapeutic outcomes for this historically “incurable” entity. With a high incidence of stage IV disease, non-small-cell lung cancer (NSCLC remains a difficult cancer to treat and cure. Recent work has proven the existence of an oligometastatic state in NSCLC in terms of properly selecting patients who may benefit from aggressive therapy and experience long-term overall survival. This review discusses the current treatment approaches used in oligometastatic NSCLC and provides the evidence and rationale for each approach. The prognostic factors of many trials are discussed, which can be used to properly select patients for aggressive treatment regimens. Future advances in both molecular profiling of NSCLC to find targetable mutations and investigating patient selection may increase the number of patients diagnosed with oligometastatic NSCLC. As this disease entity increases, it is of utmost importance for oncologists treating NSCLC to be aware of the current treatment strategies that exist and the potential advantages/disadvantages of each. Keywords: oligometastatic, non-small-cell lung cancer, oligoprogressive, treatment

  10. Selectins mediate small cell lung cancer systemic metastasis.

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    Franziska Heidemann

    Full Text Available Metastasis formation is the major reason for the extremely poor prognosis in small cell lung cancer (SCLC patients. The molecular interaction partners regulating metastasis formation in SCLC are largely unidentified, however, from other tumor entities it is known that tumor cells use the adhesion molecules of the leukocyte adhesion cascade to attach to the endothelium at the site of the future metastasis. Using the human OH-1 SCLC line as a model, we found that these cells expressed E- and P-selectin binding sites, which could be in part attributed to the selectin binding carbohydrate motif sialyl Lewis A. In addition, protein backbones known to carry these glycotopes in other cell lines including PSGL-1, CD44 and CEA could be detected in in vitro and in vivo grown OH1 SCLC cells. By intravital microscopy of murine mesenterial vasculature we could capture SCLC cells while rolling along vessel walls demonstrating that SCLC cells mimic leukocyte rolling behavior in terms of selectin and selectin ligand interaction in vivo indicating that this mechanism might indeed be important for SCLC cells to seed distant metastases. Accordingly, formation of spontaneous distant metastases was reduced by 50% when OH-1 cells were xenografted into E-/P-selectin-deficient mice compared with wild type mice (p = 0.0181. However, as metastasis formation was not completely abrogated in selectin deficient mice, we concluded that this adhesion cascade is redundant and that other molecules of this cascade mediate metastasis formation as well. Using several of these adhesion molecules as interaction partners presumably make SCLC cells so highly metastatic.

  11. Discrepancy of biologic behavior influenced by bone marrow derived cells in lung cancer.

    Science.gov (United States)

    Zhang, Jie; Niu, Xiao-Min; Liao, Mei-Lin; Liu, Yun; Sha, Hui-Fang; Zhao, Yi; Yu, Yong-Feng; Tan, Qiang; Xiang, Jia-Qing; Fang, Jing; Lv, Dan-Dan; Li, Xue-Bing; Lu, Shun; Chen, Hai-Quan

    2010-11-01

    Disseminated cancer cells may initially require local nutrients and growth factors to thrive and survive in bone marrow. However, data on the influence of bone marrow derived cells (BMDC, also called bone stromal cells in some publications) on lung cancer cells is largely unexplored. This study explored the mechanism of how bone stromal factors contribute to the bone tropism in lung cancer. The difference among lung cancer cell lines in their abilities to metastasize to bone was found using the SCID animal model. Supernatant of bone marrow aspiration (BM) and condition medium from human bone stromal cells (BSC) were used to study the activity of bone stromal factors. We found bone stromal factors significantly increased the proliferation, invasion, adhesion and expression of angiogenosis-related factors, and inhibited the apoptosis for high bone metastasis H460 lung cancer cells. These biologic effects were not seen in SPC-A1 or A549 cells, which are low bone metastasis lung cancer cells. Adhesion of H460 cells to surface coated with bone stromal cells can activate some signal transduction pathways, and alter the expression of adhesion associated factors, including integrin β 3 and ADAMTS-1, two potential targets related with bone metastasis. We concluded that bone marrow derived cells had a profound effect on biological behavior of lung cancers, therefore favoring the growth of lung cancer cells in bone.

  12. Initial observations of cell-mediated drug delivery to the deep lung.

    Science.gov (United States)

    Kumar, Arun; Glaum, Mark; El-Badri, Nagwa; Mohapatra, Shyam; Haller, Edward; Park, Seungjoo; Patrick, Leslie; Nattkemper, Leigh; Vo, Dawn; Cameron, Don F

    2011-01-01

    Using current methodologies, drug delivery to small airways, terminal bronchioles, and alveoli (deep lung) is inefficient, especially to the lower lungs. Urgent lung pathologies such as acute respiratory distress syndrome (ARDS) and post-lung transplantation complications are difficult to treat, in part due to the methodological limitations in targeting the deep lung with high efficiency drug distribution to the site of pathology. To overcome drug delivery limitations inhibiting the optimization of deep lung therapy, isolated rat Sertoli cells preloaded with chitosan nanoparticles were use to obtain a high-density distribution and concentration (92%) of the nanoparticles in the lungs of mice by way of the peripheral venous vasculature rather than the more commonly used pulmonary route. Additionally, Sertoli cells were preloaded with chitosan nanoparticles coupled with the anti-inflammatory compound curcumin and then injected intravenously into control or experimental mice with deep lung inflammation. By 24 h postinjection, most of the curcumin load (∼90%) delivered in the injected Sertoli cells was present and distributed throughout the lungs, including the perialveloar sac area in the lower lungs. This was based on the high-density, positive quantification of both nanoparticles and curcumin in the lungs. There was a marked positive therapeutic effect achieved 24 h following curcumin treatment delivered by this Sertoli cell nanoparticle protocol (SNAP). Results identify a novel and efficient protocol for targeted delivery of drugs to the deep lung mediated by extratesticular Sertoli cells. Utilization of SNAP delivery may optimize drug therapy for conditions such as ARDS, status asthmaticus, pulmonary hypertension, lung cancer, and complications following lung transplantation where the use of high concentrations of anti-inflammatory drugs is desirable, but often limited by risks of systemic drug toxicity.

  13. Endothelial cell chimerism associated with graft rejection after human lung transplantation.

    OpenAIRE

    Ratajczak , Philippe; Murata , Hideyuki; Meignin , Véronique; Groussard , Odile; Fournier , Michel; Socié , Gérard; Mal , Hervé; Janin , Anne

    2008-01-01

    International audience; Endotheliitis is a major sign of graft rejection. Recipient-derived endothelial cells found in two series of liver and kidney transplants were related to graft rejection. Here, we assessed the presence and the number of chimeric endothelial cells in lung transplants, and their relation with graft rejection. In six males grafted with female lungs out of 193 lung transplantations, endothelial chimerism was studied by combined XY-fluorescent in situ hybridization with CD3...

  14. PKC 412 sensitizes U1810 non-small cell lung cancer cells to DNA damage

    International Nuclear Information System (INIS)

    Hemstroem, Therese H.; Joseph, Bertrand; Schulte, Gunnar; Lewensohn, Rolf; Zhivotovsky, Boris

    2005-01-01

    Non-small cell lung carcinoma (NSCLC) is characterized by resistance to drug-induced apoptosis, which might explain the survival of lung cancer cells following treatment. Recently we have shown that the broad-range kinase inhibitor staurosporine (STS) reactivates the apoptotic machinery in U1810 NSCLC cells [Joseph et al., Oncogene 21 (2002) 65]. Lately, several STS analogs that are more specific in kinase inhibition have been suggested for tumor treatment. In this study the apoptosis-inducing ability of the STS analogs PKC 412 and Ro 31-8220 used alone or in combination with DNA-damaging agents in U1810 cells was investigated. In these cells Ro 31-8220 neither induced apoptosis when used alone, nor sensitized cells to etoposide treatment. PKC 412 as a single agent induced death of a small number of U1810 cells, whereas it efficiently triggered a dose- and time-dependent apoptosis in U1285 small cell lung carcinoma cells. In both cell types PKC 412 triggered release of mitochondrial proteins followed by caspase activation. However, concomitant activation of a caspase-independent pathway was essential to kill NSCLC cells. Importantly, PKC 412 was able to sensitize etoposide- and radiation-induced death of U1810 cells. The best sensitization was achieved when PKC 412 was administered 24 h after treatments. In U1810 cells, Ro 31-8220 decreased PMA-induced ERK phosphorylation as efficiently as PKC 412, indicating that the failure of Ro 31-8220 to induce apoptosis was not due to weaker inhibition of conventional and novel PKC isoforms. However, Ro 31-8220 increased the basal level of ERK and Akt phosphorylation in both cell lines, whereas Akt phosphorylation was suppressed in the U1810 cells, which might influence apoptosis. These results suggest that PKC 412 could be a useful tool in increasing the efficiency of therapy of NSCLC

  15. Identification of Novel Targets for Lung Cancer Therapy Using an Induced Pluripotent Stem Cell Model.

    Science.gov (United States)

    Shukla, Vivek; Rao, Mahadev; Zhang, Hongen; Beers, Jeanette; Wangsa, Darawalee; Wangsa, Danny; Buishand, Floryne O; Wang, Yonghong; Yu, Zhiya; Stevenson, Holly; Reardon, Emily; McLoughlin, Kaitlin C; Kaufman, Andrew; Payabyab, Eden; Hong, Julie A; Zhang, Mary; Davis, Sean R; Edelman, Daniel C; Chen, Guokai; Miettinen, Markku; Restifo, Nicholas; Ried, Thomas; Meltzer, Paul S; Schrump, David S

    2018-04-01

    Despite extensive studies, the genetic and epigenetic mechanisms that mediate initiation and progression of lung cancers have not been fully elucidated. Previously, we have demonstrated that via complementary mechanisms, including DNA methylation, polycomb repressive complexes, and noncoding RNAs, cigarette smoke induces stem-like phenotypes that coincide with progression to malignancy in normal respiratory epithelia as well as enhanced growth and metastatic potential of lung cancer cells. To further investigate epigenetic mechanisms contributing to stemness/pluripotency in lung cancers and potentially identify novel therapeutic targets in these malignancies, induced pluripotent stem cells were generated from normal human small airway epithelial cells. Lung induced pluripotent stem cells were generated by lentiviral transduction of small airway epithelial cells of OSKM (Yamanaka) factors (octamer-binding transcription factor 4 [Oct4], sex-determining region Y box 2 [SOX2], Kruppel-like factor 4 [KLF4], and MYC proto-oncogene, bHLH transcription factor [MYC]). Western blot, real-time polymerase chain reaction, and chromatin immunoprecipitation sequencing analysis were performed. The lung induced pluripotent stem cells exhibited hallmarks of pluripotency, including morphology, surface antigen and stem cell gene expression, in vitro proliferation, and teratoma formation. In addition, lung induced pluripotent stem cells exhibited no chromosomal aberrations, complete silencing of reprogramming transgenes, genomic hypermethylation, upregulation of genes encoding components of polycomb repressive complex 2, hypermethylation of stem cell polycomb targets, and modulation of more than 15,000 other genes relative to parental small airway epithelial cells. Additional sex combs like-3 (ASXL3), encoding a polycomb repressive complex 2-associated protein not previously described in reprogrammed cells, was markedly upregulated in lung induced pluripotent stem cell as well as human

  16. Cigarette Smoke Exposure during Pregnancy Alters Fetomaternal Cell Trafficking Leading to Retention of Microchimeric Cells in the Maternal Lung

    Science.gov (United States)

    Vogelgesang, Anja; Scapin, Cristina; Barone, Caroline; Tam, Elaine

    2014-01-01

    Cigarette smoke exposure causes chronic oxidative lung damage. During pregnancy, fetal microchimeric cells traffic to the mother. Their numbers are increased at the site of acute injury. We hypothesized that milder chronic diffuse smoke injury would attract fetal cells to maternal lungs. We used a green-fluorescent-protein (GFP) mouse model to study the effects of cigarette smoke exposure on fetomaternal cell trafficking. Wild-type female mice were exposed to cigarette smoke for about 4 weeks and bred with homozygote GFP males. Cigarette smoke exposure continued until lungs were harvested and analyzed. Exposure to cigarette smoke led to macrophage accumulation in the maternal lung and significantly lower fetal weights. Cigarette smoke exposure influenced fetomaternal cell trafficking. It was associated with retention of GFP-positive fetal cells in the maternal lung and a significant reduction of fetal cells in maternal livers at gestational day 18, when fetomaternal cell trafficking peaks in the mouse model. Cells quickly clear postpartum, leaving only a few, difficult to detect, persisting microchimeric cells behind. In our study, we confirmed the postpartum clearance of cells in the maternal lungs, with no significant difference in both groups. We conclude that in the mouse model, cigarette smoke exposure during pregnancy leads to a retention of fetal microchimeric cells in the maternal lung, the site of injury. Further studies will be needed to elucidate the effect of cigarette smoke exposure on the phenotypic characteristics and function of these fetal microchimeric cells, and confirm its course in cigarette smoke exposure in humans. PMID:24832066

  17. Xylitol induces cell death in lung cancer A549 cells by autophagy.

    Science.gov (United States)

    Park, Eunjoo; Park, Mi Hee; Na, Hee Sam; Chung, Jin

    2015-05-01

    Xylitol is a widely used anti-caries agent that has anti-inflammatory effects. We have evaluated the potential of xylitol in cancer treatment. It's effects on cell proliferation and cytotoxicity were measured by MTT assay and LDH assay. Cell morphology and autophagy were examined by immunostaining and immunoblotting. Xylitol inhibited cell proliferation in a dose-dependent manner in these cancer cells: A549, Caki, NCI-H23, HCT-15, HL-60, K562, and SK MEL-2. The IC50 of xylitol in human gingival fibroblast cells was higher than in cancer cells, indicating that it is more specific for cancer cells. Moreover, xylitol induced autophagy in A549 cells that was inhibited by 3-methyladenine, an autophagy inhibitor. These results indicate that xylitol has potential in therapy against lung cancer by inhibiting cell proliferation and inducing autophagy of A549 cells.

  18. MiR-122 Induces Radiosensitization in Non-Small Cell Lung Cancer Cell Line

    Directory of Open Access Journals (Sweden)

    Debin Ma

    2015-09-01

    Full Text Available MiR-122 is a novel tumor suppresser and its expression induces cell cycle arrest, or apoptosis, and inhibits cell proliferation in multiple cancer cells, including non-small cell lung cancer (NSCLC cells. Radioresistance of cancer cell leads to the major drawback of radiotherapy for NSCLC and the induction of radiosensitization could be a useful strategy to fix this problem. The present work investigates the function of miR-122 in inducing radiosensitization in A549 cell, a type of NSCLC cells. MiR-122 induces the radiosensitization of A549 cells. MiR-122 also boosts the inhibitory activity of ionizing radiation (IR on cancer cell anchor-independent growth and invasion. Moreover, miR-122 reduced the expression of its targeted genes related to tumor-survival or cellular stress response. These results indicate that miR-122 would be a novel strategy for NSCLC radiation-therapy.

  19. Decreased CXCL12 is associated with impaired alveolar epithelial cell migration and poor lung healing after lung resection.

    Science.gov (United States)

    Kanter, Jacob A; Sun, Haiying; Chiu, Stephen; DeCamp, Malcolm M; Sporn, Peter H S; Sznajder, Jacob I; Bharat, Ankit

    2015-10-01

    Prolonged air leak (PAL) is an important cause of morbidity and mortality after lung resection, but its pathogenesis has not been elucidated. Migration of alveolar type II epithelial cells is essential for lung wound repair. Here we determined the role of C-X-C motif chemokine 12 (CXCL12) on alveolar epithelial cell migration and lung wound healing. CXCL12 in the pleural fluid of patients was analyzed using enzyme-linked immunosorbent assay. Human A549 and murine MLE12 alveolar epithelial cell lines were used for wound closure, cell migration, and proliferation assays. Western blot was used to analyze Rac1 and cofilin. Pleural CXCL12 was decreased in patients with PAL (1,389 ± 192 vs 3,270 ± 247 pg/mL; P alveolar epithelial cell migration by binding to its receptor CXCR4 and may have a role in lung healing. CXCL12-mediated alveolar epithelial cell migration is associated with Rac1 and cofilin activation. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Lung-MAP: Talazoparib in Treating Patients With HRRD Positive Recurrent Stage IV Squamous Cell Lung Cancer

    Science.gov (United States)

    2018-05-31

    ATM Gene Mutation; ATR Gene Mutation; BARD1 Gene Mutation; BRCA1 Gene Mutation; BRCA2 Gene Mutation; BRIP1 Gene Mutation; CHEK1 Gene Mutation; CHEK2 Gene Mutation; FANCA Gene Mutation; FANCC Gene Mutation; FANCD2 Gene Mutation; FANCF Gene Mutation; FANCM Gene Mutation; NBN Gene Mutation; PALB2 Gene Mutation; RAD51 Gene Mutation; RAD51B Gene Mutation; RAD54L Gene Mutation; Recurrent Squamous Cell Lung Carcinoma; RPA1 Gene Mutation; Stage IV Squamous Cell Lung Carcinoma AJCC v7

  1. On the problem of roentgenological semiotics of small cell lung cancer

    International Nuclear Information System (INIS)

    Makarycheva, R.I.; Shchukina, O.P.; Gertner, K.; Vetrova, N.A.

    1985-01-01

    The study was concerned with description of roentgenologic semiotics of central and peripheral small cell lung cancer in 141 patients receiving chemoradiation therapy. The frequency of carcinoma metastatic spreading into intrathoracic lymph nodes was high. Small cell lung cancer showed a good response to conservative treatment, which, in particular, manifested itself in regression of metastases into intrathoracic lymph nodes

  2. The effect of adenovirus-mediated gene expression of FHIT in small cell lung cancer cells

    DEFF Research Database (Denmark)

    Zandi, Roza; Xu, Kai; Poulsen, Hans S

    2011-01-01

    The candidate tumor suppressor fragile histidine traid (FHIT) is frequently inactivated in small cell lung cancer (SCLC). Mutations in the p53 gene also occur in the majority of SCLC leading to the accumulation of the mutant protein. Here we evaluated the effect of FHIT gene therapy alone...

  3. Preliminary study of steep pulse irreversible electroporation technology in human large cell lung cancer cell lines L9981

    Directory of Open Access Journals (Sweden)

    Song Zuoqing

    2013-01-01

    Full Text Available Our aim was to validate the effectiveness of steep pulse irreversible electroporation technology in human large cell lung cancer cells and to screen the optimal treatment of parameters for human large cell lung cancer cells. Three different sets of steep pulse therapy parameters were applied on the lung cancer cell line L9981. The cell line L9981 inhibition rate and proliferation capacity were detected by Vi-Cell vitality analysis and MTT. Steep pulsed irreversible electroporation technology for large cell lung cancer L9981 presents killing effects with various therapy parameters. The optimal treatment parameters are at a voltage amplitude of 2000V/cm, pulse width of 100μs, pulse frequency of 1 Hz, pulse number 10. With this group of parameters, steep pulse could have the best tumor cell-killing effects.

  4. Mammalian mediator 19 mediates H1299 lung adenocarcinoma cell clone conformation, growth, and metastasis.

    Science.gov (United States)

    Xu, Lu-Lu; Guo, Shu-Liang; Ma, Su-Ren; Luo, Yong-Ai

    2012-01-01

    Mammalian mediator (MED) is a multi-protein coactivator that has been identified by several research groups. The involvement of the MED complex subunit 19 (MED 19) in the metastasis of lung adenocarcinoma cell line (H1299), which expresses the MED 19 subunit, was here investigated. When MED 19 expression was decreased by RNA interference H1299 cells demonstrated reduced clone formation, arrest in the S phase of the cell cycle, and lowered metastatic capacity. Thus, MED 19 appears to play important roles in the biological behavior of non-small cell lung carcinoma cells. These findings may be important for the development of novel lung carcinoma treatments.

  5. Identification and characterization of cells with cancer stem cell properties in human primary lung cancer cell lines.

    Directory of Open Access Journals (Sweden)

    Ping Wang

    Full Text Available Lung cancer (LC with its different subtypes is generally known as a therapy resistant cancer with the highest morbidity rate worldwide. Therapy resistance of a tumor is thought to be related to cancer stem cells (CSCs within the tumors. There have been indications that the lung cancer is propagated and maintained by a small population of CSCs. To study this question we established a panel of 15 primary lung cancer cell lines (PLCCLs from 20 fresh primary tumors using a robust serum-free culture system. We subsequently focused on identification of lung CSCs by studying these cell lines derived from 4 representative lung cancer subtypes such as small cell lung cancer (SCLC, large cell carcinoma (LCC, squamous cell carcinoma (SCC and adenocarcinoma (AC. We identified a small population of cells strongly positive for CD44 (CD44(high and a main population which was either weakly positive or negative for CD44 (CD44(low/-. Co-expression of CD90 further narrowed down the putative stem cell population in PLCCLs from SCLC and LCC as spheroid-forming cells were mainly found within the CD44(highCD90(+ sub-population. Moreover, these CD44(highCD90(+ cells revealed mesenchymal morphology, increased expression of mesenchymal markers N-Cadherin and Vimentin, increased mRNA levels of the embryonic stem cell related genes Nanog and Oct4 and increased resistance to irradiation compared to other sub-populations studied, suggesting the CD44(highCD90(+ population a good candidate for the lung CSCs. Both CD44(highCD90(+ and CD44(highCD90(- cells in the PLCCL derived from SCC formed spheroids, whereas the CD44(low/- cells were lacking this potential. These results indicate that CD44(highCD90(+ sub-population may represent CSCs in SCLC and LCC, whereas in SCC lung cancer subtype, CSC potentials were found within the CD44(high sub-population.

  6. Identification and Characterization of Cells with Cancer Stem Cell Properties in Human Primary Lung Cancer Cell Lines

    Science.gov (United States)

    Suo, Zhenhe; Munthe, Else; Solberg, Steinar; Ma, Liwei; Wang, Mengyu; Westerdaal, Nomdo Anton Christiaan; Kvalheim, Gunnar; Gaudernack, Gustav

    2013-01-01

    Lung cancer (LC) with its different subtypes is generally known as a therapy resistant cancer with the highest morbidity rate worldwide. Therapy resistance of a tumor is thought to be related to cancer stem cells (CSCs) within the tumors. There have been indications that the lung cancer is propagated and maintained by a small population of CSCs. To study this question we established a panel of 15 primary lung cancer cell lines (PLCCLs) from 20 fresh primary tumors using a robust serum-free culture system. We subsequently focused on identification of lung CSCs by studying these cell lines derived from 4 representative lung cancer subtypes such as small cell lung cancer (SCLC), large cell carcinoma (LCC), squamous cell carcinoma (SCC) and adenocarcinoma (AC). We identified a small population of cells strongly positive for CD44 (CD44high) and a main population which was either weakly positive or negative for CD44 (CD44low/−). Co-expression of CD90 further narrowed down the putative stem cell population in PLCCLs from SCLC and LCC as spheroid-forming cells were mainly found within the CD44highCD90+ sub-population. Moreover, these CD44highCD90+ cells revealed mesenchymal morphology, increased expression of mesenchymal markers N-Cadherin and Vimentin, increased mRNA levels of the embryonic stem cell related genes Nanog and Oct4 and increased resistance to irradiation compared to other sub-populations studied, suggesting the CD44highCD90+ population a good candidate for the lung CSCs. Both CD44highCD90+ and CD44highCD90− cells in the PLCCL derived from SCC formed spheroids, whereas the CD44low/− cells were lacking this potential. These results indicate that CD44highCD90+ sub-population may represent CSCs in SCLC and LCC, whereas in SCC lung cancer subtype, CSC potentials were found within the CD44high sub-population. PMID:23469181

  7. Calcification in large cell neuroendocrine carcinoma of the lung

    International Nuclear Information System (INIS)

    Takamochi, Kazuya; Yokose, Tomoyuki; Ochiai, Atsushi; Yoshida, Junji; Nishimura, Mitsuyo; Ohmatsu, Hironobu; Nagai, Kanji; Nishiwaki, Yutaka

    2003-01-01

    The aim was to investigate the prevalence of intratumoral calcification in large cell neuroendocrine carcinoma (LCNEC) and to review computed tomography (CT) and histological findings. From August 1992 through March 2000, 35 out of 1183 surgically resected lung cancer patients were histologically diagnosed as having LCNEC at our institute. We reviewed the pain radiographs and CT scans of these 35 LCNEC patients. In LCNEC cases with intratumoral calcification, we examined the size, number, distribution and pattern of intratumoral calcifications visible on the CT scans and the histological features. Three cases (9%) exhibited calcification. The calcifications were recognized by CT scans alone. The CT scans showed punctate or eccentric intratumoral calcifications, which are considered to be a malignant feature, in all three cases. In two cases, the calcifications were histologically confirmed to be located within the necrotic areas of a tumor nest. We found three LCNEC cases with intratumoral calcification. The prevalence of LCNEC calcification was similar to that in previous reports on lung cancer. The mechanism of the intratumoral calcification in our LCNEC cases is speculated to be dystrophic calcification. (author)

  8. Expression of cadherin and NCAM in human small cell lung cancer cell lines and xenografts

    DEFF Research Database (Denmark)

    Rygaard, K; Møller, C; Bock, E

    1992-01-01

    characterised, the cadherin family and the Ig superfamily member, neural cell adhesion molecule (NCAM). We investigated expression of these two adhesion molecule families in small cell lung cancer (SCLC) cell lines and xenografts by immunoblotting. Nineteen tumours established from 15 patients with SCLC were......Tumour cell adhesion, detachment and aggregation seem to play an important part in tumour invasion and metastasis, and numerous cell adhesion molecules are expressed by tumour cells. Several families of cell-cell adhesion molecules have been described, of which two groups are particularly well...... embryonic development, which may play a role in connection with tumour invasion and metastasis, was found in 14/18 NCAM expressing SCLC tumours. Individual tumours grown as cell lines and as nude mouse xenografts showed no qualitative differences in cadherin or NCAM expression....

  9. Kaempferol modulates the metastasis of human non-small cell lung cancer cells by inhibiting epithelial-mesenchymal transition

    Directory of Open Access Journals (Sweden)

    Meng Hang

    2015-06-01

    Full Text Available The present study was done to determine whether kaempferol, a natural polyphenol of the flavonoid family, affects Epithelial-Mesenchymal Transition (EMT in non-small cell lung cancer cells. Kaempferol not only inhibited cancer cell proliferation and migration in a dose-dependent manner but also modulated the expression of EMT-related proteins E-cadherin and vimentin which are indispensible to cellular motility, invasiveness and metastasis. These results indicate that kaempferol suppresses non-small cell lung cancer migration by modulating the expression of EMT proteins. Therefore, kaempferol may be useful as a potential anticancer agent for non-small cell lung cancer.

  10. Tumourigenic non-small-cell lung cancer mesenchymal circulating tumour cells: a clinical case study

    OpenAIRE

    Morrow, C. J.; Trapani, F.; Metcalf, R. L.; Bertolini, G.; Hodgkinson, C. L.; Khandelwal, G.; Kelly, P.; Galvin, M.; Carter, L.; Simpson, K. L.; Williamson, S.; Wirth, C.; Simms, N.; Frankliln, L.; Frese, K. K.

    2016-01-01

    Background Over the past decade, numerous reports describe the generation and increasing utility of non-small-cell lung cancer (NSCLC) patient-derived xenografts (PDX) from tissue biopsies. While PDX have proven useful for genetic profiling and preclinical drug testing, the requirement of a tissue biopsy limits the available patient population, particularly those with advanced oligometastatic disease. Conversely, ?liquid biopsies? such as circulating tumour cells (CTCs) are minimally invasive...

  11. In vitro evaluation of a new nitrosourea, TCNU, against human small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Roed, H; Vindeløv, L L; Spang-Thomsen, M

    1987-01-01

    The cytotoxic activity of a new nitrosourea, TCNU, was compared with that of BCNU in five human small cell lung cancer cell lines in vitro. TCNU was found to be equivalent or inferior to BCNU when compared on a microgram to microgram basis. If the potential of in vitro phase II trials for selection...... of new drugs can be validated, it can be concluded that TCNU is not superior to other nitrosoureas for the treatment of SCCL....

  12. Clarifying CB2 Receptor-Dependent and Independent Effects of THC on Human Lung Epithelial Cells

    OpenAIRE

    Sarafian, Theodore; Montes, Cindy; Harui, Airi; Beedanagari, Sudheer R.; Kiertscher, Sylvia; Stripecke, Renata; Hossepian, Derik; Kitchen, Christina; Kern, Rita; Belperio, John; Roth, Michael D.

    2008-01-01

    Marijuana smoking is associated with a number of abnormal findings in the lungs of habitual smokers. Previous studies revealed that Δ9-tetrahydrocannabinol (THC) caused mitochondrial injury in primary lung epithelial cells and in the cell line, A549 (Sarafian et al., 2003; Sarafian et al., 2005). The role of cannabinoid receptors in this injury was unclear, as was the potential impact on cell function. In order to investigate these questions, A549 cells were engineered to over-express the typ...

  13. Non-Small Cell Lung Cancer Cells Expressing CD44 Are Enriched for Stem Cell-Like Properties

    Science.gov (United States)

    Leung, Elaine Lai-Han; Fiscus, Ronald R.; Tung, James W.; Tin, Vicky Pui-Chi; Cheng, Lik Cheung; Sihoe, Alan Dart-Loon; Fink, Louis M.; Ma, Yupo; Wong, Maria Pik

    2010-01-01

    Background The cancer stem cell theory hypothesizes that cancers are perpetuated by cancer stem cells (CSC) or tumor initiating cells (TIC) possessing self-renewal and other stem cell-like properties while differentiated non-stem/initiating cells have a finite life span. To investigate whether the hypothesis is applicable to lung cancer, identification of lung CSC and demonstration of these capacities is essential. Methodology/Principal Finding The expression profiles of five stem cell markers (CD34, CD44, CD133, BMI1 and OCT4) were screened by flow cytometry in 10 lung cancer cell lines. CD44 was further investigated by testing for in vitro and in vivo tumorigenecity. Formation of spheroid bodies and in vivo tumor initiation ability were demonstrated in CD44+ cells of 4 cell lines. Serial in vivo tumor transplantability in nude mice was demonstrated using H1299 cell line. The primary xenografts initiated from CD44+ cells consisted of mixed CD44+ and CD44− cells in similar ratio as the parental H1299 cell line, supporting in vivo differentiation. Semi-quantitative Real-Time PCR (RT-PCR) showed that both freshly sorted CD44+ and CD44+ cells derived from CD44+-initiated tumors expressed the pluripotency genes OCT4/POU5F1, NANOG, SOX2. These stemness markers were not expressed by CD44− cells. Furthermore, freshly sorted CD44+ cells were more resistant to cisplatin treatment with lower apoptosis levels than CD44− cells. Immunohistochemical analysis of 141 resected non-small cell lung cancers showed tumor cell expression of CD44 in 50.4% of tumors while no CD34, and CD133 expression was observed in tumor cells. CD44 expression was associated with squamous cell carcinoma but unexpectedly, a longer survival was observed in CD44-expressing adenocarcinomas. Conclusion/Significance Overall, our results demonstrated that stem cell-like properties are enriched in CD44-expressing subpopulations of some lung cancer cell lines. Further investigation is required to clarify

  14. CD4 T Cell Epitope Specificity and Cytokine Potential Are Preserved as Cells Transition from the Lung Vasculature to Lung Tissue following Influenza Virus Infection.

    Science.gov (United States)

    DiPiazza, Anthony; Laniewski, Nathan; Rattan, Ajitanuj; Topham, David J; Miller, Jim; Sant, Andrea J

    2018-07-01

    Pulmonary CD4 T cells are critical in respiratory virus control, both by delivering direct effector function and through coordinating responses of other immune cells. Recent studies have shown that following influenza virus infection, virus-specific CD4 T cells are partitioned between pulmonary vasculature and lung tissue. However, very little is known about the peptide specificity or functional differences of CD4 T cells within these two compartments. Using a mouse model of influenza virus infection in conjunction with intravascular labeling in vivo , the cell surface phenotype, epitope specificity, and functional potential of the endogenous polyclonal CD4 T cell response was examined by tracking nine independent CD4 T cell epitope specificities. These studies revealed that tissue-localized CD4 cells were globally distinct from vascular cells in expression of markers associated with transendothelial migration, residency, and micropositioning. Despite these differences, there was little evidence for remodeling of the viral epitope specificity or cytokine potential as cells transition from vasculature to the highly inflamed lung tissue. Our studies also distinguished cells in the pulmonary vasculature from peripheral circulating CD4 T cells, providing support for the concept that the pulmonary vasculature does not simply reflect circulating cells that are trapped within the narrow confines of capillary vessels but rather is enriched in transitional cells primed in the draining lymph node that have specialized potential to enter the lung tissue. IMPORTANCE CD4 T cells convey a multitude of functions in immunity to influenza, including those delivered in the lymph node and others conveyed by CD4 T cells that leave the lymph node, enter the blood, and extravasate into the lung tissue. Here, we show that the transition of recently primed CD4 cells detected in the lung vasculature undergo profound changes in expression of markers associated with tissue localization as

  15. Intercalated radio-chemotherapy in small cell lung cancer

    International Nuclear Information System (INIS)

    Hoskin, P.J.; Parton, D.; Yarnold, J.R.; Cherryman, G.; Smith, I.E.

    1991-01-01

    36 patients with small cell lung cancer have been treated using chemotherapy comprising carboplatin, ifosphamide and etoposide. A total of 6 cycles of chemotherapy was given. In 15 patients with limited disease intercalated radio-chemotherapy was used in which two 5-day courses of hyperfractionated radiotherapy were given to the thorax after the 1st and 2nd cycles of chemotherapy. Each course of thoracic radiotherapy delivered 15 Gy in 15 fractions over 5 days. Oesophagitis occurred in 7 patients (40 percent), in 5 of whom this was severe (WHO grade 3). Radiological pneumonitis developed in 6 patients (40 percent) with subsequent fibrosis in 2 patients. These effects are greater than would be expected with this dose of radiation alone and reflect marked enhancement of normal tissue toxicity. (author). 11 refs.; 1 fig.; 1 tab

  16. Radiosensitization of C225 on human non-small cell lung cancer cell line H-520

    International Nuclear Information System (INIS)

    Zhang Yingdong; Wang Junjie; Liu Feng; Zhao Yong

    2008-01-01

    Objective: To investigate the efficacy of C225 (cetuximab), a chimeric human-mouse anti-epithelial growth factor receptor monoclonal antibody, combined with 60 Co gamma irradiation against human non-small cell lung cancer cell line H-520. Methods: H-520 cells were treated either with different dose of 60 Co irradiation (1,2,4,6,8 and 10 Gy)alone or together with C225 (100 nmol/L). Colony forming capacity was determined to create the survival curve 10 days after the treatment. Cells in different groups were harvested 72 hours after irradiation for apoptosis analysis or 48 hours after irradiation for cell cycle analysis by flow cytometry assay. Results: The clone number in combinational treatment group was less than that in irradiation only group, which suggested that the cell survival rate in the combinational treatment group was significantly decreased comparing with irradiation only group (F=6.36, P O + G 1 phases for C225 treatment, in G 2 + M phases for 60 Co irradiation, and in both G 0 + G 1 and G 2 + M phases for C225 in combination with 60 Co irradiation. Conclusions: C225 has radiosensitizing effects on H-520 cells, which may through the enhancement of 60 Co irradiation-induced cell death and cell cycle arrest. This study provides a supportive evidence for clinical treatment in non-small cell lung cancer. (authors)

  17. Human lung mast cells modulate the functions of airway smooth muscle cells in asthma.

    Science.gov (United States)

    Alkhouri, H; Hollins, F; Moir, L M; Brightling, C E; Armour, C L; Hughes, J M

    2011-09-01

    Activated mast cell densities are increased on the airway smooth muscle in asthma where they may modulate muscle functions and thus contribute to airway inflammation, remodelling and airflow obstruction. To determine the effects of human lung mast cells on the secretory and proliferative functions of airway smooth muscle cells from donors with and without asthma. Freshly isolated human lung mast cells were stimulated with IgE/anti-IgE. Culture supernatants were collected after 2 and 24 h and the mast cells lysed. The supernatants/lysates were added to serum-deprived, subconfluent airway smooth muscle cells for up to 48 h. Released chemokines and extracellular matrix were measured by ELISA, proliferation was quantified by [(3) H]-thymidine incorporation and cell counting, and intracellular signalling by phospho-arrays. Mast cell 2-h supernatants reduced CCL11 and increased CXCL8 and fibronectin production from both asthmatic and nonasthmatic muscle cells. Leupeptin reversed these effects. Mast cell 24-h supernatants and lysates reduced CCL11 release from both muscle cell types but increased CXCL8 release by nonasthmatic cells. The 24-h supernatants also reduced asthmatic, but not nonasthmatic, muscle cell DNA synthesis and asthmatic cell numbers over 5 days through inhibiting extracellular signal-regulated kinase (ERK) and phosphatidylinositol (PI3)-kinase pathways. However, prostaglandins, thromboxanes, IL-4 and IL-13 were not involved in reducing the proliferation. Mast cell proteases and newly synthesized products differentially modulated the secretory and proliferative functions of airway smooth muscle cells from donors with and without asthma. Thus, mast cells may modulate their own recruitment and airway smooth muscle functions locally in asthma. © 2011 John Wiley & Sons A/S.

  18. Chronic inorganic arsenic exposure in vitro induces a cancer cell phenotype in human peripheral lung epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Person, Rachel J.; Olive Ngalame, Ntube N.; Makia, Ngome L.; Bell, Matthew W.; Waalkes, Michael P.; Tokar, Erik J., E-mail: tokare@niehs.nih.gov

    2015-07-01

    Inorganic arsenic is a human lung carcinogen. We studied the ability of chronic inorganic arsenic (2 μM; as sodium arsenite) exposure to induce a cancer phenotype in the immortalized, non-tumorigenic human lung peripheral epithelial cell line, HPL-1D. After 38 weeks of continuous arsenic exposure, secreted matrix metalloproteinase-2 (MMP2) activity increased to over 200% of control, levels linked to arsenic-induced cancer phenotypes in other cell lines. The invasive capacity of these chronic arsenic-treated lung epithelial (CATLE) cells increased to 320% of control and colony formation increased to 280% of control. CATLE cells showed enhanced proliferation in serum-free media indicative of autonomous growth. Compared to control cells, CATLE cells showed reduced protein expression of the tumor suppressor gene PTEN (decreased to 26% of control) and the putative tumor suppressor gene SLC38A3 (14% of control). Morphological evidence of epithelial-to-mesenchymal transition (EMT) occurred in CATLE cells together with appropriate changes in expression of the EMT markers vimentin (VIM; increased to 300% of control) and e-cadherin (CDH1; decreased to 16% of control). EMT is common in carcinogenic transformation of epithelial cells. CATLE cells showed increased KRAS (291%), ERK1/2 (274%), phosphorylated ERK (p-ERK; 152%), and phosphorylated AKT1 (p-AKT1; 170%) protein expression. Increased transcript expression of metallothioneins, MT1A and MT2A and the stress response genes HMOX1 (690%) and HIF1A (247%) occurred in CATLE cells possibly in adaptation to chronic arsenic exposure. Thus, arsenic induced multiple cancer cell characteristics in human peripheral lung epithelial cells. This model may be useful to assess mechanisms of arsenic-induced lung cancer. - Highlights: • Chronic arsenic exposure transforms a human peripheral lung epithelia cell line. • Cells acquire characteristics in common with human lung adenocarcinoma cells. • These transformed cells provide a

  19. Reducing dose to the lungs through loosing target dose homogeneity requirement for radiotherapy of non small cell lung cancer.

    Science.gov (United States)

    Miao, Junjie; Yan, Hui; Tian, Yuan; Ma, Pan; Liu, Zhiqiang; Li, Minghui; Ren, Wenting; Chen, Jiayun; Zhang, Ye; Dai, Jianrong

    2017-11-01

    It is important to minimize lung dose during intensity-modulated radiation therapy (IMRT) of nonsmall cell lung cancer (NSCLC). In this study, an approach was proposed to reduce lung dose by relaxing the constraint of target dose homogeneity during treatment planning of IMRT. Ten NSCLC patients with lung tumor on the right side were selected. The total dose for planning target volume (PTV) was 60 Gy (2 Gy/fraction). For each patient, two IMRT plans with six beams were created in Pinnacle treatment planning system. The dose homogeneity of target was controlled by constraints on the maximum and uniform doses of target volume. One IMRT plan was made with homogeneous target dose (the resulting target dose was within 95%-107% of the prescribed dose), while another IMRT plan was made with inhomogeneous target dose (the resulting target dose was more than 95% of the prescribed dose). During plan optimization, the dose of cord and heart in two types of IMRT plans were kept nearly the same. The doses of lungs, PTV and organs at risk (OARs) between two types of IMRT plans were compared and analyzed quantitatively. For all patients, the lung dose was decreased in the IMRT plans with inhomogeneous target dose. On average, the mean dose, V5, V20, and V30 of lung were reduced by 1.4 Gy, 4.8%, 3.7%, and 1.7%, respectively, and the dose to normal tissue was also reduced. These reductions in DVH values were all statistically significant (P target dose could protect lungs better and may be considered as a choice for treating NSCLC. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

  20. A role for cell adhesion in beryllium-mediated lung disease

    Energy Technology Data Exchange (ETDEWEB)

    Hong-geller, Elizabeth [Los Alamos National Laboratory

    2008-01-01

    Chronic beryllium disease (CBD) is a debilitating lung disorder in which exposure to the lightweight metal beryllium (Be) causes the accumulation of beryllium-specific CD4+ T cells in the lung and formation of noncaseating pulmonary granulomas. Treatment for CBD patients who exhibit progressive pulmonary decline is limited to systemic corticosteroids, which suppress the severe host inflammatory response. Studies in the past several years have begun to highlight cell-cell adhesion interactions in the development of Be hypersensitivity and CBD. In particular, the high binding affinity between intercellular adhesion molecule 1 (I-CAM1) on lung epithelial cells and the {beta}{sub 2} integrin LFA-1 on migrating lymphocytes and macrophages regulates the concerted rolling of immune cells to sites of inflammation in the lung. In this review, we discuss the evidence that implicates cell adhesion processes in onset of Be disease and the potential of cell adhesion as an intervention point for development of novel therapies.

  1. Lung Cancer Screening

    Science.gov (United States)

    ... factors increase or decrease the risk of lung cancer. Lung cancer is a disease in which malignant (cancer) ... following PDQ summaries for more information about lung cancer: Lung Cancer Prevention Non-Small Cell Lung Cancer Treatment ...

  2. NFAT5 promotes proliferation and migration of lung adenocarcinoma cells in part through regulating AQP5 expression

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Kai, E-mail: gk161@163.com [Department of Respiration, Tangdu Hospital, Fourth Military Medical University, Xi' an 710038 (China); Department of Respiration, 161th Hospital, PLA, Wuhan 430015 (China); Jin, Faguang, E-mail: jinfag@fmmu.edu.cn [Department of Respiration, Tangdu Hospital, Fourth Military Medical University, Xi' an 710038 (China)

    2015-09-25

    The osmoregulated transcription factor nuclear factor of activated T-cells 5(NFAT5), has been found to play important roles in the development of many kinds of human cancers, including breast cancer, colon carcinoma, renal cell carcinoma and melanoma. The aim of the present study was to determine whether NFAT5 is involved in the proliferation and migration of lung adenocarcinoma cells. We found that NFAT5 was upregulated in lung adenocarcinoma cells and knockdown of NFAT5 decreased proliferation and migration of the cells, accompanied by a significant reduction in the expression of AQP5. AQP5 was upregulated in lung adenocarcinoma cells and knockdown of AQP5 also inhibited proliferation and migration of the cells as knockdown of NFAT5 did. Moreover, overexpression of NFAT5 promoted proliferation and migration of lung adenocarcinoma cells, accompanied by a significant increase in the expression of AQP5. These results indicate that NFAT5 plays important roles in proliferation and migration of human lung adenocarcinoma cells through regulating AQP5 expression, providing a new therapeutic option for lung adenocarcinoma therapy. - Highlights: • NFAT5 expression is higher in lung adenocarcinoma cells compared with normal cells. • NFAT5 knockdown decreases proliferation and migration of lung adenocarcinoma cells. • Knockdown of NFAT5 reduces AQP5 expression in human lung adenocarcinoma cells. • Overexpression of NFAT5 promotes proliferation and migration of lung adenocarcinoma cells. • Overexpression of NFAT5 increases AQP5 expression in human lung adenocarcinoma cells.

  3. NFAT5 promotes proliferation and migration of lung adenocarcinoma cells in part through regulating AQP5 expression

    International Nuclear Information System (INIS)

    Guo, Kai; Jin, Faguang

    2015-01-01

    The osmoregulated transcription factor nuclear factor of activated T-cells 5(NFAT5), has been found to play important roles in the development of many kinds of human cancers, including breast cancer, colon carcinoma, renal cell carcinoma and melanoma. The aim of the present study was to determine whether NFAT5 is involved in the proliferation and migration of lung adenocarcinoma cells. We found that NFAT5 was upregulated in lung adenocarcinoma cells and knockdown of NFAT5 decreased proliferation and migration of the cells, accompanied by a significant reduction in the expression of AQP5. AQP5 was upregulated in lung adenocarcinoma cells and knockdown of AQP5 also inhibited proliferation and migration of the cells as knockdown of NFAT5 did. Moreover, overexpression of NFAT5 promoted proliferation and migration of lung adenocarcinoma cells, accompanied by a significant increase in the expression of AQP5. These results indicate that NFAT5 plays important roles in proliferation and migration of human lung adenocarcinoma cells through regulating AQP5 expression, providing a new therapeutic option for lung adenocarcinoma therapy. - Highlights: • NFAT5 expression is higher in lung adenocarcinoma cells compared with normal cells. • NFAT5 knockdown decreases proliferation and migration of lung adenocarcinoma cells. • Knockdown of NFAT5 reduces AQP5 expression in human lung adenocarcinoma cells. • Overexpression of NFAT5 promotes proliferation and migration of lung adenocarcinoma cells. • Overexpression of NFAT5 increases AQP5 expression in human lung adenocarcinoma cells

  4. The treatment Results of Radiotherapy for nonsmall Cell Lung Cancer

    International Nuclear Information System (INIS)

    Yoon, Jong Chul; Sohn, Seung Chang; Suh, Hyun Suk; Jaun, Woo Ki; Kim, Dong Soon; Sohn, Kwang Hyun

    1986-01-01

    From Nov. 1983 through Jan. 1986, 43 patients with nonsmall cell lung cancer were treated by radiation therapy at Inje Medical College Paik Hospital. 38 patients were available for the analysis of this study. 33 patients received definite irradiation with curative intent, while 5 patients received postoperative irradiation. Chemotherapy was added in 12 patients before, during and after radio-therapy. 28 patients were squamous cell carcinoma and 10 patients were adenocarcinoma. There were 29 men and 9 women (median age, 58 years; range 34 to 74 years). Stage I was 1 patient, Stage 11, 7 patient, and Stage 111, 30 patients. Among 33 patients who received radiotherapy with curative intent, follow up radiological study revealed complete response in 12 patients (36%), partial response, in 9 patients (27%), and minimal response, in 5 patients (15%), while 7 patients (21%) were nonresponders. Median survival for all patients was 6.9 months; squamous cell carcinoma, 7.3 months, adenocarcinoma, 5.9 months. Responders survived median 7 months, while nonresponders survived median 1.9 months. Improved complete response rate and survival were shown in high radiation dose group. As prognostic factors, age, initial performance status, sex, histology and tumor location were evaluated

  5. PDGFR-Β expression in small cell lung cancer patients

    International Nuclear Information System (INIS)

    Shinohara, Eric T.; Gonzalez, Adriana; Massion, Pierre P.; Olson, Sandra J.; Albert, Jeffrey M.; Shyr, Yu; Carbone, David P.; Johnson, David H.; Hallahan, Dennis E.; Lu Bo

    2007-01-01

    Background: Platelet derived growth factor (PDGF) and PDGFR-β are expressed and have been found to have prognostic value in several human cancers. Data in non-small-cell cancer cell lines have suggested that PDGFR is a therapeutic target for drug development. In the current study PDGFR-β expression and prognostic value in small cell lung cancer (SCLC) was investigated. Methods and Materials: Paraffin-embedded tissue blocks from 53 patients with limited and extensive stage SCLC were obtained for immunohistochemical staining. Tumors from each patient were sampled 3 times and stained with PDGFR-β specific antibody. Patients were divided into low and high staining groups based on intensity. Results: There was high intensity PDGFR-β staining in 20 patients with SCLC. Another 29 expressed low intensity PDGFR-β staining, with only 4 patients showing no PDGFR-β staining. There was no statistically significant difference in 5 year overall survival between patients with low levels of PDGFR-β staining vs. those with high level staining SCLC tumors (p = 0.538). Conclusions: The present study found that the majority of SCLC patients express, at least, a low level of PDGF-β. However, the level of PDGFR-β expression was not a statistically significant predictor of 5 year overall survival in SCLC

  6. Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells: A Preclinical Study

    OpenAIRE

    Feng, Yuan; Zhou, Jihong; Li, Zhanhua; Jiang, Ying; Zhou, Ying

    2016-01-01

    Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis act...

  7. Immune-based Therapies for Non-small Cell Lung Cancer.

    Science.gov (United States)

    Rafei, Hind; El-Bahesh, Ehab; Finianos, Antoine; Nassereddine, Samah; Tabbara, Imad

    2017-02-01

    Lung cancer is the leading cause of cancer-related death worldwide. Treatment of non-small cell lung cancer has evolved tremendously over the past decade. Specifically, immune checkpoint inhibitors have become an increasingly interesting target of pharmacological blockade. These immune inhibitors have shown promising results in front-line therapy and after failure of multiple lines, as well as in monotherapy and combination with other therapies. Vaccination in non-small cell lung cancer is also an emerging field of research that holds promising results for the future of immunotherapy in non-small cell lung cancer. This review presents a concise update on the most recent data regarding the role of checkpoint inhibitors as well as vaccination in non-small cell lung cancer. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  8. More expression of BDNF associates with lung squamous cell carcinoma and is critical to the proliferation and invasion of lung cancer cells

    International Nuclear Information System (INIS)

    Zhang, Si-yang; Hui, Lin-ping; Li, Chun-yan; Gao, Jian; Cui, Ze-shi; Qiu, Xue-shan

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) has been reported to promote tumorigenesis and progression in several human malignancies. The purpose of this study was to explore the function of BDNF in lung squamous cell carcinoma (SCC) and adenocarcinoma (ADC). The expression of BDNF was examined in 110 samples of lung SCC and ADC by immunohistochemistry. The protein level of BDNF was examined in 25 lung SCC or ADC samples and paired non-tumors by western blot. BDNF expression was also evaluated in human bronchial epithelial cells (HBE) and 4 lung cancer cell lines using western blot. Three BDNF mRNA variants containing exons IV, VI and IX were evaluated in HBE, two SCC (SK, LK2) and two ADC (A549, LTE) cell lines by RT-PCR. The expression and secretion of BDNF were also determined in cells using western blot and ELISA. Then the shRNA specific for BDNF was transfected into LK2 or A549 cells to further elucidate the BDNF knockdown on cell proliferation, apoptosis and invasion, which were confirmed by MTT, flow cytometry and transwell examinations. 71.8 % (79 out of 110) of lung SCC and ADC samples were detected positive BDNF, and high expression of BDNF was significantly correlated with histological type and T stage. Compared with non-tumorous counterparts, BDNF was apparently overexpressed in SCC and ADC tissues. In cell studies, the extensive expression and secretion of BDNF were demonstrated in lung cancer cells compared with HBE cells. Interestingly, the expressions of BDNF mRNA variant IV and VI were identical in all cells examined. However, more expression of BDNF mRNA variant IX was found in SK and LK2 cells. The apoptotic cells were increased, and the cell proliferation and invasion were both attenuated once the expression of BDNF was inhibited. When retreated by rhBDNF, BDNF knockdown cells showed less apoptotic or more proliferative and invasive. Our data show that BDNF probably facilitates the tumorigenesis of lung SCC and ADC. The expression of BDNF m

  9. Pulmonary CCR2+CD4+ T cells are immune regulatory and attenuate lung fibrosis development.

    Science.gov (United States)

    Milger, Katrin; Yu, Yingyan; Brudy, Eva; Irmler, Martin; Skapenko, Alla; Mayinger, Michael; Lehmann, Mareike; Beckers, Johannes; Reichenberger, Frank; Behr, Jürgen; Eickelberg, Oliver; Königshoff, Melanie; Krauss-Etschmann, Susanne

    2017-11-01

    Animal models have suggested that CCR2-dependent signalling contributes to the pathogenesis of pulmonary fibrosis, but global blockade of CCL2 failed to improve the clinical course of patients with lung fibrosis. However, as levels of CCR2 + CD4 + T cells in paediatric lung fibrosis had previously been found to be increased, correlating with clinical symptoms, we hypothesised that distinct CCR2 + cell populations might either increase or decrease disease pathogenesis depending on their subtype. To investigate the role of CCR2 + CD4 + T cells in experimental lung fibrosis and in patients with idiopathic pulmonary fibrosis and other fibrosis. Pulmonary CCR2 + CD4 + T cells were analysed using flow cytometry and mRNA profiling, followed by in silico pathway analysis, in vitro assays and adoptive transfer experiments. Frequencies of CCR2 + CD4 + T cells were increased in experimental fibrosis-specifically the CD62L - CD44 + effector memory T cell phenotype, displaying a distinct chemokine receptor profile. mRNA profiling of isolated CCR2 + CD4 + T cells from fibrotic lungs suggested immune regulatory functions, a finding that was confirmed in vitro using suppressor assays. Importantly, adoptive transfer of CCR2 + CD4 + T cells attenuated fibrosis development. The results were partly corroborated in patients with lung fibrosis, by showing higher percentages of Foxp3 + CD25 + cells within bronchoalveolar lavage fluid CCR2 + CD4 + T cells as compared with CCR2 - CD4 + T cells. Pulmonary CCR2 + CD4 + T cells are immunosuppressive, and could attenuate lung inflammation and fibrosis. Therapeutic strategies completely abrogating CCR2-dependent signalling will therefore also eliminate cell populations with protective roles in fibrotic lung disease. This emphasises the need for a detailed understanding of the functions of immune cell subsets in fibrotic lung disease. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights

  10. An official American Thoracic Society workshop report: stem cells and cell therapies in lung biology and diseases.

    Science.gov (United States)

    Weiss, Daniel J; Chambers, Daniel; Giangreco, Adam; Keating, Armand; Kotton, Darrell; Lelkes, Peter I; Wagner, Darcy E; Prockop, Darwin J

    2015-04-01

    The University of Vermont College of Medicine and the Vermont Lung Center, in collaboration with the NHLBI, Alpha-1 Foundation, American Thoracic Society, European Respiratory Society, International Society for Cell Therapy, and the Pulmonary Fibrosis Foundation, convened a workshop, "Stem Cells and Cell Therapies in Lung Biology and Lung Diseases," held July 29 to August 1, 2013 at the University of Vermont. The conference objectives were to review the current understanding of the role of stem and progenitor cells in lung repair after injury and to review the current status of cell therapy and ex vivo bioengineering approaches for lung diseases. These are all rapidly expanding areas of study that both provide further insight into and challenge traditional views of mechanisms of lung repair after injury and pathogenesis of several lung diseases. The goals of the conference were to summarize the current state of the field, discuss and debate current controversies, and identify future research directions and opportunities for both basic and translational research in cell-based therapies for lung diseases. This conference was a follow-up to four previous biennial conferences held at the University of Vermont in 2005, 2007, 2009, and 2011. Each of those conferences, also sponsored by the National Institutes of Health, American Thoracic Society, and Respiratory Disease Foundations, has been important in helping guide research and funding priorities. The major conference recommendations are summarized at the end of the report and highlight both the significant progress and major challenges in these rapidly progressing fields.

  11. Cell killing and radiosensitization by caffeic acid phenethyl ester (CAPE) in lung cancer cells

    International Nuclear Information System (INIS)

    Chen, Miao-Fen; Chen, Wen-Cheng; Wu, Chun-Te; King, P.C.

    2004-01-01

    Caffeic acid phenethyl ester (CAPE) is a biologically active ingredient of honeybee propoplis. The cytotoxicity and radiation sensitization effects of CAPE were evaluated in human lung cancer A549 cells and normal lung fibroblast WI-38 cells. A549 cells treated with 6 μg/ml CAPE showed marked growth inhibition (60%) at 48 hr after treatments. During the same time, the number of viable cells decreased to 46% of the control value. In contrast, WI-38 cells showed 20% growth inhibition with no change in the number of viable cells under the same treatment conditions. At 72 hr after CAPE treatment (6 μg/ml), the percentage of apoptotic cells in A549 cultures increased significantly to 67% and an S/G2 arrest was also detected in the culture. Furthermore, there was a significant decrease in the level of intracellular glutathione and hydrogen peroxide contents within one hr after CAPE treatment, and the expression of cyclin B 1 was reduced 6 hr after treatment. The radiation sensitization effect of CAPE on A549 cells was determined from the clonogenic survival curves, and the results showed a small but significant difference in radiation survival between cells treated with or without CAPE. Taken together, our results suggest that the effects of CAPE on differential cytotoxicity, apoptosis, and radiosensitization are associated with glutathione depletion that occurred shortly after treatments. (author)

  12. The E3 ubiquitin ligase NEDD4 mediates cell migration signaling of EGFR in lung cancer cells.

    Science.gov (United States)

    Shao, Genbao; Wang, Ranran; Sun, Aiqin; Wei, Jing; Peng, Ke; Dai, Qian; Yang, Wannian; Lin, Qiong

    2018-02-19

    EGFR-dependent cell migration plays an important role in lung cancer progression. Our previous study observed that the HECT E3 ubiquitin ligase NEDD4 is significantly correlated with tumor metastasis and required for migration and invasion signaling of EGFR in gastric cancer cells. However, how NEDD4 promotes the EGFR-dependent lung cancer cell migration is unknown. This study is to elucidate the mechanism by which NEDD4 mediates the EGFR lung cancer migration signaling. Lentiviral vector-loaded NEDD4 shRNA was used to deplete endogenous NEDD4 in lung cancer cell lines. Effects of the NEDD4 knockdown on the EGFR-dependent or independent lung cancer cell migration were determined using the wound-healing and transwell assays. Association of NEDD4 with activated EGFR was assayed by co-immunoprecipitation. Co-expression of NEDD4 with EGFR or PTEN was determined by immunohistochemical (IHC) staining in 63 lung adenocarcinoma tissue samples. Effects of NEDD4 ectopic expression or knockdown on PTEN ubiquitination and down-regulation, AKT activation and lysosomal secretion were examined using the GST-Uba pulldown assay, immunoblotting, immunofluorescent staining and a human cathepsin B ELISA assay respectively. The specific cathepsin B inhibitor CA-074Me was used for assessing the role of cathepsin B in lung cancer cell migration. Knockdown of NEDD4 significantly reduced EGF-stimulated cell migration in non-small cell lung carcinoma (NSCLC) cells. Co-immunoprecipitation assay found that NEDD4 is associated with EGFR complex upon EGF stimulation, and IHC staining indicates that NEDD4 is co-expressed with EGFR in lung adenocarcinoma tumor tissues, suggesting that NEDD4 might mediate lung cancer cell migration by interaction with the EGFR signaling complex. Interestingly, NEDD4 promotes the EGF-induced cathepsin B secretion, possibly through lysosomal exocytosis, as overexpression of the ligase-dead mutant of NEDD4 impedes lysosomal secretion, and knockdown of NEDD4

  13. Comparison of tumor biology of two distinct cell sub-populations in lung cancer stem cells.

    Science.gov (United States)

    Wang, Jianyu; Sun, Zhiwei; Liu, Yongli; Kong, Liangsheng; Zhou, Shixia; Tang, Junlin; Xing, Hongmei Rosie

    2017-11-14

    Characterization of the stem-like properties of cancer stem cells (CSCs) remain indirect and qualitative, especially the ability of CSCs to undergo asymmetric cell division for self renewal and differentiation, a unique property of cells of stem origin. It is partly due to the lack of stable cellular models of CSCs. In this study, we developed a new approach for CSC isolation and purification to derive a CSC-enriched cell line (LLC-SE). By conducting five consecutive rounds of single cell cloning using the LLC-SE cell line, we obtained two distinct sub-population of cells within the Lewis lung cancer CSCs that employed largely symmetric division for self-renewal (LLC-SD) or underwent asymmetric division for differentiation (LLC-ASD). LLC-SD and LLC-ASD cell lines could be stably passaged in culture and be distinguished by cell morphology, stem cell marker, spheroid formation and subcutaneous tumor initiation efficiency, as well as orthotopic lung tumor growth, progression and survival. The ability LLC-ASD cells to undergo asymmetric division was visualized and quantified by the asymmetric segregation of labeled BrdU and NUMB to one of the two daughter cells in anaphase cell division. The more stem-like LLC-SD cells exhibited higher capacity for tumorigenesis and progression and shorter survival. As few as 10 LLC-SD could initiate subcutaneous tumor growth when transplanted to the athymic mice. Collectively, these observations suggest that the SD-type of cells appear to be on the top of the hierarchical order of the CSCs. Furthermore, they have lead to generated cellular models of CSC self-renewal for future mechanistic investigations.

  14. Sulforaphane?induced apoptosis in Xuanwei lung adenocarcinoma cell line XWLC?05

    OpenAIRE

    Zhou, Lan; Yao, Qian; Li, Yan; Huang, Yun?chao; Jiang, Hua; Wang, Chuan?qiong; Fan, Lei

    2016-01-01

    Background Xuanwei district in Yunnan Province has the highest incidence of lung cancer in China, especially among non?smoking women. Cruciferous vegetables can reduce lung cancer risk by prompting a protective mechanism against respiratory tract inflammation caused by air pollution, and are rich in sulforaphane, which can induce changes in gene expression. We investigated the effect of sulforaphane?induced apoptosis in Xuanwei lung adenocarcinoma cell line (XWCL?05) to explore the value of s...

  15. Durvalumab: a potential maintenance therapy in surgery-ineligible non-small-cell lung cancer

    Directory of Open Access Journals (Sweden)

    Shafique MR

    2018-05-01

    Full Text Available Michael R Shafique, Lary A Robinson, Scott Antonia Department of Thoracic Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA Abstract: Lung cancer is the most common cancer worldwide and the most common cause of cancer-related death. Non-small-cell lung cancer comprises ~87% of newly diagnosed cases of lung cancer, and nearly one-third of these patients have stage III disease. Despite improvements in the treatment of stage IV lung cancer, particularly with the introduction and dissemination of checkpoint inhibitors, very little progress has been made in the treatment of stage III lung cancer. In this article, we discuss the general staging criteria and treatment options for stage III lung cancer. We review how concurrent radiation and chemotherapy can have immunomodulatory effects, supporting the rationale for incorporating immunotherapy into existing treatment paradigms. Finally, we discuss the results of the PACIFIC trial and implications for the treatment of stage III lung cancer. In the PACIFIC trial, adding durvalumab as a maintenance therapy following the completion of chemoradiotherapy improved progression-free survival in patients with locally advanced unresectable stage III lung cancer. On the strength of these results, durvalumab has been approved by the US Food and Drug Administration for use in this setting, representing the first advance in the treatment of stage III lung cancer in nearly a decade. Keywords: non-small-cell lung cancer, maintenance therapy, staging, immunotherapy, chemoradiation, surgery-ineligible, durvalumab

  16. CDDO-Me protects normal lung and breast epithelial cells but not cancer cells from radiation.

    Directory of Open Access Journals (Sweden)

    Mariam El-Ashmawy

    Full Text Available Although radiation therapy is commonly used for treatment for many human diseases including cancer, ionizing radiation produces reactive oxygen species that can damage both cancer and healthy cells. Synthetic triterpenoids, including CDDO-Me, act as anti-inflammatory and antioxidant modulators primarily by inducing the transcription factor Nrf2 to activate downstream genes containing antioxidant response elements (AREs. In the present series of experiments, we determined if CDDO-Me can be used as a radioprotector in normal non-cancerous human lung and breast epithelial cells, in comparison to lung and breast cancer cell lines. A panel of normal non-cancerous, partially cancer progressed, and cancer cell lines from both lung and breast tissue was exposed to gamma radiation with and without pre-treatment with CDDO-Me. CDDO-Me was an effective radioprotector when given ∼18 hours before radiation in epithelial cells (average dose modifying factor (DMF = 1.3, and Nrf2 function was necessary for CDDO-Me to exert these radioprotective effects. CDDO-Me did not protect cancer lines tested from radiation-induced cytotoxicity, nor did it protect experimentally transformed human bronchial epithelial cells (HBECs with progressive oncogenic manipulations. CDDO-Me also protected human lymphocytes against radiation-induced DNA damage. A therapeutic window exists in which CDDO-Me protects normal cells from radiation by activating the Nrf2 pathway, but does not protect experimentally transformed or cancer cell lines. This suggests that use of this oral available, non-toxic class of drug can protect non-cancerous healthy cells during radiotherapy, resulting in better outcomes and less toxicity for patients.

  17. Pseudomonas aeruginosa vesicles associate with and are internalized by human lung epithelial cells

    Directory of Open Access Journals (Sweden)

    Kuehn Meta J

    2009-02-01

    Full Text Available Abstract Background Pseudomonas aeruginosa is the major pathogen associated with chronic and ultimately fatal lung infections in patients with cystic fibrosis (CF. To investigate how P. aeruginosa-derived vesicles may contribute to lung disease, we explored their ability to associate with human lung cells. Results Purified vesicles associated with lung cells and were internalized in a time- and dose-dependent manner. Vesicles from a CF isolate exhibited a 3- to 4-fold greater association with lung cells than vesicles from the lab strain PAO1. Vesicle internalization was temperature-dependent and was inhibited by hypertonic sucrose and cyclodextrins. Surface-bound vesicles rarely colocalized with clathrin. Internalized vesicles colocalized with the endoplasmic reticulum (ER marker, TRAPα, as well as with ER-localized pools of cholera toxin and transferrin. CF isolates of P. aeruginosa abundantly secrete PaAP (PA2939, an aminopeptidase that associates with the surface of vesicles. Vesicles from a PaAP knockout strain exhibited a 40% decrease in cell association. Likewise, vesicles from PAO1 overexpressing PaAP displayed a significant increase in cell association. Conclusion These data reveal that PaAP promotes the association of vesicles with lung cells. Taken together, these results suggest that P. aeruginosa vesicles can interact with and be internalized by lung epithelial cells and contribute to the inflammatory response during infection.

  18. Low tumour cell content in a lung tumour bank: implications for molecular characterisation.

    Science.gov (United States)

    Goh, Felicia; Duhig, Edwina E; Clarke, Belinda E; McCaul, Elizabeth; Passmore, Linda; Courtney, Deborah; Windsor, Morgan; Naidoo, Rishendren; Franz, Louise; Parsonson, Kylie; Yang, Ian A; Bowman, Rayleen V; Fong, Kwun M

    2017-10-01

    Lung cancer encompasses multiple malignant epithelial tumour types, each with specific targetable, potentially actionable mutations, such that precision management mandates accurate tumour typing. Molecular characterisation studies require high tumour cell content and low necrosis content, yet lung cancers are frequently a heterogeneous mixture of tumour and stromal cells. We hypothesised that there may be systematic differences in tumour cell content according to histological subtype, and that this may have implications for tumour banks as a resource for comprehensive molecular characterisation studies in lung cancer. To investigate this, we estimated tumour cell and necrosis content of 4267 samples resected from 752 primary lung tumour specimens contributed to a lung tissue bank. We found that banked lung cancer samples had low tumour cell content (33%) generally, although it was higher in carcinoids (77.5%) than other lung cancer subtypes. Tumour cells comprise a variable and often small component of banked resected tumour samples, and are accompanied by stromal reaction, inflammation, fibrosis, and normal structures. This has implications for the adequacy of unselected tumour bank samples for diagnostic and molecular investigations, and further research is needed to determine whether tumour cell content has a significant impact on analytical results in studies using tissue from tumour bank resources. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  19. Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells: A Preclinical Study.

    Science.gov (United States)

    Feng, Yuan; Zhou, Jihong; Li, Zhanhua; Jiang, Ying; Zhou, Ying

    2016-01-01

    Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis activation in lung cancer cells, which was evidenced by TRAIL/death receptor-5 (DR5) induction and caspase-8 activation. The caspase-8 inhibitor or TRAIL/DR5 siRNA knockdown alleviated ONC201's cytotoxicity against lung cancer cells. Molecularly, ONC201 in-activated Akt-S6K1 and Erk signalings in lung cancer cells, causing Foxo3a nuclear translocation. For the in vivo studies, intraperitoneal injection of ONC201 at well-tolerated doses significantly inhibited xenografted A549 tumor growth in severe combined immunodeficient (SCID) mice. Further, ONC201 administration induced TRAIL/DR5 expression, yet inactivated Akt-S6K1 and Erk in tumor tissues. These results of the study demonstrates the potent anti-lung cancer activity by ONC201.

  20. Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells: A Preclinical Study.

    Directory of Open Access Journals (Sweden)

    Yuan Feng

    Full Text Available Tumor necrosis factor (TNF-related apoptosis-inducing ligand (TRAIL selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis activation in lung cancer cells, which was evidenced by TRAIL/death receptor-5 (DR5 induction and caspase-8 activation. The caspase-8 inhibitor or TRAIL/DR5 siRNA knockdown alleviated ONC201's cytotoxicity against lung cancer cells. Molecularly, ONC201 in-activated Akt-S6K1 and Erk signalings in lung cancer cells, causing Foxo3a nuclear translocation. For the in vivo studies, intraperitoneal injection of ONC201 at well-tolerated doses significantly inhibited xenografted A549 tumor growth in severe combined immunodeficient (SCID mice. Further, ONC201 administration induced TRAIL/DR5 expression, yet inactivated Akt-S6K1 and Erk in tumor tissues. These results of the study demonstrates the potent anti-lung cancer activity by ONC201.

  1. Evaluation of pentavalent Tc-99m DMSA scintigraphy in small cell and nonsmall cell lung cancers

    Energy Technology Data Exchange (ETDEWEB)

    Atasever, T.; Guendogdu, C.; Vural, G.; Kapucu, L.Oe.; Karalezli, A.; Uenlue, M. [Gazi Univ., Faculty of Medicine, Nuclear Medicine Department and Atatuerk Chest Diseases and Surgery Center, Ankara (Turkey)

    1997-10-01

    Aim: The purpose of this study was to evaluate the clinical usefulness of Tc-99m (V) DMSA in patients suspected of lung cancer and determine whether this agent may have value in differentiation between small cell (SCLC) and non-small cell (NSCLC) lung carcinoma. Methods: Thirty-six patients with clinical and radiological suspicion of primary lung carcinoma were injected 450-600 MBq of Tc-99m (V) DMSA intravenously. Whole body and planar anterior, posterior thorax images were obtained 4-5 h after injection of the radioactive complex. Results: Histopathological results confirmed 23 NSCLC, 10 SCLC and 1 metastatic lung carcinoma and 2 lung abscess. Nineteen of the 23 (82%) NSCLC and all of the 10 (100%) SCLC cases showed Tc-99m (V) DMSA uptake. Single metastatic lung cancer also accumulated radiotracer. Lung abscess did not show uptake. Lesion/Nonlesion (L/N) ratio of SCLC (1.59{+-}0.32) and NSCLC (1.43{+-}0.19) tumour types did not show statistical difference (p>0.05). Tc-99m (V) DMSA whole body imaging also showed bone metastases. Conclusion: Tc-99m (V) DMSA is a noninvasive and cheap imaging method to detect malignant lung cancers and their bone metastases but, differentiation of SCLC and NSCLC is not possible. (orig.) [Deutsch] Ziel: Pruefung der klinischen Brauchbarkeit von {sup 99m}Tc-(V) DMSA bei Patienten mit Verdacht auf Bronchialkarzinom im Hinblick auf die Moeglichkeit einer Differenzierung zwischen Kleinzeller (KLZ) und Nichtkleinzeller (NKLZ). Methoden: Bei 36 Patienten mit klinischem und radiologischem Hinweis auf Bronchialkarzinom wurden 450 bis 600 MBq {sup 99m}Tc-(V) DMSA i.v. appliziert. 4-5 h spaeter wurden Ganzkoerper- und planare Szintigramme des Thorax durchgefuehrt. Ergebnisse: Feingewebliche Untersuchungen bestaetigten in 23 Faellen NKLZ, zehnmal KLZ, einmal ein metastasierendes Bronchialkarzinom und zwei Lungenabszesse. 19 der 23 NKLZ- (82%) und 100% der KLZ-Faelle zeigten eine {sup 99m}Tc-(V) DMSA-Speicherung ebenso wie das metastasierende

  2. [Principles of radiotherapy of non-small cell lung cancer].

    Science.gov (United States)

    Esik, Olga; Horváth, Akos; Bajcsay, András; Hideghéty, Katalin; Agócs, László; Pikó, Béla; Lengyel, Zsolt; Petrányi, Agota; Pisch, Julianna

    2002-01-01

    The long-term survival probability for Hungarian lung cancer patients is 10% worse than the best results published in the most highly developed countries (the mean 5-year survival probability in Hungary is 5%, in contrast with the 15% survival probability in the USA). On the basis of the international recommendations and personal experience, an attempt was made to formulate the guidelines for radiotherapy as one of the fundamental non-small cell lung cancer (NSCLC) treatment modalities for national use. An expert panel was set up comprising physicians from 6 radiotherapeutic centers (the National Institute of Oncology / Semmelweis University, Budapest; the Beth Israel Medical Center, New York; the University of Kaposvár; the University of Essen; the University of Debrecen; and the County Hospital of Gyula). Experts in two important medical fields closely related to radiotherapy (surgery and diagnostic imaging) were also engaged in the elaboration of the manuscript. Discussion of the most important principles of the radiotherapy and an overview of the prognostic factors was followed by a critical analysis of the protocols applied in the radiotherapy of Hungarian NSCLC patients during recent decades. The new guidelines suggested for the radiotherapy of NSCLC are presented separately for the postoperative period, marginally resectable tumors, and the aggressive or non-aggressive radiotherapy of inoperable tumors. Detailed accounts are given of the techniques of external irradiation and brachytherapy, and of the acute and late radiation-induced damage of normal tissues. The authors believe that this document may be instrumental in improving the survival index of Hungarian NSCLC patients in the near future.

  3. Treatment of Stage IV Non-small Cell Lung Cancer

    Science.gov (United States)

    Evans, Tracey; Gettinger, Scott; Hensing, Thomas A.; VanDam Sequist, Lecia; Ireland, Belinda; Stinchcombe, Thomas E.

    2013-01-01

    Background: Stage IV non-small cell lung cancer (NSCLC) is a treatable, but not curable, clinical entity in patients given the diagnosis at a time when their performance status (PS) remains good. Methods: A systematic literature review was performed to update the previous edition of the American College of Chest Physicians Lung Cancer Guidelines. Results: The use of pemetrexed should be restricted to patients with nonsquamous histology. Similarly, bevacizumab in combination with chemotherapy (and as continuation maintenance) should be restricted to patients with nonsquamous histology and an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1; however, the data now suggest it is safe to use in those patients with treated and controlled brain metastases. Data at this time are insufficient regarding the safety of bevacizumab in patients receiving therapeutic anticoagulation who have an ECOG PS of 2. The role of cetuximab added to chemotherapy remains uncertain and its routine use cannot be recommended. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as first-line therapy are the recommended treatment of those patients identified as having an EGFR mutation. The use of maintenance therapy with either pemetrexed or erlotinib should be considered after four cycles of first-line therapy in those patients without evidence of disease progression. The use of second- and third-line therapy in stage IV NSCLC is recommended in those patients retaining a good PS; however, the benefit of therapy beyond the third-line setting has not been demonstrated. In the elderly and in patients with a poor PS, the use of two-drug, platinum-based regimens is preferred. Palliative care should be initiated early in the course of therapy for stage IV NSCLC. Conclusions: Significant advances continue to be made, and the treatment of stage IV NSCLC has become nuanced and specific for particular histologic subtypes and clinical patient characteristics and according to the

  4. The role of mismatch repair in small-cell lung cancer cells

    DEFF Research Database (Denmark)

    Hansen, L T; Thykjaer, T; Ørntoft, T F

    2003-01-01

    The role of mismatch repair (MMR) in small-cell lung cancer (SCLC) is controversial, as the phenotype of a MMR-deficiency, microsatellite instability (MSI), has been reported to range from 0 to 76%. We studied the MMR pathway in a panel of 21 SCLC cell lines and observed a highly heterogeneous...... pattern of MMR gene expression. A significant correlation between the mRNA and protein levels was found. We demonstrate that low hMLH1 gene expression was not linked to promoter CpG methylation. One cell line (86MI) was found to be deficient in MMR and exhibited resistance to the alkylating agent MNNG...

  5. Vorinostat increases carboplatin and paclitaxel activity in non-small cell lung cancer cells

    OpenAIRE

    Owonikoko, Taofeek K.; Ramalingam, Suresh S.; Kanterewicz, Beatriz; Balius, Trent; Belani, Chandra P.; Hershberger, Pamela A.

    2010-01-01

    We observed a 53% response rate in non-small cell lung cancer (NSCLC) patients treated with vorinostat plus paclitaxel/carboplatin in a Phase I trial. Studies were undertaken to investigate the mechanism (s) underlying this activity. Growth inhibition was assessed in NSCLC cells by MTT assay after 72 h of continuous drug exposure. Vorinostat (1 µM) inhibited growth by: 17±7% in A549, 28±6% in 128-88T, 39±8% in Calu1, and 41±7% in 201T cells. Vorinostat addition to carboplatin or paclitaxel le...

  6. Induction of mesenchymal cell phenotypes in lung epithelial cells by adenovirus E1A.

    Science.gov (United States)

    Behzad, A R; Morimoto, K; Gosselink, J; Green, J; Hogg, J C; Hayashi, S

    2006-12-01

    Epithelial-mesenchymal transformation is now recognised as an important feature of tissue remodelling. The present report concerns the role of adenovirus infection in inducing this transformation in an animal model of chronic obstructive pulmonary disease. Guinea pig primary peripheral lung epithelial cells (PLECs) transfected with adenovirus E1A (E1A-PLECs) were compared to guinea pig normal lung fibroblasts (NLFs) transfected with E1A (E1A-NLFs). These cells were characterised by PCR, immunocytochemistry, electron microscopy, and Western and Northern blot analyses. Electrophoretic mobility shift assays were performed in order to examine nuclear factor (NF)-kappaB and activator protein (AP)-1 binding activities. E1A-PLECs and E1A-NLFs positive for E1A DNA, mRNA and protein expressed cytokeratin and vimentin but not smooth muscle alpha-actin. Both exhibited cuboidal morphology and junctional complexes, but did not contain lamellar bodies or express surfactant protein A, B or C mRNAs. These two cell types differed, however, in their NF-kappaB and AP-1 binding after lipopolysaccharide stimulation, possibly due to differences in the expression of the subunits that comprise these transcriptional complexes. E1A transfection results in the transformation of peripheral lung epithelial cells and normal lung fibroblasts to a phenotype intermediate between that of the two primary cells. It is postulated that this intermediate phenotype may play a major role in the remodelling of the airways in chronic obstructive pulmonary disease associated with persistence of adenovirus E1A DNA.

  7. Restoration of Immune Surveillance in Lung Cancer by Natural Killer Cells

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-15-1-0400 TITLE: Restoration of Immune Surveillance in Lung Cancer by Natural Killer Cells PRINCIPAL INVESTIGATOR... cancer . However, its mechanism remains obscure, especially related to natural killer (NK) cells . The goal of this application is to uncover how a...explore the viability of targeting miR183 to restore NK cells as a new form of immunotherapy for early stage lung cancer . The specific aims are 1) to

  8. XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ting; Han, Shuai; Wu, Zhipeng; Han, Zhitao; Yan, Wangjun; Liu, Tielong; Wei, Haifeng; Song, Dianwen; Zhou, Wang, E-mail: brilliant212@163.com; Yang, Xinghai, E-mail: cnspineyang@163.com; Xiao, Jianru, E-mail: jianruxiao83@163.com

    2015-08-21

    Bone metastasis occurs in approximately 30–40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis. - Highlights: • XCR1 is overexpressed in bone metastasis compared with primary NSCLC. • XCR1 activation by XCL1 promotes lung cancer cell proliferation and migration. • JAK2/STAT3 is a novel potential downstream pathway of XCR1.

  9. E-cigarette smoke damages DNA and reduces repair activity in mouse lung, heart, and bladder as well as in human lung and bladder cells

    OpenAIRE

    Lee, Hyun-Wook; Park, Sung-Hyun; Weng, Mao-wen; Wang, Hsiang-Tsui; Huang, William C.; Lepor, Herbert; Wu, Xue-Ru; Chen, Lung-Chi; Tang, Moon-shong

    2018-01-01

    Significance E-cigarette smoke (ECS) delivers nicotine through aerosols without burning tobacco. ECS is promoted as noncarcinogenic. We found that ECS induces DNA damage in mouse lung, bladder, and heart and reduces DNA-repair functions and proteins in lung. Nicotine and its nitrosation product 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone can cause the same effects as ECS and enhance mutations and tumorigenic cell transformation in cultured human lung and bladder cells. These results indica...

  10. Activation of pulmonary and lymph node dendritic cells during chronic Pseudomonas aeruginosa lung infection in mice

    DEFF Research Database (Denmark)

    Damlund, Dina S. M.; Christophersen, Lars; Jensen, Peter Østrup

    2016-01-01

    , the infection is not eradicated and the inflammatory response leads to gradual degradation of the lung tissue. In CF patients, a Th2-dominated adaptive immune response with a pronounced antibody response is correlated with poorer outcome. Dendritic cells (DCs) are crucial in bridging the innate immune system...... with the adaptive immune response. Once activated, the DCs deliver a set of signals to uncommitted T cells that induce development, such as expansion of regulatory T cells and polarization of Th1, Th2 or Th17 subsets. In this study, we characterized DCs in lungs and regional lymph nodes in BALB/c mice infected...... using intratracheal installation of P. aeruginosa embedded in seaweed alginate in the lungs. A significantly elevated concentration of DCs was detected earlier in the lungs than in the regional lymph nodes. To evaluate whether the chronic P. aeruginosa lung infection leads to activation of DCs...

  11. The differential role of human macrophage in triggering secondary bystander effects after either gamma-ray or carbon beam irradiation.

    Science.gov (United States)

    Dong, Chen; He, Mingyuan; Tu, Wenzhi; Konishi, Teruaki; Liu, Weili; Xie, Yuexia; Dang, Bingrong; Li, Wenjian; Uchihori, Yukio; Hei, Tom K; Shao, Chunlin

    2015-07-10

    The abscopal effect could be an underlying factor in evaluating prognosis of radiotherapy. This study established an in vitro system to examine whether tumor-generated bystander signals could be transmitted by macrophages to further trigger secondary cellular responses after different irradiations, where human lung cancer NCI-H446 cells were irradiated with either γ-rays or carbon ions and co-cultured with human macrophage U937 cells, then these U937 cells were used as a bystander signal transmitter and co-cultured with human bronchial epithelial cells BEAS-2B. Results showed that U937 cells were only activated by γ-irradiated NCI-H446 cells so that the secondary injuries in BEAS-2B cells under carbon ion irradiation were weaker than γ-rays. Both TNF-α and IL-1α were involved in the γ-irradiation induced secondary bystander effect but only TNF-α contributed to the carbon ion induced response. Further assay disclosed that IL-1α but not TNF-α was largely responsible for the activation of macrophages and the formation of micronucleus in BEAS-2B cells. These data suggest that macrophages could transfer secondary bystander signals and play a key role in the secondary bystander effect of photon irradiation, while carbon ion irradiation has conspicuous advantage due to its reduced secondary injury. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  12. Validation of Interobserver Agreement in Lung Cancer Assessment: Hematoxylin-Eosin Diagnostic Reproducibility for Non–Small Cell Lung Cancer

    Science.gov (United States)

    Grilley-Olson, Juneko E.; Hayes, D. Neil; Moore, Dominic T.; Leslie, Kevin O.; Wilkerson, Matthew D.; Qaqish, Bahjat F.; Hayward, Michele C.; Cabanski, Christopher R.; Yin, Xiaoying; Socinski, Mark A.; Stinchcombe, Thomas E.; Thorne, Leigh B.; Allen, Timothy Craig; Banks, Peter M.; Beasley, Mary B.; Borczuk, Alain C.; Cagle, Philip T.; Christensen, Rebecca; Colby, Thomas V.; Deblois, Georgean G.; Elmberger, Göran; Graziano, Paolo; Hart, Craig F.; Jones, Kirk D.; Maia, Diane M.; Miller, C. Ryan; Nance, Keith V.; Travis, William D.; Funkhouser, William K.

    2018-01-01

    Context Precise subtype diagnosis of non–small cell lung carcinoma is increasingly relevant, based on the availability of subtype-specific therapies, such as bevacizumab and pemetrexed, and based on the subtype-specific prevalence of activating epidermal growth factor receptor mutations. Objectives To establish a baseline measure of inter-observer reproducibility for non–small cell lung carcinoma diagnoses with hematoxylin-eosin for the current 2004 World Health Organization classification, to estimate interobserver reproducibility for the therapeutically relevant squamous/nonsquamous subsets, and to examine characteristics that improve interobserver reproducibility. Design Primary, resected lung cancer specimens were converted to digital (virtual) slides. Based on a single hematoxylin-eosin virtual slide, pathologists were asked to assign a diagnosis using the 2004 World Health Organization classification. Kappa statistics were calculated for each pathologist-pair for each slide and were summarized by classification scheme, pulmonary pathology expertise, diagnostic confidence, and neoplastic grade. Results The 12 pulmonary pathology experts and the 12 community pathologists each independently diagnosed 48 to 96 single hematoxylin-eosin digital slides derived from 96 cases of non–small cell lung carcinoma resection. Overall agreement improved with simplification from the comprehensive 44 World Health Organization diagnoses (κ = 0.25) to their 10 major header subtypes (κ = 0.48) and improved again with simplification into the therapeutically relevant squamous/nonsquamous dichotomy (κ = 0.55). Multivariate analysis showed that higher diagnostic agreement was associated with better differentiation, better slide quality, higher diagnostic confidence, similar years of pathology experience, and pulmonary pathology expertise. Conclusions These data define the baseline diagnostic agreement for hematoxylin-eosin diagnosis of non–small cell lung carcinoma

  13. Effect of BRCA1 on radiosensitivity of different lung cancer cells

    International Nuclear Information System (INIS)

    Zhang Huiwen; Wang Miao; Wang Yansu; Ren Hang; Xu Jiaying; Jiao Yang; Fan Saijun; Meng Qinghui

    2011-01-01

    Objective: To investigate the effects BRCA1 on sensitivity of lung cancer cells to γ-irradiation. Methods: A mammalian expression pcDNA3 vectors encoding a full-length of BRCA1 cDNA and BRCA1 siRNA were transfected into lung cancer cells. Western blot, MTT and clonogenic assays were used to determine BRCA1 protein expression and cell survival following γ-irradiation respectively. Results: There is a close relationship between BRCA1 level and radiosensitivity in different lung cancer cell lines. Compared with the control cells transfected with the 'empty' pcDNA3 vector and parental cells, the more survival of cells transfected with BRCA1 was observed after irradiation. The BRCA1-caused radioresistance were observed in both A549 and HTB-58 lung cancer lines. However, NIH-H2170 cells transfected with BRCA1 siRNA became more sensitive to γ-irradiation. Conclusion: This study, for the first time, demonstrates that the alteration of BRCA1 expression significantly affects radiosensitivity of lung cancer, indicating that BRCA1 may be an important mediator in radiotherapy of lung cancer cells. (authors)

  14. Cyto-adherence of Mycoplasma mycoides subsp. mycoides to bovine lung epithelial cells.

    Science.gov (United States)

    Aye, Racheal; Mwirigi, Martin Kiogora; Frey, Joachim; Pilo, Paola; Jores, Joerg; Naessens, Jan

    2015-02-07

    Mycoplasma mycoides subsp. mycoides (Mmm) is the causative agent of contagious bovine pleuropneumonia (CBPP), a respiratory disease of cattle, whereas the closely related Mycoplasma mycoides subsp. capri (Mmc) is a goat pathogen. Cyto-adherence is a crucial step in host colonization by mycoplasmas and subsequent pathogenesis. The aim of this study was to investigate the interactions between Mmm and mammalian host cells by establishing a cyto-adherence flow cytometric assay and comparing tissue and species specificity of Mmm and Mmc strains. There were little significant differences in the adherence patterns of eight different Mmm strains to adult bovine lung epithelial cells. However, there was statistically significant variation in binding to different host cells types. Highest binding was observed with lung epithelial cells, intermediate binding with endothelial cells and very low binding with fibroblasts, suggesting the presence of effective adherence of Mmm on cells lining the airways of the lung, which is the target organ for this pathogen, possibly by high expression of a specific receptor. However, binding to bovine fetal lung epithelial cells was comparably low; suggesting that the lack of severe pulmonary disease seen in many infected young calves can be explained by reduced expression of a specific receptor. Mmm bound with high efficiency to adult bovine lung cells and less efficiently to calves or goat lung cells. The data show that cyto-adherence of Mmm is species- and tissue- specific confirming its role in colonization of the target host and subsequent infection and development of CBPP.

  15. Ezh2 represses the basal cell lineage during lung endoderm development.

    Science.gov (United States)

    Snitow, Melinda E; Li, Shanru; Morley, Michael P; Rathi, Komal; Lu, Min Min; Kadzik, Rachel S; Stewart, Kathleen M; Morrisey, Edward E

    2015-01-01

    The development of the lung epithelium is regulated in a stepwise fashion to generate numerous differentiated and stem cell lineages in the adult lung. How these different lineages are generated in a spatially and temporally restricted fashion remains poorly understood, although epigenetic regulation probably plays an important role. We show that the Polycomb repressive complex 2 component Ezh2 is highly expressed in early lung development but is gradually downregulated by late gestation. Deletion of Ezh2 in early lung endoderm progenitors leads to the ectopic and premature appearance of Trp63+ basal cells that extend the entire length of the airway. Loss of Ezh2 also leads to reduced secretory cell differentiation. In their place, morphologically similar cells develop that express a subset of basal cell genes, including keratin 5, but no longer express high levels of either Trp63 or of standard secretory cell markers. This suggests that Ezh2 regulates the phenotypic switch between basal cells and secretory cells. Together, these findings show that Ezh2 restricts the basal cell lineage during normal lung endoderm development to allow the proper patterning of epithelial lineages during lung formation. © 2015. Published by The Company of Biologists Ltd.

  16. Surgical management of non-small-cell lung cancer

    Directory of Open Access Journals (Sweden)

    Bamousa Ahmed

    2008-10-01

    Full Text Available Surgery plays a major role in the management of patients with lung cancer. Surgery is not only the main curative treatment modality in patients with early-stage lung cancer but it also has a significant role in the initial workup for the diagnosis and staging of lung cancer. This article describes the surgical management of patients with lung cancer. Surgical resection for lung cancer is still regarded as the most effective method for controlling the primary tumor, provided it is resectable for cure and the risks of the procedure are low. The 5-year survival rare following complete resection (R0 of a lung cancer is stage dependent [Table 1]. [1-3] Incomplete resection (R1, R2 rarely, if ever, cures the patient.

  17. Lung cancer-associated tumor antigens and the present status of immunotherapy against non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Yasumoto, Kosei; Hanagiri, Takeshi; Takenoyama, Mitsuhiro

    2009-01-01

    Despite recent advances in surgery, irradiation, and chemotherapy, the prognosis of patients with lung cancer is still poor. Therefore, the development and application of new therapeutic strategies are essential for improving the prognosis of this disease. Significant progress in our understanding of tumor immunology and molecular biology has allowed us to identify the tumor-associated antigens recognized by cytotoxic T lymphocytes. Immune responses and tumor-associated antigens against not only malignant melanoma but also lung cancer have been elucidated at the molecular level. In a theoretical sense, tumor eradication is considered possible through antigen-based immunotherapy against such diseases. However, many clinical trials of cancer vaccination with defined tumor antigens have resulted in objective clinical responses in only a small number of patients. Tumor escape mechanisms from host immune surveillance remain a major obstacle for cancer immunotherapy. A better understanding of the immune escape mechanisms employed by tumor cells is necessary before we can develop a more effective immunotherapeutic approach to lung cancer. We review recent studies regarding the identification of tumor antigens in lung cancer, tumor immune escape mechanisms, and clinical vaccine trials in lung cancer. (author)

  18. Lung Cancer Prevention

    Science.gov (United States)

    ... Colorectal Cancer Kidney (Renal Cell) Cancer Leukemia Liver Cancer Lung Cancer Lymphoma Pancreatic Cancer Prostate Cancer Skin Cancer ... following PDQ summaries for more information about lung cancer: Lung Cancer Screening Non-Small Cell Lung Cancer Treatment ...

  19. Prognosis and Treatment Decision Making in Early Stage Non-Small Cell Lung Cancer

    NARCIS (Netherlands)

    S. Mokhles (Sahar)

    2017-01-01

    textabstractLung cancer is one of the leading causes of death worldwide, and it is the largest contributor to new cancer diagnoses (12% of total new cancer cases) and to death from cancer (18% of total cancer deaths). There are two major groups of lung cancer that arise from the cells of the

  20. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer

    NARCIS (Netherlands)

    Peifer, Martin; Fernandez-Cuesta, Lynnette; Sos, Martin L.; George, Julie; Seidel, Danila; Kasper, Lawryn H.; Plenker, Dennis; Leenders, Frauke; Sun, Ruping; Zander, Thomas; Menon, Roopika; Koker, Mirjam; Dahmen, Ilona; Mueller, Christian; Di Cerbo, Vincenzo; Schildhaus, Hans-Ulrich; Altmueller, Janine; Baessmann, Ingelore; Becker, Christian; de Wilde, Bram; Vandesompele, Jo; Boehm, Diana; Ansen, Sascha; Gabler, Franziska; Wilkening, Ines; Heynck, Stefanie; Heuckmann, Johannes M.; Lu, Xin; Carter, Scott L.; Cibulskis, Kristian; Banerji, Shantanu; Getz, Gad; Park, Kwon-Sik; Rauh, Daniel; Gruetter, Christian; Fischer, Matthias; Pasqualucci, Laura; Wright, Gavin; Wainer, Zoe; Russell, Prudence; Petersen, Iver; Chen, Yuan; Stoelben, Erich; Ludwig, Corinna; Schnabel, Philipp; Hoffmann, Hans; Muley, Thomas; Brockmann, Michael; Engel-Riedel, Walburga; Muscarella, Lucia A.; Fazio, Vito M.; Groen, Harry; Timens, Wim; Sietsma, Hannie; Thunnissen, Erik; Smit, Egbert; Heideman, Danielle A. M.; Snijders, Peter J. F.; Cappuzzo, Federico; Ligorio, Claudia; Damiani, Stefania; Field, John; Solberg, Steinar; Brustugun, Odd Terje; Lund-Iversen, Marius; Saenger, Joerg; Clement, Joachim H.; Soltermann, Alex; Moch, Holger; Weder, Walter; Solomon, Benjamin; Soria, Jean-Charles; Validire, Pierre; Besse, Benjamin; Brambilla, Elisabeth; Brambilla, Christian; Lantuejoul, Sylvie; Lorimier, Philippe; Schneider, Peter M.; Hallek, Michael; Pao, William; Meyerson, Matthew; Sage, Julien; Shendure, Jay; Schneider, Robert; Buettner, Reinhard; Wolf, Juergen; Nuernberg, Peter; Perner, Sven; Heukamp, Lukas C.; Brindle, Paul K.; Haas, Stefan; Thomas, Roman K.

    2012-01-01

    Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis(1-3). We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4 +/- 1 protein-changing mutations per million base pairs. Therefore, we conducted integrated

  1. The bisphosphonate zoledronic acid effectively targets lung cancer cells by inhibition of protein prenylation

    International Nuclear Information System (INIS)

    Xie, Fan; Li, Pengcheng; Gong, Jianhua; Zhang, Jiahong; Ma, Jingping

    2015-01-01

    Aberrant activation of oncoproteins such as members of the Ras family is common in human lung cancers. The proper function of Ras largely depends on a post-translational modification termed prenylation. Bisphosphonates have been shown to inhibit prenylation in cancer cells. In this study, we show that zoledronic acid, a third generation bisphosphonate, is effective in targeting lung cancer cells. This is achieved by the induction of apoptosis and inhibition of proliferation, through suppressing the activation of downstream Ras and EGFR signalling by zoledronic acid. The combination of zoledronic acid and paclitaxel or cisplatin (commonly used chemotherapeutic drugs for lung cancer) augmented the activity of either drug alone in in vitro lung cancer cellular system and in vivo lung xenograft mouse model. Importantly, zoledronic acid inhibits protein prenylation as shown by the increased levels of unprenylated Ras and Rap1A. In addition, the effects of zoledronic acid were reversed in the presence of geranylgeraniol and farnesol, further confirming that mechanism of zoledroinc acid's action in lung cancer cells is through prenylation inhibition. Since zoledronic acid is already available for clinic use, these results suggest that it may be an effective addition to the armamentarium of drugs for the treatment of lung cancer. - Highlights: • Zoledronic acid (ZA) is effectively against lung cancer cells in vitro and in vivo. • ZA acts on lung cancer cells through inhibition of protein prenylation. • ZA suppresses global downstream phosphorylation of Ras signalling. • ZA enhances the effects of chemotherapeutic drugs in lung cancer cells.

  2. The bisphosphonate zoledronic acid effectively targets lung cancer cells by inhibition of protein prenylation

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Fan [Department of Respiratory Medicine, Jingzhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou (China); Li, Pengcheng [Department of Oncology, Wuhan Union Hospital Affiliated to Huazhong University of Science and Technology, Wuhan (China); Gong, Jianhua; Zhang, Jiahong [Department of Respiratory Medicine, Jingzhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou (China); Ma, Jingping, E-mail: mjpjzhospital@hotmail.com [Department of Respiratory Medicine, Jingzhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou (China)

    2015-11-27

    Aberrant activation of oncoproteins such as members of the Ras family is common in human lung cancers. The proper function of Ras largely depends on a post-translational modification termed prenylation. Bisphosphonates have been shown to inhibit prenylation in cancer cells. In this study, we show that zoledronic acid, a third generation bisphosphonate, is effective in targeting lung cancer cells. This is achieved by the induction of apoptosis and inhibition of proliferation, through suppressing the activation of downstream Ras and EGFR signalling by zoledronic acid. The combination of zoledronic acid and paclitaxel or cisplatin (commonly used chemotherapeutic drugs for lung cancer) augmented the activity of either drug alone in in vitro lung cancer cellular system and in vivo lung xenograft mouse model. Importantly, zoledronic acid inhibits protein prenylation as shown by the increased levels of unprenylated Ras and Rap1A. In addition, the effects of zoledronic acid were reversed in the presence of geranylgeraniol and farnesol, further confirming that mechanism of zoledroinc acid's action in lung cancer cells is through prenylation inhibition. Since zoledronic acid is already available for clinic use, these results suggest that it may be an effective addition to the armamentarium of drugs for the treatment of lung cancer. - Highlights: • Zoledronic acid (ZA) is effectively against lung cancer cells in vitro and in vivo. • ZA acts on lung cancer cells through inhibition of protein prenylation. • ZA suppresses global downstream phosphorylation of Ras signalling. • ZA enhances the effects of chemotherapeutic drugs in lung cancer cells.

  3. Multidrug resistance and retroviral transduction potential in human small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Theilade, M D; Gram, G J; Jensen, P B

    1999-01-01

    Multidrug resistance (MDR) remains a major problem in the successful treatment of small cell lung cancer (SCLC). New treatment strategies are needed, such as gene therapy specifically targeting the MDR cells in the tumor. Retroviral LacZ gene-containing vectors that were either pseudotyped...... for the gibbon ape leukemia virus (GALV-1) receptor or had specificity for the amphotropic murine leukemia virus (MLV-A) receptor were used for transduction of five SCLC cell lines differing by a range of MDR mechanisms. Transduction efficiencies in these cell lines were compared by calculating the percentage...... of blue colonies after X-Gal staining of the cells grown in soft agar. All examined SCLC cell lines were transducible with either vector. Transduction efficiencies varied from 5.7% to 33.5% independent of the presence of MDR. These results indicate that MDR does not severely impair transduction of SCLC...

  4. Wnt/β-catenin signaling regulates cancer stem cells in lung cancer A549 cells

    International Nuclear Information System (INIS)

    Teng, Ying; Wang, Xiuwen; Wang, Yawei; Ma, Daoxin

    2010-01-01

    Wnt/β-catenin signaling plays an important role not only in cancer, but also in cancer stem cells. In this study, we found that β-catenin and OCT-4 was highly expressed in cisplatin (DDP) selected A549 cells. Stimulating A549 cells with lithium chloride (LiCl) resulted in accumulation of β-catenin and up-regulation of a typical Wnt target gene cyclin D1. This stimulation also significantly enhanced proliferation, clone formation, migration and drug resistance abilities in A549 cells. Moreover, the up-regulation of OCT-4, a stem cell marker, was observed through real-time PCR and Western blotting. In a reverse approach, we inhibited Wnt signaling by knocking down the expression of β-catenin using RNA interference technology. This inhibition resulted in down-regulation of the Wnt target gene cyclin D1 as well as the proliferation, clone formation, migration and drug resistance abilities. Meanwhile, the expression of OCT-4 was reduced after the inhibition of Wnt/β-catenin signaling. Taken together, our study provides strong evidence that canonical Wnt signaling plays an important role in lung cancer stem cell properties, and it also regulates OCT-4, a lung cancer stem cell marker.

  5. Regulation of cytochrome P4501A1 expression by hyperoxia in human lung cell lines: Implications for hyperoxic lung injury

    International Nuclear Information System (INIS)

    Bhakta, Kushal Y.; Jiang, Weiwu; Couroucli, Xanthi I.; Fazili, Inayat S.; Muthiah, Kathirvel; Moorthy, Bhagavatula

    2008-01-01

    Supplemental oxygen, used to treat pulmonary insufficiency in newborns, contributes to the development of bronchopulmonary dysplasia (BPD). Cytochrome P4501A enzymes are induced by hyperoxia in animal models, but their role in human systems is unknown. Here we investigated the molecular mechanisms of induction of CYP1A1 by hyperoxia in human lung cell lines. Three human lung cell lines were exposed to hyperoxia (95% O2) for 0-72 h, and CYP1A1 activities, apoprotein contents, and mRNA levels were determined. Hyperoxia significantly induced CYP1A1 activity and protein contents (2-4 fold), and mRNA levels (30-40 fold) over control in each cell line. Transfection of a CYP1A1 promoter/luciferase reporter construct, followed by hyperoxia (4-72 h), showed marked (2-6 fold) induction of luciferase expression. EMSA and siRNA experiments strongly suggest that the Ah receptor (AHR) is involved in the hyperoxic induction of CYP1A1. MTT reduction assays showed attenuation of cell injury with the CYP1A1 inducer beta-naphthoflavone (BNF). Our results strongly suggest that hyperoxia transcriptionally activates CYP1A1 expression in human lung cell lines by AHR-dependent mechanisms, and that CYP1A1 induction is associated with decreased toxicity. This novel finding of induction of CYP1A1 in the absence of exogenous AHR ligands could lead to novel interventions in the treatment of BPD

  6. The safety and efficacy of carboplatin plus nanoparticle albumin-bound paclitaxel in the treatment of non-small cell lung cancer patients with interstitial lung disease.

    Science.gov (United States)

    Yasuda, Yuichiro; Hattori, Yoshihiro; Tohnai, Rie; Ito, Shoichi; Kawa, Yoshitaka; Kono, Yuko; Urata, Yoshiko; Nogami, Munenobu; Takenaka, Daisuke; Negoro, Shunichi; Satouchi, Miyako

    2018-01-01

    The optimal chemotherapy regimen for non-small cell lung cancer patients with interstitial lung disease is unclear. We therefore investigated the safety and efficacy of carboplatin plus nab-paclitaxel as a first-line regimen for non-small cell lung cancer in patients with interstitial lung disease. We retrospectively reviewed advanced non-small cell lung cancer patients with interstitial lung disease who received carboplatin plus nab-paclitaxel as a first-line chemotherapy regimen at Hyogo Cancer Center between February 2013 and August 2016. interstitial lung disease was diagnosed according to the findings of pretreatment chest high-resolution computed tomography. Twelve patients were included (male, n = 11; female, n = 1). The overall response rate was 67% and the disease control rate was 100%. The median progression free survival was 5.1 months (95% CI: 2.9-8.3 months) and the median overall survival was 14.9 months (95% CI: 4.8-not reached). A chemotherapy-related acute exacerbation of interstitial lung disease was observed in one patient; the extent of this event was Grade 2. There were no treatment-related deaths. Carboplatin plus nab-paclitaxel, as a first-line chemotherapy regimen for non-small cell lung cancer, showed favorable efficacy and safety in patients with preexisting interstitial lung disease. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  7. Effective avoidance of a functional spect-perfused lung using intensity modulated radiotherapy (IMRT) for non-small cell lung cancer (NSCLC): An update of a planning study

    International Nuclear Information System (INIS)

    Lavrenkov, Konstantin; Singh, Shalini; Christian, Judith A.; Partridge, Mike; Nioutsikou, Elena; Cook, Gary; Bedford, James L.; Brada, Michael

    2009-01-01

    IMRT and 3-dimensional conformal radiotherapy (3-DCRT) plans of 25 patients with non-small cell lung (NSCLC) were compared in terms of planning target volume (PTV) coverage and sparing of functional lung (FL) defined by a SPECT perfusion scan. IMRT resulted in significant reduction of functional V 20 and mean lung dose in stage III patients with inhomogeneous hypoperfusion. If the dose to FL is shown to be the determinant of lung toxicity, IMRT would allow for effective dose escalation by specific avoidance of functional lung.

  8. Treatment of non-small-cell lung cancer in elderly patients

    International Nuclear Information System (INIS)

    Berzinec, P.

    2017-01-01

    Lung cancer is globally the leading cause of cancer-related deaths. Majority of lung cancer cases is diagnosed in elderly patients, aged ≥65 years. In Slovakia, 54% of new lung cancer cases are diagnosed in patients aged ≥65 years, and about 40% in patients aged ≥70 years. An experts panel created by EORTC (European Organisation for Research and Treatment of Cancer) and ISGO (International Society for Geriatric Oncology) published in 2014 updated recommendations for treatment of elderly patients with non-small-cell lung cancer. The brief overview of these recommendations, including a view of the new data published since 2014, is given in this article. (author)

  9. The innate immune response in fetal lung mesenchymal cells targets VEGFR2 expression and activity.

    Science.gov (United States)

    Medal, Rachel M; Im, Amanda M; Yamamoto, Yasutoshi; Lakhdari, Omar; Blackwell, Timothy S; Hoffman, Hal M; Sahoo, Debashis; Prince, Lawrence S

    2017-06-01

    In preterm infants, soluble inflammatory mediators target lung mesenchymal cells, disrupting airway and alveolar morphogenesis. However, how mesenchymal cells respond directly to microbial stimuli remains poorly characterized. Our objective was to measure the genome-wide innate immune response in fetal lung mesenchymal cells exposed to the bacterial endotoxin lipopolysaccharide (LPS). With the use of Affymetrix MoGene 1.0st arrays, we showed that LPS induced expression of unique innate immune transcripts heavily weighted toward CC and CXC family chemokines. The transcriptional response was different between cells from E11, E15, and E18 mouse lungs. In all cells tested, LPS inhibited expression of a small core group of genes including the VEGF receptor Vegfr2 Although best characterized in vascular endothelial populations, we demonstrated here that fetal mouse lung mesenchymal cells express Vegfr2 and respond to VEGF-A stimulation. In mesenchymal cells, VEGF-A increased cell migration, activated the ERK/AKT pathway, and promoted FOXO3A nuclear exclusion. With the use of an experimental coculture model of epithelial-mesenchymal interactions, we also showed that VEGFR2 inhibition prevented formation of three-dimensional structures. Both LPS and tyrosine kinase inhibition reduced three-dimensional structure formation. Our data suggest a novel mechanism for inflammation-mediated defects in lung development involving reduced VEGF signaling in lung mesenchyme. Copyright © 2017 the American Physiological Society.

  10. Proton Beam Therapy for Non-Small Cell Lung Cancer: Current Clinical Evidence and Future Directions

    International Nuclear Information System (INIS)

    Berman, Abigail T.; James, Sara St.; Rengan, Ramesh

    2015-01-01

    Lung cancer is the leading cancer cause of death in the United States. Radiotherapy is an essential component of the definitive treatment of early-stage and locally-advanced lung cancer, and the palliative treatment of metastatic lung cancer. Proton beam therapy (PBT), through its characteristic Bragg peak, has the potential to decrease the toxicity of radiotherapy, and, subsequently improve the therapeutic ratio. Herein, we provide a primer on the physics of proton beam therapy for lung cancer, present the existing data in early-stage and locally-advanced non-small cell lung cancer (NSCLC), as well as in special situations such as re-irradiation and post-operative radiation therapy. We then present the technical challenges, such as anatomic changes and motion management, and future directions for PBT in lung cancer, including pencil beam scanning

  11. Current and future molecular diagnostics in non-small-cell lung cancer.

    Science.gov (United States)

    Li, Chun Man; Chu, Wing Ying; Wong, Di Lun; Tsang, Hin Fung; Tsui, Nancy Bo Yin; Chan, Charles Ming Lok; Xue, Vivian Wei Wen; Siu, Parco Ming Fai; Yung, Benjamin Yat Ming; Chan, Lawrence Wing Chi; Wong, Sze Chuen Cesar

    2015-01-01

    The molecular investigation of lung cancer has opened up an advanced area for the diagnosis and therapeutic management of lung cancer patients. Gene alterations in cancer initiation and progression provide not only information on molecular changes in lung cancer but also opportunities in advanced therapeutic regime by personalized targeted therapy. EGFR mutations and ALK rearrangement are important predictive biomarkers for the efficiency of tyrosine kinase inhibitor treatment in lung cancer patients. Moreover, epigenetic aberration and microRNA dysregulation are recent advances in the early detection and monitoring of lung cancer. Although a wide range of molecular tests are available, standardization and validation of assay protocols are essential for the quality of the test outcome. In this review, current and new advancements of molecular biomarkers for non-small-cell lung cancer will be discussed. Recommendations on future development of molecular diagnostic services will also be explored.

  12. Proton Beam Therapy for Non-Small Cell Lung Cancer: Current Clinical Evidence and Future Directions

    Directory of Open Access Journals (Sweden)

    Abigail T. Berman

    2015-07-01

    Full Text Available Lung cancer is the leading cancer cause of death in the United States. Radiotherapy is an essential component of the definitive treatment of early-stage and locally-advanced lung cancer, and the palliative treatment of metastatic lung cancer. Proton beam therapy (PBT, through its characteristic Bragg peak, has the potential to decrease the toxicity of radiotherapy, and, subsequently improve the therapeutic ratio. Herein, we provide a primer on the physics of proton beam therapy for lung cancer, present the existing data in early-stage and locally-advanced non-small cell lung cancer (NSCLC, as well as in special situations such as re-irradiation and post-operative radiation therapy. We then present the technical challenges, such as anatomic changes and motion management, and future directions for PBT in lung cancer, including pencil beam scanning.

  13. Small cell lung cancer transformation from EGFR-mutated lung adenocarcinoma: A case report and literatures review.

    Science.gov (United States)

    Liu, Yangyang

    2018-06-03

    Epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have markedly improved the response of non-small cell lung cancer (NSCLC) with EGFR-mutant patients. However, these patients inevitably come cross acquired resistance to EGFR-TKIs. The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) following treatment with EGFR-TKIs is rare, which leads to resistance to EGFR-TKIs. The present case concerns a case of a 38-year-old man presenting with cough and dyspnea. Radical resection was performed and confirmed an EGFR exon 21 L858R lung adenocarcinoma. However, the patient suffered pleural metastasis after successful treatment with surgery and adjuvant treatment. So, erlotinib was administered with 18 months. Because of enlarged pleural nodule, repeat biopsy identified an SCLC and chemotherapy was started. However, despite the brief success of chemotherapy, our patient suffered brain metastasis. Our case emaphsizes both the profile of transformation from NSCLC to SCLC and the importance of repeat biopsy dealing with drug resistance. We also summarize the clinical characteristics, mechanisms, predictors of SCLC transformation, treatment after transformation and other types of transformation to SCLC.

  14. Role of inflammatory cells and adenosine in lung ischemia reoxygenation injury using a model of lung donation after cardiac death.

    Science.gov (United States)

    Smail, Hassiba; Baste, Jean-Marc; Gay, Arnaud; Begueret, Hugues; Noël, Romain; Morin, Jean-Paul; Litzler, Pierre-Yves

    2016-04-01

    The objective of this study is to analyze the role of inflammation in the lung ischemia reperfusion (IR) injury and determine the protective role of adenosine in an in vitro lung transplantation model. We used a hybrid model of lung donor after cardiac death, with warm ischemia in corpo of varying duration (2 h, 4 h) followed by in vitro lung slices culture for reoxygenation (1 h, 4 h and 24 h), in the presence or not of lymphocytes and of adenosine. To quantify the inflammatory lesions, we performed TNFα, IL2 assays, and histological analysis. In this model of a nonblood perfused system, the addition of lymphocytes during reoxygenation lead to higher rates of TNFα and IL2 after 4 h than after 2 h of warm ischemia (P < .05). These levels increased with the duration of reoxygenation and were maximum at 24 h (P < .05). In the presence of adenosine TNFα and IL2 decreased. After 2 h of warm ischemia, we observed a significant inflammatory infiltration, alveolar thickening and a necrosis of the bronchiolar cells. After 4 h of warm ischemia, alveolar cells necrosis was associated. This model showed that lymphocytes increased the inflammatory response and the histological lesions after 4 h of warm ischemia and that adenosine could have an anti-inflammatory role with potential reconditioning action when used in the pneumoplegia solution.

  15. Inhibitory Activity of (+-Usnic Acid against Non-Small Cell Lung Cancer Cell Motility.

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    Yi Yang

    Full Text Available Lichens are symbiotic organisms that produce various unique chemicals that can be used for pharmaceutical purposes. With the aim of screening new anti-cancer agents that inhibit cancer cell motility, we tested the inhibitory activity of seven lichen species collected from the Romanian Carpathian Mountains against migration and invasion of human lung cancer cells and further investigated the molecular mechanisms underlying their anti-metastatic activity. Among them, Alectoria samentosa, Flavocetraria nivalis, Alectoria ochroleuca, and Usnea florida showed significant inhibitory activity against motility of human lung cancer cells. HPLC results showed that usnic acid is the main compound in these lichens, and (+-usnic acid showed similar inhibitory activity that crude extract have. Mechanistically, β-catenin-mediated TOPFLASH activity and KITENIN-mediated AP-1 activity were decreased by (+-usnic acid treatment in a dose-dependent manner. The quantitative real-time PCR data showed that (+-usnic acid decreased the mRNA level of CD44, Cyclin D1 and c-myc, which are the downstream target genes of both β-catenin/LEF and c-jun/AP-1. Also, Rac1 and RhoA activities were decreased by treatment with (+-usnic acid. Interestingly, higher inhibitory activity for cell invasion was observed when cells were treated with (+-usnic acid and cetuximab. These results implied that (+-usnic acid might have potential activity in inhibition of cancer cell metastasis, and (+-usnic acid could be used for anti-cancer therapy with a distinct mechanisms of action.

  16. Chlorella vulgaris Induces Apoptosis of Human Non-Small Cell Lung Carcinoma (NSCLC) Cells.

    Science.gov (United States)

    Zhang, Zhi-Dong; Liang, Kai; Li, Kun; Wang, Guo-Quan; Zhang, Ke-Wei; Cai, Lei; Zhai, Shui-Ting; Chou, Kuo-Chen

    2017-01-01

    Chlorella vulgaris (C. vulgaris), a unicellular green microalga, has been widely used as a food supplement and reported to have antioxidant and anticancer properties. The current study was designed to assess the cytotoxic, apoptotic, and DNA-damaging effects of C. vulgaris growth factor (CGF), hot water C. vulgaris extracts, inlung tumor A549 and NCI-H460 cell lines. A549 cells, NCI-H460 cells, and normal human fibroblasts were treated with CGF at various concentrations (0-300 μg/ml) for 24 hr. The comet assay and γH2AX assay showed DNA damage in A549 and NCI-H460 cells upon CGF exposure. Evaluation of apoptosis by the TUNEL assay and DNA fragmentation analysis by agarose gel electrophoresis showed that CGF induced apoptosis in A549 and NCI-H460 cells. Chlorella vulgaris hot water extract induced apoptosis and DNA damage in human lung carcinoma cells. CGF can thus be considered a potential cytotoxic or genotoxic drug for treatment of lung carcinoma. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Inhibitory Activity of (+)-Usnic Acid against Non-Small Cell Lung Cancer Cell Motility

    Science.gov (United States)

    Yang, Yi; Nguyen, Thanh Thi; Jeong, Min-Hye; Crişan, Florin; Yu, Young Hyun; Ha, Hyung-Ho; Choi, Kyung Hee; Jeong, Hye Gwang; Jeong, Tae Cheon; Lee, Kwang Youl; Kim, Kyung Keun; Hur, Jae-Seoun; Kim, Hangun

    2016-01-01

    Lichens are symbiotic organisms that produce various unique chemicals that can be used for pharmaceutical purposes. With the aim of screening new anti-cancer agents that inhibit cancer cell motility, we tested the inhibitory activity of seven lichen species collected from the Romanian Carpathian Mountains against migration and invasion of human lung cancer cells and further investigated the molecular mechanisms underlying their anti-metastatic activity. Among them, Alectoria samentosa, Flavocetraria nivalis, Alectoria ochroleuca, and Usnea florida showed significant inhibitory activity against motility of human lung cancer cells. HPLC results showed that usnic acid is the main compound in these lichens, and (+)-usnic acid showed similar inhibitory activity that crude extract have. Mechanistically, β-catenin-mediated TOPFLASH activity and KITENIN-mediated AP-1 activity were decreased by (+)-usnic acid treatment in a dose-dependent manner. The quantitative real-time PCR data showed that (+)-usnic acid decreased the mRNA level of CD44, Cyclin D1 and c-myc, which are the downstream target genes of both β-catenin/LEF and c-jun/AP-1. Also, Rac1 and RhoA activities were decreased by treatment with (+)-usnic acid. Interestingly, higher inhibitory activity for cell invasion was observed when cells were treated with (+)-usnic acid and cetuximab. These results implied that (+)-usnic acid might have potential activity in inhibition of cancer cell metastasis, and (+)-usnic acid could be used for anti-cancer therapy with a distinct mechanisms of action. PMID:26751081

  18. Middle infrared radiation induces G2/M cell cycle arrest in A549 lung cancer cells.

    Science.gov (United States)

    Chang, Hsin-Yi; Shih, Meng-Her; Huang, Hsuan-Cheng; Tsai, Shang-Ru; Juan, Hsueh-Fen; Lee, Si-Chen

    2013-01-01

    There were studies investigating the effects of broadband infrared radiation (IR) on cancer cell, while the influences of middle-infrared radiation (MIR) are still unknown. In this study, a MIR emitter with emission wavelength band in the 3-5 µm region was developed to irradiate A549 lung adenocarcinoma cells. It was found that MIR exposure inhibited cell proliferation and induced morphological changes by altering the cellular distribution of cytoskeletal components. Using quantitative PCR, we found that MIR promoted the expression levels of ATM (ataxia telangiectasia mutated), ATR (ataxia-telangiectasia and Rad3-related and Rad3-related), TP53 (tumor protein p53), p21 (CDKN1A, cyclin-dependent kinase inhibitor 1A) and GADD45 (growth arrest and DNA-damage inducible), but decreased the expression levels of cyclin B coding genes, CCNB1 and CCNB2, as well as CDK1 (Cyclin-dependent kinase 1). The reduction of protein expression levels of CDC25C, cyclin B1 and the phosphorylation of CDK1 at Thr-161 altogether suggest G(2)/M arrest occurred in A549 cells by MIR. DNA repair foci formation of DNA double-strand breaks (DSB) marker γ-H2AX and sensor 53BP1 was induced by MIR treatment, it implies the MIR induced G(2)/M cell cycle arrest resulted from DSB. This study illustrates a potential role for the use of MIR in lung cancer therapy by initiating DSB and blocking cell cycle progression.

  19. Presence of urokinase plasminogen activator, its inhibitor and receptor in small cell lung cancer and non-small cell lung cancer

    DEFF Research Database (Denmark)

    Pappot, H.; Pfeiffer, P.; Grøndahl Hansen, J.

    1997-01-01

    Spreading of cancer cells is dependent on the combined action of several proteolytic enzymes, such as serine proteases, comprising the urokinase pathway of plasminogen activation. Previous studies of lung cancer indicate that expression, localization and prognostic impact of the components...... of the plasminogen activation system differ in the different non-small cell lung cancer (NSCLC) types, whereas the expression of the components in small cell lung cancer (SCLC) has only sparingly been investigated. In the present study we investigate the presence of the components of the plasminogen activation...... that the plasminogen activation system could play a role in this type of cancer during invasion. In addition a difference in the levels of the components of the plasminogen activation system in NSCLC and SCLC is found, which could contribute to the differences in biology....

  20. TGF-β1 induced epithelial to mesenchymal transition (EMT in human bronchial epithelial cells is enhanced by IL-1β but not abrogated by corticosteroids

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    Zuraw Bruce L

    2009-10-01

    Full Text Available Abstract Background Chronic persistent asthma is characterized by ongoing airway inflammation and airway remodeling. The processes leading to airway remodeling are poorly understood, and there is increasing evidence that even aggressive anti-inflammatory therapy does not completely prevent this process. We sought to investigate whether TGFβ1 stimulates bronchial epithelial cells to undergo transition to a mesenchymal phenotype, and whether this transition can be abrogated by corticosteroid treatment or enhanced by the pro-inflammatory cytokine IL-1β. Methods BEAS-2B and primary normal human bronchial epithelial cells were stimulated with TGFβ1 and expression of epithelial and mesenchymal markers assessed by quantitative real-time PCR, immunoblotting, immunofluorescence microscopy and zymography. In some cases the epithelial cells were also incubated with corticosteroids or IL-1β. Results were analyzed using non-parametric statistical tests. Results Treatment of BEAS-2B or primary human bronchial epithelial cells with TGFβ1 significantly reduced the expression level of the epithelial adherence junction protein E-cadherin. TGFβ1 then markedly induced mesenchymal marker proteins such as collagen I, tenascin C, fibronectin and α-smooth muscle actin mRNA in a dose dependant manner. The process of mesenchymal transition was accompanied by a morphological change towards a more spindle shaped fibroblast cell type with a more motile and invasive phenotype. Corticosteroid pre-treatment did not significantly alter the TGFβ1 induced transition but IL-1β enhanced the transition. Conclusion Our results indicate, that TGFβ1 can induce mesenchymal transition in the bronchial epithelial cell line and primary cells. Since asthma has been strongly associated with increased expression of TGFβ1 in the airway, epithelial to mesenchymal transition may contribute to the contractile and fibrotic remodeling process that accompanies chronic asthma.

  1. Identification of Gene Biomarkers for Distinguishing Small-Cell Lung Cancer from Non-Small-Cell Lung Cancer Using a Network-Based Approach

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    Fei Long

    2015-01-01

    Full Text Available Lung cancer consists of two main subtypes: small-cell lung cancer (SCLC and non-small-cell lung cancer (NSCLC that are classified according to their physiological phenotypes. In this study, we have developed a network-based approach to identify molecular biomarkers that can distinguish SCLC from NSCLC. By identifying positive and negative coexpression gene pairs in normal lung tissues, SCLC, or NSCLC samples and using functional association information from the STRING network, we first construct a lung cancer-specific gene association network. From the network, we obtain gene modules in which genes are highly functionally associated with each other and are either positively or negatively coexpressed in the three conditions. Then, we identify gene modules that not only are differentially expressed between cancer and normal samples, but also show distinctive expression patterns between SCLC and NSCLC. Finally, we select genes inside those modules with discriminating coexpression patterns between the two lung cancer subtypes and predict them as candidate biomarkers that are of diagnostic use.

  2. Nubp1 is required for lung branching morphogenesis and distal progenitor cell survival in mice.

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    Carsten Schnatwinkel

    Full Text Available The lung is a complex system in biology and medicine alike. Whereas there is a good understanding of the anatomy and histology of the embryonic and adult lung, less is known about the molecular details and the cellular pathways that ultimately orchestrate lung formation and affect its health. From a forward genetic approach to identify novel genes involved in lung formation, we identified a mutated Nubp1 gene, which leads to syndactyly, eye cataract and lung hypoplasia. In the lung, Nubp1 is expressed in progenitor cells of the distal epithelium. Nubp1(m1Nisw mutants show increased apoptosis accompanied by a loss of the distal progenitor markers Sftpc, Sox9 and Foxp2. In addition, Nubp1 mutation disrupts localization of the polarity protein Par3 and the mitosis relevant protein Numb. Using knock-down studies in lung epithelial cells, we also demonstrate a function of Nubp1 in regulating centrosome dynamics and microtubule organization. Together, Nubp1 represents an essential protein for lung progenitor survival by coordinating vital cellular processes including cell polarity and centrosomal dynamics.

  3. Methylation Status of miR-182 Promoter in Lung Cancer Cell Lines

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    Yongwen LI

    2015-05-01

    Full Text Available Background and objective It has been proven that the abnormal expression of miR-182 was related to the occurrence and development of tumors. The aim of this study is to explore the relationship between the methylation of miR-182 promoter and its expression in lung cancer cell lines. Methods Real-time quantitative PCR and methylation-specific PCR were used to detect the expression level of miR-182 and its promoter methylation status in five lung cancer cell lines (A549, L9981, NL9980, 95C and 95D. DNA sequencing was used to confirm the methylation results. Results The level of miR-182 expression significantly differs among these lung cancer cell lines. The highly metastatic human lung cancer cell lines, namely, A549 and L9981, demonstrate a relatively lower expression level of miR-182 compared with the lowly metastatic human lung cancer cell line 95C. Methylation-specific PCR and DNA sequencing assay results indicate that these lung cancer cell lines present different levels of miR-182 promoter methylation, and the highest methylation level is observed in A549 cells. Furthermore, the expression of miR-182 in these cell lines significantly increases when treated with 10 μM 5’-Aza-dC. Conclusion DNA methylation occurs in the miR-182 promoter region in lung cancer cell lines. This methylation can regulate the expression level of miR-182. Further study must be conducted to explore the function of miR-182 promoter methylation in lung cancer occurrence and development.

  4. HOXA9 inhibits migration of lung cancer cells and its hypermethylation is associated with recurrence in non-small cell lung cancer.

    Science.gov (United States)

    Hwang, Jung-Ah; Lee, Bo Bin; Kim, Yujin; Hong, Seung-Hyun; Kim, Young-Ho; Han, Joungho; Shim, Young Mog; Yoon, Chae-Yeong; Lee, Yeon-Su; Kim, Duk-Hwan

    2015-06-01

    This study was aimed at understanding the clinicopathological significance of HOXA9 hypermethylation in non-small cell lung cancer (NSCLC). HOXA9 hypermethylation was characterized in six lung cancer cell lines, and its clinicopathological significance was analyzed using methylation-specific PCR in 271 formalin-fixed paraffin-embedded tissues and 27 fresh-frozen tumor and matched normal tissues from 298 NSCLC patients, and Ki-67 expression was analyzed using immunohistochemistry. The promoter region of HOXA9 was highly methylated in six lung cancer cell lines, but not in normal bronchial epithelial cells. The loss of expression was restored by treatment of the cells with a demethylating agent, 5-aza-2'-deoxycytidine (5-Aza-dC). Transient transfection of HOXA9 into H23 lung cancer cells resulted in the inhibition of cell migration but not proliferation. Conversely, sequence-specific siRNA-mediated knockdown of HOXA9 enhanced cell migration. The mRNA levels of HOXA9 in 27 fresh-frozen tumor tissues were significantly lower than in matched normal tissues (Precurrence-free survival (hazard ratio=3.98, 95% confidence interval = 1.07-17.09, P=0.01) in never-smokers, after adjusting for age, sex, tumor size, adjuvant therapy, pathologic stage, and histology. In conclusion, the present study suggests that HOXA9 inhibits migration of lung cancer cells and its hypermethylation is an independent prognostic factor for recurrence-free survival in never-smokers with NSCLC. © 2014 Wiley Periodicals, Inc.

  5. Acacetin enhances the therapeutic efficacy of doxorubicin in non-small-cell lung carcinoma cells.

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    Reenu Punia

    Full Text Available Anthracyclines are efficient and potent agents to treat broad range of cancers but cytotoxicity induced by them limits their use in therapeutics. Use of plant-derived agents help to prevent or delay the process of cancer progression and their combination increases the anti-cancer potential of mainstream compound. However, multidrug resistance is major cause of treatment failure in cancer patients.In this study, combination treatments of fisetin or acacetin with doxorubicin were explored for their potential synergistic effect on non-small-cell lung carcinoma (NSCLC cells.During this study, NSCLC model cell lines A549 and H1299 were used to determine the combinatorial effect of phytochemicals namly acacetin and fisetin with doxorubicin.The effects of individual compounds and their combination on cell viability, clonogenic potential and cell cycle progression were studied. Efflux of doxorubicin was measured by spectrofluorophotometer, whereas accumulation inside the cells was analyzed by flow cytometry and confocal microscopy. Expression of MDR1 was checked by semi-quantitative PCR.The results showed that the cell viability of A549 and H1299 cells were significantly decreased in time- and dose-dependent manner, although A549 cells showed more sensitivity toward doxorubicin than H1299 cells. Mostly, combination of doxorubicin showed good synergy with acacetin in both the cell lines whereas, fisetin exerted synergistic effect only at 72 h of treatment in H1299 cells. Acacetin with doxorubicin caused G2/M arrest by downregulating CDK-cyclin complex in A549 cells. Acacetin-doxorubicin combination decreased the clonogenic potential of A549 and H1299 cells upto 82% and 59%, respectively, as compared to control. Acacetin also decreased efflux of doxorubicin by 59% after 30 mins of exposure to A549 cells and further increased accumulation of doxorubicin inside the cells upto 55% in 2 h. The modulatory effect of acacetin-doxorubicin combination on

  6. Prophylactic cranial irradiation in patients with small cell lung cancer

    DEFF Research Database (Denmark)

    Ramlov, Anne; Tietze, Anna; Khalil, Azza Ahmed

    2012-01-01

    BACKGROUND: Prophylactic cerebral irradiation (PCI) is a standard treatment for all small cell lung cancer (SCLC) patients with response to chemotherapy. The aims of this study were: to evaluate patients undergoing PCI with regard to cerebral recurrence rate, site of recurrence, and overall...... retrospectively with regard to disease stage, treatment, date of PCI, steroid dose during PCI, toxicity, time to recurrence, site of recurrence and time of death. The median follow up time was 16.6months (range 3-54months). RESULTS: Of the 118 patients undergoing PCI, 74 had limited disease (LD-SCLC) and 44 had...... extensive disease (ED-SCLC). The median age was 65years (range 46-80years). The median overall survival of all patients from the time of diagnosis was 16.0months (CI 95% 13.0-19.0), in LD-SCLC it was 24.0months (CI 95% 19.6-28.3), and in ED-SCLC it was 12.0months (CI 95% 9.6-14.4). Twenty-one patients (17...

  7. Cetuximab and biomarkers in non-small-cell lung carcinoma

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    Patil N

    2012-07-01

    Full Text Available Nitin Patil, Mohammed Abba, Heike AllgayerDepartment of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg and Molecular Oncology of Solid Tumors Unit, German Cancer Research Center (DKFZ, Heidelberg, GermanyAbstract: Cancer progression is a highly complex process that is driven by a constellation of deregulated signaling pathways and key molecular events. In non-small-cell lung cancer (NSCLC, as in several other cancer types, the epidermal growth factor receptor (EGFR and its downstream signaling components represent a key axis that has been found not only to trigger cancer progression but also to support advanced disease leading to metastasis. Two major therapeutic approaches comprising monoclonal antibodies and small molecule tyrosine kinase inhibitors have so far been used to target this pathway, with a combination of positive, negative, and inconsequential results, as judged by patient survival indices. Since these drugs are expensive and not all patients derive benefits from taking them, it has become both pertinent and paramount to identify biomarkers that can predict not only beneficial response but also resistance. This review focuses on the chimeric monoclonal antibody, cetuximab, its application in the treatment of NSCLC, and the biomarkers that may guide its use in the clinical setting. A special emphasis is placed on the EGFR, including its structural and mechanistic attributes.Keywords: NSCLC, cetuximab, biomarker, cancer progression

  8. Cetuximab for treating non-small cell lung cancer.

    Science.gov (United States)

    Mazzarella, Luca; Guida, Alessandro; Curigliano, Giuseppe

    2018-04-01

    Epidermal Growth Factor Receptor (EGFR)-dependent signaling plays a crucial role in epithelial cancer biology, and dictated the development of several targeting agents. The mouse-human chimeric antibody Cetuximab was among the first to be developed. After about two decades of clinical research it has gained a significant place in the management of advanced colorectal and head and neck cancers, whereas its development in non small cell lung cancer (NSCLC) has not led to a place in routine clinical practice, because of marginal clinical benefit despite statistically significant Phase III trials. Recent data from ongoing trials suggest that more careful selection based on molecular markers may identify good responders. Areas covered: In this article, the authors review the literature concerning basic science studies identifying EGFR as a therapeutic target, pharmacological development of Cetuximab, its pharmacodynamics and pharmacokinetics, and clinical trials on Cetuximab in NSCLC, focusing on recent findings on putative predictive biomarkers. Expert opinion: Cetuximab currently has no role in NSCLC treatment outside of research settings. We argue that failure to identify a predictive biomarker early on has hampered its chances to enter routine practice. Although recent research suggests benefit in highly selected patient subsets, its potential impact is severely dampened by lack of regulatory body approval and the emergence of competitors for the same niches.

  9. Radiotherapy in non-oat cell lung cancer

    International Nuclear Information System (INIS)

    Barriga T, O.; Echegaray, A.; Barriga T, L.; Mayer Z, T.

    1995-01-01

    96 clinical histories of patients with non-oat cell lung cancer treated with Rt or Rt post surgery from 1988 to 1990 in the National Institute of Neoplasmic Diseases were revised. most of the patients were in their is 60 and the range was between 30 and 91 years; 776 were male and 20 female. Epidermoid carcinoma was found in 53 cases, adenocarcinoma in 37, others in 4 and 2 have no histological data. Most were advanced cases with following distribution by clinical stages: I:0, II:3, IIIA: 21, IIIB:37, IV:33 and 2 no determined. In the present evaluation patients treated with systemic therapy had not been considered. All patients have been treated with external radiotherapy with Co-60 with different fractionation schedules. The present study evaluates the completion and the results about the clinical response making an intent to establish the best schedule because most of the patients have advanced illness with short hope of life. The clinical improvement was obtained in 53.12% with similar over life for the different fractionation schedules being only 4 patients alive. (authors). 9 refs., 9 tabs

  10. Radiofrequency Ablation for Early-Stage Nonsmall Cell Lung Cancer

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    Takao Hiraki

    2014-01-01

    Full Text Available This review examines studies of radiofrequency ablation (RFA of nonsmall cell lung cancer (NSCLC and discusses the role of RFA in treatment of early-stage NSCLC. RFA is usually performed under local anesthesia with computed tomography guidance. RFA-associated mortality, while being rare, can result from pulmonary events. RFA causes pneumothorax in up to 63% of cases, although pneumothorax requiring chest drainage occurs in less than 15% of procedures. Other severe complications are rare. After RFA of stage I NSCLC, 31–42% of patients show local progression. The 1-, 2-, 3-, and 5-year overall survival rates after RFA of stage I NSCLC were 78% to 100%, 53% to 86%, 36% to 88%, and 25% to 61%, respectively. The median survival time ranged from 29 to 67 months. The 1-, 2-, and 3-year cancer-specific survival rates after RFA of stage I NSCLC were 89% to 100%, 92% to 93%, and 59% to 88%, respectively. RFA has a higher local failure rate than sublobar resection and stereotactic body radiation therapy (SBRT. Therefore, RFA may currently be reserved for early-stage NSCLC patients who are unfit for sublobar resection or SBRT. Various technologies are being developed to improve clinical outcomes of RFA for early-stage NSCLC.

  11. Non small cell carcinoma of the lung: a retrospective study

    International Nuclear Information System (INIS)

    Stevens, G.; Firth, I.

    1992-01-01

    A retrospective study was undertaken in 1990 of 188 patients with the diagnosis of non small cell carcinoma of the lung referred to the Department of Radiation Oncology in 1984. Most patients (178 out of 188) received a course of radiotherapy. This was definitive in 23, palliative in 148 (primary site in 113, metastases in 16, primary plus metastases in 19) and postoperative in 7. This report is a 5 year follow-up of the 171 patients treated by radiation alone, to assess factors that influence survival. Palliative intent of treatment and poorer performance status were related significantly to increasing stage of disease. The effects of palliative treatment were recorded in 79 cases: in 71 there was a reduction in symptoms. The median survival from diagnosis was 8 months. Using univariate and multi-variate analyses, significant and independent prognostic factors for improved survival were good performance status, absence of systemic symptoms, lower tumour stage and curative intent of treatment (higher radiation dose). However the 5-year survival was only 2%. Long-term survival was associated predominantly with early stage disease but not with the type or intent of treatment. Age, sex, histology and apical site did not influence survival. These results are comparable to those found in the literature and emphasize the need to select patients carefully for either palliative or aggressive treatment. 29 refs., 4 tabs., 3 figs

  12. MEK inhibition in non-small cell lung cancer.

    Science.gov (United States)

    Stinchcombe, Thomas E; Johnson, Gary L

    2014-11-01

    KRAS mutations are the most common mutations in non-small cell lung cancer (NSCLC) with adenocarcinoma histology. KRAS mutations result in the activation of the RAF-MEK-ERK pathway, and agents that target RAF-MEK-ERK pathways have been investigated in KRAS mutant NSCLC. The two agents furthest in development are selumetinib and trametinib. Trametinib has greater binding for the MEK1/2 allosteric site, and generally has superior pharmacokinetics. A randomized phase II trial of docetaxel with and without selumetinib revealed that the combination resulted numerically superior overall survival, and a statistically significant improvement in progression-free survival and objective response rate. However, a concerning rate of hospital admission, grade 3 or 4 neutropenia, and febrile neutropenia was observed with the combination. Trials have investigated MEK inhibitors as single agents and in combination with erlotinib, and the data do not support the further development. The activity of MEK inhibitors appears to be similar in patients with KRAS mutant and wild-type NSCLC suggesting KRAS mutation status is not a reliable biomarker for efficacy. It is possible that mutations of genes in addition to KRAS mutations impact the activity of MEK inhibitors, or specific subsets of KRAS mutations may be resistant or susceptible to MEK inhibition. Other potential explanations are gene amplifications, alternative RNA splicing of genes resulting in activation of their protein products, and deregulation of noncoding RNAs and consequent altered protein expression. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  13. Refractory Lactic Acidosis in Small Cell Carcinoma of the Lung

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    Daniel J. Oh

    2017-01-01

    Full Text Available Background. Elevated lactate levels in critically ill patients are most often thought to be indicative of relative tissue hypoxia or type A lactic acidosis. Shock, severe anemia, and thromboembolic events can all cause elevated lactate due to tissue hypoperfusion, as well as the mitochondrial dysfunction thought to occur in sepsis and other critically ill states. Malignancy can also lead to elevation in lactate, a phenomenon described as type B lactic acidosis, which is much less commonly encountered in the critically ill. Case Presentation. We present the case of a 73-year-old Caucasian woman with type 2 diabetes and hypertension who presented with abdominal pain, nausea, vomiting, nonbloody diarrhea, and weight loss over five weeks and was found to have unexplained refractory lactic acidosis despite fluids and antibiotics. She was later diagnosed with small cell carcinoma of the lung. Conclusions. In this case report, we describe a critically ill patient whose elevated lactate was incorrectly attributed to her acute illness, when in truth it was an indicator of an underlying, as yet undiagnosed, malignancy. We believe this case is instructive to the critical care clinician as a reminder of the importance of considering malignancy on the differential diagnosis of a patient presenting with elevated lactate out of proportion to their critical illness.

  14. Interaction of the pathogenic mold Aspergillus fumigatus with lung epithelial cells

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    Nir eOsherov

    2012-09-01

    Full Text Available Aspergillus fumigatus is an opportunistic environmental mold that can cause severe allergic responses in atopic individuals and poses a life-threatening risk for severely immunocompromised patients. Infection is caused by inhalation of fungal spores (conidia into the lungs. The initial point of contact between the fungus and the host is a monolayer of lung epithelial cells. Understanding how these cells react to fungal contact is crucial to elucidating the pathobiology of Aspergillus-related disease states. The experimental systems, both in vitro and in vivo, used to study these interactions, are described. Distinction is made between bronchial and alveolar epithelial cells. The experimental findings suggest that lung epithelial cells are more than just innocent bystanders or a purely physical barrier against infection. They can be better described as an active extension of our innate immune system, operating as a surveillance mechanism that can specifically identify fungal spores and activate an offensive response to block infection. This response includes the internalization of adherent conidia and the release of cytokines, antimicrobial peptides and reactive oxygen species. In the case of allergy, lung epithelial cells can dampen an over-reactive immune response by releasing anti-inflammatory compounds such as kinurenine. This review summarizes our current knowledge regarding the interaction of A. fumigatus with lung epithelial cells. A better understanding of the interactions between A. fumigatus and lung epithelial cells has therapeutic implications, as stimulation or inhibition of the epithelial response may alter disease outcome.

  15. Gigantol Inhibits Epithelial to Mesenchymal Process in Human Lung Cancer Cells

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    Thitita Unahabhokha

    2016-01-01

    Full Text Available Lung cancer remains a leading public health problem as evidenced by its increasing death rate. The main cause of death in lung cancer patients is cancer metastasis. The metastatic behavior of lung cancer cells becomes enhanced when cancer cells undergo epithelial to mesenchymal transition (EMT. Gigantol, a bibenzyl compound extracted from the Thai orchid, Dendrobium draconis, has been shown to have promising therapeutic potential against cancer cells, which leads to the hypothesis that gigantol may be able to inhibit the fundamental EMT process in cancer cells. This study has demonstrated for the first time that gigantol possesses the ability to suppress EMT in non-small cell lung cancer H460 cells. Western blot analysis has revealed that gigantol attenuates the activity of ATP-dependent tyrosine kinase (AKT, thereby inhibiting the expression of the major EMT transcription factor, Slug, by both decreasing its transcription and increasing its degradation. The inhibitory effects of gigantol on EMT result in a decrease in the level of migration in H460 lung cancer cells. The results of this study emphasize the potential of gigantol for further development against lung cancer metastasis.

  16. Squamous cell lung carcinoma presenting as melena: a case report and review of the literature

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    Ibrahim Azar

    2017-10-01

    Full Text Available Lung cancer has a predilection to widely metastasize to the liver, bone, brain and adrenal glands. Metastasis of primary lung tumors to the stomach is infrequent, with only sporadic cases reported. Most cases are asymptomatic and diagnosed post-mortem on autopsy. The incidence of symptomatic gastrointestinal metastases is extremely rare. Herein, we describe a case of gastric metastasis by squamous cell lung carcinoma, presenting as melena and diagnosed by esophagogastroduodenoscopy. To the best of our knowledge, only twenty other cases in the English literature have reported symptomatic gastric metastasis of lung cancer diagnosed by endoscopic biopsy. A brief review of the literature shows gastric metastasis of lung cancer to have a predilection to occur most frequently in male smokers with the most common type of tumor likely to be squamous cell carcinoma.

  17. A comparison of the recruitment of antibody forming cells in the nose and lung: Preliminary findings

    Energy Technology Data Exchange (ETDEWEB)

    King-Herbert, A P; Bice, D E; Harkema, J R

    1988-12-01

    Instillation of a particulate antigen into a selected lung lobe leads to an accumulation of antibody forming cells in the exposed lung lobe. Our goal in this preliminary study was to determine if an immune response could be elicited in the nasal mucosa of Beagle dogs exposed to a particulate antigen, and if so, to compare this immune response with that of the lungs when the nasal mucosa and the lungs are each immunized with a different particulate antigen. An Immune response was observed when the nasal mucosa was exposed to particulate antigen, but numbers of antibody-forming cells and levels of antibody in the nose were much lower than observed in an immunized lung lobe. (author)

  18. A comparison of the recruitment of antibody forming cells in the nose and lung: Preliminary findings

    International Nuclear Information System (INIS)

    King-Herbert, A.P.; Bice, D.E.; Harkema, J.R.

    1988-01-01

    Instillation of a particulate antigen into a selected lung lobe leads to an accumulation of antibody forming cells in the exposed lung lobe. Our goal in this preliminary study was to determine if an immune response could be elicited in the nasal mucosa of Beagle dogs exposed to a particulate antigen, and if so, to compare this immune response with that of the lungs when the nasal mucosa and the lungs are each immunized with a different particulate antigen. An Immune response was observed when the nasal mucosa was exposed to particulate antigen, but numbers of antibody-forming cells and levels of antibody in the nose were much lower than observed in an immunized lung lobe. (author)

  19. Mesenchymal Stem Cells From Bone Marrow, Adipose Tissue, and Lung Tissue Differentially Mitigate Lung and Distal Organ Damage in Experimental Acute Respiratory Distress Syndrome.

    Science.gov (United States)

    Silva, Johnatas D; Lopes-Pacheco, Miquéias; Paz, Ana H R; Cruz, Fernanda F; Melo, Elga B; de Oliveira, Milena V; Xisto, Débora G; Capelozzi, Vera L; Morales, Marcelo M; Pelosi, Paolo; Cirne-Lima, Elizabeth; Rocco, Patricia R M

    2018-02-01

    Mesenchymal stem cells-based therapies have shown promising effects in experimental acute respiratory distress syndrome. Different mesenchymal stem cells sources may result in diverse effects in respiratory diseases; however, there is no information regarding the best source of mesenchymal stem cells to treat pulmonary acute respiratory distress syndrome. We tested the hypothesis that mesenchymal stem cells derived from bone marrow, adipose tissue, and lung tissue would lead to different beneficial effects on lung and distal organ damage in experimental pulmonary acute respiratory distress syndrome. Animal study and primary cell culture. Laboratory investigation. Seventy-five Wistar rats. Wistar rats received saline (control) or Escherichia coli lipopolysaccharide (acute respiratory distress syndrome) intratracheally. On day 2, acute respiratory distress syndrome animals were further randomized to receive saline or bone marrow, adipose tissue, or lung tissue mesenchymal stem cells (1 × 10 cells) IV. Lung mechanics, histology, and protein levels of inflammatory mediators and growth factors were analyzed 5 days after mesenchymal stem cells administration. RAW 264.7 cells (a macrophage cell line) were incubated with lipopolysaccharide followed by coculture or not with bone marrow, adipose tissue, and lung tissue mesenchymal stem cells (10 cells/mL medium). Regardless of mesenchymal stem cells source, cells administration improved lung function and reduced alveolar collapse, tissue cellularity, collagen, and elastic fiber content in lung tissue, as well as decreased apoptotic cell counts in liver. Bone marrow and adipose tissue mesenchymal stem cells administration also reduced levels of tumor necrosis factor-α, interleukin-1β, keratinocyte-derived chemokine, transforming growth factor-β, and vascular endothelial growth factor, as well as apoptotic cell counts in lung and kidney, while increasing expression of keratinocyte growth factor in lung tissue

  20. Angiogenesis gene expression in murine endothelial cells during post-pneumonectomy lung growth

    Directory of Open Access Journals (Sweden)

    Konerding Moritz A

    2011-07-01

    Full Text Available Abstract Although blood vessel growth occurs readily in the systemic bronchial circulation, angiogenesis in the pulmonary circulation is rare. Compensatory lung growth after pneumonectomy is an experimental model with presumed alveolar capillary angiogenesis. To investigate the genes participating in murine neoalveolarization, we studied the expression of angiogenesis genes in lung endothelial cells. After left pneumonectomy, the remaining right lung was examined on days 3, 6, 14 and 21days after surgery and compared to both no surgery and sham thoracotomy controls. The lungs were enzymatically digested and CD31+ endothelial cells were isolated using flow cytometry cell sorting. The transcriptional profile of the CD31+ endothelial cells was assessed using quantitative real-time polymerase chain reaction (PCR arrays. Focusing on 84 angiogenesis-associated genes, we identified 22 genes with greater than 4-fold regulation and significantly enhanced transcription (p

  1. Lysophosphatidic acid generation by pulmonary NKT cell ENPP-2/autotaxin exacerbates hyperoxic lung injury.

    Science.gov (United States)

    Nowak-Machen, Martina; Lange, Martin; Exley, Mark; Wu, Sherry; Usheva, Anny; Robson, Simon C

    2015-12-01

    Hyperoxia is still broadly used in clinical practice in order to assure organ oxygenation in critically ill patients, albeit known toxic effects. In this present study, we hypothesize that lysophosphatidic acid (LPA) mediates NKT cell activation in a mouse model of hyperoxic lung injury. In vitro, pulmonary NKT cells were exposed to hyperoxia for 72 h, and the induction of the ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP-2) was examined and production of lysophosphatidic acid (LPA) was measured. In vivo, animals were exposed to 100 % oxygen for 72 h and lungs and serum were harvested. Pulmonary NKT cells were then incubated with the LPA antagonist Brp-LPA. Animals received BrP-LPA prior to oxygen exposure. Autotaxin (ATX, ENPP-2) was significantly up-regulated on pulmonary NKT cells after hyperoxia (p NKT cells. LPA levels were significantly reduced by incubating NKT cells with LPA-BrP during oxygen exposure (p NKT cell numbers in vivo. BrP-LPA injection significantly improved survival as well as significantly decreased lung injury and lowered pulmonary NKT cell numbers. We conclude that NKT cell-induced hyperoxic lung injury is mediated by pro-inflammatory LPA generation, at least in part, secondary to ENPP-2 up-regulation on pulmonary NKT cells. Being a potent LPA antagonist, BrP-LPA prevents hyperoxia-induced lung injury in vitro and in vivo.

  2. An Official American Thoracic Society Workshop Report 2015. Stem Cells and Cell Therapies in Lung Biology and Diseases.

    Science.gov (United States)

    Wagner, Darcy E; Cardoso, Wellington V; Gilpin, Sarah E; Majka, Susan; Ott, Harald; Randell, Scott H; Thébaud, Bernard; Waddell, Thomas; Weiss, Daniel J

    2016-08-01

    The University of Vermont College of Medicine, in collaboration with the NHLBI, Alpha-1 Foundation, American Thoracic Society, Cystic Fibrosis Foundation, European Respiratory Society, International Society for Cellular Therapy, and the Pulmonary Fibrosis Foundation, convened a workshop, "Stem Cells and Cell Therapies in Lung Biology and Lung Diseases," held July 27 to 30, 2015, at the University of Vermont. The conference objectives were to review the current understanding of the role of stem and progenitor cells in lung repair after injury and to review the current status of cell therapy and ex vivo bioengineering approaches for lung diseases. These are all rapidly expanding areas of study that both provide further insight into and challenge traditional views of mechanisms of lung repair after injury and pathogenesis of several lung diseases. The goals of the conference were to summarize the current state of the field, discuss and debate current controversies, and identify future research directions and opportunities for both basic and translational research in cell-based therapies for lung diseases. This 10th anniversary conference was a follow up to five previous biennial conferences held at the University of Vermont in 2005, 2007, 2009, 2011, and 2013. Each of those conferences, also sponsored by the National Institutes of Health, American Thoracic Society, and respiratory disease foundations, has been important in helping guide research and funding priorities. The major conference recommendations are summarized at the end of the report and highlight both the significant progress and major challenges in these rapidly progressing fields.

  3. MicroRNA-133a suppresses multiple oncogenic membrane receptors and cell invasion in non-small cell lung carcinoma.

    Directory of Open Access Journals (Sweden)

    Lu-Kai Wang

    Full Text Available Non-small cell lung cancers (NSCLCs cause high mortality worldwide, and the cancer progression can be activated by several genetic events causing receptor dysregulation, including mutation or amplification. MicroRNAs are a group of small non-coding RNA molecules that function in gene silencing and have emerged as the fine-tuning regulators during cancer progression. MiR-133a is known as a key regulator in skeletal and cardiac myogenesis, and it acts as a tumor suppressor in various cancers. This study demonstrates that miR-133a expression negatively correlates with cell invasiveness in both transformed normal bronchial epithelial cells and lung cancer cell lines. The oncogenic receptors in lung cancer cells, including insulin-like growth factor 1 receptor (IGF-1R, TGF-beta receptor type-1 (TGFBR1, and epidermal growth factor receptor (EGFR, are direct targets of miR-133a. MiR-133a can inhibit cell invasiveness and cell growth through suppressing the expressions of IGF-1R, TGFBR1 and EGFR, which then influences the downstream signaling in lung cancer cell lines. The cell invasive ability is suppressed in IGF-1R- and TGFBR1-repressed cells and this phenomenon is mediated through AKT signaling in highly invasive cell lines. In addition, by using the in vivo animal model, we find that ectopically-expressing miR-133a dramatically suppresses the metastatic ability of lung cancer cells. Accordingly, patients with NSCLCs who have higher expression levels of miR-133a have longer survival rates compared with those who have lower miR-133a expression levels. In summary, we identified the tumor suppressor role of miR-133a in lung cancer outcome prognosis, and we demonstrated that it targets several membrane receptors, which generally produce an activating signaling network during the progression of lung cancer.

  4. The intracellular redox stress caused by hexavalent chromium is selective for proteins that have key roles in cell survival and thiol redox control

    International Nuclear Information System (INIS)

    Myers, Judith M.; Antholine, William E.; Myers, Charles R.

    2011-01-01

    Hexavalent chromium [Cr(VI)] compounds (e.g. chromates) are strong oxidants that readily enter cells where they are reduced to reactive Cr intermediates that can directly oxidize some cell components and can promote the generation of reactive oxygen and nitrogen species. Inhalation is a major route of exposure which directly exposes the bronchial epithelium. Previous studies with non-cancerous human bronchial epithelial cells (BEAS-2B) demonstrated that Cr(VI) treatment results in the irreversible inhibition of thioredoxin reductase (TrxR) and the oxidation of thioredoxins (Trx) and peroxiredoxins (Prx). The mitochondrial Trx/Prx system is somewhat more sensitive to Cr(VI) than the cytosolic Trx/Prx system, and other redox-sensitive mitochondrial functions are subsequently affected including electron transport complexes I and II. Studies reported here show that Cr(VI) does not cause indiscriminant thiol oxidation, and that the Trx/Prx system is among the most sensitive of cellular protein thiols. Trx/Prx oxidation is not unique to BEAS-2B cells, as it was also observed in primary human bronchial epithelial cells. Increasing the intracellular levels of ascorbate, an endogenous Cr(VI) reductant, did not alter the effects on TrxR, Trx, or Prx. The peroxynitrite scavenger MnTBAP did not protect TrxR, Trx, Prx, or the electron transport chain from the effects of Cr(VI), implying that peroxynitrite is not required for these effects. Nitration of tyrosine residues of TrxR was not observed following Cr(VI) treatment, further ruling out peroxynitrite as a significant contributor to the irreversible inhibition of TrxR. Cr(VI) treatments that disrupt the TrxR/Trx/Prx system did not cause detectable mitochondrial DNA damage. Overall, the redox stress that results from Cr(VI) exposure shows selectivity for key proteins which are known to be important for redox signaling, antioxidant defense, and cell survival.

  5. Edaravone Decreases Paraquat Toxicity in A549 Cells and Lung Isolated Mitochondria

    OpenAIRE

    Shokrzadeh, Mohammad; Shaki, Fatemeh; Mohammadi, Ebrahim; Rezagholizadeh, Neda; Ebrahimi, Fatemeh

    2014-01-01

    Edaravone, an antioxidant and radical scavenger, showed protective effects against oxidative stress-like condition. Paraquat (PQ) is toxic herbicide considerable evidence suggests that oxidative stress and mitochondrial dysfunction contribute to PQ toxicity. In this study, protective effect of edaravone against PQ induced toxicity and reactive oxygen species (ROS) generation in A549 cells and lung isolated mitochondria were evaluated. A549 cells and lung isolated mitochondria were divided int...

  6. Genetic and Epigenetic Determinants of Lung Cancer Subtype: Adenocarcinoma to Small Cell Conversion

    Science.gov (United States)

    2016-10-01

    reported in other contexts including breast cancer and bladder cancer . While beyond the scope of this grant, and not funded by this mechanism, we...have participated in a recent collaborative analysis of common genomic alterations in small cell bladder cancer vs. small cell lung cancer . A paper...of the project is to study drug resistance mechanisms in vitro and using tumors from lung cancer patients with epidermal growth factor receptor

  7. SHP1-mediated cell cycle redistribution inhibits radiosensitivity of non-small cell lung cancer

    International Nuclear Information System (INIS)

    Cao, Rubo; Ding, Qian; Li, Pindong; Xue, Jun; Zou, Zhenwei; Huang, Jing; Peng, Gang

    2013-01-01

    Radioresistance is the common cause for radiotherapy failure in non-small cell lung cancer (NSCLC), and the degree of radiosensitivity of tumor cells is different during different cell cycle phases. The objective of the present study was to investigate the effects of cell cycle redistribution in the establishment of radioresistance in NSCLC, as well as the signaling pathway of SH2 containing Tyrosine Phosphatase (SHP1). A NSCLC subtype cell line, radioresistant A549 (A549S1), was induced by high-dose hypofractionated ionizing radiations. Radiosensitivity-related parameters, cell cycle distribution and expression of cell cycle-related proteins and SHP1 were investigated. siRNA was designed to down-regulate SHP1expression. Compared with native A549 cells, the proportion of cells in the S phase was increased, and cells in the G0/G1 phase were consequently decreased, however, the proportion of cells in the G2/M phase did not change in A549S1 cells. Moreover, the expression of SHP1, CDK4 and CylinD1 were significantly increased, while p16 was significantly down-regulated in A549S1 cells compared with native A549 cells. Furthermore, inhibition of SHP1 by siRNA increased the radiosensitivity of A549S1 cells, induced a G0/G1 phase arrest, down-regulated CDK4 and CylinD1expressions, and up-regulated p16 expression. SHP1 decreases the radiosensitivity of NSCLC cells through affecting cell cycle distribution. This finding could unravel the molecular mechanism involved in NSCLC radioresistance

  8. Gigantol Suppresses Cancer Stem Cell-Like Phenotypes in Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Narumol Bhummaphan

    2015-01-01

    Full Text Available As cancer stem cells (CSCs contribute to malignancy, metastasis, and relapse of cancers, potential of compound in inhibition of CSCs has garnered most attention in the cancer research as well as drug development fields recently. Herein, we have demonstrated for the first time that gigantol, a pure compound isolated from Dendrobium draconis, dramatically suppressed stem-like phenotypes of human lung cancer cells. Gigantol at nontoxic concentrations significantly reduced anchorage-independent growth and survival of the cancer cells. Importantly, gigantol significantly reduced the ability of the cancer cells to form tumor spheroids, a critical hallmark of CSCs. Concomitantly, the treatment of the compound was shown to reduce well-known lung CSCs markers, including CD133 and ALDH1A1. Moreover, we revealed that gigantol decreased stemness in the cancer cells by suppressing the activation of protein kinase B (Akt signal which in turn decreased the cellular levels of pluripotency and self-renewal factors Oct4 and Nanog. In conclusion, gigantol possesses CSCs suppressing activity which may facilitate the development of this compound for therapeutic approaches by targeting CSCs.

  9. Enhanced Heme Function and Mitochondrial Respiration Promote the Progression of Lung Cancer Cells

    Science.gov (United States)

    Alam, Md Maksudul; Shah, Ajit; Cao, Thai M.; Sullivan, Laura A.; Brekken, Rolf; Zhang, Li

    2013-01-01

    Lung cancer is the leading cause of cancer-related mortality, and about 85% of the cases are non-small-cell lung cancer (NSCLC). Importantly, recent advance in cancer research suggests that altering cancer cell bioenergetics can provide an effective way to target such advanced cancer cells that have acquired mutations in multiple cellular regulators. This study aims to identify bioenergetic alterations in lung cancer cells by directly measuring and comparing key metabolic activities in a pair of cell lines representing normal and NSCLC cells developed from the same patient. We found that the rates of oxygen consumption and heme biosynthesis were intensified in NSCLC cells. Additionally, the NSCLC cells exhibited substantially increased levels in an array of proteins promoting heme synthesis, uptake and function. These proteins include the rate-limiting heme biosynthetic enzyme ALAS, transporter proteins HRG1 and HCP1 that are involved in heme uptake, and various types of oxygen-utilizing hemoproteins such as cytoglobin and cytochromes. Several types of human tumor xenografts also displayed increased levels of such proteins. Furthermore, we found that lowering heme biosynthesis and uptake, like lowering mitochondrial respiration, effectively reduced oxygen consumption, cancer cell proliferation, migration and colony formation. In contrast, lowering heme degradation does not have an effect on lung cancer cells. These results show that increased heme flux and function are a key feature of NSCLC cells. Further, increased generation and supply of heme and oxygen-utilizing hemoproteins in cancer cells will lead to intensified oxygen consumption and cellular energy production by mitochondrial respiration, which would fuel cancer cell proliferation and progression. The results show that inhibiting heme and respiratory function can effectively arrest the progression of lung cancer cells. Hence, understanding heme function can positively impact on research in lung cancer

  10. Uncommon of the uncommon: Malignant Perivascular epithelioid cell tumor of the lung

    International Nuclear Information System (INIS)

    Lim, Hyun Ju; Lee, Ho Yun; Han, Joung Ho; Choi, Yong Soo; Lee, Kyung Soo

    2013-01-01

    A perivascular epithelioid cell (PEC) tumor is a rare mesenchymal tumor characterized by abundant cytoplasmic Periodic acid-Schiff positive glycogen (also called sugar tumor or clear cell tumor of the lung for this characteristic) and is mostly benign. We report a case of a 63-year-old man who presented with an enlarging mass on chest radiograph. After a thorough workup, diagnosis of malignant pulmonary PEC tumor with lung to lung metastases was established. Herein, the difficulties of diagnosis and management we confronted are described.

  11. Subtyping of nonsmall cell lung cancer on cytology specimens: Reproducibility of cytopathologic diagnoses on sparse material

    DEFF Research Database (Denmark)

    Haukali, O. S.; Henrik, H.; Olsen, Karen Ege

    2014-01-01

    Cytologic examination of fine-needle aspiration (material is increasingly used in diagnosing lung cancer. High interobserver agreement in distinguishing small-cell lung cancer from nonsmall-cell lung cancer (NSCLC) on cytologic material has been demonstrated. Because of new treatment......, cytoscrape (CS) can convert cytologic material into tissue fragments useful for IHC. The purpose of this study was to test the reproducibility of pulmonary malignant diagnoses, in particular distinction between subgroups of NSCLC, based on smeared material and IHC on CS. A consecutive series of May...

  12. Uncommon of the uncommon: Malignant Perivascular epithelioid cell tumor of the lung

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Hyun Ju; Lee, Ho Yun; Han, Joung Ho; Choi, Yong Soo; Lee, Kyung Soo [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2013-08-15

    A perivascular epithelioid cell (PEC) tumor is a rare mesenchymal tumor characterized by abundant cytoplasmic Periodic acid-Schiff positive glycogen (also called sugar tumor or clear cell tumor of the lung for this characteristic) and is mostly benign. We report a case of a 63-year-old man who presented with an enlarging mass on chest radiograph. After a thorough workup, diagnosis of malignant pulmonary PEC tumor with lung to lung metastases was established. Herein, the difficulties of diagnosis and management we confronted are described.

  13. In vitro invasion of small-cell lung cancer cell lines correlates with expression of epidermal growth factor receptor

    DEFF Research Database (Denmark)

    Damstrup, L; Rude Voldborg, B; Spang-Thomsen, M

    1998-01-01

    receptor (EGFR) in a panel of 21 small-cell lung cancer (SCLC) cell lines. We have previously reported that ten of these cell lines expressed EGFR protein detected by radioreceptor and affinity labelling assays. In 11 small-cell lung cancer (SCLC) cell lines, EGFR mRNA was detected by Northern blot...... analysis. In vitro invasion in a Boyden chamber assay was found in all EGFR-positive cell lines, whereas no invasion was detected in the EGFR-negative cell lines. Quantification of the in vitro invasion in 12 selected SCLC cell lines demonstrated that, in the EGFR-positive cell lines, between 5% and 16......-PCR). However, in vitro invasive SCLC cell lines could not be distinguished from non-invasive cell lines based on the expression pattern of these molecules. In six SCLC cell lines, in vitro invasion was also determined in the presence of the EGFR-neutralizing monoclonal antibody mAb528. The addition...

  14. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8)

    DEFF Research Database (Denmark)

    Soria, Jean-Charles; Felip, Enriqueta; Cobo, Manuel

    2015-01-01

    BACKGROUND: There is a major unmet need for effective treatments in patients with squamous cell carcinoma of the lung. LUX-Lung 8 compared afatinib (an irreversible ErbB family blocker) with erlotinib (a reversible EGFR tyrosine kinase inhibitor), as second-line treatment for patients with advanced...... squamous cell carcinoma of the lung. METHODS: We did this open-label, phase 3 randomised controlled trial at 183 cancer centres in 23 countries worldwide. We enrolled adults with stage IIIB or IV squamous cell carcinoma of the lung who had progressed after at least four cycles of platinum...... be an additional option for the treatment of patients with squamous cell carcinoma of the lung. FUNDING: Boehringer Ingelheim....

  15. Advanced Research of Fibroblast Growth Factor Receptor 
in Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Dan PU

    2013-11-01

    Full Text Available Lung cancer is severely threatening human health. In recent years, the treatment for lung adenocarcinoma has made a great progress, targeted therapy has been widely applied in clinic, and benefits amount of patients. However, in squamous cell lung cancer, the incidence of epidermal growth factor receptor (EGFR gene mutant and ALK fusion gene are low,and targeted therapy like Tarceva and crizotinib, can hardly work. Since the fibroblast growth factors (fibroblast growth factor, FGF pathway is considered to be related to tumor cell proliferation, metastasis and angiogenesis, more and more researches proved the amplification of fibroblast growth factor receptor (FGFR in squamous cell lung cancer. Experiments in vivo and in vitro found that blocking FGF pathway could reduce the proliferation of tumor cells and inhibit metastasis. The FGF pathway might be a new target for treatment of squamous cell lung cancer. This article reviews the effect of FGFR in tumorigenesis,as well as the prospect as a therapeutic target in non-small cell lung cancer.

  16. 8-aminoadenosine enhances radiation-induced cell death in human lung carcinoma A549 cells

    International Nuclear Information System (INIS)

    Meike, Shunsuke; Yamamori, Tohru; Yasui, Hironobu; Eitaki, Masato; Inanami, Osamu; Matsuda, Akira

    2011-01-01

    The combination of a chemotherapeutic agent and radiation is widely applied to enhance cell death in solid tumor cells in cancer treatment. The purine analogue 8-aminoadenosine (8-NH 2 -Ado) is known to be a transcription inhibitor that has proved very effective in multiple myeloma cell lines and primary indolent leukemia cells. In this report, to examine whether 8-NH 2 -Ado had the ability to enhance the radiation-induced cell killing in solid tumor cells, human lung adenocarcinoma A549 cells were irradiated in the presence and absence of 8-NH 2 -Ado. 8-NH 2 -Ado significantly increased reproductive cell death and apoptosis in A549 cells exposed to X-rays. When peptide inhibitors against caspase-3, -8, and -9 were utilized to evaluate the involvement of caspases, all inhibitors suppressed the enhancement of radiation-induced apoptosis, suggesting that not only mitochondria-mediated apoptotic signal transduction pathways but also death receptor-mediated pathways were involved in this enhancement of apoptosis. In addition, in the cells exposed to the treatment combining X-irradiation and 8-NH 2 -Ado, reduction of the intracellular ATP concentration was essential for survival, and down-regulation of the expression of antiapoptotic proteins such as survivin and X-linked inhibitor of apoptosis protein (XIAP) was observed. These results indicate that 8-NH 2 -Ado has potential not only as an anti-tumor drug for leukemia and lymphoma but also as a radiosensitizing agent for solid tumors. (author)

  17. Breviscapine suppresses the growth of non-small cell lung cancer

    Indian Academy of Sciences (India)

    Breviscapine (BVP) has previously been shown to inhibit the proliferation of hepatocellular carcinoma cells.However, little is known about the effects of BVP on non-small cell lung cancer (NSCLC) growth. Here, we aimedto study the effects of BVP on human NSCLC growth. We employed A549, NCL-H460 and A549 cells ...

  18. Bone-marrow-derived mesenchymal stem cells inhibit gastric aspiration lung injury and inflammation in rats.

    Science.gov (United States)

    Zhou, Jing; Jiang, Liyan; Long, Xuan; Fu, Cuiping; Wang, Xiangdong; Wu, Xiaodan; Liu, Zilong; Zhu, Fen; Shi, Jindong; Li, Shanqun

    2016-09-01

    Gastric aspiration lung injury is one of the most common clinical events. This study investigated the effects of bone-marrow-derived mesenchymal stem cells (BMSCs) on combined acid plus small non-acidified particle (CASP)-induced aspiration lung injury. Enhanced green fluorescent protein (EGFP(+) ) or EGFP(-) BMSCs or 15d-PGJ2 were injected via the tail vein into rats immediately after CASP-induced aspiration lung injury. Pathological changes in lung tissues, blood gas analysis, the wet/dry weight ratio (W/D) of the lung, levels of total proteins and number of total cells and neutrophils in bronchoalveolar lavage fluid (BALF) were determined. The cytokine levels were measured using ELISA. Protein expression was determined by Western blot. Bone-marrow-derived mesenchymal stem cells treatment significantly reduced alveolar oedema, exudation and lung inflammation; increased the arterial partial pressure of oxygen; and decreased the W/D of the lung, the levels of total proteins and the number of total cells and neutrophils in BALF in the rats with CASP-induced lung injury. Bone-marrow-derived mesenchymal stem cells treatment decreased the levels of tumour necrosis factor-α and Cytokine-induced neutrophil chemoattractant (CINC)-1 and the expression of p-p65 and increased the levels of interleukin-10 and 15d-PGJ2 and the expression of peroxisome proliferator-activated receptor (PPAR)-γ in the lung tissue in CASP-induced rats. Tumour necrosis factor-α stimulated BMSCs to secrete 15d-PGJ2 . A tracking experiment showed that EGFP(+) BMSCs were able to migrate to local lung tissues. Treatment with 15d-PGJ2 also significantly inhibited CASP-induced lung inflammation and the production of pro-inflammatory cytokines. Our results show that BMSCs can protect lung tissues from gastric aspiration injury and inhibit lung inflammation in rats. A beneficial effect might be achieved through BMSC-derived 15d-PGJ2 activation of the PPAR-γ receptor, reducing the production of

  19. TUCAN/CARDINAL/CARD8 and apoptosis resistance in non-small cell lung cancer cells

    International Nuclear Information System (INIS)

    Checinska, Agnieszka; Giaccone, Giuseppe; Hoogeland, Bas SJ; Ferreira, Carlos G; Rodriguez, Jose A; Kruyt, Frank AE

    2006-01-01

    Activation of caspase-9 in response to treatment with cytotoxic drugs is inhibited in NSCLC cells, which may contribute to the clinical resistance to chemotherapy shown in this type of tumor. The aim of the present study was to investigate the mechanism of caspase-9 inhibition, with a focus on a possible role of TUCAN as caspase-9 inhibitor and a determinant of chemosensitivity in NSCLC cells. Caspase-9 processing and activation were investigated by Western blot and by measuring the cleavage of the fluorogenic substrate LEHD-AFC. Proteins interaction assays, and RNA interference in combination with cell viability and apoptosis assays were used to investigate the involvement of TUCAN in inhibition of caspase-9 and chemosensitivity NSCLC. Analysis of the components of the caspase-9 activation pathway in a panel of NSCLC and SCLC cells revealed no intrinsic defects. In fact, exogenously added cytochrome c and dATP triggered procaspase-9 cleavage and activation in lung cancer cell lysates, suggesting the presence of an inhibitor. The reported inhibitor of caspase-9, TUCAN, was exclusively expressed in NSCLC cells. However, interactions between TUCAN and procaspase-9 could not be demonstrated by any of the assays used. Furthermore, RNA interference-mediated down-regulation of TUCAN did not restore cisplatin-induced caspase-9 activation or affect cisplatin sensitivity in NSCLC cells. These results indicate that procaspase-9 is functional and can undergo activation and full processing in lung cancer cell extracts in the presence of additional cytochrome c/dATP. However, the inhibitory protein TUCAN does not play a role in inhibition of procaspase-9 and in determining the sensitivity to cisplatin in NSCLC

  20. Lung

    International Nuclear Information System (INIS)

    DeNardo, G.L.; Blankenship, W.J.; Burdine, J.A. Jr.; DeNardo, S.J.

    1975-01-01

    At present no simple statement can be made relative to the role of radionuclidic lung studies in the pediatric population. It is safe to assume that they will be used with increasing frequency for research and clinical applications because of their sensitivity and ready applicability to the pediatric patient. Methods comparable to those used in adults can be used in children older than 4 years. In younger children, however, a single injection of 133 Xe in solution provides an index of both regional perfusion and ventilation which is easier to accomplish. This method is particularly valuable in infants and neonates because it is rapid, requires no patient cooperation, results in a very low radiation dose, and can be repeated in serial studies. Radionuclidic studies of ventilation and perfusion can be performed in almost all children if the pediatrician and the nuclear medicine specialist have motivation and ingenuity. S []ontaneous pulmonary vascular occlusive disease which occurs in infants and pulmonary emboli in children are easily detected using radionuclides. The pathophysiologic defects of pulmonary agenesis, bronchopulmonary sequestration, and foreign body aspiration may be demonstrated by these techniques. These techniques also appear to be useful in following patients with bronchial asthma, cystic fibrosis, congenital emphysema, and postinfection pulmonary abnormalities. (auth)

  1. Small cell lung cancer with metastasis to the thyroid in a patient with toxic multinodular goiter.

    Science.gov (United States)

    Ozgu, Eylem Sercan; Gen, Ramazan; Ilvan, Ahmet; Ozge, Cengiz; Polat, Ayşe; Vayisoglu, Yusuf

    2012-11-01

    Thyroid metastasis of lung cancer is rarely observed in clinical practice. The primary cancers which metastasize to the thyroid gland are mostly renal cell carcinoma, lung cancer, and breast cancer. Transient destructive thyrotoxicosis is caused by massive metastasis of extrathyroid tumors. We herein present a case report of a patient with small cell carcinoma of lung with metastasis to the thyroid and thyrotoxicosis due to toxic multinodular goiter. A 66-year-old man complained of swelling around the right side of the neck, dyspnea, progressive weight loss, and palpitation starting since 3 months before his admission. The patient was diagnosed with small cell carcinoma of lung with metastasis to the thyroid and thyrotoxicosis due to toxic multinodular goiter. The case report presented here illustrates the challenge of making a definitive and adequate diagnosis, particularly if the patient presents with 2 potential causes of thyrotoxicosis. Thyroid scintigraphy is an important tool for differential diagnosis of thyrotoxicosis.

  2. An overview of mortality & predictors of small-cell and non-small cell lung cancer among Saudi patients

    Directory of Open Access Journals (Sweden)

    Hatim I. Alghamdi

    2018-03-01

    Full Text Available Lung cancer ranks as the top cancer worldwide in terms of incidence and constitutes a major health problem. About 90% of lung cancer cases are diagnosed at advance stage where treatment is not available. Despite evidence that lung cancer screening improves survival, guidelines for lung cancer screening are still a subject for debate. In Saudi Arabia, only 14% of lung cancers are diagnosed at early stage and researches on survival and its predictors are lacking. This overview analysis was conducted on predictors of lung cancer mortality according to the two major cancer types, small-cell lung cancers (SCLCs and non-small cell lung cancers (NSCLCs in Saudi Arabia. A secondary data analysis was performed on small-cell lung cancers (SCLCs and Non-small cell lung cancers (NSCLCs registered in the Saudi Cancer Registry (SCR for the period 2009–2013 to estimate predictors of mortality for both lung cancer types. A total of 404 cases (197 SCLC and 207 NSCLC were included in the analysis, all Saudi nationals. A total of 213 (52.75% deaths occurred among lung cancer patients, 108 (54.82% among SCLCs and 105 (50.72% among NCSLCs. Three quarter of patients are diagnosis with advance stage for both SCLC & NSCLC. Univariate analysis revealed higher mean age at diagnosis in dead patients compared to alive patients for SCLCs (p = 0.04; but not NSCLCs, a lower mortality for NSCLCs diagnosed in 2013 (p = 0.025 and a significant difference in stage of tumor (p = 0.006 and (p = 0.035 for both SCLC and NSCLC respectively. In multiple logistic regression, stage of tumor was a strong predictor of mortality, where distant metastasis increased morality by 6-fold (OR = 5.87, 95% CI: 2.01 – 17.19 in SCLC and by 3-fold (OR = 3.29, 95% CI: 1.22 – 8.85 in NSCLC, compared to localized tumors. Those with NSCLC who were diagnosed in 2013 were less likely to die by 64% compared to NSCLC diagnosed in 2009 (OR = 0.36, 95% CI: 0.14 – 0.93. Age, sex, topography

  3. An overview of mortality & predictors of small-cell and non-small cell lung cancer among Saudi patients.

    Science.gov (United States)

    Alghamdi, Hatim I; Alshehri, Ali F; Farhat, Ghada N

    2018-03-01

    Lung cancer ranks as the top cancer worldwide in terms of incidence and constitutes a major health problem. About 90% of lung cancer cases are diagnosed at advance stage where treatment is not available. Despite evidence that lung cancer screening improves survival, guidelines for lung cancer screening are still a subject for debate. In Saudi Arabia, only 14% of lung cancers are diagnosed at early stage and researches on survival and its predictors are lacking. This overview analysis was conducted on predictors of lung cancer mortality according to the two major cancer types, small-cell lung cancers (SCLCs) and non-small cell lung cancers (NSCLCs) in Saudi Arabia. A secondary data analysis was performed on small-cell lung cancers (SCLCs) and Non-small cell lung cancers (NSCLCs) registered in the Saudi Cancer Registry (SCR) for the period 2009-2013 to estimate predictors of mortality for both lung cancer types. A total of 404 cases (197 SCLC and 207 NSCLC) were included in the analysis, all Saudi nationals. A total of 213 (52.75%) deaths occurred among lung cancer patients, 108 (54.82%) among SCLCs and 105 (50.72%) among NCSLCs. Three quarter of patients are diagnosis with advance stage for both SCLC & NSCLC. Univariate analysis revealed higher mean age at diagnosis in dead patients compared to alive patients for SCLCs (p=0.04); but not NSCLCs, a lower mortality for NSCLCs diagnosed in 2013 (p=0.025) and a significant difference in stage of tumor (p=0.006) and (p=0.035) for both SCLC and NSCLC respectively. In multiple logistic regression, stage of tumor was a strong predictor of mortality, where distant metastasis increased morality by 6-fold (OR=5.87, 95% CI: 2.01 - 17.19) in SCLC and by 3-fold (OR=3.29, 95% CI: 1.22 - 8.85) in NSCLC, compared to localized tumors. Those with NSCLC who were diagnosed in 2013 were less likely to die by 64% compared to NSCLC diagnosed in 2009 (OR=0.36, 95% CI: 0.14 - 0.93). Age, sex, topography and laterality were not associated with

  4. Romo1 expression contributes to oxidative stress-induced death of lung epithelial cells

    International Nuclear Information System (INIS)

    Shin, Jung Ar; Chung, Jin Sil; Cho, Sang-Ho; Kim, Hyung Jung; Yoo, Young Do

    2013-01-01

    Highlights: •Romo1 mediates oxidative stress-induced mitochondrial ROS production. •Romo1 induction by oxidative stress plays an important role in oxidative stress-induced apoptosis. •Romo1 overexpression correlates with epithelial cell death in patients with IPF. -- Abstract: Oxidant-mediated death of lung epithelial cells due to cigarette smoking plays an important role in pathogenesis in lung diseases such as idiopathic pulmonary fibrosis (IPF). However, the exact mechanism by which oxidants induce epithelial cell death is not fully understood. Reactive oxygen species (ROS) modulator 1 (Romo1) is localized in the mitochondria and mediates mitochondrial ROS production through complex III of the mitochondrial electron transport chain. Here, we show that Romo1 mediates mitochondrial ROS production and apoptosis induced by oxidative stress in lung epithelial cells. Hydrogen peroxide (H 2 O 2 ) treatment increased Romo1 expression, and Romo1 knockdown suppressed the cellular ROS levels and cell death triggered by H 2 O 2 treatment. In immunohistochemical staining of lung tissues from patients with IPF, Romo1 was mainly localized in hyperplastic alveolar and bronchial epithelial cells. Romo1 overexpression was detected in 14 of 18 patients with IPF. TUNEL-positive alveolar epithelial cells were also detected in most patients with IPF but not in normal controls. These findings suggest that Romo1 mediates apoptosis induced by oxidative stress in lung epithelial cells

  5. Romo1 expression contributes to oxidative stress-induced death of lung epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Jung Ar [Department of Internal Medicine, Yonsei University College of Medicine, Yonsei University Health System, Seoul 135-270 (Korea, Republic of); Chung, Jin Sil [Laboratory of Molecular Cell Biology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Cho, Sang-Ho [Department of Pathology, Pochon CHA University, College of Medicine, Gyeonggi-do (Korea, Republic of); Kim, Hyung Jung, E-mail: khj57@yuhs.ac.kr [Department of Internal Medicine, Yonsei University College of Medicine, Yonsei University Health System, Seoul 135-270 (Korea, Republic of); Yoo, Young Do, E-mail: ydy1130@korea.ac.kr [Laboratory of Molecular Cell Biology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of)

    2013-09-20

    Highlights: •Romo1 mediates oxidative stress-induced mitochondrial ROS production. •Romo1 induction by oxidative stress plays an important role in oxidative stress-induced apoptosis. •Romo1 overexpression correlates with epithelial cell death in patients with IPF. -- Abstract: Oxidant-mediated death of lung epithelial cells due to cigarette smoking plays an important role in pathogenesis in lung diseases such as idiopathic pulmonary fibrosis (IPF). However, the exact mechanism by which oxidants induce epithelial cell death is not fully understood. Reactive oxygen species (ROS) modulator 1 (Romo1) is localized in the mitochondria and mediates mitochondrial ROS production through complex III of the mitochondrial electron transport chain. Here, we show that Romo1 mediates mitochondrial ROS production and apoptosis induced by oxidative stress in lung epithelial cells. Hydrogen peroxide (H{sub 2}O{sub 2}) treatment increased Romo1 expression, and Romo1 knockdown suppressed the cellular ROS levels and cell death triggered by H{sub 2}O{sub 2} treatment. In immunohistochemical staining of lung tissues from patients with IPF, Romo1 was mainly localized in hyperplastic alveolar and bronchial epithelial cells. Romo1 overexpression was detected in 14 of 18 patients with IPF. TUNEL-positive alveolar epithelial cells were also detected in most patients with IPF but not in normal controls. These findings suggest that Romo1 mediates apoptosis induced by oxidative stress in lung epithelial cells.

  6. Biologic characteristics of the side population of human small cell lung cancer cell line H446.

    Science.gov (United States)

    Wang, Bo; Yang, Huan; Huang, Yu-Zheng; Yan, Ru-Hong; Liu, Fen-Ju; Zhang, Jun-Ning

    2010-03-01

    Recently, the theory of cancer stem cells (CSCs) has presented new targets and orientations for tumor therapy. The major difficulties in researching CSCs include their isolation and purification. The aim of this study is to identify and characterize the side population (SP) cells in small cell lung cancer (SCLC) cell line H446, which lays the foundation for the isolation and purification of CSCs. Fluorescence-activated cell sorting (FACS) was used to sort SP and non-SP (NSP) cells from H446. Both subgroups were cultivated to survey the capacity to form into suspended tumor cell spheres. Reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR were used to evaluate the expression levels of the mRNA of CD133, ABCG2, and nucleostemin in both subgroups. The capacity of proliferation and the differences in drug resistance of both subgroups and unsorted cells were tested by the MTT method. The differentiation ability of both subgroups was determined by FACS. Proliferation was determined by subcutaneous tumor formation in nude mice. The percent of Hoechst 33342 negative cells was about (5.1 +/- 0.2)% in H446 by fluorescence microscopy. The percent of SP cells was (6.3 +/- 0.1)% by flow cytometry. SP cells had a stronger capability of forming into tumor spheres than NSP cells. The mRNA expression levels of ABCG2, CD133, and nucleostemin in SP cells were 21.60 +/- 0.26, 7.10 +/- 0.14, and 1.02 +/- 0.08 folds higher than that in NSP cells (P 0.05, respectively). In vivo, SP cells showed better proliferative ability and tougher viability when treated with drugs. SP cells can differentiate into NSP cells, but NSP cells cannot differentiate into SP cells. SP cells had a greater ability to form tumors. The H446 cell line contained some SP cells with stem cell properties. CD133 and ABCG2 may be cancer stem cell markers of SCLC.

  7. Unusual case of cavitary lung metastasis from squamous cell ...

    African Journals Online (AJOL)

    We report a rare case of cavitary lung metastasis of a uterine cervix cancer, ... A month later, the patient presented with gynecological bleeding and a pneumothorax. ... Pelvic examination and MRI showed a subsequent local cervix recurrence.

  8. Crizotinib for Advanced Non-Small Cell Lung Cancer

    Science.gov (United States)

    A summary of results from an international phase III clinical trial that compared crizotinib versus chemotherapy in previously treated patients with advanced lung cancer whose tumors have an EML4-ALK fusion gene.

  9. Tangeretin sensitises human lung cancer cells to TRAIL- induced ...

    African Journals Online (AJOL)

    Keywords: Apoptosis, Death receptors, Lung cancer, Tangeretin, Reactive oxygen ... strategies that specifically target molecules .... concentrations were determined using a Bio-Rad ..... suppresses invasion of colon and pancreatic cancer.

  10. New data for venous thromboembolism in patients with small cell lung cancer: A review.

    Science.gov (United States)

    Dimakakos, Evangelos; Livanios, Konstantinos; Gkiozos, Ioannis; Charpidou, Adriani; Ntalakou, Eleutheria; Kainis, Llias; Syrigos, Konstantinos

    2017-01-01

    Malignancy is an important predisposing factor for thromboembolic disease. Patients with malignancy display 4 to 10 times greater risk than the general population. As for lung cancer, that risk seems to further increase and become up to 20 times higher. The aim of this article is to review the International literature in order to highlight for the first time, the correlation between thromboembolic disease and small cell lung cancer. PubMed, Medline and Embase databases were searched from 1990 up to 2016, for retrospective and prospective studies that investigate the correlation between thromboembolic disease and small cell lung cancer. The incidence rate of thromboembolic disease found in these studies ranged between 6.8% and 11.5%. Thromboembolic disease is associated with a reduced survival in patients with small cell lung cancer and six factors seemed to increase the risk of thromboembolism: chemotherapy, cisplatin treatment, smoking, extensive disease, the infiltration of the superior vena cava and multiple concomitant diseases. Thromboembolic disease shows an increased incidence in patients with small cell lung cancer and more research with well-designed studies is required in order to study in detail the anticoagulation treatment and the survival in small cell lung cancer patients.

  11. Loss of expression of BAP1 is very rare in non-small cell lung carcinoma.

    Science.gov (United States)

    Andrici, Juliana; Parkhill, Thomas R; Jung, Jason; Wardell, Kathryn L; Verdonk, Brandon; Singh, Arjun; Sioson, Loretta; Clarkson, Adele; Watson, Nicole; Sheen, Amy; Farzin, Mahtab; Toon, Christopher W; Gill, Anthony J

    2016-06-01

    Germline mutations of the BAP1 gene have been implicated in a cancer predisposition syndrome which includes mesothelioma, uveal melanoma, cutaneous melanocytic lesions, renal cell carcinoma, and possibly other malignancies. Double hit inactivation of BAP1 with subsequent loss of expression of the BAP1 protein also occurs in approximately 50% of mesotheliomas. The link between BAP1 mutation and lung cancer is yet to be fully explored. We sought to assess BAP1 expression in a large cohort of lung cancers undergoing surgery with curative intent. We searched the Anatomical Pathology database of our institution for lung cancer patients undergoing surgery with curative intent between 2000 and 2010. Immunohistochemistry for BAP1 was then performed in tissue microarray format. Our cohort included 257 lung cancer patients, of which 155 (60%) were adenocarcinomas and 72 (28%) were squamous cell carcinomas, with no other subtype comprising more than 3%. BAP1 loss of expression was found in only one lung cancer. We conclude that BAP1 mutation occurs very infrequently (0.4%) in non-small cell lung cancer. Given that the pathological differential diagnosis between lung carcinoma and mesothelioma may sometimes be difficult, this finding increases the specificity of loss of expression for BAP1 for the diagnosis of mesothelioma. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

  12. Surgical management of oligometastatic non-small cell lung cancer.

    Science.gov (United States)

    Novoa, Nuria M; Varela, Gonzalo; Jiménez, Marcelo F

    2016-11-01

    The oligometastatic stage IV non-small cell lung cancer (NSCLC) offers a new surgical opportunity. New reported data is showing that surgery can offer a reasonable benefit, in terms of long-term survival, to some patients. The advantages of surgical treatment rely on a more adequate patient selection and a better understanding of the biology of these tumors. Currently, mediastinal involvement of the primary tumor can be identified as the most important prognostic variable after curative-intent of synchronous or metachronous metastasis. It seems clear that the routine use of combined FDG-PET and CT will help to detect the more favorable cohort of oligometastatic patients. As expected, pathological T staging of the primary tumor and the completeness of its resection are also crucial factors influencing final results. The real benefit of the local treatment over synchronous or metachronous metastasis is controversial with series showing better outcomes for metachronous lesions than for synchronous and others offering equal results. Also non conclusive results appear when analyzing different sites of metastasis. Retrospective series tend to show different outcomes depending on the affected organ while usually no differences are found in prospective ones. Most of the current evidence is based on retrospective studies on patients collected along extended periods of time. That represents a great limitation to the knowledge on this topic. Some prospective analyses have added some insight, but still the quality of the evidence is too low to allow drawing robust conclusions. As frequently concluded, prospective well designed investigation is requested to ascertain the value of surgery in this specific population of patients with extended NSCLC.

  13. Combination chemotherapy and radiotherapy of small cell lung cancer

    International Nuclear Information System (INIS)

    Saito, Yasuo; Chohtoh, Shuichi; Nishijima, Hiroshi; Kobayashi, Akihiko; Hirose, Jin-ichiro; Kamimura, Ryoichi; Takashima, Tsutomu; Konishi, Hideo; Miyata, Samon.

    1986-01-01

    Treatment results of 49 patients (25, limited disease, LD, 24, extensive disease, ED) with small cell lung cancer were retrospectively analyzed. Fifteen patients received chemotherapy with Cyclophosphamide (CPM) and Vincristine (VCR) following thoracic radiotherapy (RT). Twenty-two patients were given induction chemotherapy with CPM, Adriamycin (ADM), and VCR and were followed by thoracic RT. Other chemotherapy consisted of CPM, VCR, Methotrexate, and ADM in 2 patients, 5-FU, CPM, Mitomycin C, and Toyomycin in 1 patient. The remaining 9 patients (2, LD, 7, ED) were treated with RT alone. The response rate was 80 % (64 % CR; 16 % PR) for LD patients and 33 % (4 % CR; 29 % PR) for ED patients (P < 0.001). The three-year survival (Kaplan-Meier's product) of all patients was 14 %, with a median survival time (MST) of 8 months. For patients with LD, the 3-year survival was 27 % (MST 15 months). Survival of patients with ED was 14 % at 1 year, 0 % at 2 year (MST 5.5 months). The difference between these figures was statistically significant (P < 0.0003). The 3-year survival and relapse-free survival for complete responders with LD were 43 % (MST 21 months) and 36 % (median CR duration, 11.5 months) respectively. Six of 16 complete responders with LD are alive and well at over 2 years. Local recurrence rate of the complete responders with LD was 28.8 %. None of the 7 complete responders given more than 48 Gy relapsed within the radiation field. We believe that the addition of thoracic RT to patients with LD is necessary for the control of the primary tumors and for long-term disease-free survival. (author)

  14. Downregulated TIPE2 is associated with poor prognosis and promotes cell proliferation in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Li, Yuexia; Li, Xiaohui; Liu, Gang; Sun, Rongqing; Wang, Lirui; Wang, Jing; Wang, Hongmin

    2015-01-01

    Highlights: • TIPE2 is down-regulated in NSCLC tissues. • TIPE2 inhibits NSCLC cell proliferation, colony formation and invasion. • TIPE2 reduces the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. - Abstract: The present study aims to investigate the expression pattern of TIPE2 protein and its clinical significance in human non-small cell lung cancer (NSCLC). We investigated the expression levels of TIPE2 in 96 NSCLC tumor samples by immunohistochemistry and then analyzed its clinical significance. Furthermore, the role of TIPE2 on the biological properties of the NSCLC cell line H1299 and A549 was experimentally tested in vitro and in vivo. We found that the expression level of TIPE2 was significantly higher in normal lung tissues compared with NSCLC tissues (P < 0.001), and TIPE2 downregulation was significantly correlated with advanced TNM stage (P = 0.006). TIPE2 expression was lower in lung cancer cell lines than normal bronchial cell line HBE. Transfection of TIPE2 plasmid was performed in H1299 and A549 cells. TIPE2 overexpression inhibited lung cancer cell proliferation, colony formation and cell invasive in vitro, and prevented lung tumor growth in vivo. In addition, TIPE2 transfection reduced the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. Taken together, our results demonstrate that TIPE2 might serve as a tumor suppressor in NSCLC progression

  15. Downregulated TIPE2 is associated with poor prognosis and promotes cell proliferation in non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yuexia [Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052 (China); Li, Xiaohui [Department of Cardiovascular Surgery, Henan Provincial People’s Hospital, Zhengzhou, Henan 450003 (China); Liu, Gang; Sun, Rongqing; Wang, Lirui [Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052 (China); Wang, Jing, E-mail: jing_wang1980@163.com [Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052 (China); Wang, Hongmin, E-mail: hmwangzz@126.com [Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052 (China)

    2015-01-30

    Highlights: • TIPE2 is down-regulated in NSCLC tissues. • TIPE2 inhibits NSCLC cell proliferation, colony formation and invasion. • TIPE2 reduces the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. - Abstract: The present study aims to investigate the expression pattern of TIPE2 protein and its clinical significance in human non-small cell lung cancer (NSCLC). We investigated the expression levels of TIPE2 in 96 NSCLC tumor samples by immunohistochemistry and then analyzed its clinical significance. Furthermore, the role of TIPE2 on the biological properties of the NSCLC cell line H1299 and A549 was experimentally tested in vitro and in vivo. We found that the expression level of TIPE2 was significantly higher in normal lung tissues compared with NSCLC tissues (P < 0.001), and TIPE2 downregulation was significantly correlated with advanced TNM stage (P = 0.006). TIPE2 expression was lower in lung cancer cell lines than normal bronchial cell line HBE. Transfection of TIPE2 plasmid was performed in H1299 and A549 cells. TIPE2 overexpression inhibited lung cancer cell proliferation, colony formation and cell invasive in vitro, and prevented lung tumor growth in vivo. In addition, TIPE2 transfection reduced the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. Taken together, our results demonstrate that TIPE2 might serve as a tumor suppressor in NSCLC progression.

  16. Does advanced lung inflammation index (ALI) have prognostic significance in metastatic non-small cell lung cancer?

    Science.gov (United States)

    Ozyurek, Berna Akinci; Ozdemirel, Tugce Sahin; Ozden, Sertac Buyukyaylaci; Erdoğan, Yurdanur; Ozmen, Ozlem; Kaplan, Bekir; Kaplan, Tugba

    2018-01-22

    Lung cancer is the most commonly diagnosed and death-related cancer type and is more frequent in males. Non-small-cell lung cancer (NSCLC) accounts for about 85% of all case. In this study, it was aimed to research the relationship between advanced lung inflammation index (ALI) and the primary mass maximum standardized uptake value (SUVmax) and C-reactive protein (CRP) at initial diagnosis and the prognostic value of ALI in determining the survival in metastatic NSCLC. A total of 112 patients diagnosed as stage 4 non-small-lung cancer in our hospital between January 2006 and December 2013 were included in this study. ALI was calculated as body mass index (BMI) × serum albumin/neutrophil-to-lymphocyte ratio (NLR). The patients were divided into two groups as ALI ALI ≥ 18 (low inflammation). The log-rank test and Cox proportional hazard model were used to identify predictors of mortality. Evaluation was made of 94 male and 18 female patients with a mean age of 59.7 ± 9.9 years. A statistically significant negative relationship was determined between ALI and CRP values (P ALI and SUVmax values (P = .436). The median survival time in patients with ALI ALI ≥ 18, it was 16 months (P = .095). ALI is an easily calculated indicator of inflammation in lung cancer patients. Values <18 can be considered to predict a poor prognosis. © 2018 John Wiley & Sons Ltd.

  17. Sulforaphane-induced apoptosis in Xuanwei lung adenocarcinoma cell line XWLC-05.

    Science.gov (United States)

    Zhou, Lan; Yao, Qian; Li, Yan; Huang, Yun-Chao; Jiang, Hua; Wang, Chuan-Qiong; Fan, Lei

    2017-01-01

    Xuanwei district in Yunnan Province has the highest incidence of lung cancer in China, especially among non-smoking women. Cruciferous vegetables can reduce lung cancer risk by prompting a protective mechanism against respiratory tract inflammation caused by air pollution, and are rich in sulforaphane, which can induce changes in gene expression. We investigated the effect of sulforaphane-induced apoptosis in Xuanwei lung adenocarcinoma cell line (XWCL-05) to explore the value of sulforaphane in lung cancer prevention and treatment. Cell growth inhibition was determined by methyl thiazolyl tetrazolium assay; cell morphology and apoptosis were observed under transmission electron microscope; cell cycle and apoptosis rates were detected using flow cytometry; B-cell lymphoma 2 (Bcl-2) and Bcl-2-like protein 4 (Bax) messenger RNA expression were determined by quantitative PCR; and p53, p73, p53 upregulated modulator of apoptosis (PUMA), Bax, Bcl-2, and caspase-9 protein expression were detected by Western blotting. Sulforaphane inhibited XWLC-05 cell growth with inhibitory concentration (IC) 50 of 4.04, 3.38, and 3.02 μg/mL at 24, 48, and 72 hours, respectively. Sulforaphane affected the XWLC-05 cell cycle as cells accumulated in the G2/M phase. The proportion of apoptotic cells observed was 27.6%. Compared with the control, the sulforaphane group showed decreased Bcl-2 and p53 expression, and significantly increased p73, PUMA, Bax, and caspase-9 protein expression (P cell apoptosis. Its possible mechanism may involve the upregulation of p73 expression and its effector target genes PUMA and Bax in lung cancer cells, downregulation of the anti-apoptotic gene B cl -2, and activation of caspase-9. It may also involve downregulation of the mutant p53 protein. © 2016 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

  18. CXCR4/CXCL12 in Non-Small-Cell Lung Cancer Metastasis to the Brain

    Directory of Open Access Journals (Sweden)

    Sebastiano Cavallaro

    2013-01-01

    Full Text Available Lung cancer represents the leading cause of cancer-related mortality throughout the world. Patients die of local progression, disseminated disease, or both. At least one third of the people with lung cancer develop brain metastases at some point during their disease, even often before the diagnosis of lung cancer is made. The high rate of brain metastasis makes lung cancer the most common type of tumor to spread to