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Sample records for lung cancer xenograft

  1. Ketogenic Diets Enhance Oxidative Stress and Radio-Chemo-Therapy Responses in Lung Cancer Xenografts

    PubMed Central

    Allen, Bryan G.; Bhatia, Sudershan K.; Buatti, John M.; Brandt, Kristin E.; Lindholm, Kaleigh E.; Button, Anna M.; Szweda, Luke I.; Smith, Brian J.; Spitz, Douglas R.; Fath, Melissa A.

    2014-01-01

    Purpose Ketogenic diets (KDs) are high in fat and low in carbohydrates as well as protein which forces cells to rely on lipid oxidation and mitochondrial respiration rather than glycolysis for energy metabolism. Cancer cells (relative to normal cells) are believed to exist in a state of chronic oxidative stress mediated by mitochondrial metabolism. The current study tests the hypothesis that KDs enhance radio-chemo-therapy responses in lung cancer xenografts by enhancing oxidative stress. Experimental Design Mice bearing NCI-H292 and A549 lung cancer xenografts were fed a KD (KetoCal® 4:1 fats: proteins+carbohydrates) and treated with either conventionally fractionated (1.8-2 Gy) or hypofractionated (6 Gy) radiation as well as conventionally fractionated radiation combined with carboplatin. Mice weights and tumor size were monitored. Tumors were assessed for immuno-reactive 4-hydroxy-2-nonenal-(4HNE) modified proteins as a marker of oxidative stress as well as PCNA and γH2AX as indices of proliferation and DNA damage, respectively. Results The KD combined with radiation resulted in slower tumor growth in both NCI-H292 and A549 xenografts (p<0.05), relative to radiation alone. The KD also slowed tumor growth when combined with carboplatin and radiation, relative to control. Tumors from animals fed a KD in combination with radiation demonstrated increases in oxidative damage mediated by lipid peroxidation as determined by 4HNE-modified proteins as well as decreased proliferation as assessed by decreased immunoreactive PCNA. Conclusions These results show that a KD enhances radio-chemo-therapy responses in lung cancer xenografts by a mechanism that may involve increased oxidative stress. PMID:23743570

  2. Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts.

    PubMed

    Allen, Bryan G; Bhatia, Sudershan K; Buatti, John M; Brandt, Kristin E; Lindholm, Kaleigh E; Button, Anna M; Szweda, Luke I; Smith, Brian J; Spitz, Douglas R; Fath, Melissa A

    2013-07-15

    Ketogenic diets are high in fat and low in carbohydrates as well as protein which forces cells to rely on lipid oxidation and mitochondrial respiration rather than glycolysis for energy metabolism. Cancer cells (relative to normal cells) are believed to exist in a state of chronic oxidative stress mediated by mitochondrial metabolism. The current study tests the hypothesis that ketogenic diets enhance radio-chemo-therapy responses in lung cancer xenografts by enhancing oxidative stress. Mice bearing NCI-H292 and A549 lung cancer xenografts were fed a ketogenic diet (KetoCal 4:1 fats: proteins+carbohydrates) and treated with either conventionally fractionated (1.8-2 Gy) or hypofractionated (6 Gy) radiation as well as conventionally fractionated radiation combined with carboplatin. Mice weights and tumor size were monitored. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)-modified proteins as a marker of oxidative stress as well as proliferating cell nuclear antigen (PCNA) and γH2AX as indices of proliferation and DNA damage, respectively. The ketogenic diets combined with radiation resulted in slower tumor growth in both NCI-H292 and A549 xenografts (P < 0.05), relative to radiation alone. The ketogenic diet also slowed tumor growth when combined with carboplatin and radiation, relative to control. Tumors from animals fed a ketogenic diet in combination with radiation showed increases in oxidative damage mediated by lipid peroxidation as determined by 4HNE-modified proteins as well as decreased proliferation as assessed by decreased immunoreactive PCNA. These results show that a ketogenic diet enhances radio-chemo-therapy responses in lung cancer xenografts by a mechanism that may involve increased oxidative stress.

  3. Raman spectroscopy identifies radiation response in human non-small cell lung cancer xenografts

    NASA Astrophysics Data System (ADS)

    Harder, Samantha J.; Isabelle, Martin; Devorkin, Lindsay; Smazynski, Julian; Beckham, Wayne; Brolo, Alexandre G.; Lum, Julian J.; Jirasek, Andrew

    2016-02-01

    External beam radiation therapy is a standard form of treatment for numerous cancers. Despite this, there are no approved methods to account for patient specific radiation sensitivity. In this report, Raman spectroscopy (RS) was used to identify radiation-induced biochemical changes in human non-small cell lung cancer xenografts. Chemometric analysis revealed unique radiation-related Raman signatures that were specific to nucleic acid, lipid, protein and carbohydrate spectral features. Among these changes was a dramatic shift in the accumulation of glycogen spectral bands for doses of 5 or 15 Gy when compared to unirradiated tumours. When spatial mapping was applied in this analysis there was considerable variability as we found substantial intra- and inter-tumour heterogeneity in the distribution of glycogen and other RS spectral features. Collectively, these data provide unique insight into the biochemical response of tumours, irradiated in vivo, and demonstrate the utility of RS for detecting distinct radiobiological responses in human tumour xenografts.

  4. Curcumin inhibits human non-small cell lung cancer xenografts by targeting STAT3 pathway

    PubMed Central

    Xu, Xiaofang; Zhu, Yuping

    2017-01-01

    Human non-small cell lung cancer (NSCLC) is the most common cause of cancer-related death in men. Signal transducers and activators of transcription 3 (STAT3) is a potential molecular target in angiogenesis-mediated cancer therapy. In this study, we subcutaneously injected athymic nude mice with NCI-H460 cells to induce ectopic xenograft model, and treated the animals with curcumin (100 mg/kg) or vehicle by oral gavage. Tumor size and tumor weight were significantly reduced by curcumin treatment. Besides, curcumin significantly decreased hemoglobin content and mRNA expression of CD31 and CD105 in tumor tissue, suggesting that curcumin could inhibit angiogenesis in NSCLC xenograft. Similarly, we intrathoracally injected athymic nude mice with H1975 cells to induce orthotopic xenograft model, in which curcumin significantly reduced tumor weight as well as improved the survival rate of mice. STAT3 pathway was involved in curcumin-induced tumor inhibition, in which phosphorylation of STAT3 and JAK in ectopic xenograft were both declined after curcumin treatment, and the STAT3-regulated promoter activation of VEGF, Bcl-xL, Cyclin D1 was also significantly reduced after treatment. In in vitro assays, curcumin significantly inhibited cell migration and tube formation of NCI-H460 cells, but transfection with pMXs-Stat3C, a dominant active mutant, could abolish the inhibitory effects of curcumin on the cells, suggesting curcumin inhibited tumor angiogenesis of NCI-H460 cells through the inactivation of STAT3. All data showed that curcumin could be a potential drug targeting STAT3 to treat NSCLC. PMID:28861154

  5. Epigenetic modulation of endogenous tumor suppressor expression in lung cancer xenografts suppresses tumorigenicity.

    PubMed

    Cantor, Joshua P; Iliopoulos, Dimitrios; Rao, Atul S; Druck, Teresa; Semba, Shuho; Han, Shuang-Yin; McCorkell, Kelly A; Lakshman, Thiru V; Collins, Joshua E; Wachsberger, Phyllis; Friedberg, Joseph S; Huebner, Kay

    2007-01-01

    Epigenetic changes involved in cancer development, unlike genetic changes, are reversible. DNA methyltransferase and histone deacetylase inhibitors show antiproliferative effects in vitro, through tumor suppressor reactivation and induction of apoptosis. Such inhibitors have shown activity in the treatment of hematologic disorders but there is little data concerning their effectiveness in treatment of solid tumors. FHIT, WWOX and other tumor suppressor genes are frequently epigenetically inactivated in lung cancers. Lung cancer cell clones carrying conditional FHIT or WWOX transgenes showed significant suppression of xenograft tumor growth after induction of expression of the FHIT or WWOX transgene, suggesting that treatments to restore endogenous Fhit and Wwox expression in lung cancers would result in decreased tumorigenicity. H1299 lung cancer cells, lacking Fhit, Wwox, p16(INK4a) and Rassf1a expression due to epigenetic modifications, were used to assess efficacy of epigenetically targeted protocols in suppressing growth of lung tumors, by injection of 5-aza-2-deoxycytidine (AZA) and trichostatin A (TSA) in nude mice with established H1299 tumors. High doses of intraperitoneal AZA/TSA suppressed growth of small tumors but did not affect large tumors (200 mm(3)); lower AZA doses, administered intraperitoneally or intratumorally, suppressed growth of small tumors without apparent toxicity. Responding tumors showed restoration of Fhit, Wwox, p16(INKa), Rassf1a expression, low mitotic activity, high apoptotic fraction and activation of caspase 3. These preclinical studies show the therapeutic potential of restoration of tumor suppressor expression through epigenetic modulation and the promise of re-expressed tumor suppressors as markers and effectors of the responses.

  6. Antitumor effect of para-toluenesulfonamide against lung cancer xenograft in a mouse model

    PubMed Central

    Gao, Yang; Gao, Yonghua; Guan, Weijie; Huang, Liyan; Xu, Xiaoming; Zhang, Chenting; Chen, Xiuqing; Wu, Yizhuang; Zeng, Guangqiao

    2013-01-01

    Background Conventional chemotherapy and radiation therapy against non-small cell lung cancer (NSCLC) are relatively insensitive and unsatisfactory. Para-toluenesulfonamide (PTS), a unique antitumor drug for local intratumoral injection, shows an efficacy of severely suppressing solid tumor growth with mild side effects in clinical trials. The aim of this study was to investigate the effect of PTS on lung cancer H460 cells in vivo in nude mice and its underlying mechanisms in vitro. Methods A lung cancer model for in vivo experiment was established in BALB/c nude mice using H460 cells to examine the effect of local injection of PTS on tumor suppression. We also assessed the injury to the normal tissue by subcutaneous injection of PTS. In vitro, PTS was diluted into different doses for study on its antitumor mechanisms. We evaluated the necrotic effect of PTS on H460 cells by PI and Hoechst 33342 staining. Cell viability and membrane permeability were also determined by using CCK-8 and LDH assays respectively. All these tests were conducted in comparison with traditional local injection of anhydrous ethanol. Results PTS was shown to significantly inhibit the growth of H460 tumor xenografts in nude mice by inducing necrosis of the tumor histologically. Its effect on tumor growth was significantly stronger than that of anhydrous ethanol. By contrast, the injured normal tissue by PTS injection was less than that by ethanol. In vitro, PTS still demonstrated excellent necrotizing effect on H460 cells when diluted to a lower concentration. Detailed analysis of PTS on H460 cells indicated that PTS had a better effect on attenuating the cell viability and increasing the cell membrane permeability than ethanol at the same level. Conclusions PTS exhibits excellent inhibition effect on the growth of lung cancer by necrotizing tumor in vivo and in vitro, reducing tumor cell viability and augmenting the membrane permeability in vitro, with only mild injury to normal tissue. The

  7. Clonal dominance between subpopulations of mixed small cell lung cancer xenografts implanted ectopically in nude mice.

    PubMed

    Aabo, K; Vindeløv, L L; Spang-Thomsen, M

    1995-01-01

    Clonal evolution of neoplastic cells during solid tumour growth leads to the emergence of new tumour cell subpopulations with diverging phenotypic characteristics which may alter the behaviour of a malignant disease. Cellular interaction was studied in mixed xenografts in nude mice and during in vitro growth of two sets of small cell lung cancer (SCLC) subpopulations (54A, 54B and NYH, NYH2). The tumour cell lines differed in cellular DNA content enabling flow cytometric DNA analysis (FCM) to be used to monitor changes in the fractional composition of the mixed cell populations. The progeny clone 54B was found to dominate the parent 54A clone when grown as mixed subcutaneous xenografts in nude mice, whereas no dominance was exerted during in vitro growth. The in vivo dominance could not be explained by differences in growth kinetics between the two tumour cell lines, and the interaction was not dependent on 54B being in excess in mixed tumours. The dominance was dependent on close in vivo contact as no remote effect on the growth of 54A was found when the dominating 54B cells were growing in the opposite flank of tumour-bearing mice. Irradiation inactivated 54B cells were unable to exert the dominating effect, indicating that the interaction required viable and proliferating cells. Clonal dominance was not found in mixed NYH-NYH2 tumours indicating that the dominance mechanism(s) may not always be operational between subpopulations in heterogeneous tumours. Recognition of interaction between tumour cell populations may result in a better understanding of the behaviour of heterogeneous human malignancies.

  8. Cisplatin and photodynamic therapy exert synergistic inhibitory effects on small-cell lung cancer cell viability and xenograft tumor growth.

    PubMed

    Chen, You-Shuang; Peng, Yin-Bo; Yao, Min; Teng, Ji-Ping; Ni, Da; Zhu, Zhi-Jun; Zhuang, Bu-Feng; Yang, Zhi-Yin

    2017-06-03

    Lung cancer is the leading cause of cancer death worldwide. Small-cell lung cancer (SCLC) is an aggressive type of lung cancer that shows an overall 5-year survival rate below 10%. Although chemotherapy using cisplatin has been proven effective in SCLC treatment, conventional dose of cisplatin causes adverse side effects. Photodynamic therapy, a form of non-ionizing radiation therapy, is increasingly used alone or in combination with other therapeutics in cancer treatment. Herein, we aimed to address whether low dose cisplatin combination with PDT can effectively induce SCLC cell death by using in vitro cultured human SCLC NCI-H446 cells and in vivo tumor xenograft model. We found that both cisplatin and PDT showed dose-dependent cytotoxic effects in NCI-H446 cells. Importantly, co-treatment with low dose cisplatin (1 μM) and PDT (1.25 J/cm(2)) synergistically inhibited cell viability and cell migration. We further showed that the combined therapy induced a higher level of intracellular ROS in cultured NCI-H446 cells. Moreover, the synergistic effect by cisplatin and PDT was recapitulated in tumor xenograft as revealed by a more robust increase in the staining of TUNEL (a marker of cell death) and decrease in tumor volume. Taken together, our findings suggest that low dose cisplatin combination with PDT can be an effective therapeutic modality in the treatment of SCLC patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Biosynthesized Platinum Nanoparticles Inhibit the Proliferation of Human Lung-Cancer Cells in vitro and Delay the Growth of a Human Lung-Tumor Xenograft in vivo

    PubMed Central

    Yogesh, Bendale; Vineeta, Bendale; Rammesh, Natu; Saili, Paul

    2016-01-01

    Objectives: Lung cancer remains a deadly disease with unsatisfactory overall survival. Cisplatin, a standard platinum (Pt)-based chemotherapeutic agent, has the potential to inhibit the growth of lung cancer. Its use, however, is occasionally limited by severe organ toxicity. However, until now, no systematic study has been conducted to verify its efficacy with proper experimental support in vivo. Therefore, we examined whether biosynthesized Pt nanoparticles (NPs) inhibited human lung cancer in vitro and in vivo to validate their use in alternative and complementary medicine. Methods: We evaluated the in vitro and the in vivo anticancer efficiencies of biosynthesized Pt NPs in a subcutaneous xenograft model with A549 cells. Severe combined immune deficient mice (SCID) were divided into four groups: group 1 being the vehicle control group and groups 2, 3 and 4 being the experimental groups. Once the tumor volume had reached 70 ─ 75 mm3, the progression profile of the tumor growth kinetics and the body weights of the mice were measured every week for 6 weeks after oral administration of Pt NPs. Doses of Pt NPs of 500, 1,000 and 2,000 mg/kg of body weight were administered to the experimental groups and a dose of honey was administered to the vehicle control group. The efficacy was quantified by using the delay in tumor growth following the administration of Pt NPs of A549 human-lung-cancer xenografts growing in SCID mice. Results: The in vitro cytotoxicity evaluation indicated that Pt NPs, in a dose-dependent manner, inhibited the growth of A549 cells, and the in vivo evaluation showed that Pt NPs at the mid and high doses effectively inhibited and delayed the growth of lung cancer in SCID mice. Conclusion: These findings confirm the antitumor properties of biosynthesized Pt NPs and suggest that they may be a cost-effective alternative for the treatment of patients with lung cancer. PMID:27386144

  10. Bevacizumab radiosensitizes non-small cell lung cancer xenografts by inhibiting DNA double-strand break repair in endothelial cells.

    PubMed

    Gao, Hui; Xue, Jianxin; Zhou, Lin; Lan, Jie; He, Jiazhuo; Na, Feifei; Yang, Lifei; Deng, Lei; Lu, You

    2015-08-28

    The aims of this study were to evaluate the effects of biweekly bevacizumab administration on a tumor microenvironment and to investigate the mechanisms of radiosensitization that were induced by it. Briefly, bevacizumab was administered intravenously to Balb/c nude mice bearing non-small cell lung cancer (NSCLC) H1975 xenografts; in addition, bevacizumab was added to NSCLC or endothelial cells (ECs) in vitro, followed by irradiation (IR). The anti-tumor efficacy, anti-angiogenic efficacy and repair of DNA double-strand breaks (DSBs) were evaluated. The activation of signaling pathways was determined using immunoprecipitation (IP) and WB analyses. Finally, biweekly bevacizumab administration inhibited the growth of H1975 xenografts and induced vascular normalization periodically. Bevacizumab more significantly increased cellular DSB and EC apoptosis when administered 1 h prior to 12 Gy/1f IR than when administered 5 days prior to IR, thereby inhibiting tumor angiogenesis and growth. In vitro, bevacizumab more effectively increased DSBs and apoptosis prior to IR and inhibited the clonogenic survival of ECs but not NSCLC cells. Using IP and WB analyses, we confirmed that bevacizumab can directly inhibit the phosphorylation of components of the VEGR2/PI3K/Akt/DNA-PKcs signaling pathway that are induced by IR in ECs. In conclusion, bevacizumab radiosensitizes NSCLC xenografts mainly by inhibiting DSB repair in ECs rather than by inducing vascular normalization.

  11. Effects of green-synthesized silver nanoparticles on lung cancer cells in vitro and grown as xenograft tumors in vivo

    PubMed Central

    He, Yan; Du, Zhiyun; Ma, Shijing; Liu, Yue; Li, Dongli; Huang, Huarong; Jiang, Sen; Cheng, Shupeng; Wu, Wenjing; Zhang, Kun; Zheng, Xi

    2016-01-01

    Silver nanoparticles (AgNPs) have now been recognized as promising therapeutic molecules and are extending their use in cancer diagnosis and therapy. This study demonstrates for the first time the antitumor activity of green-synthesized AgNPs against lung cancer in vitro and in vivo. Cytotoxicity effect was explored on human lung cancer H1299 cells in vitro by MTT and trypan blue assays. Apoptosis was measured by morphological assessment, and nuclear factor-κB (NF-κB) transcriptional activity was determined by a luciferase reporter gene assay. The expressions of phosphorylated stat3, bcl-2, survivin, and caspase-3 were examined by Western blot analysis. AgNPs showed dose-dependent cytotoxicity and stimulation of apoptosis in H1299 cells. The effects on H1299 cells correlated well with the inhibition of NF-κB activity, a decrease in bcl-2, and an increase in caspase-3 and survivin expression. AgNPs significantly suppressed the H1299 tumor growth in a xenograft severe combined immunodeficient (SCID) mouse model. The results demonstrate the anticancer activities of AgNPs, suggesting that they may act as potential beneficial molecules in lung cancer chemoprevention and chemotherapy, especially for early-stage intervention. PMID:27217750

  12. Effects of green-synthesized silver nanoparticles on lung cancer cells in vitro and grown as xenograft tumors in vivo.

    PubMed

    He, Yan; Du, Zhiyun; Ma, Shijing; Liu, Yue; Li, Dongli; Huang, Huarong; Jiang, Sen; Cheng, Shupeng; Wu, Wenjing; Zhang, Kun; Zheng, Xi

    2016-01-01

    Silver nanoparticles (AgNPs) have now been recognized as promising therapeutic molecules and are extending their use in cancer diagnosis and therapy. This study demonstrates for the first time the antitumor activity of green-synthesized AgNPs against lung cancer in vitro and in vivo. Cytotoxicity effect was explored on human lung cancer H1299 cells in vitro by MTT and trypan blue assays. Apoptosis was measured by morphological assessment, and nuclear factor-κB (NF-κB) transcriptional activity was determined by a luciferase reporter gene assay. The expressions of phosphorylated stat3, bcl-2, survivin, and caspase-3 were examined by Western blot analysis. AgNPs showed dose-dependent cytotoxicity and stimulation of apoptosis in H1299 cells. The effects on H1299 cells correlated well with the inhibition of NF-κB activity, a decrease in bcl-2, and an increase in caspase-3 and survivin expression. AgNPs significantly suppressed the H1299 tumor growth in a xenograft severe combined immunodeficient (SCID) mouse model. The results demonstrate the anticancer activities of AgNPs, suggesting that they may act as potential beneficial molecules in lung cancer chemoprevention and chemotherapy, especially for early-stage intervention.

  13. Phospho-sulindac (OXT-328) Inhibits the Growth of Human Lung Cancer Xenografts in Mice: Enhanced Efficacy and Mitochondria Targeting by Its Formulation in Solid Lipid Nanoparticles

    PubMed Central

    Zhu, Rongrong; Cheng, Ka-Wing; Mackenzie, Gerardo; Huang, Liqun; Sun, Yu; Xie, Gang; Vrankova, Kveta; Rigas, Basil; Constantinides, Panayiotis P.

    2013-01-01

    Purpose To evaluate the antitumor efficacy of solid lipid nanoparticle–encapsulated phospho-sulindac (SLN-PS) in human lung cancer. Methods PS was incorporated into SLNs using the emulsion evaporation technique. We determined the antitumor activity of SLN-PS in cultured lung cancer cells. The performance of SLN-PS was further evaluated by pharmacokinetic studies in mice and in a model of human lung cancer xenografts in nude mice. Results SLN-PS was >4-fold more potent than PS in inhibiting the growth of A549 and H510 cells in vitro. SLN-PS enhanced cellular uptake and facilitated PS accumulation in mitochondria, leading to oxidative stress and apoptosis via the mitochondrial-apoptosis pathway. SLN-PS was highly effective in suppressing the growth of A549 xenografts (78% inhibition compared to control, p < 0.01); while PS had no significant effect. Formulation of PS in SLNs resulted in improved pharmacokinetics in mice and an enhanced (~14-fold) accumulation of PS and its metabolites in A549 xenografts. Finally, SLN-PS enhanced urinary F2-isoprostane uniquely in mice bearing A549 xenografts compared to untreated controls, suggesting that SLN-PS specifically induced oxidative stress in tumors. Conclusions Our results show that SLN-PS is efficacious in suppressing the growth of lung cancer and merits further evaluation. PMID:22723123

  14. Phospho-sulindac (OXT-328) inhibits the growth of human lung cancer xenografts in mice: enhanced efficacy and mitochondria targeting by its formulation in solid lipid nanoparticles.

    PubMed

    Zhu, Rongrong; Cheng, Ka-Wing; Mackenzie, Gerardo; Huang, Liqun; Sun, Yu; Xie, Gang; Vrankova, Kveta; Constantinides, Panayiotis P; Rigas, Basil

    2012-11-01

    To evaluate the antitumor efficacy of solid lipid nanoparticle-encapsulated phospho-sulindac (SLN-PS) in human lung cancer. PS was incorporated into SLNs using the emulsion evaporation technique. We determined the antitumor activity of SLN-PS in cultured lung cancer cells. The performance of SLN-PS was further evaluated by pharmacokinetic studies in mice and in a model of human lung cancer xenografts in nude mice. SLN-PS was >4-fold more potent than PS in inhibiting the growth of A549 and H510 cells in vitro. SLN-PS enhanced cellular uptake and facilitated PS accumulation in mitochondria, leading to oxidative stress and apoptosis via the mitochondrial-apoptosis pathway. SLN-PS was highly effective in suppressing the growth of A549 xenografts (78% inhibition compared to control, p < 0.01); while PS had no significant effect. Formulation of PS in SLNs resulted in improved pharmacokinetics in mice and an enhanced (≈ 14-fold) accumulation of PS and its metabolites in A549 xenografts. Finally, SLN-PS enhanced urinary F2-isoprostane uniquely in mice bearing A549 xenografts compared to untreated controls, suggesting that SLN-PS specifically induced oxidative stress in tumors. Our results show that SLN-PS is efficacious in suppressing the growth of lung cancer and merits further evaluation.

  15. Visualization of Inflammation at Early Stage of Lung Cancer in Xenografted Temporally Immunosuppression Rats by Ferrioxamine Magnetic Resonance Imaging

    PubMed Central

    Dechsupa, Nathupakorn; Udomtanakunchai, Chatchanok; Udom-Utraracheva, Anan; Suttho, Dutsadee; Pazart, Lionel; Humbert, Philippe; Garrigos, Manuel

    2016-01-01

    Physiological responses such as chronic inflammation and angiogenesis could be used as biomarkers for early detection of cancer with noninvasive imaging modalities. The present study reports the application of magnetic resonance imaging instrument to image the binding of ferrioxamine with hemin that allows visualizing the chronic inflammation foci of lung tissue of immunocompromised rats xenografted using small cell lung carcinoma. A low concentration of ferrioxamine (0.05 ± 0.02 μM·kg−1 of rat weight) deposited on tissue outside the vasculature was found to diffuse across the capillary walls to the interstitial space and inflammation foci, which provided a clear enhancement of T1-weighted gradient-echo sequence images. Ferrioxamine imaging allowed the determination of inflammatory sites and their localization in 3D fat-suppressed maximum intensity projections. The smallest dimension of foci that can be clearly determined is about 0.1 mm3. In concomitant to the in vivo imaging, analysis of histological tissue section showed the development of inflammatory sites. This study provides evidence that medical imaging instrument such as MRI scanner allows researchers to correlate images taken with MRI with those using high-resolution microscopy. Moreover, ferrioxamine is a useful molecular probe for determining chronic inflammation particularly at the very early stages of cancer. PMID:28074158

  16. Patient-Derived Xenograft Models of Non-Small Cell Lung Cancer and Their Potential Utility in Personalized Medicine.

    PubMed

    Morgan, Katherine M; Riedlinger, Gregory M; Rosenfeld, Jeffrey; Ganesan, Shridar; Pine, Sharon R

    2017-01-01

    Traditional preclinical studies of cancer therapeutics have relied on the use of established human cell lines that have been adapted to grow in the laboratory and, therefore, may deviate from the cancer they were meant to represent. With the emphasis of cancer drug development shifting from non-specific cytotoxic agents to rationally designed molecularly targeted therapies or immunotherapy comes the need for better models with predictive value regarding therapeutic activity and response in clinical trials. Recently, the diversity and accessibility of immunodeficient mouse strains has greatly enhanced the production and utility of patient-derived xenograft (PDX) models for many tumor types, including non-small cell lung cancer (NSCLC). Combined with next-generation sequencing, NSCLC PDX mouse models offer an exciting tool for drug development and for studying targeted therapies while utilizing patient samples with the hope of eventually aiding in clinical decision-making. Here, we describe NSCLC PDX mouse models generated by us and others, their ability to reflect the parental tumors' histomorphological characteristics, as well as the effect of clonal selection and evolution on maintaining genomic integrity in low-passage PDXs compared to the donor tissue. We also raise vital questions regarding the practical utility of PDX and humanized PDX models in predicting patient response to therapy and make recommendations for addressing those questions. Once collaborations and standardized xenotransplantation and data management methods are established, NSCLC PDX mouse models have the potential to be universal and invaluable as a preclinical tool that guides clinical trials and standard therapeutic decisions.

  17. 90Y-Labeled Anti-ROBO1 Monoclonal Antibody Exhibits Antitumor Activity against Small Cell Lung Cancer Xenografts

    PubMed Central

    Fujiwara, Kentaro; Koyama, Keitaro; Suga, Kosuke; Ikemura, Masako; Saito, Yasutaka; Hino, Akihiro; Iwanari, Hiroko; Kusano-Arai, Osamu; Mitsui, Kenichi; Kasahara, Hiroyuki; Fukayama, Masashi; Kodama, Tatsuhiko; Hamakubo, Takao; Momose, Toshimitsu

    2015-01-01

    Introduction ROBO1 is a membrane protein that contributes to tumor metastasis and angiogenesis. We previously reported that 90Y-labeled anti-ROBO1 monoclonal antibody (90Y-anti-ROBO1 IgG) showed an antitumor effect against ROBO1-positive tumors. In this study, we performed a biodistribution study and radioimmunotherapy (RIT) against ROBO1-positive small cell lung cancer (SCLC) models. Methods For the biodistribution study, 111In-labeled anti-ROBO1 monoclonal antibody (111In-anti-ROBO1 IgG) was injected into ROBO1-positive SCLC xenograft mice via the tail vein. To evaluate antitumor effects, an RIT study was performed, and SCLC xenograft mice were treated with 90Y-anti-ROBO1 IgG. Tumor volume and body weight were periodically measured throughout the experiments. The tumors and organs of mice were then collected, and a pathological analysis was carried out. Results As a result of the biodistribution study, we observed tumor uptake of 111In-anti-ROBO1 IgG. The liver, kidney, spleen, and lung showed comparably high accumulation of 111In-labeled anti-ROBO1. In the RIT study, 90Y-anti-ROBO1 IgG significantly reduced tumor volume compared with baseline. Pathological analyses of tumors revealed coagulation necrosis and fatal degeneration of tumor cells, significant reduction in the number of Ki-67-positive cells, and an increase in the number of apoptotic cells. A transient reduction of hematopoietic cells was observed in the spleen, sternum, and femur. Conclusions These results suggest that RIT with 90Y-anti-ROBO1 IgG is a promising treatment for ROBO1-positive SCLC. PMID:26017283

  18. Growth and Metastases of Human Lung Cancer Are Inhibited in Mouse Xenografts by a Transition State Analogue of 5′-Methylthioadenosine Phosphorylase*

    PubMed Central

    Basu, Indranil; Locker, Joseph; Cassera, Maria B.; Belbin, Thomas J.; Merino, Emilio F.; Dong, Xinyuan; Hemeon, Ivan; Evans, Gary B.; Guha, Chandan; Schramm, Vern L.

    2011-01-01

    The S-adenosylmethionine (AdoMet) salvage enzyme 5′-methylthioadenosine phosphorylase (MTAP) has been implicated as both a cancer target and a tumor suppressor. We tested these hypotheses in mouse xenografts of human lung cancers. AdoMet recycling from 5′-methylthioadenosine (MTA) was blocked by inhibition of MTAP with methylthio-DADMe-Immucillin-A (MTDIA), an orally available, nontoxic, picomolar transition state analogue. Blood, urine, and tumor levels of MTA increased in response to MTDIA treatment. MTDIA treatment inhibited A549 (human non-small cell lung carcinoma) and H358 (human bronchioloalveolar non-small cell lung carcinoma cells) xenograft tumor growth in immunodeficient Rag2−/−γC−/− and NCr-nu mice. Systemic MTA accumulation is implicated as the tumor-suppressive metabolite because MTDIA is effective for in vivo treatment of A549 MTAP−/− and H358 MTAP+/+ tumors. Tumors from treated mice showed increased MTA and decreased polyamines but little alteration in AdoMet, methionine, or adenine levels. Gene expression profiles of A549 tumors from treated and untreated mice revealed only modest alterations with 62 up-regulated and 63 down-regulated mRNAs (≥3-fold). MTDIA antitumor activity in xenografts supports MTAP as a target for lung cancer therapy. PMID:21135097

  19. Gene mutations in primary tumors and corresponding patient-derived xenografts derived from non-small cell lung cancer.

    PubMed

    Hao, Chuncheng; Wang, Li; Peng, Shaohua; Cao, Mengru; Li, Hongyu; Hu, Jing; Huang, Xiao; Liu, Wei; Zhang, Hui; Wu, Shuhong; Pataer, Apar; Heymach, John V; Eterovic, Agda Karina; Zhang, Qingxiu; Shaw, Kenna R; Chen, Ken; Futreal, Andrew; Wang, Michael; Hofstetter, Wayne; Mehran, Reza; Rice, David; Roth, Jack A; Sepesi, Boris; Swisher, Stephen G; Vaporciyan, Ara; Walsh, Garrett L; Johnson, Faye M; Fang, Bingliang

    2015-02-01

    Molecular annotated patient-derived xenograft (PDX) models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. We established 23 PDXs from 88 surgical specimens of lung cancer patients and determined gene mutations in these PDXs and their paired primary tumors by ultradeep exome sequencing on 202 cancer-related genes. The numbers of primary tumors with deleterious mutations in TP53, KRAS, PI3KCA, ALK, STK11, and EGFR were 43.5%, 21.7%, 17.4%, 17.4%, 13.0%, and 8.7%, respectively. Other genes with deleterious mutations in ≥3 (13.0%) primary tumors were MLL3, SETD2, ATM, ARID1A, CRIPAK, HGF, BAI3, EP300, KDR, PDGRRA and RUNX1. Of 315 mutations detected in the primary tumors, 293 (93%) were also detected in their corresponding PDXs, indicating that PDXs have the capacity to recapitulate the mutations in primary tumors. Nevertheless, a substantial number of mutations had higher allele frequencies in the PDXs than in the primary tumors, or were not detectable in the primary tumor, suggesting the possibility of tumor cell enrichment in PDXs or heterogeneity in the primary tumors. The molecularly annotated PDXs generated from this study could be useful for future translational studies. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. Patient-Derived Xenograft Models of Non-Small Cell Lung Cancer and Their Potential Utility in Personalized Medicine

    PubMed Central

    Morgan, Katherine M.; Riedlinger, Gregory M.; Rosenfeld, Jeffrey; Ganesan, Shridar; Pine, Sharon R.

    2017-01-01

    Traditional preclinical studies of cancer therapeutics have relied on the use of established human cell lines that have been adapted to grow in the laboratory and, therefore, may deviate from the cancer they were meant to represent. With the emphasis of cancer drug development shifting from non-specific cytotoxic agents to rationally designed molecularly targeted therapies or immunotherapy comes the need for better models with predictive value regarding therapeutic activity and response in clinical trials. Recently, the diversity and accessibility of immunodeficient mouse strains has greatly enhanced the production and utility of patient-derived xenograft (PDX) models for many tumor types, including non-small cell lung cancer (NSCLC). Combined with next-generation sequencing, NSCLC PDX mouse models offer an exciting tool for drug development and for studying targeted therapies while utilizing patient samples with the hope of eventually aiding in clinical decision-making. Here, we describe NSCLC PDX mouse models generated by us and others, their ability to reflect the parental tumors’ histomorphological characteristics, as well as the effect of clonal selection and evolution on maintaining genomic integrity in low-passage PDXs compared to the donor tissue. We also raise vital questions regarding the practical utility of PDX and humanized PDX models in predicting patient response to therapy and make recommendations for addressing those questions. Once collaborations and standardized xenotransplantation and data management methods are established, NSCLC PDX mouse models have the potential to be universal and invaluable as a preclinical tool that guides clinical trials and standard therapeutic decisions. PMID:28154808

  1. Antitumor effects of deguelin on H460 human lung cancer cells in vitro and in vivo: Roles of apoptotic cell death and H460 tumor xenografts model.

    PubMed

    Hsu, Yu-Chieh; Chiang, Jo-Hua; Yu, Chun-Shu; Hsia, Te-Chun; Wu, Rick Sai-Chuen; Lien, Jin-Cherng; Lai, Kuang-Chi; Yu, Fu-Shun; Chung, Jing-Gung

    2017-01-01

    Deguelin, a naturally occurring rotenoid of the flavonoid family, is known to be an Akt inhibitor, to have chemopreventive activities and anti-tumor effect on several cancers. In this study, investigation to elucidate the effect of deguelin on apoptotic pathways in human lung cancer cells and on the anti-tumor effect in lung cancer xenograft nu/nu mice was performed. In vitro studies, found that deguelin induced cell morphological changes, and decreased the percentage of viability through the induction of apoptosis in H460 lung cancer cells. Deguelin triggered apoptosis in H460 cells was also confirmed by DAPI staining, DNA gel electrophoresis, and Annexin V-FITC staining and these effects are dose-dependent manners. It was also found that deguelin promoted the Ca(2+) production and activation of caspase-3 but decreased the level of ΔΨm in H460 cells. Western blots indicated that the protein levels of cytochrome c, AIF, and pro-apoptotic Bax and Bak protein were increased, but the anti-apoptotic Bcl-2 and Bcl-x were decreased that may have led to apoptosis in H460 cells after exposure to deguelin. It was also confirmed by confocal laser microscope examination that deguelin promoted the release of AIF from mitochondria to cytosol. In vivo studies, found that in immunodeficient nu/nu mice bearing H460 tumor xenografts showed that the deguelin significantly suppressed tumor growth. Deguelin might be a potential therapeutic agent for the treatment of lung cancer in the future. This finding might fully support a critical event for deguelin via induction of apoptotic cell death and H460 tumor xenografts model against human lung cancer. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 84-98, 2017.

  2. Stromal platelet-derived growth factor receptor α (PDGFRα) provides a therapeutic target independent of tumor cell PDGFRα expression in lung cancer xenografts

    PubMed Central

    Gerber, David E.; Gupta, Puja; Dellinger, Michael T.; Toombs, Jason E.; Peyton, Michael; Duignan, Inga; Malaby, Jennifer; Bailey, Timothy; Burns, Colleen; Brekken, Rolf A.; Loizos, Nick

    2012-01-01

    In lung cancer, platelet-derived growth factor receptor α (PDGFRα) is expressed frequently by tumor-associated stromal cells and by cancer cells in a subset of tumors. We sought to determine the effect of targeting stromal PDGFRα in preclinical lung tumor xenograft models (human tumor, mouse stroma). Effects of anti-human (IMC-3G3) and anti-mouse (1E10) PDGFRα mAbs on proliferation and PDGFRα signaling were evaluated in lung cancer cell lines and mouse fibroblasts. Therapy studies were performed using established PDGFRα-positive H1703 cells and PDGFRα-negative Calu-6, H1993, and A549 subcutaneous tumors in immunocompromised mice treated with vehicle, anti-PDGFRα mAbs, chemotherapy, or combination therapy. Tumors were analyzed for growth and levels of growth factors. IMC-3G3 inhibited PDGFRα activation and the growth of H1703 cells in vitro and tumor growth in vivo, but had no effect on PDGFRα-negative cell lines or mouse fibroblasts. 1E10 inhibited growth and PDGFRα activation of mouse fibroblasts, but had no effect on human cancer cell lines in vitro. In vivo, 1E10-targeted inhibition of murine PDGFRα reduced tumor growth as single-agent therapy in Calu-6 cells and enhanced the effect of chemotherapy in xenografts derived from A549 cells. We also identified that low expression cancer cell expression of VEGF-A and elevated expression of PDGF-AA were associated with response to stromal PDGFRα targeting. We conclude that stromal PDGFRα inhibition represents a means for enhancing control of lung cancer growth in some cases, independent of tumor cell PDGFRα expression. PMID:22933705

  3. Suppression of tumor growth in lung cancer xenograft model mice by poly(sorbitol-co-PEI)-mediated delivery of osteopontin siRNA.

    PubMed

    Cho, Won-Young; Hong, Seong-Ho; Singh, Bijay; Islam, Mohammad Ariful; Lee, Somin; Lee, Ah Young; Gankhuyag, Nomundelger; Kim, Ji-Eun; Yu, Kyeong-Nam; Kim, Kwang-Ho; Park, Young-Chan; Cho, Chong-Su; Cho, Myung-Haing

    2015-08-01

    Small interfering RNA (siRNA)-mediated gene silencing represents a promising strategy for treating diseases such as cancer; however, specific gene silencing requires an effective delivery system to overcome the instability and low transfection efficiency of siRNAs. To address this issue, a polysorbitol-based transporter (PSOT) was prepared by low molecular weight branched polyethylenimine (bPEI) crosslinked with sorbitol diacrylate (SDA). Osteopontin (OPN) gene, which is highly associated with non-small cell lung cancer (NSCLC) was targeted by siRNA therapy using siRNA targeting OPN (siOPN). Characterization study confirmed that PSOT formed compact complexes with siOPN and protected siOPN against degradation by RNase. PSOT/siOPN complexes demonstrated low cytotoxicity and enhanced transfection efficiency in vitro, suggesting that this carrier may be suitable for gene silencing. In the A549 and H460 lung cancer cell lines, PSOT/siOPN complexes demonstrated significant silencing efficiency at both RNA and protein levels. To study in vivo tumor growth suppression, two lung cancer cell-xenograft mouse models were prepared and PSOT/siOPN complexes were delivered into the mice through intravenous injection. The siOPN-treated groups demonstrated significantly reduced OPN expression at both the RNA and protein levels as well as suppression of tumor volume and weight. Taken together, siOPN delivery using PSOT may present an effective and novel therapeutic system for lung cancer treatment.

  4. Imaging of small-cell lung cancer xenografts with I-125, In-111, and Re-188 octreotides

    SciTech Connect

    Hosono, M.; Hosono, M.N.; Haberberger, T. ||

    1995-05-01

    Somatostatin receptor imaging has been reported to be valuable for the localization of small-cell lung cancer (SCLC). We estimated the efficiency of I-125-Tyr-3-octreotide(I-125-octreotide), In-111-DTPA-D-Phe-1-octreotide (in-111-octreotide), and Re-188-octreotide in a mouse model of SCLC. Tyr-3-octreotide was labeled with I-125 by the chloramine T method, and In-111-octreotide was supplied by Mallinckrodt Medical (The Netherlands), while Re-188 was obtained from a W-188/Re-188 generator, and octreotide was labeled with Re-188 efficiently by a direct labeling using stannous chloride as a reduction agent. The expression of somatostatin receptor on NCI-H69 cells (a SCLC cell line) had been previously reported and we confirmed it by a cell binding assay. I-125-, In-111-, and Re-188-octreotides were injected i.v. into nude mice bearing NCI-H69 xenografts. Biodistributions were determined at 15 min, 2, 4, 8, and 24 h after injection. Specific binding of radiolabeled octreotides was observed by pretreatment of mice with unlabeled octreotide. Tumor uptake of I-125-, In-111-, and Re-188-octreotides at 2 h was 0.9{plus_minus}0.3, 0.3{plus_minus}0.1, 0.5{plus_minus}0.1% ID/g, respectively. Tumor-to-blood ratios were 0.91, 7.45, 0.41 at 2 h, 1.66, 11.16, 1.23 at 8 h for I-125-, In-111-, and Rej-188-octreotides, respectively. I-125-and Re-188 octreotides showed significant accumulations in the liver and GI tract. By contrast, In-111-octreotide cleared more rapidly from the blood and accumulated in normal tissues less than I-125- and Re-188- octreotides, resulting in high tumor-to-normal tissue ratios. In conclusion, as absolute level of tumor uptake of Re-188-octreotide is higher than that of In-111-octreotide, and Re-188-octreotide can be prepared easily as a kit, Re-188-octreotide is useful for the targeting of SCLC as well as I-125-octreotide, while In-111-octreotide is potent to achieve clear tumor-to-normal tissue contrast.

  5. Chlorella sorokiniana induces mitochondrial-mediated apoptosis in human non-small cell lung cancer cells and inhibits xenograft tumor growth in vivo.

    PubMed

    Lin, Ping-Yi; Tsai, Ching-Tsan; Chuang, Wan-Ling; Chao, Ya-Hsuan; Pan, I-Horng; Chen, Yu-Kuo; Lin, Chi-Chen; Wang, Bing-Yen

    2017-02-01

    Lung cancer is one of the leading causes of cancer related deaths worldwide. Marine microalgae are a source of biologically active compounds and are widely consumed as a nutritional supplement in East Asian countries. It has been reported that Chlorella or Chlorella extracts have various beneficial pharmacological compounds that modulate immune responses; however, no studies have investigated the anti-cancer effects of Chlorella sorokiniana (CS) on non-small cell lung cancer (NSCLC). In this study, we evaluated the anti-cancer effects of CS in two human NSCLC cell lines (A549 and CL1-5 human lung adenocarcinoma cells), and its effects on tumor growth in a subcutaneous xenograft tumor model. We also investigated the possible molecular mechanisms governing the pharmacological function of CS. Our results showed that exposure of the two cell lines to CS resulted in a concentration-dependent reduction in cell viability. In addition, the percentage of apoptotic cells increased in a dose-dependent manner, suggesting that CS might induce apoptosis in human NSCLC cells. Western blot analysis revealed that exposure to CS resulted in increased protein expression of the cleaved/activated forms of caspase-3, caspase-9, and PARP, except caspase-8. ZDEVD (caspase-3 inhibitor) and Z-LEHD (caspase-9 inhibitor) were sufficient at preventing apoptosis in both A549 and CL1-5 cells, proving that CS induced cell death via the mitochondria-mediated apoptotic pathway. Exposure of A549 and CL1-5 cells to CS for 24 h resulted in decreased expression of Bcl-2 protein and increased expression of Bax protein as well as decreased expression of two IAP family proteins, survivin and XIAP. We demonstrated that CS induces mitochondrial-mediated apoptosis in NSCLC cells via downregulation of Bcl-2, XIAP and survivin. In addition, we also found that the tumors growth of subcutaneous xenograft in vivo was markedly inhibited after oral intake of CS.

  6. Protracted dosing of the lipophilic camptothecin analogue AR-67 in non-small cell lung cancer xenografts and humans.

    PubMed

    Tsakalozou, Eleftheria; Adane, Eyob D; Liang, Yali; Arnold, Susanne M; Leggas, Markos

    2014-07-01

    Although preclinical studies on camptothecin antitumor effect have demonstrated the superiority of low-dose protracted dosing, these findings were not replicated in the clinic. 7-t-butyldimethylsilyl-10-hydroxycamptothecin (AR-67) is a camptothecin analogue currently under investigation in early phase clinical trials. To maximize the therapeutic potential of AR-67, we sought to identify factors that affect response to treatment. After determining the maximum tolerated dose using neutropenia as a toxicity endpoint, xenografts received AR-67 under varying dosing schedules and were monitored for survival. On the last treatment day, tumor tissue was collected and topoisomerase 1 (Top1), γH2AX, caspase 3 and PARP protein content was evaluated. AR-67 plasma and tumor pharmacokinetics were also studied in mice and cancer patients who were administered AR-67 as a 1-h intravenous infusion on days 1, 4, 8, 12 and 15 every 21 days. Low-dose protracted dosing schedules increased animal survival compared to less frequent, but higher-dose courses and the expression of Top1 and γH2AX were schedule dependent. Fatigue and neutropenia were the dose-limiting toxicities identified in patients receiving AR-67. Finally, elimination of AR-67 from the tumor site was slower in both xenografts and tumor of a patient enrolled in the pilot clinical trial. We demonstrated that low-dose protracted dosing schedules of AR-67 are therapeutically effective and Top1 reflects the biological activity of AR-67 in xenografts. Moreover, the tumor pharmacokinetics as well as the efficacy and safety of AR-67 given intermittently to cancer patients warrant further investigation.

  7. 18F-fluorothymidine PET/CT as an early predictor of tumor response to treatment with cetuximab in human lung cancer xenografts.

    PubMed

    Takeuchi, Satoshi; Zhao, Songji; Kuge, Yuji; Zhao, Yan; Nishijima, Ken-Ichi; Hatano, Toshiyuki; Shimizu, Yasushi; Kinoshita, Ichiro; Tamaki, Nagara; Dosaka-Akita, Hirotoshi

    2011-09-01

    We investigated whether 18F-fluorothymidine-positron-emission tomography/computed tomography (18F-FLT-PET/CT) is useful for the evaluation of the very early response to anti-epidermal growth factor receptor (EGFR) antibody cetuximab therapy in human lung cancer xenografts. A human tumor xenograft model was established with a human non-small cell lung cancer cell line. The mice were randomly assigned to four groups: tumor growth follow-up, ex vivo study, PET/CT imaging and non-treated control. Mice were administered saline as control or cetuximab on day 1. An immunohistochemical study with Ki-67 was performed. Tumor volume treated with cetuximab was kept significantly smaller than control after day 8, although there was no difference on day 3. On day 3, 18F-FLT distribution was higher in the tumor than in other tissues, and was significantly decreased by treatment with cetuximab. On PET/CT imaging, 18F-FLT distribution in the tumor was clearly visualized, and the maximum standardized uptake value (SUV) was significantly decreased after treatment with cetuximab (p<0.01). Ki-67 expression was also significantly decreased on day 3 (p=0.01). These results suggest that 18F-FLT-PET/CT can be a useful predictor to determine the response to molecular targeted drugs such as cetuximab at an earlier time point than the change of tumor size.

  8. Tumor growth inhibition with cetuximab and chemotherapy in non-small cell lung cancer xenografts expressing wild-type and mutated epidermal growth factor receptor.

    PubMed

    Steiner, Philipp; Joynes, Christopher; Bassi, Rajiv; Wang, Su; Tonra, James R; Hadari, Yaron R; Hicklin, Daniel J

    2007-03-01

    Targeting the epidermal growth factor receptor (EGFR) is a validated approach to treat cancer. In non-small cell lung cancer (NSCLC), EGFR contains somatic mutations in 10% of patients, which correlates with increased response rates to small molecule inhibitors of EGFR. We analyzed the effects of the monoclonal IgG1 antibody Erbitux (cetuximab) in NSCLC xenografts with wild-type (wt) or mutated EGFR. NSCLC cell lines were grown s.c. in nude mice. Dose-dependent efficacy was established for cetuximab. To determine whether combination therapy produces tumor regressions, cetuximab was dosed at half-maximal efficacy with chemotherapy used at maximum tolerated dose. Cetuximab showed antitumor activity in wt (A549, NCI-H358, NCI-H292) and mutated [HCC-827 (delE746-A750), NCI-H1975 (L858R, T790M)] EGFR-expressing xenografts. In the H292 model, cetuximab and docetaxel combination therapy was more potent to inhibit tumor growth than cetuximab or docetaxel alone. Cisplatin augmented efficacy of cetuximab to produce 6 of 10 regressions, whereas 1 of 10 regressions was found with cetuximab and no regression was found with cisplatin. Using H1975 xenografts, gemcitabine increased efficacy of cetuximab resulting in 12 of 12 regressions. Docetaxel with cetuximab was more efficacious with seven of nine regressions compared with single treatments. Cetuximab inhibited autophosphorylation of EGFR in both H292 and H1975 tumor lysates. Exploring the underlying mechanism for combination effects in the H1975 xenograft model, docetaxel in combination with cetuximab added to the antiproliferative effects of cetuximab but was the main component in this drug combination to induce apoptosis. Cetuximab showed antitumor activity in NSCLC models expressing wt and mutated EGFR. Combination treatments increased the efficacy of cetuximab, which may be important for the management of patients with chemorefractory NSCLC.

  9. High-resolution dynamic imaging and quantitative analysis of lung cancer xenografts in nude mice using clinical PET/CT

    PubMed Central

    Wang, Ying Yi; Wang, Kai; Xu, Zuo Yu; Song, Yan; Wang, Chu Nan; Zhang, Chong Qing; Sun, Xi Lin; Shen, Bao Zhong

    2017-01-01

    Considering the general application of dedicated small-animal positron emission tomography/computed tomography is limited, an acceptable alternative in many situations might be clinical PET/CT. To estimate the feasibility of using clinical PET/CT with [F-18]-fluoro-2-deoxy-D-glucose for high-resolution dynamic imaging and quantitative analysis of cancer xenografts in nude mice. Dynamic clinical PET/CT scans were performed on xenografts for 60 min after injection with [F-18]-fluoro-2-deoxy-D-glucose. Scans were reconstructed with or without SharpIR method in two phases. And mice were sacrificed to extracting major organs and tumors, using ex vivo γ-counting as a reference. Strikingly, we observed that the image quality and the correlation between the all quantitive data from clinical PET/CT and the ex vivo counting was better with the SharpIR reconstructions than without. Our data demonstrate that clinical PET/CT scanner with SharpIR reconstruction is a valuable tool for imaging small animals in preclinical cancer research, offering dynamic imaging parameters, good image quality and accurate data quatification. PMID:28881772

  10. High-resolution dynamic imaging and quantitative analysis of lung cancer xenografts in nude mice using clinical PET/CT.

    PubMed

    Wang, Ying Yi; Wang, Kai; Xu, Zuo Yu; Song, Yan; Wang, Chu Nan; Zhang, Chong Qing; Sun, Xi Lin; Shen, Bao Zhong

    2017-08-08

    Considering the general application of dedicated small-animal positron emission tomography/computed tomography is limited, an acceptable alternative in many situations might be clinical PET/CT. To estimate the feasibility of using clinical PET/CT with [F-18]-fluoro-2-deoxy-D-glucose for high-resolution dynamic imaging and quantitative analysis of cancer xenografts in nude mice. Dynamic clinical PET/CT scans were performed on xenografts for 60 min after injection with [F-18]-fluoro-2-deoxy-D-glucose. Scans were reconstructed with or without SharpIR method in two phases. And mice were sacrificed to extracting major organs and tumors, using ex vivo γ-counting as a reference. Strikingly, we observed that the image quality and the correlation between the all quantitive data from clinical PET/CT and the ex vivo counting was better with the SharpIR reconstructions than without. Our data demonstrate that clinical PET/CT scanner with SharpIR reconstruction is a valuable tool for imaging small animals in preclinical cancer research, offering dynamic imaging parameters, good image quality and accurate data quatification.

  11. Tumor growth affects the metabonomic phenotypes of multiple mouse non-involved organs in an A549 lung cancer xenograft model

    PubMed Central

    Xu, Shan; Tian, Yuan; Hu, Yili; Zhang, Nijia; Hu, Sheng; Song, Dandan; Wu, Zhengshun; Wang, Yulan; Cui, Yanfang; Tang, Huiru

    2016-01-01

    The effects of tumorigenesis and tumor growth on the non-involved organs remain poorly understood although many research efforts have already been made for understanding the metabolic phenotypes of various tumors. To better the situation, we systematically analyzed the metabolic phenotypes of multiple non-involved mouse organ tissues (heart, liver, spleen, lung and kidney) in an A549 lung cancer xenograft model at two different tumor-growth stages using the NMR-based metabonomics approaches. We found that tumor growth caused significant metabonomic changes in multiple non-involved organ tissues involving numerous metabolic pathways, including glycolysis, TCA cycle and metabolisms of amino acids, fatty acids, choline and nucleic acids. Amongst these, the common effects are enhanced glycolysis and nucleoside/nucleotide metabolisms. These findings provided essential biochemistry information about the effects of tumor growth on the non-involved organs. PMID:27329570

  12. Anti-tumor activity of fenretinide complexed with human serum albumin in lung cancer xenograft mouse model.

    PubMed

    Durante, Sandra; Orienti, Isabella; Teti, Gabriella; Salvatore, Viviana; Focaroli, Stefano; Tesei, Anna; Pignatta, Sara; Falconi, Mirella

    2014-07-15

    Sufficient knowledge regarding cellular and molecular basis of lung cancer progression and metastasis would help in the development of novel and effective strategies for the treatment of lung cancer. 4HPR is a synthetic retinoid with potential anti-tumor activity but is still limited because of its poor bioavailability. The use of albumin as a complexing agent for a hydrophobic drug is expected to improve the water solubility and consequently their bioavailability.This study investigated the antitumor activity of a novel complex between albumin and 4-HPR in a mouse model of human lung cancer and focuses on role and mechanism of Cav-1 mainly involved in regulating cancer and ACSVL3 mainly connected with tumor growth. Their expressions were assayed by immunohistochemistry and qRT-PCR, to demonstrate the reduction of the tumor growth following the drug treatment. Our results showed a high antitumor activity of 4HPR-HSA by reduction of the volume of tumor mass and the presence of a high level of apoptotic cell by TUNEL assay. The downregulation of Cav-1 and ACSVL3 suggested a reduction of tumor growth. In conclusion, we demonstrated the great potential of 4HPR-HSA in the treatment of lung cancer. More data about the mechanism of drug delivery the 4HPR-HSA are necessary.

  13. Lung cancer

    SciTech Connect

    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.

  14. PKM2 Thr454 phosphorylation increases its nuclear translocation and promotes xenograft tumor growth in A549 human lung cancer cells

    SciTech Connect

    Yu, Zhenhai; Huang, Liangqian; Qiao, Pengyun; Jiang, Aifang; Wang, Li; Yang, Tingting; Tang, Shengjian; Zhang, Wei; Ren, Chune

    2016-05-13

    Pyruvate kinase M2 (PKM2) is a key enzyme of glycolysis which is highly expressed in many tumor cells, and plays an important role in the Warburg effect. In previous study, we found PIM2 phosphorylates PKM2 at Thr454 residue (Yu, etl 2013). However, the functions of PKM2 Thr454 modification in cancer cells still remain unclear. Here we find PKM2 translocates into the nucleus after Thr454 phosphorylation. Replacement of wild type PKM2 with a mutant (T454A) enhances mitochondrial respiration, decreases pentose phosphate pathway, and enhances chemosensitivity in A549 cells. In addition, the mutant (T454A) PKM2 reduces xenograft tumor growth in nude mice. These findings demonstrate that PKM2 T454 phosphorylation is a potential therapeutic target in lung cancer.

  15. Nicotine induces resistance to erlotinib via cross-talk between α 1 nAChR and EGFR in the non-small cell lung cancer xenograft model.

    PubMed

    Li, Heyan; Wang, Shuo; Takayama, Koichi; Harada, Taishi; Okamoto, Isamu; Iwama, Eiji; Fujii, Akiko; Ota, Keiichi; Hidaka, Noriko; Kawano, Yuko; Nakanishi, Yoichi

    2015-04-01

    Given our previously published study, α 1 nicotinic acetylcholine receptor (nAChR) plays an essential role in nicotine-induced cell signaling and nicotine-induced resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in non-small cell lung cancer (NSCLC) PC9 cells. The aim of this study was to investigate the potential mechanism between nAChR and EGFR for nicotine-induced resistance to EGFR-TKI erlotinib in the NSCLC xenograft model. We identified the role of nicotine to EGFR/AKT/ERK pathways and to erlotinib-resistance in NSCLC PC9 and HCC827 cells by MTS assay and western blot. Then, we established the PC9 xenograft model with nicotine exposure and treated mice with erlotinib combined with vehicle or nicotine. We confirmed the effects of nicotine on EGFR/AKT/ERK pathways and determined nicotine's potential in preventing from the effect of erlotinib on NSCLC cells. Then, we showed that nicotine exposures can promote tumor growth and induce resistance to erlotinib in the PC9 xenograft model. Our results also indicated that chronic oral administration of nicotine can cause more significant erlotinib-resistance compared with acute i.v. injection of nicotine through activating α 1 nAChR and EGFR pathways. These results suggest that nicotine contributes to the progression and erlotinib-resistance of the NSCLC xenograft model via the cooperation between nAChR and EGFR. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  16. [Immunoscintigraphy of anti-type IV collagenase monoclonal antibody in nude mice bearing human lung cancer xenograft].

    PubMed

    Dai, Yao; Jia, Bing; Wang, Fan; Du, Jin; Shang, Bo-Yang; Zhen, Yong-Su

    2003-12-01

    Matrix metalloproteinases (MMPs)play the important role in many steps of tumor growth and metastasis. Type IV collagenase, which is a key member of MMPs family, has been viewed as a promising target in tumor study. The aim of this study was to evaluate the tumor-specific distribution of the anti-type IV collagenase monoclonal antibody (mAb) 3G11 by radioimaging in tumor-bearing nude mice. MAb 3G11 purified by affinity chromatography was labeled with either 131- or 125- iodide by the Iodogen method. Immunoreactivity of mAb 3G11 was determined by ELISA. (131)I-labeled 3G11 was incubated in three different media at 37 Celsius degree and its in vitro stability was tested. Normal BALB/c mice were injected intravenously with 388.5 kBq per mouse of (125)I-labeled 3G11 to explore the pharmacokinetic patterns. The scintigraphic images of human lung carcinoma PG xenografts grown subcutaneously in BALB/c nude mice were made after intravenously administrating of 6.44 MBq per mouse of (131)I-labeled 3G11. MAb 3G11 was more than 98% in purity via affinity purification. The immunoreactivity of mAb 3G11 decreased by approximately 10%-20% after cold iodination. Patterns of blood clearance of mAb 3G11 was defined as two-compartment model, with T(1/2alpha) and T(1/2beta) calculated to be 7.2 h and 345.2 h, respectively. (131)I-labeled 3G11 was almost stable in vitro for 72 h. A clear image of the xenografted tumor was obtained at 72 h, and it further improved at 120 h. MAb 3G11 showed high specificity and affinity with tumor tissue through scintiscanning.

  17. Lung Cancer

    MedlinePlus

    ... version of this page please turn Javascript on. Lung Cancer What is Lung Cancer? How Tumors Form The body is made ... button on your keyboard.) Two Major Types of Lung Cancer There are two major types of lung ...

  18. Patient-derived xenografts from non-small cell lung cancer brain metastases are valuable translational platforms for the development of personalized targeted therapy.

    PubMed

    Lee, Hye Won; Lee, Jung-Il; Lee, Se Jeong; Cho, Hyun Jung; Song, Hye Jin; Jeong, Da Eun; Seo, Yun Jee; Shin, Sang; Joung, Je-Gun; Kwon, Yong-Jun; Choi, Yoon-La; Park, Woong-Yang; Lee, Hyun Moo; Seol, Ho Jun; Shim, Young Mog; Joo, Kyeung Min; Nam, Do-Hyun

    2015-03-01

    The increasing prevalence of distant metastases from non-small cell lung cancer (NSCLC) indicates an urgent need for novel therapeutic modalities. Brain metastasis is particularly common in NSCLC, with severe adverse effects on clinical prognosis. Although the molecular heterogeneity of NSCLC and availability of various targeted agents suggest personalized therapeutic approaches for such brain metastases, further development of appropriate preclinical models is needed to validate the strategies. We established patient-derived xenografts (PDX) using NSCLC brain metastasis surgical samples and elucidated their possible preclinical and clinical implications for personalized treatment. NSCLC brain metastases (n = 34) showed a significantly higher successful PDX establishment rate than primary specimens (n = 64; 74% vs. 23%). PDXs derived from NSCLC brain metastases recapitulated the pathologic, genetic, and functional properties of corresponding parental tumors. Furthermore, tumor spheres established in vitro from the xenografts under serum-free conditions maintained their in vivo brain metastatic potential. Differential phenotypic and molecular responses to 20 targeted agents could subsequently be screened in vitro using these NSCLC PDXs derived from brain metastases. Although PDX establishment from primary NSCLCs was significantly influenced by histologic subtype, clinical aggressiveness, and genetic alteration status, the brain metastases exhibited consistently adequate in vivo tumor take rate and in vitro tumor sphere formation capacity, regardless of clinical and molecular conditions. Therefore, PDXs from NSCLC brain metastases may better represent the heterogeneous advanced NSCLC population and could be utilized as preclinical models to meet unmet clinical needs such as drug screening for personalized treatments. ©2014 American Association for Cancer Research.

  19. Antitumor efficacy of the cytotoxic RNase, ranpirnase, on A549 human lung cancer xenografts of nude mice.

    PubMed

    Lee, Intae; Kalota, Anna; Gewirtz, Alan M; Shogen, Kuslima

    2007-01-01

    The cytotoxic RNase, ranpirnase (ONCONASE, ONC), may have promising therapeutic implication as an alternative for cisplatin for the treatment of lung cancer, due to inhibition of protein synthesis by t-RNA cleavage. A549 and NCI-H1975 human NSCLC cell lines were cultured in the presence and absence of ONC. Cytotoxicity was monitored using a clonogenic assay. Using an inverted phase and fluorescence microscope, we studied whether apoptosis was induced by ONC in gefitinib-induced apoptosis-resistant A549 tumor cells. The therapeutic effectiveness of ONC was studied via single and multiple administrations on A549 human non-small cell lung cancer (NSCLC), including tumors previously untreatable by cisplatin. ONC-induced changes in ATP levels were also monitored by non-localized phosphorus MR spectroscopy. ONC significantly inhibited the cell growth of A549 tumors. Apoptosis was significantly induced by ONC in a dose-dependent manner. In animal studies, multiple small doses of ONC were more effective than one large single dose for the inhibition of tumor growth with reduced side-effects, probably due to the normalization of leaky tumor vessels. ONC in combination with cisplatin significantly reduced tumor growth of A549 tumors. In large tumors, including those unsuccessfully treated with cisplatin, ONC showed inhibition of tumor growth, while a second treatment of cisplatin did not. During monitoring by non-localized phosphorus MR spectroscopy, ATP levels decreased, likely due to ONC-induced inhibition of oxygen consumption (QO2). ONC significantly inhibited tumor growth of A549 NSCLC cells in both in vitro and in vivo studies. This investigation suggests important potential clinical uses of ONC for the treatment of NSCLC cancer patients.

  20. Treatment of small-cell lung cancer xenografts with iodine-313-anti-neural cell adhesion molecule monoclonal antibody and evaluation of absorbed dose in tissue

    SciTech Connect

    Hosono, Makoto; Endo, Keigo; Hosono, Masako N.

    1994-02-01

    Human small-cell lung cancer (SCLC) is considered a feasible target for immunotherapy using a radiolabeled monoclonal antibody (Mab). A murine Mab, NE150 (IgG1), reacts with the neural cell adhesion molecule, which is identical to cluster 1 antigen of SCLC. To estimate their therapeutic effects, NE150 and an isotype-matched control Mab were labeled with {sup 131}I and administered intravenously as a single dose into athymic mice inoculated with a NCI-H69 SCLC xenograft. The absorbed dose in organs was also examined based upon a long-term biodistribution study of {sup 131}I-NE150. Tumors initial volume 563.4 {plus_minus} 223.5 mm{sup 3} treated with 11.1 MBq (300 {mu}Ci) of {sup 131}I-NE150 diminished and became invisible at days 30-33, demonstrating a 60-day mean growth delay to reach a tripled initial volume compared with sham-treated tumors. Cumulative absorbed doses were estimated to be 2310, 410, 500, 330, and 790 cGy for the tumor, liver, kidney, spleen and lung, respectively. Iodine-131-NE150 had potent therapeutic effects against SCLC transplants in athymic mice, however, careful assessment of the side effects, improvement of radioiodination and chimerization of the Mab might be necessary to achieve efficient targeting in clinical therapeutic applications. 25 refs., 2 figs., 3 tabs.

  1. Hypoxia Potentiates the Radiation-Sensitizing Effect of Olaparib in Human Non-Small Cell Lung Cancer Xenografts by Contextual Synthetic Lethality.

    PubMed

    Jiang, Yanyan; Verbiest, Tom; Devery, Aoife M; Bokobza, Sivan M; Weber, Anika M; Leszczynska, Katarzyna B; Hammond, Ester M; Ryan, Anderson J

    2016-06-01

    Poly(ADP-ribose) polymerase (PARP) inhibitors potentiate radiation therapy in preclinical models of human non-small cell lung cancer (NSCLC) and other types of cancer. However, the mechanisms underlying radiosensitization in vivo are incompletely understood. Herein, we investigated the impact of hypoxia on radiosensitization by the PARP inhibitor olaparib in human NSCLC xenograft models. NSCLC Calu-6 and Calu-3 cells were irradiated in the presence of olaparib or vehicle under normoxic (21% O2) or hypoxic (1% O2) conditions. In vitro radiosensitivity was assessed by clonogenic survival assay and γH2AX foci assay. Established Calu-6 and Calu-3 subcutaneous xenografts were treated with olaparib (50 mg/kg, daily for 3 days), radiation (10 Gy), or both. Tumors (n=3/group) were collected 24 or 72 hours after the first treatment. Immunohistochemistry was performed to assess hypoxia (carbonic anhydrase IX [CA9]), vessels (CD31), DNA double strand breaks (DSB) (γH2AX), and apoptosis (cleaved caspase 3 [CC3]). The remaining xenografts (n=6/group) were monitored for tumor growth. In vitro, olaparib showed a greater radiation-sensitizing effect in Calu-3 and Calu-6 cells in hypoxic conditions (1% O2). In vivo, Calu-3 tumors were well-oxygenated, whereas Calu-6 tumors had extensive regions of hypoxia associated with down-regulation of the homologous recombination protein RAD51. Olaparib treatment increased unrepaired DNA DSB (P<.001) and apoptosis (P<.001) in hypoxic cells of Calu-6 tumors following radiation, whereas it had no significant effect on radiation-induced DNA damage response in nonhypoxic cells of Calu-6 tumors or in the tumor cells of well-oxygenated Calu-3 tumors. Consequently, olaparib significantly increased radiation-induced growth inhibition in Calu-6 tumors (P<.001) but not in Calu-3 tumors. Our data suggest that hypoxia potentiates the radiation-sensitizing effects of olaparib by contextual synthetic killing, and that tumor hypoxia may be a

  2. Mangosenone F, A Furanoxanthone from Garciana mangostana, Induces Reactive Oxygen Species-Mediated Apoptosis in Lung Cancer Cells and Decreases Xenograft Tumor Growth.

    PubMed

    Seo, Kyung Hye; Ryu, Hyung Won; Park, Mi Jin; Park, Ki Hun; Kim, Jin Hyo; Lee, Mi-Ja; Kang, Hyeon Jung; Kim, Sun Lim; Lee, Jin Hwan; Seo, Woo Duck

    2015-11-01

    Mangosenone F (MSF), a natural xanthone, was isolated form Carcinia mangotana, and a few studies have reported its glycosidase inhibitor effect. In this study we investigated the anti lung cancer effect of MSF both in vitro and in vivo. MSF inhibited cancer cell cytotoxicity and induced and induced apoptosis via reactive oxygen species (ROS) generation in NCI-H460. MSF treatment also showed in pronounced release of apoptogenic cytochrome c from the mitochondria to the cytosol, downregulation of Bcl-2 and Bcl-xL, and upregulation of Bax, suggesting that caspase-mediated pathways were involved in MSF-induced apoptosis. ROS activation of the mitogen-activated protein kinase signaling pathway was shown to play a predominant role in the apoptosis mechanism of MSF. Compared with cisplatin treatment, MSF treatment showed significantly increased inhibition of the growth of NCI-H460 cells xenografted in nude mice. Together, these results indicate the potential of MSF as a candidate natural anticancer drug by promoting ROS production. Copyright © 2015 John Wiley & Sons, Ltd.

  3. Tubeimoside-1 suppresses tumor angiogenesis by stimulation of proteasomal VEGFR2 and Tie2 degradation in a non-small cell lung cancer xenograft model

    PubMed Central

    Gu, Yuan; Körbel, Christina; Scheuer, Claudia; Nenicu, Anca; Menger, Michael D.; Laschke, Matthias W.

    2016-01-01

    Tubeimoside-1 (TBMS1) is a potent anti-tumor phytochemical. Its functional and molecular mode of action, however, remains elusive so far. Since angiogenesis is essential for tumor progression and metastasis, we herein investigated the anti-angiogenic effects of the compound. In a non-small cell lung cancer (NSCLC) xenograft model we found that treatment of CD1 nu/nu mice with TBMS1 (5mg/kg) significantly suppressed the growth and vascularization of NCI-H460 flank tumors. Moreover, TBMS1 dose-dependently reduced vascular sprouting in a rat aortic ring assay. In vitro, TBMS1 induced endothelial cell apoptosis without decreasing the viability of NSCLC tumor cells and inhibited the migration of endothelial cells by disturbing their actin filament organization. TBMS1 further stimulated the proteasomal degradation of vascular endothelial growth factor receptor-2 (VEGFR2) and Tie2 in endothelial cells, which down-regulated AKT/mTOR signaling. These findings indicate that TBMS1 represents a novel phytochemical for anti-angiogenic treatment of cancer and other angiogenesis-related diseases. PMID:26701724

  4. Optimized S-trityl-L-cysteine-based inhibitors of kinesin spindle protein with potent in vivo antitumor activity in lung cancer xenograft models.

    PubMed

    Good, James A D; Wang, Fang; Rath, Oliver; Kaan, Hung Yi Kristal; Talapatra, Sandeep K; Podgórski, Dawid; MacKay, Simon P; Kozielski, Frank

    2013-03-14

    The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-L-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activity. We report here their further optimization to produce extremely potent inhibitors of Eg5 (K(i)(app) < 10 nM) with broad-spectrum activity against cancer cell lines comparable to the Phase II drug candidates ispinesib and SB-743921. They have good oral bioavailability and pharmacokinetics and induced complete tumor regression in nude mice explanted with lung cancer patient xenografts. Furthermore, they display fewer liabilities with CYP-metabolizing enzymes and hERG compared with ispinesib and SB-743921, which is important given the likely application of Eg5 inhibitors in combination therapies. We present the case for this preclinical series to be investigated in single and combination chemotherapies, especially targeting hematological malignancies.

  5. Tumor-specific targeting by Bavituximab, a phosphatidylserine-targeting monoclonal antibody with vascular targeting and immune modulating properties, in lung cancer xenografts

    PubMed Central

    Gerber, David E; Hao, Guiyang; Watkins, Linda; Stafford, Jason H; Anderson, Jon; Holbein, Blair; Öz, Orhan K; Mathews, Dana; Thorpe, Philip E; Hassan, Gedaa; Kumar, Amit; Brekken, Rolf A; Sun, Xiankai

    2015-01-01

    Bavituximab is a chimeric monoclonal antibody with immune modulating and tumor-associated vascular disrupting properties demonstrated in models of non-small cell lung cancer (NSCLC). The molecular target of Bavituximab, phosphatidylserine (PS), is exposed on the outer leaflet of the membrane bi-layer of malignant vascular endothelial cells and tumor cells to a greater extent than on normal tissues. We evaluated the tumor-targeting properties of Bavituximab for imaging of NSCLC xenografts when radiolabeled with 111In through conjugation with a bifunctional chelating agent, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). In vitro binding of 111In-DOTA-Bavituximab to PS was determined by enzyme-linked immunosorbent assay (ELISA). Biodistribution of 111In-DOTA-Bavituximab was conducted in normal rats, which provided data for dosimetry calculation. Single-photon emission computed tomography/computed tomography (SPECT/CT) imaging was performed in athymic nude rats bearing A549 NSCLC xenografts. At the molar conjugation ratio of 0.54 DOTA per Bavituximab, the PS binding affinity of 111In-DOTA-Bavituximab was comparable to that of unmodified Bavituximab. Based on the quantitative SPECT/CT imaging data analysis, 111In-DOTA-Bavituximab demonstrated tumor-specific uptake as measured by the tumor-tomuscle ratio, which peaked at 5.2 at 72 hr post-injection. In contrast, the control antibody only presented a contrast of 1.2 at the same time point.These findings may underlie the diagnostic efficacy and relative low rates of systemic vascular and immune-related toxicities of this immunoconjugate. Future applications of 111In-DOTA-bavituximab may include prediction of efficacy, indication of tumor immunologic status, or characterization of radiographic findings. PMID:26550540

  6. Localization of small-cell lung cancer xenografts with iodine-125-, indium-111-, and rhenium-188-somatostatin analogs.

    PubMed

    Hosono, M; Hosono, M N; Haberberger, T; Zamora, P O; Guhlke, S; Bender, H; Knapp, F F; Biersack, H J

    1996-09-01

    We examined the potential of radiolabeled somatostatin analogs, 125I-Tyr-3-octreotide (125I-octreotide), (111)In-DTPA(diethylenetriaminepentaacetatic acid)-D-Phe-1-octreotide (111In-octreotide), and 188Re-octreotide for targeting small-cell lung cancer (SCLC) in a mouse model. Tyr-3-octreotide was labeled with 125I by the chloramine T method, and (111)In-octreotide was obtained as a kit, while 188Re was eluted from a 188W/188Re generator, and octreotide was directly labeled with 188Re by reducing disulfide bonds. The 125I-, 111In-, and 188Re-octreotides were injected i.v. into athymic mice bearing NCI-H69 tumors, and the biodistributions were determined at 15 min, and 2, 4, 8, and 24 h. Tumor uptakes were 0.5+/-0.2, 0.3+/-0.1, 0.3+/-0.1 %ID/g, and tumor-to-blood ratios were 1.8, 11.9, 1.2 at 8 h for 125I-, 111In-, and 188Re-octreotides, respectively. Accumulations of 111In-octreotide in normal tissues were lower than those of 125I- and 188Re-octreotides. 188Re-octreotide can be used to localize SCLC lesions as efficiently as radioiodinated octreotide. However, 111In-octreotide was the most suitable agent to obtain high tumor-to-normal tissue contrast for localizing SCLC.

  7. The Influence of Tissue Ischemia Time on RNA Integrity and Patient-Derived Xenografts (PDX) Engraftment Rate in a Non-Small Cell Lung Cancer (NSCLC) Biobank

    PubMed Central

    Maletta, Francesca; Gaudiano, Marcello; Ercole, Elisabetta; Annaratone, Laura; Todaro, Maria; Boita, Monica; Filosso, Pier Luigi; Solidoro, Paolo; Delsedime, Luisa; Oliaro, Alberto; Sapino, Anna; Ruffini, Enrico; Inghirami, Giorgio

    2016-01-01

    Introduction Bio-repositories are invaluable resources to implement translational cancer research and clinical programs. They represent one of the most powerful tools for biomolecular studies of clinically annotated cohorts, but high quality samples are required to generate reliable molecular readouts and functional studies. The objective of our study was to define the impact of cancer tissue ischemia time on RNA and DNA quality, and for the generation of Patient-Derived Xenografts (PDXs). Methods One-hundred thirty-five lung cancer specimens were selected among our Institutional BioBank samples. Associations between different warm (surgical) and cold (ex-vivo) ischemia time ranges and RNA quality or PDXs engraftment rates were assessed. RNA quality was determined by RNA integrity number (RINs) values. Fresh viable tissue fragments were implanted subcutaneously in NSG mice and serially transplanted. Results RNAs with a RIN>7 were detected in 51% of the sample (70/135), with values of RIN significantly lower (OR 0.08, P = 0.01) in samples preserved for more than 3 hours before cryopreservation. Higher quality DNA samples had a concomitant high RIN. Sixty-three primary tumors (41 adenocarcinoma) were implanted with an overall engraftment rate of 33%. Both prolonged warm (>2 hours) and ex-vivo ischemia time (>10 hours) were associated to a lower engraftment rate (OR 0.09 P = 0.01 and OR 0.04 P = 0.008, respectively). Conclusion RNA quality and PDXs engraftment rate were adversely affected by prolonged ischemia times. Proper tissue collection and processing reduce failure rate. Overall, NSCLC BioBanking represents an innovative modality, which can be successfully executed in routine clinical settings, when stringent Standard Operating Procedures are adopted. PMID:26731692

  8. hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing

    PubMed Central

    Goehe, Rachel Wilson; Shultz, Jacqueline C.; Murudkar, Charuta; Usanovic, Sanja; Lamour, Nadia F.; Massey, Davis H.; Zhang, Lian; Camidge, D. Ross; Shay, Jerry W.; Minna, John D.; Chalfant, Charles E.

    2010-01-01

    Caspase-9 is involved in the intrinsic apoptotic pathway and suggested to play a role as a tumor suppressor. Little is known about the mechanisms governing caspase-9 expression, but post-transcriptional pre-mRNA processing generates 2 splice variants from the caspase-9 gene, pro-apoptotic caspase-9a and anti-apoptotic caspase-9b. Here we demonstrate that the ratio of caspase-9 splice variants is dysregulated in non–small cell lung cancer (NSCLC) tumors. Mechanistic analysis revealed that an exonic splicing silencer (ESS) regulated caspase-9 pre-mRNA processing in NSCLC cells. Heterogeneous nuclear ribonucleoprotein L (hnRNP L) interacted with this ESS, and downregulation of hnRNP L expression induced an increase in the caspase-9a/9b ratio. Although expression of hnRNP L lowered the caspase-9a/9b ratio in NSCLC cells, expression of hnRNP L produced the opposite effect in non-transformed cells, suggesting a post-translational modification specific for NSCLC cells. Indeed, Ser52 was identified as a critical modification regulating the caspase-9a/9b ratio. Importantly, in a mouse xenograft model, downregulation of hnRNP L in NSCLC cells induced a complete loss of tumorigenic capacity that was due to the changes in caspase-9 pre-mRNA processing. This study therefore identifies a cancer-specific mechanism of hnRNP L phosphorylation and subsequent lowering of the caspase-9a/9b ratio, which is required for the tumorigenic capacity of NSCLC cells. PMID:20972334

  9. Antitumor effectiveness of a combined therapy with a new cucurbitacin B derivative and paclitaxel on a human lung cancer xenograft model.

    PubMed

    Marostica, Lucas Lourenço; de Barros, André Luís Branco; Oliveira, Juliana; Salgado, Breno Souza; Cassali, Geovanni Dantas; Leite, Elaine Amaral; Cardoso, Valbert Nascimento; Lang, Karen Luise; Caro, Miguel Soriano Balparda; Durán, Fernando Javier; Schenkel, Eloir Paulo; de Oliveira, Mônica Cristina; Simões, Cláudia Maria Oliveira

    2017-08-15

    Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors, with a high mortality rate due to the elevated risk of resistance. Natural cucurbitacins and their derivatives are recognized as promising antitumor compounds for several types of cancer, including NSCLC. In a recent study published by our research group, DACE (2-deoxy-2-amine-cucurbitacin E), which is a semisynthetic derivative of cucurbitacin B, showed potential in vitro synergistic antiproliferative effects combined with paclitaxel (PTX) in A549 cells. In sequence, the purpose of this study was to evaluate the in vivo antitumor efficacy of this combined therapy as well as with these drugs individually, using a human NSCLC xenograft model. Some indicators of sub chronic toxicity that could be affected by treatments were also assessed. The results obtained in vivo with the combined treatment (1mg/kg+PTX 10mg/kg) showed the most effective reduction of the relative tumor volume and the highest inhibition of tumor growth and proliferation, when compared with those of the single treatments. Furthermore, scintigraphic images, obtained before and after the treatments, showed that the most effective protocol able to reduce the residual viable tumor mass was the combined treatment. All treatment regimens were well tolerated without significant changes in body weight and no histological and functional damage to liver and kidney tissues. These results corroborate our previous in vitro synergistic effects published. Taken together, these insights are novel and highlight the therapeutic potential of DACE and PTX combination scheme for NSCLC. Copyright © 2017. Published by Elsevier Inc.

  10. Lung Cancer

    MedlinePlus

    Lung cancer is one of the most common cancers in the world. It is a leading cause of cancer death in men and women in the United States. Cigarette smoking causes most lung cancers. The more cigarettes you smoke per day and ...

  11. Impact of bevacizumab in combination with erlotinib on EGFR-mutated non-small cell lung cancer xenograft models with T790M mutation or MET amplification.

    PubMed

    Furugaki, Koh; Fukumura, Junko; Iwai, Toshiki; Yorozu, Keigo; Kurasawa, Mitsue; Yanagisawa, Mieko; Moriya, Yoichiro; Yamamoto, Kaname; Suda, Kenichi; Mizuuchi, Hiroshi; Mitsudomi, Tetsuya; Harada, Naoki

    2016-02-15

    Erlotinib (ERL), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, shows notable efficacy against non-small cell lung cancer (NSCLC) harboring EGFR mutations. Bevacizumab (BEV), a humanized monoclonal antibody to vascular endothelial cell growth factor (VEGF), in combination with ERL (BEV+ERL) significantly extended progression-free survival in patients with EGFR-mutated NSCLC compared with ERL alone. However, the efficacy of BEV+ERL against EGFR-mutated NSCLC harboring T790M mutation or MET amplification, is unclear. Here, we examined the antitumor activity of BEV+ERL in four xenograft models of EGFR-mutated NSCLC (three harboring ERL resistance mutations). In the HCC827 models (exon 19 deletion: DEL), ERL significantly inhibited tumor growth by blocking EGFR signal transduction. Although there was no difference between ERL and BEV+ERL in maximum tumor growth inhibition, BEV+ERL significantly suppressed tumor regrowth during a drug-cessation period. In the HCC827-EPR model (DEL+T790M) and HCC827-vTR model (DEL+MET amplification), ERL reduced EGFR signal transduction and showed less pronounced but still significant tumor growth inhibition than in the HCC827 model. In these models, tumor growth inhibition was significantly stronger with BEV+ERL than with each single agent. In the NCI-H1975 model (L858R+T790M), ERL did not inhibit growth or EGFR signal transduction, and BEV+ERL did not inhibit growth more than BEV. BEV alone significantly decreased microvessel density in each tumor. In conclusion, addition of BEV to ERL did not enhance antitumor activity in primarily ERL-resistant tumors with T790M mutation; however, BEV+ERL enhanced antitumor activity in T790M mutation- or MET amplification-positive tumors as long as their growth remained significantly suppressed by ERL. © 2015 UICC.

  12. Isoliquiritigenin Induces Apoptosis and Inhibits Xenograft Tumor Growth of Human Lung Cancer Cells by Targeting Both Wild Type and L858R/T790M Mutant EGFR*

    PubMed Central

    Jung, Sung Keun; Lee, Mee-Hyun; Lim, Do Young; Kim, Jong Eun; Singh, Puja; Lee, Sung-Young; Jeong, Chul-Ho; Lim, Tae-Gyu; Chen, Hanyong; Chi, Young-In; Kundu, Joydeb Kumar; Lee, Nam Hyouck; Lee, Charles C.; Cho, Yong-Yeon; Bode, Ann M.; Lee, Ki Won; Dong, Zigang

    2014-01-01

    Non-small-cell lung cancer (NSCLC) is associated with diverse genetic alterations including mutation of epidermal growth factor receptor (EGFR). Isoliquiritigenin (ILQ), a chalcone derivative, possesses anticancer activities. In the present study, we investigated the effects of ILQ on the growth of tyrosine kinase inhibitor (TKI)-sensitive and -resistant NSCLC cells and elucidated its underlying mechanisms. Treatment with ILQ inhibited growth and induced apoptosis in both TKI-sensitive and -resistant NSCLC cells. ILQ-induced apoptosis was associated with the cleavage of caspase-3 and poly-(ADP-ribose)-polymerase, increased expression of Bim, and reduced expression of Bcl-2. In vitro kinase assay results revealed that ILQ inhibited the catalytic activity of both wild type and double mutant (L858R/T790M) EGFR. Treatment with ILQ inhibited the anchorage-independent growth of NIH3T3 cells stably transfected with either wild type or double-mutant EGFR with or without EGF stimulation. ILQ also reduced the phosphorylation of Akt and ERK1/2 in both TKI-sensitive and -resistant NSCLC cells, and attenuated the kinase activity of Akt1 and ERK2 in vitro. ILQ directly interacted with both wild type and double-mutant EGFR in an ATP-competitive manner. A docking model study showed that ILQ formed two hydrogen bonds (Glu-762 and Met-793) with wild type EGFR and three hydrogen bonds (Lys-745, Met-793, and Asp-855) with mutant EGFR. ILQ attenuated the xenograft tumor growth of H1975 cells, which was associated with decreased expression of Ki-67 and diminished phosphorylation of Akt and ERK1/2. Taken together, ILQ suppresses NSCLC cell growth by directly targeting wild type or mutant EGFR. PMID:25368326

  13. Isoliquiritigenin induces apoptosis and inhibits xenograft tumor growth of human lung cancer cells by targeting both wild type and L858R/T790M mutant EGFR.

    PubMed

    Jung, Sung Keun; Lee, Mee-Hyun; Lim, Do Young; Kim, Jong Eun; Singh, Puja; Lee, Sung-Young; Jeong, Chul-Ho; Lim, Tae-Gyu; Chen, Hanyong; Chi, Young-In; Kundu, Joydeb Kumar; Lee, Nam Hyouck; Lee, Charles C; Cho, Yong-Yeon; Bode, Ann M; Lee, Ki Won; Dong, Zigang

    2014-12-26

    Non-small-cell lung cancer (NSCLC) is associated with diverse genetic alterations including mutation of epidermal growth factor receptor (EGFR). Isoliquiritigenin (ILQ), a chalcone derivative, possesses anticancer activities. In the present study, we investigated the effects of ILQ on the growth of tyrosine kinase inhibitor (TKI)-sensitive and -resistant NSCLC cells and elucidated its underlying mechanisms. Treatment with ILQ inhibited growth and induced apoptosis in both TKI-sensitive and -resistant NSCLC cells. ILQ-induced apoptosis was associated with the cleavage of caspase-3 and poly-(ADP-ribose)-polymerase, increased expression of Bim, and reduced expression of Bcl-2. In vitro kinase assay results revealed that ILQ inhibited the catalytic activity of both wild type and double mutant (L858R/T790M) EGFR. Treatment with ILQ inhibited the anchorage-independent growth of NIH3T3 cells stably transfected with either wild type or double-mutant EGFR with or without EGF stimulation. ILQ also reduced the phosphorylation of Akt and ERK1/2 in both TKI-sensitive and -resistant NSCLC cells, and attenuated the kinase activity of Akt1 and ERK2 in vitro. ILQ directly interacted with both wild type and double-mutant EGFR in an ATP-competitive manner. A docking model study showed that ILQ formed two hydrogen bonds (Glu-762 and Met-793) with wild type EGFR and three hydrogen bonds (Lys-745, Met-793, and Asp-855) with mutant EGFR. ILQ attenuated the xenograft tumor growth of H1975 cells, which was associated with decreased expression of Ki-67 and diminished phosphorylation of Akt and ERK1/2. Taken together, ILQ suppresses NSCLC cell growth by directly targeting wild type or mutant EGFR. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Targeting tissue factor as a novel therapeutic oncotarget for eradication of cancer stem cells isolated from tumor cell lines, tumor xenografts and patients of breast, lung and ovarian cancer

    PubMed Central

    Hu, Zhiwei; Xu, Jie; Cheng, Jijun; McMichael, Elizabeth; Yu, Lianbo; Carson, William E.

    2017-01-01

    Targeting cancer stem cell (CSC) represents a promising therapeutic approach as it can potentially fight cancer at its root. The challenge is to identify a surface therapeutic oncotarget on CSC. Tissue factor (TF) is known as a common yet specific surface target for cancer cells and tumor neovasculature in several solid cancers. However, it is unknown if TF is expressed by CSCs. Here we demonstrate that TF is constitutively expressed on CD133 positive (CD133+) or CD24-CD44+ CSCs isolated from human cancer cell lines, tumor xenografts from mice and breast tumor tissues from patients. TF-targeted agents, i.e., a factor VII (fVII)-conjugated photosensitizer (fVII-PS for targeted photodynamic therapy) and fVII-IgG1Fc (Immunoconjugate or ICON for immunotherapy), can eradicate CSC via the induction of apoptosis and necrosis and via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, respectively. In conclusion, these results demonstrate that TF is a novel surface therapeutic oncotarget for CSC, in addition to cancer cell TF and tumor angiogenic vascular endothelial TF. Moreover, this research highlights that TF-targeting therapeutics can effectively eradicate CSCs, without drug resistance, isolated from breast, lung and ovarian cancer with potential to translate into other most commonly diagnosed solid cancer, in which TF is also highly expressed. PMID:27903969

  15. Targeting tissue factor as a novel therapeutic oncotarget for eradication of cancer stem cells isolated from tumor cell lines, tumor xenografts and patients of breast, lung and ovarian cancer.

    PubMed

    Hu, Zhiwei; Xu, Jie; Cheng, Jijun; McMichael, Elizabeth; Yu, Lianbo; Carson, William E

    2017-01-03

    Targeting cancer stem cell (CSC) represents a promising therapeutic approach as it can potentially fight cancer at its root. The challenge is to identify a surface therapeutic oncotarget on CSC. Tissue factor (TF) is known as a common yet specific surface target for cancer cells and tumor neovasculature in several solid cancers. However, it is unknown if TF is expressed by CSCs. Here we demonstrate that TF is constitutively expressed on CD133 positive (CD133+) or CD24-CD44+ CSCs isolated from human cancer cell lines, tumor xenografts from mice and breast tumor tissues from patients. TF-targeted agents, i.e., a factor VII (fVII)-conjugated photosensitizer (fVII-PS for targeted photodynamic therapy) and fVII-IgG1Fc (Immunoconjugate or ICON for immunotherapy), can eradicate CSC via the induction of apoptosis and necrosis and via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, respectively. In conclusion, these results demonstrate that TF is a novel surface therapeutic oncotarget for CSC, in addition to cancer cell TF and tumor angiogenic vascular endothelial TF. Moreover, this research highlights that TF-targeting therapeutics can effectively eradicate CSCs, without drug resistance, isolated from breast, lung and ovarian cancer with potential to translate into other most commonly diagnosed solid cancer, in which TF is also highly expressed.

  16. Dose-biomarker-response modeling of the anticancer effect of ethaselen in a human non-small cell lung cancer xenograft mouse model

    PubMed Central

    Ye, Suo-fu; Li, Jian; Ji, Shuang-min; Zeng, Hui-hui; Lu, Wei

    2017-01-01

    Thioredoxin reductase (TrxR) is a component of several redox-sensitive signaling cascades that mediate important biological processes such as cell survival, maturation, growth, migration and inhibition of apoptosis. The expression levels of TrxR1 in some human carcinoma cell lines are nearly 10 times higher than those in normal cells. Ethaselen is a novel antitumor candidate that exerts potent inhibition on non-small cell lung cancer (NSCLC) by targeting TrxR. In this study we explored the relationship between the ethaselen dose and TrxR activity level and the relationship between TrxR degradation and tumor apoptosis in a human lung carcinoma A549 xenograft model. BALB/c nude mice implanted with human NSCLC cell line A54 were administered ethaselen (36, 72, 108 mg·kg−1·d−1, ig) or vehicle for 10 d. The tumor size and TrxR activity levels in tumor tissues were daily recorded and detected. Based on the experimental data, NONMEM 7.2 was used to develop an integrated dose-biomarker-response model for describing the quantitative relationship between ethaselen dose and tumor eradication effects. The time course of TrxR activity levels was modeled using an indirect response model (IDR model), in which the influence of the tumor growth rates on Kin with the linear correction factor γ1 (0.021 d/mm). The drug binding-inhibition effects on Kout was described using a sigmoidal Emax model with Smax (5.95), SC50 (136 mg/kg) and Hill's coefficient γ2 (2.29). The influence of TrxR activity inhibition on tumor eradication was characterized by an Emax model with an Emax (130 mm3/d) and EC50 (0.0676). This model was further validated using a visual predictive check (VPC) and was used to predict the efficacy of different doses. In conclusion, the properties and characteristics of ethaselen acting on TrxR degradation and subsequently resulting in tumor apoptosis are characterized by the IDR model and integrated dose-biomarker-response model with high goodness-of-fit and great

  17. Anti-tumor activity of high-dose EGFR tyrosine kinase inhibitor and sequential docetaxel in wild type EGFR non-small cell lung cancer cell nude mouse xenografts.

    PubMed

    Tang, Ning; Zhang, Qianqian; Fang, Shu; Han, Xiao; Wang, Zhehai

    2017-02-07

    Treatment of non-small-cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR) is still a challenge. This study explored antitumor activity of high-dose icotinib (an EGFR tyrosine kinase inhibitor) plus sequential docetaxel against wild-type EGFR NSCLC cells-generated nude mouse xenografts. Nude mice were subcutaneously injected with wild-type EGFR NSCLC A549 cells and divided into different groups for 3-week treatment. Tumor xenograft volumes were monitored and recorded, and at the end of experiments, tumor xenografts were removed for Western blot and immunohistochemical analyses. Compared to control groups (negative control, regular-dose icotinib [IcoR], high-dose icotinib [IcoH], and docetaxel [DTX]) and regular icotinib dose (60 mg/kg) with docetaxel, treatment of mice with a high-dose (1200 mg/kg) of icotinib plus sequential docetaxel for 3 weeks (IcoH-DTX) had an additive effect on suppression of tumor xenograft size and volume (P < 0.05). Icotinib-containing treatments markedly reduced phosphorylation of EGFR, mitogen activated protein kinase (MAPK), and protein kinase B (Akt), but only the high-dose icotinib-containing treatments showed an additive effect on CD34 inhibition (P < 0.05), an indication of reduced microvessel density in tumor xenografts. Moreover, high-dose icotinib plus docetaxel had a similar effect on mouse weight loss (a common way to measure adverse reactions in mice), compared to the other treatment combinations. The study indicate that the high dose of icotinib plus sequential docetaxel (IcoH-DTX) have an additive effect on suppressing the growth of wild-type EGFR NSCLC cell nude mouse xenografts, possibly through microvessel density reduction. Future clinical trials are needed to confirm the findings of this study.

  18. Lung Cancer Prevention

    MedlinePlus

    ... Treatment Lung Cancer Prevention Lung Cancer Screening Research Lung Cancer Prevention (PDQ®)–Patient Version What is prevention? ... to keep cancer from starting. General Information About Lung Cancer Key Points Lung cancer is a disease ...

  19. What Is Lung Cancer?

    MedlinePlus

    ... Graphics Infographic Stay Informed Cancer Home What Is Lung Cancer? Language: English Español (Spanish) Recommend on Facebook Tweet ... cancer starts in the lungs, it is called lung cancer. Lung cancer begins in the lungs and may ...

  20. Lung Cancer Screening

    MedlinePlus

    ... Treatment Lung Cancer Prevention Lung Cancer Screening Research Lung Cancer Screening (PDQ®)–Patient Version What is screening? ... These are called diagnostic tests . General Information About Lung Cancer Key Points Lung cancer is a disease ...

  1. Lung cancer

    MedlinePlus

    ... Sputum test to look for cancer cells Thoracentesis (sampling of fluid buildup around the lung) In most ... quitting, talk with your provider. There are many methods to help you quit, from support groups to ...

  2. A novel ligand-independent peptide inhibitor of TREM-1 suppresses tumor growth in human lung cancer xenografts and prolongs survival of mice with lipopolysaccharide-induced septic shock

    PubMed Central

    Sigalov, Alexander B.

    2014-01-01

    Triggering receptor expressed on myeloid cells-1 (TREM-1) amplifies the inflammatory response and plays a role in cancer and sepsis. Inhibition of TREM-1 by short hairpin RNA (shRNA) in macrophages suppresses cancer cell invasion in vitro. In the clinical setting, high levels of TREM-1 expression on tumor-associated macrophages are associated with cancer recurrence and poor survival of patients with non-small cell lung cancer (NSCLC). TREM-1 upregulation on peritoneal neutrophils has been found in human sepsis patients and in mice with experimental lipopolysaccharide (LPS)-induced septic shock. However, the precise function of TREM-1 and the nature of its ligand are not yet known. In this study, we used the signaling chain homooligomerization (SCHOOL) model of immune signaling to design a novel, ligand-independent peptide-based TREM-1 inhibitor and demonstrated that this peptide specifically silences TREM-1 signaling in vitro and in vivo. Utilizing two human lung tumor xenograft nude mouse models (H292 and A549) and mice with LPS-induced sepsis, we show for the first time that blockade of TREM-1 function using non-toxic and non-immunogenic SCHOOL peptide inhibitors: 1) delays tumor growth in xenograft models of human NSCLC, 2) prolongs survival of mice with LPS-induced septic shock, and 3) substantially decreases cytokine production in vitro and in vivo. In addition, targeted delivery of SCHOOL peptides to macrophages utilizing lipoprotein-mimicking nanoparticles significantly increased peptide half-life and dosage efficacy. Together, the results suggest that ligand-independent modulation of TREM-1 function using small synthetic peptides might be a suitable treatment for sepsis and NSCLC and possibly other types of inflammation-associated disorders. PMID:24836682

  3. Lung Cancer Screening

    MedlinePlus

    Lung cancer screening Overview By Mayo Clinic Staff Lung cancer screening is a process that's used to detect the presence ... with a high risk of lung cancer. Lung cancer screening is recommended for older adults who are longtime ...

  4. Lung cancer - small cell

    MedlinePlus

    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 ...

  5. 6 Common Cancers - Lung Cancer

    MedlinePlus

    ... Home Current Issue Past Issues 6 Common Cancers - Lung Cancer Past Issues / Spring 2007 Table of Contents ... for Desperate Housewives. (Photo ©2005 Kathy Hutchins / Hutchins) Lung Cancer Lung cancer causes more deaths than the ...

  6. 2′-(2-bromohexadecanoyl)-paclitaxel conjugate nanoparticles for the treatment of non-small cell lung cancer in an orthotopic xenograft mouse model

    PubMed Central

    Peng, Lei; Schorzman, Allison N; Ma, Ping; Madden, Andrew J; Zamboni, William C; Benhabbour, Soumya Rahima; Mumper, Russell J

    2014-01-01

    A nanoparticle (NP) formulation with 2′-(2-bromohexadecanoyl)-paclitaxel (Br-16-PX) conjugate was developed in these studies for the treatment of non-small cell lung cancer (NSCLC). The lipophilic paclitaxel conjugate Br-C16-PX was synthesized and incorporated into lipid NPs where the 16-carbon chain enhanced drug entrapment in the drug delivery system and improved in vivo pharmacokinetics. The electron-withdrawing bromine group was used to facilitate the conversion of Br-C16-PX to paclitaxel at the tumor site. The developed system was evaluated in luciferase-expressing A549 cells in vitro and in an orthotopic NSCLC mouse model. The results demonstrated that the Br-C16-PX NPs had a higher maximum tolerated dose (75 mg/kg) than Taxol® (19 mg/kg) and provided significantly longer median survival (88 days versus 70 days, P<0.05) in the orthotopic NSCLC model. An improved pharmacokinetic profile was observed for the Br-C16-PX NPs at 75 mg/kg compared to Taxol at 19 mg/kg. The area under the concentration versus time curve (AUC)0–96 h of Br-C16-PX from the NPs was 91.7-fold and 49.6-fold greater than Taxol in plasma and tumor-bearing lungs, respectively, which provided sustained drug exposure and higher antitumor efficacy in the NP-treated group. PMID:25114529

  7. Nutrition for Lung Cancer

    MedlinePlus

    ... by zip code or Select your state State Lung Cancer www.lung.org > Lung Health and Diseases > ... I Stay Healthy Share this page: Nutrition for Lung Cancer Key Points There is no prescribed diet ...

  8. Human pancreatic cancer xenografts recapitulate key aspects of cancer cachexia

    PubMed Central

    Delitto, Andrea E.; Nosacka, Rachel L.; Rocha, Fernanda G.; DiVita, Bayli B.; Gerber, Michael H.; George, Thomas J.; Behrns, Kevin E.; Hughes, Steven J.; Wallet, Shannon M.; Judge, Andrew R.; Trevino, Jose G.

    2017-01-01

    Cancer cachexia represents a debilitating syndrome that diminishes quality of life and augments the toxicities of conventional treatments. Cancer cachexia is particularly debilitating in patients with pancreatic cancer (PC). Mechanisms responsible for cancer cachexia are under investigation and are largely derived from observations in syngeneic murine models of cancer which are limited in PC. We evaluate the effect of human PC cells on both muscle wasting and the systemic inflammatory milieu potentially contributing to PC-associated cachexia. Specifically, human PC xenografts were generated by implantation of pancreatic cancer cells, L3.6pl and PANC-1, either in the flank or orthotopically within the pancreas. Mice bearing orthotopic xenografts demonstrated significant muscle wasting and atrophy-associated gene expression changes compared to controls. Further, despite the absence of adaptive immunity, splenic tissue from orthotopically engrafted mice demonstrated elevations in several pro-inflammatory cytokines associated with cancer cachexia, including TNFα, IL1β, IL6 and KC (murine IL8 homologue), when compared to controls. Therefore, data presented here support further investigation into the complexity of cancer cachexia in PC to identify potential targets for this debilitating syndrome. PMID:27901481

  9. Risks of Lung Cancer Screening

    MedlinePlus

    ... Treatment Lung Cancer Prevention Lung Cancer Screening Research Lung Cancer Screening (PDQ®)–Patient Version What is screening? ... These are called diagnostic tests . General Information About Lung Cancer Key Points Lung cancer is a disease ...

  10. Comparative oncological studies of feline bronchioloalveolar lung carcinoma, its derived cell line and xenograft.

    PubMed

    Grossman, Deborah A; Hiti, Alan L; McNiel, Elizabeth A; Ye, Yin; Alpaugh, Mary L; Barsky, Sanford H

    2002-07-01

    Although certain neoplasms are unique to man, others occur across species. One such neoplasm is bronchioloalveolar lung carcinoma (BAC), a neoplasm of the Type II pneumocyte that affects humans, sheep, and small animals (dogs and cats). Human BAC occurs largely in nonsmokers. Sheep BAC is caused by the jaagsiekte retrovirus and is endemic and contagious. Feline BAC is neither endemic nor contagious and occurs sporadically and spontaneously in older purebred cats. In these respects, feline BAC is more closely similar to human BAC than sheep BAC (jaagsiekte) is. To study feline BAC further, we established the first immortal cell line (SPARKY) and transplantable scid mouse xenograft (Sparky-X) from a malignant pleural effusion of a 12-year-old Persian male with autopsy-confirmed BAC. SPARKY exhibited a Type II pneumocyte phenotype characterized by surfactant and thyroid-transcription factor-1 immunoreactivities and lamellar bodies. SPARKY's karyotype was aneuploid (66 chromosomes: 38, normal cat) and showed evidence of genomic instability analogous to human lung cancers. p53 showed a homozygous G to T transversion at codon 167, the feline equivalent of human codon 175, one of the many hot spots mutated in the lung cancers of smokers. H-ras and K-ras were not altered. By reverse transcription-PCR, SPARKY lacked expression of retroviral JSRVgag transcripts that were present in the lungs of sheep BAC (jaagsiekte). Unlike human BAC xenografts, SPARKY-X retained its unique lepidic BAC growth pattern even though it was grown in murine s.c. tissues. This property may be related to the ability of SPARKY-X to up-regulate its surfactant genes (SP-A, SP-B, and SP-D). These studies of feline BAC may allow insights into the human disease that are not possible by studying human BAC directly.

  11. The Angiogenic Secretome in VEGF overexpressing Breast Cancer Xenografts

    PubMed Central

    Dore-Savard, Louis; Lee, Esak; Kakkad, Samata; Popel, Aleksander S.; Bhujwalla, Zaver M.

    2016-01-01

    The plasticity of cancer cells and the fluidity of the tumor microenvironment continue to present major challenges in the comprehensive understanding of cancer that is essential to design effective treatments. The tumor interstitial fluid (TIF) encompasses the secretome and holds the key to several of the phenotypic characteristics of cancer. Difficulties in sampling this fluid have resulted in limited characterization of its components. Here we have sampled TIF from triple negative and estrogen receptor (ER)-positive human breast tumor xenografts with or without VEGF overexpression. Angiogenesis-related factors were characterized in the TIF and plasma, to understand the relationship between the TIF and plasma secretomes. Clear differences were observed between the TIF and plasma angiogenic secretomes in triple negative MDA-MB-231 breast cancer xenografts compared to ER-positive MCF-7 xenografts with or without VEGF overexpression that provide new insights into TIF components and the role of VEGF in modifying the angiogenic secretome. PMID:27995973

  12. Targeted Imaging of the Atypical Chemokine Receptor 3 (ACKR3/CXCR7) in Human Cancer Xenografts.

    PubMed

    Behnam Azad, Babak; Lisok, Ala; Chatterjee, Samit; Poirier, John T; Pullambhatla, Mrudula; Luker, Gary D; Pomper, Martin G; Nimmagadda, Sridhar

    2016-06-01

    The atypical chemokine receptor ACKR3 (formerly CXCR7), overexpressed in various cancers compared with normal tissues, plays a pivotal role in adhesion, angiogenesis, tumorigenesis, metastasis, and tumor cell survival. ACKR3 modulates the tumor microenvironment and regulates tumor growth. The therapeutic potential of ACKR3 has also been demonstrated in various murine models of human cancer. Literature findings underscore the importance of ACKR3 in disease progression and suggest it as an important diagnostic marker for noninvasive imaging of ACKR3-overexpressing malignancies. There are currently no reports on direct receptor-specific detection of ACKR3 expression. Here we report the evaluation of a radiolabeled ACKR3-targeted monoclonal antibody (ACKR3-mAb) for the noninvasive in vivo nuclear imaging of ACKR3 expression in human breast, lung, and esophageal squamous cell carcinoma cancer xenografts. ACKR3 expression data were extracted from Cancer Cell Line Encyclopedia, The Cancer Genome Atlas, and the Clinical Lung Cancer Genome Project. (89)Zr-ACKR3-mAb was evaluated in vitro and subsequently in vivo by PET and ex vivo biodistribution studies in mice xenografted with breast (MDA-MB-231-ACKR3 [231-ACKR3], MDA-MB-231 [231], MCF7), lung (HCC95), or esophageal (KYSE520) cancer cells. In addition, ACKR3-mAb was radiolabeled with (125)I and evaluated by SPECT imaging and ex vivo biodistribution studies. ACKR3 transcript levels were highest in lung squamous cell carcinoma among the 21 cancer type data extracted from The Cancer Genome Atlas. Also, Clinical Lung Cancer Genome Project data showed that lung squamous cell carcinoma had the highest CXCR7 transcript levels compared with other lung cancer subtypes. The (89)Zr-ACKR3-mAb was produced in 80% ± 5% radiochemical yields with greater than 98% radiochemical purity. In vitro cell uptake of (89)Zr-ACKR3-mAb correlated with gradient levels of cell surface ACKR3 expression observed by flow cytometry. In vivo PET imaging

  13. Erlotinib pretreatment improves photodynamic therapy of non-small cell lung carcinoma xenografts via multiple mechanisms

    PubMed Central

    Gallagher-Colombo, Shannon M.; Miller, Joann; Cengel, Keith A.; Putt, Mary E.; Vinogradov, Sergei A.; Busch, Theresa M.

    2015-01-01

    Aberrant expression of the epidermal growth factor receptor (EGFR) is a common characteristic of many cancers including non-small cell lung carcinoma (NSCLC), head and neck squamous cell carcinoma, and ovarian cancer. While EGFR is currently a favorite molecular target for treatment of these cancers, inhibition of the receptor with small molecule inhibitors (i.e.- erlotinib) or monoclonal antibodies (i.e.- cetuximab) does not provide long-term therapeutic benefit as standalone treatment. Interestingly, we have found that addition of erlotinib to photodynamic therapy (PDT) can improve treatment response in typically erlotinib-resistant NSCLC tumor xenografts. Ninety-day complete response rates of 63% are achieved when erlotinib is administered in three doses before PDT of H460 human tumor xenografts, compared to 16% after PDT-alone. Similar benefit is found when erlotinib is added to PDT of A549 NCSLC xenografts. Improved response is accompanied by increased vascular shutdown, and erlotinib increases the in vitro cytotoxicity of PDT to endothelial cells. Tumor uptake of the photosensitizer (benzoporphyrin derivative monoacid ring A; BPD) is increased by the in vivo administration of erlotinib; nevertheless, this elevation of BPD levels only partially accounts for the benefit of erlotinib to PDT. Thus, pretreatment with erlotinib augments multiple mechanisms of PDT effect that collectively lead to large improvements in therapeutic efficacy. These data demonstrate that short-duration administration of erlotinib before PDT can greatly improve the responsiveness of even erlotinib-resistant tumors to treatment. Results will inform clinical investigation of EGFR-targeting therapeutics in conjunction with PDT. PMID:26054596

  14. Next generation patient-derived prostate cancer xenograft models

    PubMed Central

    Lin, Dong; Xue, Hui; Wang, Yuwei; Wu, Rebecca; Watahiki, Akira; Dong, Xin; Cheng, Hongwei; Wyatt, Alexander W; Collins, Colin C; Gout, Peter W; Wang, Yuzhuo

    2014-01-01

    There is a critical need for more effective therapeutic approaches for prostate cancer. Research in this area, however, has been seriously hampered by a lack of clinically relevant, experimental in vivo models of the disease. This review particularly focuses on the development of prostate cancer xenograft models based on subrenal capsule grafting of patients’ tumor tissue into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This technique allows successful development of transplantable, patient-derived cancer tissue xenograft lines not only from aggressive metastatic, but also from localized prostate cancer tissues. The xenografts have been found to retain key biological properties of the original malignancies, including histopathological and molecular characteristics, tumor heterogeneity, response to androgen ablation and metastatic ability. As such, they are highly clinically relevant and provide valuable tools for studies of prostate cancer progression at cellular and molecular levels, drug screening for personalized cancer therapy and preclinical drug efficacy testing; especially when a panel of models is used to cover a broader spectrum of the disease. These xenograft models could therefore be viewed as next-generation models of prostate cancer. PMID:24589467

  15. Radiation Therapy for Lung Cancer

    MedlinePlus

    ... are available to help. HELPFUL WEB SITES ON LUNG CANCER American Lung Association www.lung.org Lungcancer.org www.lungcancer.org Lung Cancer Alliance www.lungcanceralliance.org Lung Cancer Online www. ...

  16. Lung cancer screening update

    PubMed Central

    Dhillon, Samjot Singh; Loewen, Gregory; Jayaprakash, Vijayvel; Reid, Mary E.

    2013-01-01

    Lung cancer is the leading cause of cancer-related mortality globally and the American cancer society estimates approximately 226,160 new cases and 160,340 deaths from lung cancer in the USA in the year 2012. The majority of lung cancers are diagnosed in the later stages which impacts the overall survival. The 5-year survival rate for pathological st age IA lung cancer is 73% but drops to only 13% for stage IV. Thus, early detection through screening and prevention are the keys to reduce the global burden of lung cancer. This article discusses the current state of lung cancer screening, including the results of the National Lung Cancer Screening Trial, the consideration of implementing computed tomography screening, and a brief overview of the role of bronchoscopy in early detection and potential biomarkers that may aid in the early diagnosis of lung cancer. PMID:23599684

  17. Lung cancer prevention.

    PubMed

    Slatore, Christopher; Sockrider, Marianna

    2014-11-15

    Lung cancer is a common form of cancer.There are things you can do to lower your risk of lung cancer. Stop smoking tobacco. Ask your health care provider for help in quitting, including use of medicines to help with nicotine dependence. discuss with your healthcare provider,what you are taking or doing to decrease your risk for lung cancer

  18. Epidemiology of Lung Cancer

    PubMed Central

    Brock, Malcolm V.; Ford, Jean G.; Samet, Jonathan M.; Spivack, Simon D.

    2013-01-01

    Background: Ever since a lung cancer epidemic emerged in the mid-1900s, the epidemiology of lung cancer has been intensively investigated to characterize its causes and patterns of occurrence. This report summarizes the key findings of this research. Methods: A detailed literature search provided the basis for a narrative review, identifying and summarizing key reports on population patterns and factors that affect lung cancer risk. Results: Established environmental risk factors for lung cancer include smoking cigarettes and other tobacco products and exposure to secondhand tobacco smoke, occupational lung carcinogens, radiation, and indoor and outdoor air pollution. Cigarette smoking is the predominant cause of lung cancer and the leading worldwide cause of cancer death. Smoking prevalence in developing nations has increased, starting new lung cancer epidemics in these nations. A positive family history and acquired lung disease are examples of host factors that are clinically useful risk indicators. Risk prediction models based on lung cancer risk factors have been developed, but further refinement is needed to provide clinically useful risk stratification. Promising biomarkers of lung cancer risk and early detection have been identified, but none are ready for broad clinical application. Conclusions: Almost all lung cancer deaths are caused by cigarette smoking, underscoring the need for ongoing efforts at tobacco control throughout the world. Further research is needed into the reasons underlying lung cancer disparities, the causes of lung cancer in never smokers, the potential role of HIV in lung carcinogenesis, and the development of biomarkers. PMID:23649439

  19. Targeted Imaging of the Atypical Chemokine Receptor 3 (ACKR3/CXCR7) in Human Cancer Xenografts

    PubMed Central

    Azad, Babak Behnam; Lisok, Ala; Chatterjee, Samit; Poirier, John T.; Pullambhatla, Mrudula; Luker, Gary D.; Pomper, Martin G.; Nimmagadda, Sridhar

    2017-01-01

    The atypical chemokine receptor ACKR3 (formerly CXCR7), overexpressed in various cancers compared to normal tissues, plays a pivotal role in adhesion, angiogenesis, tumorigenesis, metastasis and tumor cell survival. ACKR3 modulates the tumor microenvironment and regulates tumor growth. The therapeutic potential of ACKR3 has also been demonstrated in various murine models of human cancer. Literature findings underscore the importance of ACKR3 in disease progression and suggest it as an important diagnostic maker for non-invasive imaging of ACKR3 overexpressing malignancies. There are currently no reports on direct receptor-specific detection of ACKR3 expression. Here we report the evaluation of a radiolabeled ACKR3-targeted monoclonal antibody (ACKR3-mAb) for the non-invasive in vivo nuclear imaging of ACKR3 expression in human breast, lung and esophageal squamous cell carcinoma cancer xenografts. Methods ACKR3 transcripts were extracted from Cancer Cell Line Encyclopedia (CCLE), The Cancer Genome Atlas (TCGA) and the Clinical Lung Cancer Genome Project (CLCGP). 89Zr-ACKR3-mAb was evaluated in vitro and subsequently in vivo by positron emission tomography (PET) and ex vivo biodistribution studies in mice xenografted with breast (MDA-MB-231-ACKR3 (231-AC-KR3), MDA-MB-231 (231), MCF7), lung (HCC95) or esophageal (KYSE520) cancer cells. In addition, ACKR3-mAb was radiolabeled with Iodine-125 and evaluated by single photon emission computed tomography (SPECT) imaging and ex vivo biodistribution studies. Results ACKR3 transcript levels were highest in lung squamous cell carcinoma (LUSC) among the 21 cancer type data extracted from TCGA. Also, CLCGP data showed that LUSC has the highest CXCR7 transcript levels compared to other lung cancer subtypes. The 89Zr-ACKR3-mAb was produced in 80±5% radiochemical yields with >98% radiochemical purity. In vitro cell uptake of 89Zr-ACKR3-mAb correlated with gradient levels of cell surface ACKR3 expression observed by flow cytometry

  20. Tumor growth-inhibitory effect of an angiotensin-converting enzyme inhibitor (captopril) in a lung cancer xenograft model analyzed using 18F-FDG-PET/CT.

    PubMed

    Nakaya, Koji; Otsuka, Hideki; Kondo, Kazuya; Otani, Tamaki; Nagata, Motoi

    2016-02-01

    We administered an angiotensin-converting enzyme inhibitor (captopril) to mice implanted with a human lung adenocarcinoma epithelial cell line (A549 cells) and investigated the tumor growth-inhibitory effect of captopril from the viewpoint of glucose metabolism using (18)F-fluorodeoxyglucose ((18)F-FDG)-PET/CT. Subcutaneous implantation of A549 cells (1.9×10(6) cells) was carried out in the lower right flank of mice. Fifteen days after the transplantation of A549 cells, mice (six in each group) were treated with captopril (3.0 mg/mouse) or saline (1000 μl/mouse) for 5 days. We performed (18)F-FDG-PET/CT imaging of the mice before and after the treatment and evaluated the degree of (18)F-FDG accumulation in tumors. In both groups (the captopril-administrated and control groups), values for the metabolic tumor volume (MTV), maximum standardized uptake value, total lesion glycolysis, and tumor volume after treatment had a tendency to increase. However, tumor growth was suppressed in the captopril-administrated group compared with the control group. In terms of the growth rate, the MTV and tumor volume were significantly different (P<0.05). It was found that captopril exerted a potential tumor growth-inhibitory effect; this was because the captopril-administrated group showed low values of MTV, maximum standardized uptake value, total lesion glycolysis, and tumor volume in comparison with the control group.

  1. Pim Kinases Promote Migration and Metastatic Growth of Prostate Cancer Xenografts

    PubMed Central

    Santio, Niina M.; Eerola, Sini K.; Paatero, Ilkka; Yli-Kauhaluoma, Jari; Anizon, Fabrice; Moreau, Pascale; Tuomela, Johanna; Härkönen, Pirkko; Koskinen, Päivi J.

    2015-01-01

    Background and methods Pim family proteins are oncogenic kinases implicated in several types of cancer and involved in regulation of cell proliferation, survival as well as motility. Here we have investigated the ability of Pim kinases to promote metastatic growth of prostate cancer cells in two xenograft models for human prostate cancer. We have also evaluated the efficacy of Pim-selective inhibitors to antagonize these effects. Results We show here that tumorigenic growth of both subcutaneously and orthotopically inoculated prostate cancer xenografts is enhanced by stable overexpression of either Pim-1 or Pim-3. Moreover, Pim-overexpressing orthotopic prostate tumors are highly invasive and able to migrate not only to the nearby prostate-draining lymph nodes, but also into the lungs to form metastases. When the xenografted mice are daily treated with the Pim-selective inhibitor DHPCC-9, both the volumes as well as the metastatic capacity of the tumors are drastically decreased. Interestingly, the Pim-promoted metastatic growth of the orthotopic xenografts is associated with enhanced angiogenesis and lymphangiogenesis. Furthermore, forced Pim expression also increases phosphorylation of the CXCR4 chemokine receptor, which may enable the tumor cells to migrate towards tissues such as the lungs that express the CXCL12 chemokine ligand. Conclusions Our results indicate that Pim overexpression enhances the invasive properties of prostate cancer cells in vivo. These effects can be reduced by the Pim-selective inhibitor DHPCC-9, which can reach tumor tissues without serious side effects. Thus, Pim-targeting therapies with DHPCC-9-like compounds may help to prevent progression of local prostate carcinomas to fatally metastatic malignancies. PMID:26075720

  2. Chlorin e6 – polyvinylpyrrolidone mediated photosensitization is effective against human non-small cell lung carcinoma compared to small cell lung carcinoma xenografts

    PubMed Central

    Chin, William WL; Heng, Paul WS; Olivo, Malini

    2007-01-01

    Background Photodynamic therapy (PDT) is an effective local cancer treatment that involves light activation of a photosensitizer, resulting in oxygen-dependent, free radical-mediated cell death. Little is known about the comparative efficacy of PDT in treating non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC), despite ongoing clinical trials treating lung cancers. The present study evaluated the potential use of chlorin e6 – polyvinylpyrrolidone (Ce6-PVP) as a multimodality photosensitizer for fluorescence detection and photodynamic therapy (PDT) on NSCLC and SCLC xenografts. Results Human NSCLC (NCI-H460) and SCLC (NCI-H526) tumor cell lines were used to establish tumor xenografts in the chick chorioallantoic membrane (CAM) model as well as in the Balb/c nude mice. In the CAM model, Ce6-PVP was applied topically (1.0 mg/kg) and fluorescence intensity was charted at various time points. Tumor-bearing mice were given intravenous administration of Ce6-PVP (2.0 mg/kg) and laser irradiation at 665 nm (fluence of 150 J/cm2 and fluence rate of 125 mW/cm2). Tumor response was evaluated at 48 h post PDT. Studies of temporal fluorescence pharmacokinetics in CAM tumor xenografts showed that Ce6-PVP has a selective localization and a good accuracy in demarcating NSCLC compared to SCLC from normal surrounding CAM after 3 h post drug administration. Irradiation at 3 h drug-light interval showed greater tumor necrosis against human NSCLC xenografts in nude mice. SCLC xenografts were observed to express resistance to photosensitization with Ce6-PVP. Conclusion The formulation of Ce6-PVP is distinctly advantageous as a diagnostic and therapeutic agent for fluorescence diagnosis and PDT of NSCLC. PMID:18053148

  3. Survivin inhibitor YM155 suppresses gastric cancer xenograft growth in mice without affecting normal tissues.

    PubMed

    Cheng, Xiao Jiao; Lin, Jia Cheng; Ding, Yan Fei; Zhu, Liming; Ye, Jing; Tu, Shui Ping

    2016-02-09

    Survivin overexpression is associated with poor prognosis of human gastric cancer, and is a target for gastric cancer therapy. YM155 is originally identified as a specific inhibitor of survivin. In this study, we investigated the antitumor effect of YM155 on human gastric cancer. Our results showed that YM155 treatment significantly inhibited cell proliferation, reduced colony formation and induced apoptosis of gastric cancer cells in a dose-dependent manner. Accordingly, YM155 treatment significantly decreased survivin expression without affecting XIAP expression and increased the cleavage of apoptosis-associated proteins caspase 3, 7, 8, 9. YM155 significantly inhibited sphere formation of gastric cancer cells, suppressed expansion and growth of the formed spheres (cancer stem cell-like cells, CSCs) and downregulated the protein levels of β-catenin, c-Myc, Cyclin D1 and CD44 in gastric cancer cells. YM155 infusion at 5 mg/kg/day for 7 days markedly inhibited growth of gastric cancer xenograft in a nude mouse model. Immunohistochemistry staining and Western Blot showed that YM155 treatment inhibited expression of survivin and CD44, induced apoptosis and reduced CD44+ CSCs in xenograft tumor tissues in vivo. No obvious pathological changes were observed in organs (e.g. heart, liver, lung and kidney) in YM155-treated mice. Our results demonstrated that YM155 inhibits cell proliferation, induces cell apoptosis, reduces cancer stem cell expansion, and inhibits xenograft tumor growth in gastric cancer cells. Our results elucidate a new mechanism by which YM155 inhibits gastric cancer growth by inhibition of CSCs. YM155 may be a promising agent for gastric cancer treatment.

  4. [Lung cancer screening].

    PubMed

    Sánchez González, M

    2014-01-01

    Lung cancer is a very important disease, curable in early stages. There have been trials trying to show the utility of chest x-ray or computed tomography in Lung Cancer Screening for decades. In 2011, National Lung Screening Trial results were published, showing a 20% reduction in lung cancer mortality in patients with low dose computed tomography screened for three years. These results are very promising and several scientific societies have included lung cancer screening in their guidelines. Nevertheless we have to be aware of lung cancer screening risks, such as: overdiagnosis, radiation and false positive results. Moreover, there are many issues to be solved, including choosing the appropriate group to be screened, the duration of the screening program, intervals between screening and its cost-effectiveness. Ongoing trials will probably answer some of these questions. This article reviews the current evidence on lung cancer screening.

  5. Lung Cancer Indicators Recurrence

    Cancer.gov

    This study describes prognostic factors for lung cancer spread and recurrence, as well as subsequent risk of death from the disease. The investigators observed that regardless of cancer stage, grade, or type of lung cancer, patients in the study were more

  6. Regression of prostate cancer xenografts by RLIP76 depletion

    PubMed Central

    Singhal, Sharad S.; Roth, Cherice; Leake, Kathryn; Singhal, Jyotsana; Yadav, Sushma; Awasthi, Sanjay

    2009-01-01

    RLIP76 plays a central role in radiation and chemotherapy resistance through its activity as a multi-specific ATP-dependent transporter which is over-expressed in a number of types of cancers. RLIP76 appears to be necessary for cancer cell survival because both in vitro cell culture and in vivo animal tumor studies show that depletion or inhibition of RLIP76 causes selective toxicity in malignant cells. RLIP76 induces apoptosis in cancer cells through the accumulation of endogenously formed GS-E. The results of our in vivo studies demonstrate that administration of RLIP76 antibodies, siRNA or anti-sense to mice bearing xenografts of PC-3 prostate cancer cells leads to near complete regression of established subcutaneous xenografts with no apparent toxic effects. Since anti-RLIP76 IgG (which inhibit RLIP76- mediated transport), siRNA and antisense (which deplete RLIP76) showed similar tumor regressing activities, our results indicate that the inhibition of RLIP76 transport activity at the cell surface is sufficient for observed anti-tumor activity. These studies indicate that RLIP76 serves a key effector function for the survival of prostate cancer cells and that it is a valid target for cancer therapy. PMID:19073149

  7. Immunotherapy for lung cancer.

    PubMed

    Steven, Antonius; Fisher, Scott A; Robinson, Bruce W

    2016-07-01

    Treatment of lung cancer remains a challenge, and lung cancer is still the leading cause of cancer-related mortality. Immunotherapy has previously failed in lung cancer but has recently emerged as a very effective new therapy, and there is now growing worldwide enthusiasm in cancer immunotherapy. We summarize why immune checkpoint blockade therapies have generated efficacious and durable responses in clinical trials and why this has reignited interest in this field. Cancer vaccines have also been explored in the past with marginal success. Identification of optimal candidate neoantigens may improve cancer vaccine efficacy and may pave the way to personalized immunotherapy, alone or in combination with other immunotherapy such as immune checkpoint blockade. Understanding the steps in immune recognition and eradication of cancer cells is vital to understanding why previous immunotherapies failed and how current therapies can be used optimally. We hold an optimistic view for the future prospect in lung cancer immunotherapy.

  8. Genetics Home Reference: lung cancer

    MedlinePlus

    ... Me Understand Genetics Home Health Conditions lung cancer lung cancer Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Lung cancer is a disease in which certain cells ...

  9. Lung cancer in women

    PubMed Central

    Barrera-Rodriguez, Raúl; Morales-Fuentes, Jorge

    2012-01-01

    Recent biological advances in tumor research provide clear evidence that lung cancer in females is different from that in males. These differences appear to have a direct impact on the clinical presentation, histology, and outcomes of lung cancer. Women are more likely to present with lung adenocarcinoma, tend to receive a diagnosis at an earlier age, and are more likely to be diagnosed with localized disease. Women may also be more predisposed to molecular aberrations resulting from the carcinogenic effects of tobacco, but do not appear to be more susceptible than men to developing lung cancer. The gender differences found in female lung cancer make it mandatory that gender stratification is used in clinical trials in order to improve the survival rates of patients with lung cancer. PMID:28210127

  10. Justice and lung cancer.

    PubMed

    Wilson, Aaron

    2013-04-01

    Lung cancer is the leading cause of cancer deaths, yet research funding is by far the lowest for lung cancer than for any other cancer compared with respective death rates. Although this discrepancy should appear alarming, one could argue that lung cancer deserves less attention because it is more attributable to poor life choices than other common cancers. Accordingly, the general question that I ask in this article is whether victims of more avoidable diseases, such as lung cancer, deserve to have their needs taken into less consideration than those of less avoidable diseases, on the grounds of either retributive or distributive justice. Such unequal treatment may be the "penalty" one incurs for negligent or reckless behavior. However, I hope to show that such unequal treatment cannot be supported by any coherent accounts of retributive or distributive justice.

  11. Immunotherapy in Lung Cancer.

    PubMed

    Castellanos, Emily H; Horn, Leora

    2016-01-01

    Lung cancer has not traditionally been viewed as an immune-responsive tumor. However, it is becoming evident that tumor-induced immune suppression is vital to malignant progression. Immunotherapies act by enhancing the patient's innate immune response and hold promise for inducing long-term responses in select patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Immune checkpoint inhibitors, in particular, inhibitors to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) and programmed death receptor ligand 1 (PD-L1) have shown promise in early studies and are currently in clinical trials in both small cell lung cancer and non-small cell lung cancer patients. Two large randomized phase III trials recently demonstrated superior overall survival (OS) in patients treated with anti-PD-1 therapy compared to chemotherapy in the second-line setting.

  12. A Renewable Tissue Resource of Phenotypically Stable, Biologically and Ethnically Diverse, Patient-derived Human Breast Cancer Xenograft (PDX) Models

    PubMed Central

    Zhang, Xiaomei; Claerhout, Sofie; Pratt, Aleix; Dobrolecki, Lacey E.; Petrovic, Ivana; Lai, Qing; Landis, Melissa D.; Wiechmann, Lisa; Schiff, Rachel; Giuliano, Mario; Wong, Helen; Fuqua, Suzanne W.; Contreras, Alejandro; Gutierrez, Carolina; Huang, Jian; Mao, Sufeng; Pavlick, Anne C.; Froehlich, Amber M.; Wu, Meng-Fen; Tsimelzon, Anna; Hilsenbeck, Susan G.; Chen, Edward S.; Zuloaga, Pavel; Shaw, Chad A.; Rimawi, Mothaffar F.; Perou, Charles M.; Mills, Gordon B.; Chang, Jenny C.; Lewis, Michael T.

    2013-01-01

    Breast cancer research is hampered by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that reflect patient tumor biology accurately. To overcome these limitations, we propagated a cohort of human breast tumors grown in the epithelium-free mammary fat pad of SCID/Beige and NOD/SCID/IL2γ-receptor null (NSG) mice, under a series of transplant conditions. Both models yielded stably transplantable xenografts at comparably high rates (~21% and ~19%, respectively). Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 32 stably transplantable xenograft lines were established, representing 25 unique patients. Most tumors yielding xenografts were “triple-negative” (ER-PR-HER2+) (n=19). However, we established lines from three ER-PR-HER2+ tumors, one ER+PR-HER2−, one ER+PR+HER2− and one “triple-positive” (ER+PR+HER2+) tumor. Serially passaged xenografts show biological consistency with the tumor of origin, are phenotypically stable across multiple transplant generations at the histologic, transcriptomic, proteomic, and genomic levels, and show comparable treatment responses as those observed clinically. Xenografts representing 12 patients, including two ER+ lines, showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource for preclinical studies investigating treatment response and metastasis. PMID:23737486

  13. Occupational lung cancer

    SciTech Connect

    Coultas, D.B.; Samet, J.M. )

    1992-06-01

    The overall importance of occupational agents as a cause of lung cancer has been a controversial subject since the 1970s. A federal report, released in the late 1970s, projected a surprisingly high burden of occupational lung cancer; for asbestos and four other agents, from 61,000 to 98,000 cases annually were attributed to these agents alone. Many estimates followed, some much more conservative. For example, Doll and Peto estimated that 15% of lung cancer in men and 5% in women could be attributed to occupational exposures. A number of population-based case-control studies also provide relevant estimates. In a recent literature review, Vineis and Simonato cited attributable risk estimates for occupation and lung cancer that ranged from 4% to 40%; for asbestos alone, the estimates ranged from 1% to 5%. These estimates would be expected to vary across locations and over time. Nevertheless, these recent estimates indicate that occupation remains an important cause of lung cancer. Approaches to Prevention. Prevention of lung cancer mortality among workers exposed to agents or industrial processes that cause lung cancer may involve several strategies, including eliminating or reducing exposures, smoking cessation, screening, and chemo-prevention. For example, changes in industrial processes that have eliminated or reduced exposures to chloromethyl ethers and nickel compounds have provided evidence of reduced risk of lung cancer following these changes. Although occupational exposures are important causes of lung cancer, cigarette smoking is the most important preventable cause of lung cancer. For adults, the work site offers an important location to target smoking cessation efforts. In fact, the work site may be the only place to reach many smokers.

  14. Cullin7 is required for lung cancer cell proliferation and is overexpressed in lung cancer.

    PubMed

    Men, Xuelin; Wang, Lingcheng; Yu, Wenfei; Ju, Yuanrong

    2015-01-01

    Ubiquitin ligase Cullin7 has been identified as an oncogene in some malignant diseases such as choriocarcinoma and neuroblastoma. However, the role of Cullin7 in lung cancer carcinogenesis remains unclear. In this study, we explored the functional role of Cullin7 in lung cancer cell proliferation and tumorigenesis and determined its expression profile in lung cancer. Knocking down Cullin7 expression by small interfering RNA (siRNA) in lung cancer cells inhibited cell proliferation and elevated the expression of p53, p27, and p21 proteins. The enhanced p53 expression resulted from activation of the DNA damage response pathway. Cullin7 knockdown markedly suppressed xenograft tumor growth in vivo in mice. Moreover, Cullin7 expression was increased in primary lung cancer tissues of humans. Thus, Cullin7 is required for sustained proliferation and survival of tumor cells in vitro and in vivo, and its aberrant expression may contribute to the pathogenesis of lung cancer. Thus, our study provided evidence that Cullin7 functions as a novel oncogene in lung cancer and may be a potential therapeutic target for lung cancer management.

  15. Lung Cancer Screening.

    PubMed

    Hoffman, Richard M; Sanchez, Rolando

    2017-07-01

    Lung cancer is the leading cause of cancer death in the United States. More than 80% of these deaths are attributed to tobacco use, and primary prevention can effectively reduce the cancer burden. The National Lung Screening Trial showed that low-dose computed tomography (LDCT) screening could reduce lung cancer mortality in high-risk patients by 20% compared with chest radiography. The US Preventive Services Task Force recommends annual LDCT screening for persons aged 55 to 80 years with a 30-pack-year smoking history, either currently smoking or having quit within 15 years. Published by Elsevier Inc.

  16. Lung cancer screening.

    PubMed

    Tanoue, Lynn T; Tanner, Nichole T; Gould, Michael K; Silvestri, Gerard A

    2015-01-01

    The United States Preventive Services Task Force recommends lung cancer screening with low-dose computed tomography (LDCT) in adults of age 55 to 80 years who have a 30 pack-year smoking history and are currently smoking or have quit within the past 15 years. This recommendation is largely based on the findings of the National Lung Screening Trial. Both policy-level and clinical decision-making about LDCT screening must consider the potential benefits of screening (reduced mortality from lung cancer) and possible harms. Effective screening requires an appreciation that screening should be limited to individuals at high risk of death from lung cancer, and that the risk of harm related to false positive findings, overdiagnosis, and unnecessary invasive testing is real. A comprehensive understanding of these aspects of screening will inform appropriate implementation, with the objective that an evidence-based and systematic approach to screening will help to reduce the enormous mortality burden of lung cancer.

  17. Familial risk for lung cancer

    PubMed Central

    Kanwal, Madiha; Ding, Xiao-Ji; Cao, Yi

    2017-01-01

    Lung cancer, which has a low survival rate, is a leading cause of cancer-associated mortality worldwide. Smoking and air pollution are the major causes of lung cancer; however, numerous studies have demonstrated that genetic factors also contribute to the development of lung cancer. A family history of lung cancer increases the risk for the disease in both smokers and never-smokers. This review focuses on familial lung cancer, in particular on the familial aggregation of lung cancer. The development of familial lung cancer involves shared environmental and genetic factors among family members. Familial lung cancer represents a good model for investigating the association between environmental and genetic factors, as well as for identifying susceptibility genes for lung cancer. In addition, studies on familial lung cancer may help to elucidate the etiology and mechanism of lung cancer, and may identify novel biomarkers for early detection and diagnosis, targeted therapy and improved prevention strategies. This review presents the aetiology and molecular biology of lung cancer and then systematically introduces and discusses several aspects of familial lung cancer, including the characteristics of familial lung cancer, population-based studies on familial lung cancer and the genetics of familial lung cancer. PMID:28356926

  18. Proteogenomic integration reveals therapeutic targets in breast cancer xenografts

    PubMed Central

    Huang, Kuan-lin; Li, Shunqiang; Mertins, Philipp; Cao, Song; Gunawardena, Harsha P.; Ruggles, Kelly V.; Mani, D. R.; Clauser, Karl R.; Tanioka, Maki; Usary, Jerry; Kavuri, Shyam M.; Xie, Ling; Yoon, Christopher; Qiao, Jana W; Wrobel, John; Wyczalkowski, Matthew A.; Erdmann-Gilmore, Petra; Snider, Jacqueline E.; Hoog, Jeremy; Singh, Purba; Niu, Beifung; Guo, Zhanfang; Sun, Sam Qiancheng; Sanati, Souzan; Kawaler, Emily; Wang, Xuya; Scott, Adam; Ye, Kai; McLellan, Michael D.; Wendl, Michael C.; Malovannaya, Anna; Held, Jason M.; Gillette, Michael A.; Fenyö, David; Kinsinger, Christopher R.; Mesri, Mehdi; Rodriguez, Henry; Davies, Sherri R.; Perou, Charles M.; Ma, Cynthia; Reid Townsend, R.; Chen, Xian; Carr, Steven A.; Ellis, Matthew J.; Ding, Li

    2017-01-01

    Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities. PMID:28348404

  19. Integrated Analysis of Transcriptome in Cancer Patient-Derived Xenografts

    PubMed Central

    Li, Hong; Zhu, Yinjie; Tang, Xiaoyan; Li, Junyi; Li, Yuanyuan; Zhong, Zhaomin; Ding, Guohui; Li, Yixue

    2015-01-01

    Patient-derived xenograft (PDX) tumor model is a powerful technology in evaluating anti-cancer drugs and facilitating personalized medicines. Multiple research centers and commercial companies have put huge efforts into building PDX mouse models. However, PDX models have not been widely available and their molecular features have not been systematically characterized. In this study, we provided a comprehensive survey of PDX transcriptome by integrating analysis of 58 patients involving 8 different tumors. The median correlation coefficient between patients and xenografts is 0.94, which is higher than that between patients and cell line panel or between patients with the same tumor. Major differential gene expressions in PDX occur in the engraftment of human tumor tissue into mice, while gene expressions are relatively stable over passages. 48 genes are frequently differentially expressed in PDX mice of multiple cancers. They are enriched in extracellular matrix and immune response, and some are reported as targets for anticancer drugs. A simulation study showed that expression change between PDX and patient tumor (6%) would result in acceptable change in drug sensitivity (3%). Our findings demonstrate that PDX mice represent the gene-expression and drug-response features of primary tumors effectively, and it is recommended to monitoring the overall expression profiles and drug target genes in clinical application. PMID:25951608

  20. Photodynamic therapy using methylene blue in lung adenocarcinoma xenograft and hamster cheek pouch induced squamous cell carcinoma.

    PubMed

    Obstoy, Bérengère; Salaun, Mathieu; Bohn, Pierre; Veresezan, Liana; Sesboué, Richard; Thiberville, Luc

    2016-09-01

    Photodynamic therapy (PDT) is used to treat early proximal bronchial cancer during a flexible bronchoscopy. The technique relies on the excitation of a photosensitizer by an appropriate wavelength, which is delivered into the bronchus in close contact with the tumor. To assess methylene blue (MB) as a PDT agent for the treatment of respiratory tract cancer in animal models. MB-induced PDT was performed on 7 subcutaneous NCI-H460 lung adenocarcinoma xenografts in nude mice and 9 induced squamous cell cancer in the hamster cheek pouch model. In mice, PDT was carried out on right-sided tumors after intratumoral injection of methylene blue 1% (w/v) and illumination at 630nm at 200J/cm (Diomed PDT 630), with the left tumor used as control (illumination alone or MB alone). The tumoral volume was assessed before and 15 days after PDT. Fourteen xenografts were treated in mice, including seven treated with MB-PDT, producing a 52% mean tumor volume regression (1568mm(3)vs. 544mm(3)) compared to seven control cases in which tumor volume increased (p=0.007; Mann-Whitney test). Nine cheek pouch induced carcinomas were treated in the hamster group, with a mean volume decrease of 85.8% (from 44.8% to 100%) (initial mean volume=210mm(3)vs. post PDT mean volume=97mm(3)). Histology analysis showed 4/9 complete responses. Intratumoral MB appears efficient as PDT agent for cancer treatment in animal models. Further studies are needed to assess the safety and efficacy of MB-associated PDT for the treatment of lung cancer in humans. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  1. Lung Cancer Biomarkers.

    PubMed

    I, Hoseok; Cho, Je-Yoel

    2015-01-01

    Lung cancer is the most frequently occurring cancer in the world and continually leads in mortality among cancers. The overall 5-year survival rate for lung cancer has risen only 4% (from 12% to 16%) over the past 4 decades, and late diagnosis is a major obstacle in improving lung cancer prognosis. Survival of patients undergoing lung resection is greater than 80%, suggesting that early detection and diagnosis of cancers before they become inoperable and lethal will greatly improve mortality. Lung cancer biomarkers can be used for screening, detection, diagnosis, prognosis, prediction, stratification, therapy response monitoring, and so on. This review focuses on noninvasive diagnostic and prognostic biomarkers. For that purpose, our discussion in this review will focus on biological fluid-based biomarkers. The body fluids include blood (serum or plasma), sputum, saliva, BAL, pleural effusion, and VOC. Since it is rich in different cellular and molecular elements and is one of the most convenient and routine clinical procedures, serum or plasma is the main source for the development and validation of many noninvasive biomarkers. In terms of molecular aspects, the most widely validated ones are proteins, some of which are used in the clinical sector, though in limited accessory purposes. We will also discuss the lung cancer (protein) biomarkers in clinical trials and currently in the validation phase with hundreds of samples. After proteins, we will discuss microRNAs, methylated DNA, and circulating tumor cells, which are being vigorously developed and validated as potential lung cancer biomarkers. The main aim of this review is to provide researchers and clinicians with an understanding of the potential noninvasive lung cancer biomarkers in biological fluids that have recently been discovered.

  2. Lung Cancer Screening Update.

    PubMed

    Ruchalski, Kathleen L; Brown, Kathleen

    2016-07-01

    Since the release of the US Preventive Services Task Force and Centers for Medicare and Medicaid Services recommendations for lung cancer screening, low-dose chest computed tomography screening has moved from the research arena to clinical practice. Lung cancer screening programs must reach beyond image acquisition and interpretation and engage in a multidisciplinary effort of clinical shared decision-making, standardization of imaging and nodule management, smoking cessation, and patient follow-up. Standardization of radiologic reports and nodule management will systematize patient care, provide quality assurance, further reduce harm, and contain health care costs. Although the National Lung Screening Trial results and eligibility criteria of a heavy smoking history are the foundation for the standard guidelines for low-dose chest computed tomography screening in the United States, currently only 27% of patients diagnosed with lung cancer would meet US lung cancer screening recommendations. Current and future efforts must be directed to better delineate those patients who would most benefit from screening and to ensure that the benefits of screening reach all socioeconomic strata and racial and ethnic minorities. Further optimization of lung cancer screening program design and patient eligibility will assure that lung cancer screening benefits will outweigh the potential risks to our patients.

  3. Imaging Axl expression in pancreatic and prostate cancer xenografts

    SciTech Connect

    Nimmagadda, Sridhar; Pullambhatla, Mrudula; Lisok, Ala; Hu, Chaoxin; Maitra, Anirban; Pomper, Martin G

    2014-01-10

    Highlights: •Axl is overexpressed in a variety of cancers. •Axl overexpression confers invasive phenotype. •Axl imaging would be useful for therapeutic guidance and monitoring. •Axl expression imaging is demonstrated in pancreatic and prostate cancer xenografts. •Graded levels of Axl expression imaging is feasible. -- Abstract: The receptor tyrosine kinase Axl is overexpressed in and leads to patient morbidity and mortality in a variety of cancers. Axl–Gas6 interactions are critical for tumor growth, angiogenesis and metastasis. The goal of this study was to investigate the feasibility of imaging graded levels of Axl expression in tumors using a radiolabeled antibody. We radiolabeled anti-human Axl (Axl mAb) and control IgG1 antibodies with {sup 125}I with high specific radioactivity and radiochemical purity, resulting in an immunoreactive fraction suitable for in vivo studies. Radiolabeled antibodies were investigated in severe combined immunodeficient mice harboring subcutaneous CFPAC (Axl{sup high}) and Panc1 (Axl{sup low}) pancreatic cancer xenografts by ex vivo biodistribution and imaging. Based on these results, the specificity of [{sup 125}I]Axl mAb was also validated in mice harboring orthotopic Panc1 or CFPAC tumors and in mice harboring subcutaneous 22Rv1 (Axl{sup low}) or DU145 (Axl{sup high}) prostate tumors by ex vivo biodistribution and imaging studies at 72 h post-injection of the antibody. Both imaging and biodistribution studies demonstrated specific and persistent accumulation of [{sup 125}I]Axl mAb in Axl{sup high} (CFPAC and DU145) expression tumors compared to the Axl{sup low} (Panc1 and 22Rv1) expression tumors. Axl expression in these tumors was further confirmed by immunohistochemical studies. No difference in the uptake of radioactivity was observed between the control [{sup 125}I]IgG1 antibody in the Axl{sup high} and Axl{sup low} expression tumors. These data demonstrate the feasibility of imaging Axl expression in pancreatic

  4. TMEM45B, up-regulated in human lung cancer, enhances tumorigenicity of lung cancer cells.

    PubMed

    Hu, Rui; Hu, Fengqing; Xie, Xiao; Wang, Lei; Li, Guoqing; Qiao, Tong; Wang, Mingsong; Xiao, Haibo

    2016-09-01

    Transmembrane protein 45B (TMEM45B) is a member of TMEMs. Altered expression of TMEMs is frequently observed in a variety of human cancers, but the expression and functional roles of TMEM45B in lung cancer is not reported. In the present study, levels of mRNA expression of TMEM45B in lung cancer tissues were assessed using re-analyzing expression data of The Cancer Genome Atlas (TCGA) lung cancer cohort and real-time PCR analysis on our own cohort. Lung cancer cells, A549 and NCI-H1975, infected with TMEM45B short hairpin RNA were examined in cell proliferation, cell cycle, cell apoptosis, wound-healing, and cell invasion assays as well as mouse xenograft models. Here, we demonstrated that TMEM45B was overexpressed in lung cancer and its expression correlated with overall survival of patients. In addition, silencing of TMEM45B expression reduced cell proliferation in vitro and in vivo, induced cell cycle arrest and cell apoptosis, and blocked cell migration and invasion. Moreover, knockdown of TMEM45B significantly suppressed G1/S transition, induced cell apoptosis, and inhibited cell invasion via regulating the expression of cell cycle-related proteins (CDK2, CDC25A, and PCNA), cell apoptosis-related proteins (Bcl2, Bax, and Cleaved Caspase 3), and metastasis-related proteins (MMP-9, Twist, and Snail), respectively. Thus, TMEM45B is a potential prognostic marker and cancer-selective therapeutic target in lung cancer.

  5. Lycopene and Lung Cancer

    USDA-ARS?s Scientific Manuscript database

    Although epidemiological studies have shown dietary intake of lycopene is associated with decreased risk of lung cancer, the effect of lycopene on lung carcinogenesis has not been well studied. A better understanding of lycopene metabolism and the mechanistic basis of lycopene chemoprevention must ...

  6. Native MAG-1 antibody almost destroys human breast cancer xenografts.

    PubMed

    North, William G; Pang, Roy H L; Gao, Guohong; Memoli, Vincent A; Cole, Bernard F

    2011-06-01

    A native form of mouse monoclonal IgG1 antibody called MAG-1, which recognizes an epitope on provasopressin, has been found to shrink and produce extensive necrosis of human breast tumor xenografts in nu/nu mice. We examined the ability of (90)Yttrium-labeled and native MAG-1 to affect the growth in nu/nu mice of cancer xenografts that were estrogen-responsive (from MCF-7 cells) and triple-negative (from MDA-MB231 cells). The growth rates of treated cells were compared to those receiving saline vehicle and those receiving (90)Yttrium-labeled and native forms of the ubiquitous antibody, MOPC21. Short-term treatments (4 doses over 6 days) not only with (90)Yttrium-MAG-1 but also native MAG-1 produced large reductions in size of rapidly growing tumors of both types, while both (90)Yttrium- MOPC21 and native MOPC21 had no effect. Native and (90)Yttrium-MAG-1 effects were similar, and arrested tumors recommenced growing soon after treatments stopped. Increasing native MAG-1 treatment to single dosing for 16 consecutive days shrank tumors of both types with no regrowth apparent over a 20-day post-treatment period of observation. Pathological examination of such tumors revealed they had undergone very extensive (>66%) necrosis.

  7. Women and Lung Cancer

    MedlinePlus

    ... Horrigan Conners Center for Women’s Health and Gender Biology, Brigham and Women’s Hospital, Harvard Medical School, April, ... Lung Cancer in Women: The Differences in Epidemiology, Biology and Treatment Outcomes, Maria Patricia Rivera MD Expert ...

  8. PPARGC1A is upregulated and facilitates lung cancer metastasis.

    PubMed

    Li, Jin-Dong; Feng, Qing-Chuan; Qi, Yu; Cui, Guanghui; Zhao, Song

    2017-10-15

    Lung cancer remains a leading cause of cancer-related mortality, with metastatic progression remaining the single largest cause of lung cancer mortality. Hence it is imperative to determine reliable biomarkers for lung cancer prognosis. We performed quantitative real-time PCR (qRT-PCR) analysis to explore epithelial-mesenchymal transition (EMT) inducers that regulate EMT process in three patients with advanced lung cancer disease. Peroxisome proliferator-activated receptor gamma (PPARGC1A) was uniformly the topmost overexpressed gene in all three human non-small cell lung cancer (NSCLC) patient samples. Further evaluation in human normal lung and metastatic lung cancer cell lines revealed that the expression of PPARGC1A was upregulated in metastatic lung cancer cell lines. Metagenomic analysis revealed direct correlation among PPARGC1A, zinc-finger transcription factor snail homolog 1 (SNAI1), and metastatic lung disease. Upregulation of PPARGC1A transcript expression was independent of a differential upregulation of the upstream AMP-dependent protein kinase (AMPK) activation or steady state expression of the silent mating type information regulation 2 homolog 1 (SIRT1). Xenograft tail vein colonization assays proved that the high expression of PPARGC1A was a prerequisite for metastatic progression of lung cancer to brain. Our results indicate that PPARGC1A might be a potential biomarker for lung cancer prognosis. Copyright © 2017. Published by Elsevier Inc.

  9. Lung Cancer Rates by State

    MedlinePlus

    ... HPV-Associated Ovarian Prostate Skin Uterine Cancer Home Lung Cancer Rates by State Language: English Español (Spanish) ... incidence data are currently available. Rates of Getting Lung Cancer by State The number of people who ...

  10. Cisplatin Increases Sensitivity to FGFR Inhibition in Patient-Derived Xenograft Models of Lung Squamous Cell Carcinoma.

    PubMed

    Weeden, Clare E; Holik, Aliaksei Z; Young, Richard J; Ma, Stephen B; Garnier, Jean-Marc; Fox, Stephen B; Antippa, Phillip; Irving, Louis B; Steinfort, Daniel P; Wright, Gavin M; Russell, Prudence A; Ritchie, Matthew E; Burns, Christopher J; Solomon, Benjamin; Asselin-Labat, Marie-Liesse

    2017-08-01

    Lung squamous cell carcinoma (SqCC) is a molecularly complex and genomically unstable disease. No targeted therapy is currently approved for lung SqCC, although potential oncogenic drivers of SqCC have been identified, including amplification of the fibroblast growth factor receptor 1 (FGFR1). Reports from a recently completed clinical trial indicate low response rates in patients treated with FGFR tyrosine kinase inhibitors, suggesting inadequacy of FGFR1 amplification as a biomarker of response, or the need for combination treatment. We aimed to develop accurate models of lung SqCC and determine improved targeted therapies for these tumors. We show that detection of FGFR1 mRNA by RNA in situ hybridization is a better predictor of response to FGFR inhibition than FGFR1 gene amplification using clinically relevant patient-derived xenograft (PDX) models of lung SqCC. FGFR1-overexpressing tumors were observed in all histologic subtypes of non-small cell lung cancers (NSCLC) as assessed on a tissue microarray, indicating a broader range of tumors that may respond to FGFR inhibitors. In FGFR1-overexpressing PDX tumors, we observed increased differentiation and reduced proliferation following FGFR inhibition. Combination therapy with cisplatin was able to increase tumor cell death, and dramatically prolonged animal survival compared to single-agent treatment. Our data suggest that FGFR tyrosine kinase inhibitors can benefit NSCLC patients with FGFR1-overexpressing tumors and provides a rationale for clinical trials combining cisplatin with FGFR inhibitors. Mol Cancer Ther; 16(8); 1610-22. ©2017 AACR. ©2017 American Association for Cancer Research.

  11. Patient-derived tumour xenografts for breast cancer drug discovery

    PubMed Central

    Batra, Ankita S; Greenwood, Wendy

    2016-01-01

    Despite remarkable advances in our understanding of the drivers of human malignancies, new targeted therapies often fail to show sufficient efficacy in clinical trials. Indeed, the cost of bringing a new agent to market has risen substantially in the last several decades, in part fuelled by extensive reliance on preclinical models that fail to accurately reflect tumour heterogeneity. To halt unsustainable rates of attrition in the drug discovery process, we must develop a new generation of preclinical models capable of reflecting the heterogeneity of varying degrees of complexity found in human cancers. Patient-derived tumour xenograft (PDTX) models prevail as arguably the most powerful in this regard because they capture cancer’s heterogeneous nature. Herein, we review current breast cancer models and their use in the drug discovery process, before discussing best practices for developing a highly annotated cohort of PDTX models. We describe the importance of extensive multidimensional molecular and functional characterisation of models and combination drug–drug screens to identify complex biomarkers of drug resistance and response. We reflect on our own experiences and propose the use of a cost-effective intermediate pharmacogenomic platform (the PDTX-PDTC platform) for breast cancer drug and biomarker discovery. We discuss the limitations and unanswered questions of PDTX models; yet, still strongly envision that their use in basic and translational research will dramatically change our understanding of breast cancer biology and how to more effectively treat it. PMID:27702751

  12. Screening for Lung Cancer

    PubMed Central

    Mazzone, Peter J.; Naidich, David P.; Bach, Peter B.

    2013-01-01

    Background: Lung cancer is by far the major cause of cancer deaths largely because in the majority of patients it is at an advanced stage at the time it is discovered, when curative treatment is no longer feasible. This article examines the data regarding the ability of screening to decrease the number of lung cancer deaths. Methods: A systematic review was conducted of controlled studies that address the effectiveness of methods of screening for lung cancer. Results: Several large randomized controlled trials (RCTs), including a recent one, have demonstrated that screening for lung cancer using a chest radiograph does not reduce the number of deaths from lung cancer. One large RCT involving low-dose CT (LDCT) screening demonstrated a significant reduction in lung cancer deaths, with few harms to individuals at elevated risk when done in the context of a structured program of selection, screening, evaluation, and management of the relatively high number of benign abnormalities. Whether other RCTs involving LDCT screening are consistent is unclear because data are limited or not yet mature. Conclusions: Screening is a complex interplay of selection (a population with sufficient risk and few serious comorbidities), the value of the screening test, the interval between screening tests, the availability of effective treatment, the risk of complications or harms as a result of screening, and the degree with which the screened individuals comply with screening and treatment recommendations. Screening with LDCT of appropriate individuals in the context of a structured process is associated with a significant reduction in the number of lung cancer deaths in the screened population. Given the complex interplay of factors inherent in screening, many questions remain on how to effectively implement screening on a broader scale. PMID:23649455

  13. Lung cancer - non-small cell

    MedlinePlus

    Cancer - lung - non-small cell; Non-small cell lung cancer; NSCLC; Adenocarcinoma - lung; Squamous cell carcinoma - lung ... Smoking causes most cases (around 90%) of lung cancer. The risk depends on the number of cigarettes ...

  14. Nanomicellar TGX221 blocks xenograft tumor growth of prostate cancer in nude mice

    PubMed Central

    Chen, Ruibao; Zhao, Yunqi; Huang, Yan; Yang, Qiuhong; Zeng, Xing; Jiang, Wencong; Liu, Jihong; Thrasher, J. Brantley; Forrest, M. Laird; Li, Benyi

    2014-01-01

    Background Combination of androgen ablation along with early detection and surgery has made prostate cancer highly treatable at the initial stage. However, this cancer remains the second leading cause of cancer death among American men due to castration-resistant progression, suggesting that novel therapeutic agents are urgently needed for this life-threaten condition. Phosphatidylinositol 3-kinase p110β is a major cellular signaling molecule and has been identified as a critical factor in prostate cancer progression. In a recent report, we established a nanomicelle-based strategy to deliver p110β-specific inhibitor TGX221 to prostate cancer cells by conjugating the surface of nanomicelles with a RNA aptamer against prostate membrane specific antigen (PSMA) present in all clinical prostate cancers. In this study, we tested this nanomicellar TGX221 for its in vivo anti-tumor effect in mouse xenograft models. Methods Prostate cancer cell lines LAPC-4, LNCaP, C4-2 and 22RV1 were used to establish subcutaneous xenograft tumors in nude mice. Paraffin sections from xenograft tumor specimens were used in immunohistochemistry assays to detect AKT phosphorylation, cell proliferation marker Ki67 and PCNA, as well as BrdU incorporation. Quantitative PCR assay was conducted to determine PSA gene expression in xenograft tumors. Results Although systemic delivery of unconjugated TGX221 significantly reduced xenograft tumor growth in nude mice compared to solvent control, the nanomicellar TGX221 conjugates completely blocked tumor growth of xenografts derived from multiple prostate cancer cell lines. Further analyses revealed that AKT phosphorylation and cell proliferation indexes were dramatically reduced in xenograft tumors received nanomicellar TGX221 compared to xenograft tumors received unconjugated TGX221 treatment. There was no noticeable side effect by gross observation or at microscopic level of organ tissue section. Conclusion These data strongly suggest that prostate

  15. Immunohistochemical demonstration of epidermal growth factor in human gastric cancer xenografts of nude mice.

    PubMed

    Yoshiyuki, T; Shimizu, Y; Onda, M; Tokunaga, A; Kiyama, T; Nishi, K; Mizutani, T; Matsukura, N; Tanaka, N; Akimoto, M

    1990-02-15

    Thirty-two surgical specimens and three cell lines of human gastric cancers were used for subcutaneous transplantation into nude mice, resulting in the establishment of eight (25%) xenografts from the surgical specimens and two (67%) from the cell lines. The localization of epidermal growth factor (EGF) in the surgical specimens and cell lines of the gastric cancers and their xenografts in nude mice was then investigated immunohistochemically. Epidermal growth factor was stained in the cytoplasm of the cancer cells, being detected in 16 (50%) of the 32 surgical specimens and in all of the cell lines. Seven (44%) of the sixteen EGF-positive surgical specimens and one (6%) of the 16 EGF-negative ones were tumorigenic in nude mice. All of the xenografts in nude mice were positive for EGF. The tumorigenicity of human gastric cancer xenografts in nude mice may, therefore, be correlated with the presence of EGF in cancer cells.

  16. The ALCHEMIST Lung Cancer Trial

    Cancer.gov

    A collection of material about the ALCHEMIST lung cancer trial that will examine tumor tissue from patients with early-stage, completely resected lung cancer for gene mutations in the EGFR and ALK genes, and a

  17. Small Cell Lung Cancer

    PubMed Central

    Kalemkerian, Gregory P.; Akerley, Wallace; Bogner, Paul; Borghaei, Hossein; Chow, Laura QM; Downey, Robert J.; Gandhi, Leena; Ganti, Apar Kishor P.; Govindan, Ramaswamy; Grecula, John C.; Hayman, James; Heist, Rebecca Suk; Horn, Leora; Jahan, Thierry; Koczywas, Marianna; Loo, Billy W.; Merritt, Robert E.; Moran, Cesar A.; Niell, Harvey B.; O’Malley, Janis; Patel, Jyoti D.; Ready, Neal; Rudin, Charles M.; Williams, Charles C.; Gregory, Kristina; Hughes, Miranda

    2013-01-01

    Neuroendocrine tumors account for approximately 20% of lung cancers; most (≈15%) are small cell lung cancer (SCLC). These NCCN Clinical Practice Guidelines in Oncology for SCLC focus on extensive-stage SCLC because it occurs more frequently than limited-stage disease. SCLC is highly sensitive to initial therapy; however, most patients eventually die of recurrent disease. In patients with extensive-stage disease, chemotherapy alone can palliate symptoms and prolong survival in most patients; however, long-term survival is rare. Most cases of SCLC are attributable to cigarette smoking; therefore, smoking cessation should be strongly promoted. PMID:23307984

  18. Small cell lung cancer.

    PubMed

    Kalemkerian, Gregory P; Akerley, Wallace; Bogner, Paul; Borghaei, Hossein; Chow, Laura Qm; Downey, Robert J; Gandhi, Leena; Ganti, Apar Kishor P; Govindan, Ramaswamy; Grecula, John C; Hayman, James; Heist, Rebecca Suk; Horn, Leora; Jahan, Thierry; Koczywas, Marianna; Loo, Billy W; Merritt, Robert E; Moran, Cesar A; Niell, Harvey B; O'Malley, Janis; Patel, Jyoti D; Ready, Neal; Rudin, Charles M; Williams, Charles C; Gregory, Kristina; Hughes, Miranda

    2013-01-01

    Neuroendocrine tumors account for approximately 20% of lung cancers; most (≈15%) are small cell lung cancer (SCLC). These NCCN Clinical Practice Guidelines in Oncology for SCLC focus on extensive-stage SCLC because it occurs more frequently than limited-stage disease. SCLC is highly sensitive to initial therapy; however, most patients eventually die of recurrent disease. In patients with extensive-stage disease, chemotherapy alone can palliate symptoms and prolong survival in most patients; however, long-term survival is rare. Most cases of SCLC are attributable to cigarette smoking; therefore, smoking cessation should be strongly promoted.

  19. Radiotherapy for lung cancer

    SciTech Connect

    Bleehen, N.M.; Cox, J.D.

    1985-05-01

    The role of radiation therapy in the management of lung cancer was reviewed at a workshop held in Cambridge, England, in June 1984. It was concluded that there was a continuing role for radiation therapy in the primary management of small cell lung cancer, including the loco-regional treatment for patients with limited disease. Radical radiotherapy for patients with non-small cell carcinoma could be curative for a proportion of patients with limited disease. Careful planning and quality control was essential. Palliative radiotherapy provided useful treatment for many other patients. Other related aspects of treatment are also presented.

  20. Lung Cancer Brain Metastases.

    PubMed

    Goldberg, Sarah B; Contessa, Joseph N; Omay, Sacit B; Chiang, Veronica

    2015-01-01

    Brain metastases are common among patients with lung cancer and have been associated with significant morbidity and limited survival. However, the treatment of brain metastases has evolved as the field has advanced in terms of central nervous system imaging, surgical technique, and radiotherapy technology. This has allowed patients to receive improved treatment with less toxicity and more durable benefit. In addition, there have been significant advances in systemic therapy for lung cancer in recent years, and several treatments including chemotherapy, targeted therapy, and immunotherapy exhibit activity in the central nervous system. Utilizing systemic therapy for treating brain metastases can avoid or delay local therapy and often allows patients to receive effective treatment for both intracranial and extracranial disease. Determining the appropriate treatment for patients with lung cancer brain metastases therefore requires a clear understanding of intracranial disease burden, tumor histology, molecular characteristics, and overall cancer prognosis. This review provides updates on the current state of surgery and radiotherapy for the treatment of brain metastases, as well as an overview of systemic therapy options that may be effective in select patients with intracranial metastases from lung cancer.

  1. [Epidemiology of lung cancer].

    PubMed

    Becker, N

    2010-08-01

    Lung cancer is by far the most common form of cancer worldwide and in Germany is now "only" still the commonest cause of death from cancer. The most important single risk factor is smoking but in selected population groups, for example in the professional area, other factors can also play a role which cannot be ignored and open up a corresponding potential for prevention. Effective early detection procedures are at present unknown. The most promising, however, is multislice computed tomography (MSCT) which for this reason is presently being tested for effectiveness in several large research projects. The results are not expected for some years. Until then the early detection of lung cancer with MSCT cannot be considered suitable for routine use but can only be justified within the framework of research studies.

  2. [Secondary lung cancers].

    PubMed

    Etienne-Mastroïanni, Bénédicte; Freyer, Gilles; Cordier, Jean-François

    2003-04-01

    Lung is the most common site of metastatic involvement for many malignant tumors. The most frequent abnormalities are solitary or multiple pulmonary nodules (large "cannonball" nodules or diffuse miliary pattern), and lymphangitic carcinomatosis. Pulmonary metastases usually occur in a context of a previously known tumour, but sometimes may reveal a latent tumour. Most patients receive palliative treatment with chemotherapy, or hormone therapy (for metastases of breast cancer, thyroid, endometrial carcinoma or prostatic cancer). Patients may rarely benefit from resection of pulmonary metastases.

  3. Nutrition aspects of lung cancer.

    PubMed

    Cranganu, Andreea; Camporeale, Jayne

    2009-12-01

    Lung cancer is the most common type of cancer, excluding nonmelanoma skin cancer, and is the leading cause of cancer death in the United States. Notable carcinogens involved in the development of lung cancer include smoking, secondhand smoke, and radon. Lung cancer is divided into 2 major types: non-small-cell lung cancer, the most prevalent, and small-cell lung cancer. Treatment includes surgery, chemotherapy, radiation, or a combination of the same. Medical nutrition therapy is often required for nutrition-related side effects of cancer treatment, which include but are not limited to anorexia, nausea and vomiting, and esophagitis. The best protection against lung cancer is avoidance of airborne carcinogens and increased consumption of fruits and vegetables. Studies have shown that smokers taking large amounts of beta-carotene and vitamin A supplements had increased lung cancer incidence and mortality. However, ingestion of beta-carotene from foods, along with a diet rich in fruits and vegetables, has a protective role against lung disease. The use of complementary and alternative medicine by lung cancer patients is prevalent; therefore, clinicians should investigate whether complementary and alternative therapies are used by patients and advise them on the use of these therapies to avoid any potential side effects and interactions with conventional therapies. The article concludes with a case study of a patient with non-small-cell lung cancer and illustrates the use of medical nutrition therapy in relation to cancer treatment side effects.

  4. Antitumor Activity of VB-111, a Novel Antiangiogenic Virotherapeutic, in Thyroid Cancer Xenograft Mouse Models

    PubMed Central

    Reddi, H. V.; Madde, P.; Cohen, Y. C.; Bangio, L.; Breitbart, E.; Harats, D.; Bible, K. C.

    2011-01-01

    VB-111 is an engineered antiangiogenic adenovirus that expresses Fas-c in angiogenic blood vessels and has previously been shown to have significant antitumor activity in vitro and in vivo in Lewis lung carcinoma, melanoma, and glioblastoma models. To evaluate the efficacy of VB-111 in thyroid cancer, we conducted in vivo xenograft nude mouse studies using multiple thyroid cancer-derived cell lines models. VB-111 treatment resulted in 26.6% (P = 0.0596), 34.4% (P = 0.0046), and 37.6% (P = 0.0249) inhibition of tumor growth in follicular, papillary and anaplastic thyroid cancer models, respectively. No toxicity was observed in any model. All tumor types showed a consistent and significant reduction of CD-31 staining (P < 0.05), reflecting a reduction of angiogenic activity in the tumors, consistent with the intended targeting of the virus. A phase 2 clinical trial of VB-111 in patients with advanced differentiated thyroid cancer is ongoing. PMID:22701765

  5. Chemoprevention of Lung Cancer

    PubMed Central

    Szabo, Eva; Mao, Jenny T.; Lam, Stephen; Reid, Mary E.

    2013-01-01

    Background: Lung cancer is the most common cause of cancer death in men and women in the United States. Cigarette smoking is the main risk factor. Former smokers are at a substantially increased risk of developing lung cancer compared with lifetime never smokers. Chemoprevention refers to the use of specific agents to reverse, suppress, or prevent the process of carcinogenesis. This article reviews the major agents that have been studied for chemoprevention. Methods: Articles of primary, secondary, and tertiary prevention trials were reviewed and summarized to obtain recommendations. Results: None of the phase 3 trials with the agents β-carotene, retinol, 13-cis-retinoic acid, α-tocopherol, N-acetylcysteine, acetylsalicylic acid, or selenium has demonstrated beneficial and reproducible results. To facilitate the evaluation of promising agents and to lessen the need for a large sample size, extensive time commitment, and expense, surrogate end point biomarker trials are being conducted to assist in identifying the most promising agents for later-stage chemoprevention trials. With the understanding of important cellular signaling pathways and the expansion of potentially important targets, agents (many of which target inflammation and the arachidonic acid pathway) are being developed and tested which may prevent or reverse lung carcinogenesis. Conclusions: By integrating biologic knowledge, additional early-phase trials can be performed in a reasonable time frame. The future of lung cancer chemoprevention should entail the evaluation of single agents or combinations that target various pathways while working toward identification and validation of intermediate end points. PMID:23649449

  6. Evaluation of 89Zr-pertuzumab in Breast Cancer Xenografts

    PubMed Central

    2015-01-01

    Pertuzumab is a monoclonal antibody that binds to HER2 and is used in combination with another HER2–specific monoclonal antibody, trastuzumab, for the treatment of HER2+ metastatic breast cancer. Pertuzumab binds to an HER2 binding site distinct from that of trastuzumab, and its affinity is enhanced when trastuzumab is present. We aim to exploit this enhanced affinity of pertuzumab for its HER2 binding epitope and adapt this antibody as a PET imaging agent by radiolabeling with 89Zr to increase the sensitivity of HER2 detection in vivo. Here, we investigate the biodistribution of 89Zr-pertuzumab in HER2–expressing BT-474 and HER2–nonexpressing MDA-MB-231 xenografts to quantitatively assess HER2 expression in vivo. In vitro cell binding studies were performed resulting in retained immunoreactivity and specificity for HER2–expressing cells. In vivo evaluation of 89Zr-pertuzumab was conducted in severely combined immunodeficient mice, subcutaneously inoculated with BT-474 and MDA-MB-231 cells. 89Zr-pertuzumab was systemically administered and imaged at 7 days postinjection (p.i.) followed by terminal biodistribution studies. Higher tumor uptake was observed in BT-474 compared to MDA-MB-231 xenografts with 47.5 ± 32.9 and 9.5 ± 1.7% ID/g, respectively at 7 days p.i (P = 0.0009) and blocking studies with excess unlabeled pertuzumab showed a 5-fold decrease in BT-474 tumor uptake (P = 0.0006), confirming the in vivo specificity of this radiotracer. Importantly, we observed that the tumor accumulation of 89Zr-pertuzumab was increased in the presence of unlabeled trastuzumab, at 173 ± 74.5% ID/g (P = 0.01). Biodistribution studies correlate with PET imaging quantification using max SUV (r = 0.98, P = 0.01). Collectively, these results illustrate that 89Zr-pertuzumab as a PET imaging agent may be beneficial for the quantitative and noninvasive assessment of HER2 expression in vivo especially for patients undergoing trastuzumab therapy. PMID:25058168

  7. Experimental Lung Cancer Drug Shows Early Promise | Poster

    Cancer.gov

    By Frank Blanchard, Staff Writer A first-of-its-kind drug is showing early promise in attacking certain lung cancers that are hard to treat because they build up resistance to conventional chemotherapy. The drug, CO-1686, performed well in a preclinical study involving xenograft and transgenic mice, as reported in the journal Cancer Discovery. It is now being evaluated for safety and efficacy in Phase I and II clinical trials.

  8. Experimental Lung Cancer Drug Shows Early Promise | Poster

    Cancer.gov

    By Frank Blanchard, Staff Writer A first-of-its-kind drug is showing early promise in attacking certain lung cancers that are hard to treat because they build up resistance to conventional chemotherapy. The drug, CO-1686, performed well in a preclinical study involving xenograft and transgenic mice, as reported in the journal Cancer Discovery. It is now being evaluated for safety and efficacy in Phase I and II clinical trials.

  9. Lung cancer in Brazil.

    PubMed

    Algranti, E; Menezes, A M; Achutti, A C

    2001-04-01

    Lung cancer is the second leading cause of death in Brazil, after exclusion of external causes. Registries in the country are not reliable because of under-registration and limited coverage. Incidence rates for Brazil are less then half those for selected areas with good registries. Crude and adjusted incidence and mortality rates for lung cancer are rising, particularly among women. The main reason is the acceleration in tobacco consumption and the spread of smoking among women. At present, approximately 40% of men and 25% of women, 15 years of age or older, are current smokers. In the state of Rio Grande do Sul, where registries are reliable, incidence and mortality for males are similar to US data and the figures for women are rapidly approaching those for men. Occupations associated with risks of exposure to respiratory carcinogens show a rise in the incidence of lung cancer in the industrialized area of São Paulo. The main occupational risk in Brazil is exposure to mineral dusts, silica, or asbestos. Although about 15 million Brazilians are exposed to pesticides, agricultural workers were not a risk group for lung cancer in a case-control study. Pesticides containing arsenic and dichlorodiphenyltrichloroethane (DDT) are banned. In recent years, a trend towards a decrease in male smoking has been noted, but there is still a high tobacco exposure burden in both males and females, with a forecast of a further increase in rates of lung cancer incidence and deaths. Control of respiratory carcinogens at work continues to be a problem, particularly in the present scenario of economic and political pressures on Brazil and other developing nations. Semin Oncol 28:143-152. Copyright 2001 by W.B. Saunders Company.

  10. Lung Cancer Biomarkers.

    PubMed

    Villalobos, Pamela; Wistuba, Ignacio I

    2017-02-01

    The molecular characterization of lung cancer has changed the classification and treatment of these tumors, becoming an essential component of pathologic diagnosis and oncologic therapy decisions. Through the recognition of novel biomarkers, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocations, it is possible to identify subsets of patients who benefit from targeted molecular therapies. The success of targeted anticancer therapies and new immunotherapy approaches has created a new paradigm of personalized therapy and has led to accelerated development of new drugs for lung cancer treatment. This article focuses on clinically relevant cancer biomarkers as targets for therapy and potential new targets for drug development. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Coffee inhibits nuclear factor-kappa B in prostate cancer cells and xenografts.

    PubMed

    Kolberg, Marit; Pedersen, Sigrid; Mitake, Maiko; Holm, Kristine Lillebø; Bøhn, Siv Kjølsrud; Blomhoff, Heidi Kiil; Carlsen, Harald; Blomhoff, Rune; Paur, Ingvild

    2016-01-01

    Chronic inflammation contributes to prostate cancer and the transcription factor Nuclear Factor-kappa B (NF-κB) is constitutively active in most such cancers. We examine the effects of coffee on NF-κB and on the regulation of selected genes in human-derived prostate cancer cells (PC3) and in PC3 xenografts in athymic nude mice. PC3 cells stably transduced with an NF-κB-luciferase reporter were used both in vitro and for xenografts. NF-κB activity was measured by reporter assays, DNA binding and in vivo imaging. Gene expression was measured in PC3 cells, xenografts and tumor microenvironment by low-density arrays. Western blotting of activated caspases was used to quantify apoptosis. Coffee inhibited TNFα-induced NF-κB activity and DNA-binding in PC3 cells. Furthermore, coffee increased apoptosis and modulated expression of a number of inflammation- and cancer-related genes in TNFα-treated PC3 cells. In vivo imaging revealed a 31% lower NF-κB-luciferase activation in the xenografts of the mice receiving 5% coffee compared to control mice. Interestingly, we observed major changes in gene expression in the PC3 cells in xenografts as compared to PC3 cells in vitro. In PC3 xenografts, genes related to inflammation, apoptosis and cytoprotection were down-regulated in mice receiving coffee, and coffee also affected the gene expression in the xenograft microenvironment. Our data demonstrate that coffee inhibits NF-κB activity in PC3 cells in vitro and in xenografts. Furthermore, coffee modulates transcription of genes related to prostate cancer and inflammation. Our results are the first to suggest mechanistic links between coffee consumption and prostate cancer in an experimental mouse model. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Stages of Small Cell Lung Cancer

    MedlinePlus

    ... 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 ...

  13. Treatment Option Overview (Small Cell Lung Cancer)

    MedlinePlus

    ... 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 ...

  14. General Information about Small Cell Lung Cancer

    MedlinePlus

    ... 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 ...

  15. Establishing Prostate Cancer Patient Derived Xenografts: Lessons Learned From Older Studies

    PubMed Central

    Russell, Pamela J; Russell, Peter; Rudduck, Christina; Tse, Brian W-C; Williams, Elizabeth D; Raghavan, Derek

    2015-01-01

    Background Understanding the progression of prostate cancer to androgen-independence/castrate resistance and development of preclinical testing models are important for developing new prostate cancer therapies. This report describes studies performed 30 years ago, which demonstrate utility and shortfalls of xenografting to preclinical modeling. Methods We subcutaneously implanted male nude mice with small prostate cancer fragments from transurethral resection of the prostate (TURP) from 29 patients. Successful xenografts were passaged into new host mice. They were characterized using histology, immunohistochemistry for marker expression, flow cytometry for ploidy status, and in some cases by electron microscopy and response to testosterone. Two xenografts were karyotyped by G-banding. Results Tissues from 3/29 donors (10%) gave rise to xenografts that were successfully serially passaged in vivo. Two, (UCRU-PR-1, which subsequently was replaced by a mouse fibrosarcoma, and UCRU-PR-2, which combined epithelial and neuroendocrine features) have been described. UCRU-PR-4 line was a poorly differentiated prostatic adenocarcinoma derived from a patient who had undergone estrogen therapy and bilateral castration after his cancer relapsed. Histologically, this comprised diffusely infiltrating small acinar cell carcinoma with more solid aggregates of poorly differentiated adenocarcinoma. The xenografted line showed histology consistent with a poorly differentiated adenocarcinoma and stained positively for prostatic acid phosphatase (PAcP), epithelial membrane antigen (EMA) and the cytokeratin cocktail, CAM5.2, with weak staining for prostate specific antigen (PSA). The line failed to grow in female nude mice. Castration of three male nude mice after xenograft establishment resulted in cessation of growth in one, growth regression in another and transient growth in another, suggesting that some cells had retained androgen sensitivity. The karyotype (from passage 1) was 43

  16. Multifunctional fluorescent magnetic nanoparticles for lung cancer stem cells research.

    PubMed

    Zhou, Xuan; Chen, Lisha; Wang, Anxin; Ma, Yufei; Zhang, Hailu; Zhu, Yimin

    2015-10-01

    In this paper, a multifunctional peptide-fluorescent-magnetic nanocomposites (Fe₃O₄@PEI@Cy5.5@PEG@HCBP-1 NPs) was synthesized via a layer-by-layer approach for potential application to cancer diagnoses. The multifunctional nanocomposites have great dispersibility and homogeneous particle sizes in aqueous solution. Meanwhile, it has perfect hemocompatibility and satisfying cytocompatibility in a relatively high concentration. Data from in vitro cytotoxicity assay indicated that the nanocomposites could recognize the lung cancer stem cells (CSCs) specifically and enrich the HCBP-1 positive CSCs from H460 tumor xenografts effectively. Additionally, the results of in vivo live fluorescent imaging and magnetic resonance imaging (MRI) showed that the nanocomposites could identify lung CSCs in tumor xenografts. These results suggested that the nanocomposites could be used as a potential cancer diagnostic agent through modifying diverse fluorescence dyes and targeting ligands on its surface.

  17. Pulmonary Rehabilitation in Lung Cancer.

    PubMed

    Wang, Hongmei; Liu, Xin; Rice, Shawn J; Belani, Chandra P

    2016-10-01

    Lung cancer remains a challenging disease with high morbidity and mortality despite targeted therapy. Symptom burden related to cancer impairs quality of life and functional status in patients with lung cancer and in survivors. Pulmonary rehabilitation has been recognized as an effective, noninvasive intervention for patients with chronic respiratory disease. It is well established that pulmonary rehabilitation benefits patients with chronic obstruction pulmonary disease through improved exercise capacity and symptoms. Evidence is increasing that the benefit of pulmonary rehabilitation can be applied to patients with lung cancer. Comprehensive pulmonary rehabilitation has made its way as a cornerstone of integrated care for patients with lung cancer.

  18. Immunotherapy in Lung Cancer.

    PubMed

    Du, Lingling; Herbst, Roy S; Morgensztern, Daniel

    2017-02-01

    The treatment of patients with good performance status and advanced stage non-small cell lung cancer has been based on the use of first-line platinum-based doublet and second-line docetaxel. Immunotherapy represents a new therapeutic approach with the potential for prolonged benefit. Although the vaccines studied have not shown benefit in patients with non-small cell lung cancer, immune checkpoint inhibitors against the PD-1/PD-L1 axis showed increased overall survival compared with docetaxel in randomized clinical trials, which led to the approval of nivolumab and pembrolizumab. Because only a minority of patients benefit from this class of drugs, there has been an intense search for biomarkers.

  19. Phenotypic and Transcriptional Fidelity of Patient-Derived Colon Cancer Xenografts in Immune-Deficient Mice

    PubMed Central

    Chou, Jeffrey; Fitzgibbon, Matthew P.; Mortales, Christie-Lynn L.; Towlerton, Andrea M. H.; Upton, Melissa P.; Yeung, Raymond S.; McIntosh, Martin W.; Warren, Edus H.

    2013-01-01

    Xenografts of human colorectal cancer (CRC) in immune-deficient mice have great potential for accelerating the study of tumor biology and therapy. We evaluated xenografts established in NOD/scid/IL2Rγ-null mice from the primary or metastatic tumors of 27 patients with CRC to estimate their capacity for expanding tumor cells for in vitro studies and to assess how faithfully they recapitulated the transcriptional profile of their parental tumors. RNA-seq analysis of parental human CRC tumors and their derivative xenografts demonstrated that reproducible transcriptional changes characterize the human tumor to murine xenograft transition. In most but not all cases, the human stroma, vasculature, and hematopoietic elements were systematically replaced by murine analogues while the carcinoma component persisted. Once established as xenografts, human CRC cells that could be propagated by serial transplantation remained transcriptionally stable. Three histologically atypical xenografts, established from patients with peritoneal metastases, contained abundant human stromal elements and blood vessels in addition to human tumor cells. The transcriptomes of these mixed tumor/stromal xenografts did not closely resemble those of their parental tumors, and attempts to propagate such xenografts by serial transplantation were unsuccessful. Stable expression of numerous genes previously identified as high priority targets for immunotherapy was observed in most xenograft lineages. Aberrant expression in CRC cells of human genes that are normally only expressed in hematopoietic cells was also observed. Our results suggest that human CRC cells expanded in murine xenografts have great utility for studies of tumor immunobiology and targeted therapies such as immunotherapy but also identify potential limitations. PMID:24278200

  20. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types.

    PubMed

    Iliopoulos, Dimitrios; Hirsch, Heather A; Struhl, Kevin

    2011-05-01

    Metformin, the first-line drug for treating diabetes, selectively kills the chemotherapy resistant subpopulation of cancer stem cells (CSC) in genetically distinct types of breast cancer cell lines. In mouse xenografts, injection of metformin and the chemotherapeutic drug doxorubicin near the tumor is more effective than either drug alone in blocking tumor growth and preventing relapse. Here, we show that metformin is equally effective when given orally together with paclitaxel, carboplatin, and doxorubicin, indicating that metformin works together with a variety of standard chemotherapeutic agents. In addition, metformin has comparable effects on tumor regression and preventing relapse when combined with a four-fold reduced dose of doxorubicin that is not effective as a monotherapy. Finally, the combination of metformin and doxorubicin prevents relapse in xenografts generated with prostate and lung cancer cell lines. These observations provide further evidence for the CSC hypothesis for cancer relapse, an experimental rationale for using metformin as part of combinatorial therapy in a variety of clinical settings, and for reducing the chemotherapy dose in cancer patients.

  1. A dominated and resistant subpopulation causes regrowth after response to 1,3-bis(2-chloroethyl)-1-nitrosourea treatment of a heterogeneous small cell lung cancer xenograft in nude mice.

    PubMed

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

    1994-06-15

    In order to address the question of the influence of a primarily chemoresistant tumor cell subpopulation on the progression of a heterogeneous tumor after cytotoxic therapy, in vitro established human small cell lung cancer cell lines of a 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-sensitive (592) and a resistant (NYH) tumor were used to produce mixed solid tumors in nude mice. Mixtures of 592/NYH (9:1 and 1:1) were inoculated s.c. After 3-4 weeks of tumor growth, the mice were stratified according to tumor size and randomized to treatment with BCNU 40 mg/kg i.p. (10% of lethal dose) or no treatment. Tumor growth curves were used to calculate the effect of the treatment, and changes in the relative proportions of 592 and NYH in the mixed tumors were monitored by flow cytometric DNA analysis by which the two cell lines were distinguishable due to differences in DNA content. A significant response was demonstrated in the 9:1 mixed tumors in which only 592 cells were detectable at the start of the treatment. The response was short and less pronounced compared with tumors containing only 592. In the regrowing tumors after treatment, only NYH was detected. In untreated 9:1 mixed control tumors, only 592 cells were detectable throughout the entire observation period. It is substantiated that the 592 cells were able to inhibit the growth of the NYH cells completely when grown together in 9:1 mixed tumors. This was not the case in the 1:1 mixed tumors. The 1:1 mixed tumors did not respond to BCNU, although 592 was eradicated. These results indicate that resistant and undetectable (dominated) subpopulations in heterogeneous tumors may be responsible for relapse and that the fractional size and the growth characteristics of the resistant subpopulation may determine the magnitude of the clinical response to cytotoxic treatment.

  2. Cholinergic Targets in Lung Cancer.

    PubMed

    Spindel, Eliot R

    2016-01-01

    Lung cancers express an autocrine cholinergic loop in which secreted acetylcholine can stimulate tumor growth through both nicotinic and muscarinic receptors. Because activation of mAChR and nAChR stimulates growth; tumor growth can be stimulated by both locally synthesized acetylcholine as well as acetylcholine from distal sources and from nicotine in the high percentage of lung cancer patients who are smokers. The stimulation of lung cancer growth by cholinergic agonists offers many potential new targets for lung cancer therapy. Cholinergic signaling can be targeted at the level of choline transport; acetylcholine synthesis, secretion and degradation; and nicotinic and muscarinic receptors. In addition, the newly describe family of ly-6 allosteric modulators of nicotinic signaling such as lynx1 and lynx2 offers yet another new approach to novel lung cancer therapeutics. Each of these targets has their potential advantages and disadvantages for the development of new lung cancer therapies which are discussed in this review.

  3. Pain management in lung cancer.

    PubMed

    Nurwidya, Fariz; Syahruddin, Elisna; Yunus, Faisal

    2016-01-01

    Lung cancer is the leading cause of cancer-related mortality worldwide. Not only burdened by the limited overall survival, lung cancer patient also suffer from various symptoms, such as pain, that implicated in the quality of life. Cancer pain is a complicated and transiently dynamic symptom that results from multiple mechanisms. This review will describe the pathophysiology of cancer pain and general approach in managing a patient with lung cancer pain. The use of opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and adjuvant analgesia, as part of the pharmacology therapy along with interventional strategy, will also be discussed.

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

    SciTech Connect

    Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T.; Aftab, Blake T.; Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John; Rudin, Charles M.; Tran, Phuoc T.; Hales, Russell K.

    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.

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

    PubMed Central

    Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T.; Aftab, Blake T.; Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John; Rudin, Charles M.; Tran, Phuoc T.; Hales, Russell K.

    2012-01-01

    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 KrasG12D-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 radio-sensitivity. 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. PMID:23182391

  6. American Cancer Society lung cancer screening guidelines.

    PubMed

    Wender, Richard; Fontham, Elizabeth T H; Barrera, Ermilo; Colditz, Graham A; Church, Timothy R; Ettinger, David S; Etzioni, Ruth; Flowers, Christopher R; Gazelle, G Scott; Kelsey, Douglas K; LaMonte, Samuel J; Michaelson, James S; Oeffinger, Kevin C; Shih, Ya-Chen Tina; Sullivan, Daniel C; Travis, William; Walter, Louise; Wolf, Andrew M D; Brawley, Otis W; Smith, Robert A

    2013-01-01

    Findings from the National Cancer Institute's National Lung Screening Trial established that lung cancer mortality in specific high-risk groups can be reduced by annual screening with low-dose computed tomography. These findings indicate that the adoption of lung cancer screening could save many lives. Based on the results of the National Lung Screening Trial, the American Cancer Society is issuing an initial guideline for lung cancer screening. This guideline recommends that clinicians with access to high-volume, high-quality lung cancer screening and treatment centers should initiate a discussion about screening with apparently healthy patients aged 55 years to 74 years who have at least a 30-pack-year smoking history and who currently smoke or have quit within the past 15 years. A process of informed and shared decision-making with a clinician related to the potential benefits, limitations, and harms associated with screening for lung cancer with low-dose computed tomography should occur before any decision is made to initiate lung cancer screening. Smoking cessation counseling remains a high priority for clinical attention in discussions with current smokers, who should be informed of their continuing risk of lung cancer. Screening should not be viewed as an alternative to smoking cessation. Copyright © 2013 American Cancer Society, Inc.

  7. GLI pathogenesis-related 1 functions as a tumor-suppressor in lung cancer.

    PubMed

    Sheng, Xiumei; Bowen, Nathan; Wang, Zhengxin

    2016-03-18

    GLI pathogenesis-related 1 (GLIPR1) was originally identified in glioblastomas and its expression was also found to be down-regulated in prostate cancer. Functional studies revealed both growth suppression and proapoptotic activities for GLIPR1 in multiple cancer cell lines. GLIPR1's role in lung cancer has not been investigated. Protein arginine methyltransferase 5 (PRMT5) is a protein arginine methyltransferase and forms a stoichiometric complex with the WD repeat domain 77 (WDR77) protein. Both PRMT5 and WDR77 are essential for growth of lung epithelial and cancer cells. But additional gene products that interact genetically or biochemichally with PRMT5 and WDR77 in the control of lung cancer cell growth are not characterized. DNA microarray and immunostaining were used to detect GLIPR1 expression during lung development and lung tumorigenesis. GLIPR1 expression was also analyzed in the TCGA lung cancer cohort. The consequence of GLIPR1 on growth of lung cancer cells in the tissue culture and lung tumor xenografts in the nude mice was observed. We found that GLIPR1 expression is negatively associated with PRMT5/WDR77. GLIPR1 is absent in growing epithelial cells at the early stages of mouse lung development and highly expressed in the adult lung. Expression of GLIPR1 was down-regulated during lung tumorigenesis and its expression suppressed growth of lung cancer cells in the tissue culture and lung tumor xenografts in mice. GLIPR1 regulates lung cancer growth through the V-Erb-B avian erythroblastic leukemia viral oncogene homolog 3 (ErbB3). This study reveals a novel pathway that PRMT5/WDR77 regulates GLIPR1 expression to control lung cancer cell growth and GLIPR1 as a potential therapeutic agent for lung cancer.

  8. American Cancer Society Lung Cancer Screening Guidelines

    PubMed Central

    Wender, Richard; Fontham, Elizabeth T. H.; Barrera, Ermilo; Colditz, Graham A.; Church, Timothy R.; Ettinger, David S.; Etzioni, Ruth; Flowers, Christopher R.; Gazelle, G. Scott; Kelsey, Douglas K.; LaMonte, Samuel J.; Michaelson, James S.; Oeffinger, Kevin C.; Shih, Ya-Chen Tina; Sullivan, Daniel C.; Travis, William; Walter, Louise; Wolf, Andrew M. D.; Brawley, Otis W.; Smith, Robert A.

    2013-01-01

    Findings from the National Cancer Institute’s National Lung Screening Trial established that lung cancer mortality in specific high-risk groups can be reduced by annual screening with low-dose computed tomography. These findings indicate that the adoption of lung cancer screening could save many lives. Based on the results of the National Lung Screening Trial, the American Cancer Society is issuing an initial guideline for lung cancer screening. This guideline recommends that clinicians with access to high-volume, high-quality lung cancer screening and treatment centers should initiate a discussion about screening with apparently healthy patients aged 55 years to 74 years who have at least a 30-pack-year smoking history and who currently smoke or have quit within the past 15 years. A process of informed and shared decision-making with a clinician related to the potential benefits, limitations, and harms associated with screening for lung cancer with low-dose computed tomography should occur before any decision is made to initiate lung cancer screening. Smoking cessation counseling remains a high priority for clinical attention in discussions with current smokers, who should be informed of their continuing risk of lung cancer. Screening should not be viewed as an alternative to smoking cessation. PMID:23315954

  9. Drugs Approved for Lung Cancer

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for lung cancer. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters.

  10. Radiation Therapy for Lung Cancer

    MedlinePlus

    ... of the lung cancer and your overall health. Radiation Therapy Radiation is a high-energy X-ray that can ... surgery, chemotherapy or both depending upon the circumstances. Radiation therapy works within cancer cells by damaging their ...

  11. [Asbestos-related lung cancer].

    PubMed

    Lotti, M

    2010-01-01

    Lung cancer is the leading cause of tumour death and a large percentage of it is associated with tobacco smoking. Epidemiology has shown that asbestos cumulative exposures increase the risk of lung cancer to a variable extent, depending on the manufacturing process and the specific job. The risk appears relatively small (< or = 2) and is detectable after massive exposures only. Clinical diagnosis of asbestos-related lung cancer is based upon medical history (exposures > 25 ff.ml years double the risk), possible lung fibrosis and counts of asbestos bodies and fibers in bronchoalveolar lavage and lung tissues. Pleural plaques do not correlate with the cumulative exposures that are associated with lung cancer. The multiplicative interaction between smoke and asbestos is only detectable when the risk associated with asbestos exposure is increased, i.e. after high exposures.

  12. Patient-derived xenografts: A platform for accelerating translational research in prostate cancer.

    PubMed

    Davies, Alastair H; Wang, Yuzhuo; Zoubeidi, Amina

    2017-03-15

    Recently, there has been renewed interest in the development and characterization of patient-derived tumour xenograft (PDX) models. Numerous PDX models have been established for prostate cancer and, importantly, retain the principal molecular, genetic, and histological characteristics of the donor tumour. As such, these models provide significant improvements over standard cell line xenograft models for biological studies, preclinical drug development, and personalized medicine strategies. This review summarizes the current state of the art in this field, illustrating the opportunities and limitations of PDX models in translational prostate cancer research.

  13. Antitumor effect of Kanglaite® injection in human pancreatic cancer xenografts

    PubMed Central

    2014-01-01

    Background Kanglaite® injection (KLT), with a main ingredient of Coix seed oil (a traditional Chinese medicine), has been widely used for cancer treatment in China. KLT has an inhibitory effect on many kinds of tumors and PI3K/Akt/mTOR signaling promotes cell survival, proliferation, and progression in cancer cells. Therefore, targeting this pathway may lead to the development of novel therapeutic approaches for human cancers. Methods Here, we examined the effects of KLT on the PI3K/Akt/mTOR pathway in pancreatic cancer xenografts in mice, and assessed its therapeutic potential. Growth and apoptosis of tumor xenografts were examined, and the expression levels of genes and proteins involved in the PI3K/Akt/mTOR pathway were measured by RT-PCR and western blotting, respectively. Results Our results revealed that KLT dramatically inhibited the growth of pancreatic cancer xenografts and induced apoptosis simultaneously. Furthermore, it downregulated the expression of phospho-Akt and phospho-mTOR. Conclusions These results suggest that KLT can suppress growth and induce apoptosis of pancreatic cancer xenografts. Moreover, KLT can downregulate the expression of phospho-Akt and phospho-mTOR to modulate the PI3K/Akt/mTOR signaling pathway. PMID:25005526

  14. Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts.

    PubMed

    Zhu, Yin; Cheng, Ming; Yang, Zhen; Zeng, Chun-Yan; Chen, Jiang; Xie, Yong; Luo, Shi-Wen; Zhang, Kun-He; Zhou, Shu-Feng; Lu, Nong-Hua

    2014-01-01

    Mesenchymal stem cells (MSCs) have been recognized as promising delivery vehicles for gene therapy of tumors. Gastric cancer is the third leading cause of worldwide cancer mortality, and novel treatment modalities are urgently needed. NK4 is an antagonist of hepatocyte growth factor receptors (Met) which are often aberrantly activated in gastric cancer and thus represent a useful candidate for targeted therapies. This study investigated MSC-delivered NK4 gene therapy in nude mice bearing gastric cancer xenografts. MSCs were transduced with lentiviral vectors carrying NK4 complementary DNA or enhanced green fluorescent protein (GFP). Such transduction did not change the phenotype of MSCs. Gastric cancer xenografts were established in BALB/C nude mice, and the mice were treated with phosphate-buffered saline (PBS), MSCs-GFP, Lenti-NK4, or MSCs-NK4. The tropism of MSCs toward gastric cancer cells was determined by an in vitro migration assay using MKN45 cells, GES-1 cells and human fibroblasts and their presence in tumor xenografts. Tumor growth, tumor cell apoptosis and intratumoral microvessel density of tumor tissue were measured in nude mice bearing gastric cancer xenografts treated with PBS, MSCs-GFP, Lenti-NK4, or MSCs-NK4 via tail vein injection. The results showed that MSCs migrated preferably to gastric cancer cells in vitro. Systemic MSCs-NK4 injection significantly suppressed the growth of gastric cancer xenografts. MSCs-NK4 migrated and accumulated in tumor tissues after systemic injection. The microvessel density of tumor xenografts was decreased, and tumor cellular apoptosis was significantly induced in the mice treated with MSCs-NK4 compared to control mice. These findings demonstrate that MSC-based NK4 gene therapy can obviously inhibit the growth of gastric cancer xenografts, and MSCs are a better vehicle for NK4 gene therapy than lentiviral vectors. Further studies are warranted to explore the efficacy and safety of the MSC-based NK4 gene therapy in

  15. LUNG CANCER AND PULMONARY THROMBOEMBOLISM

    PubMed Central

    Cukic, Vesna; Ustamujic, Aida

    2015-01-01

    Introduction: Malignant diseases including lung cancer are the risk for development of pulmonary thromboembolism (PTE). Objective: To show the number of PTE in patients with lung cancer treated in Clinic for pulmonary diseases and TB “Podhrastovi” in three-year period: from 2012-2014. Material and methods: This is the retrospective study in which we present the number of various types of lung cancer treated in three-year period, number and per cent of PTE in different types of lung carcinoma, number and per cent of PTE of all diagnosed PTE in lung carcinoma according to the type of carcinoma. Results: In three-year period (from 2012 to 2014) 1609 patients with lung cancer were treated in Clinic for pulmonary diseases and TB “Podhrastovi” Clinical Centre of Sarajevo University. 42 patients: 25 men middle –aged 64.4 years and 17 women middle- aged 66.7 or 2.61% of all patients with lung cancer had diagnosed PTE. That was the 16. 7% of all patients with PTE treated in Clinic “Podhrastovi “in that three-year period. Of all 42 patients with lung cancer and diagnosed PTE 3 patients (7.14%) had planocellular cancer, 4 patients (9.53%) had squamocellular cancer, 9 (21.43%) had adenocarcinoma, 1 (2.38%) had NSCLC, 3 (7.14 %) had microcellular cancer, 1 (2.38%) had neuroendocrine cancer, 2 (4.76%) had large cell-macrocellular and 19 (45.24%) had histological non-differentiated lung carcinoma. Conclusion: Malignant diseases, including lung cancer, are the risk factor for development of PTE. It is important to consider the including anticoagulant prophylaxis in these patients and so to slow down the course of diseases in these patients. PMID:26622205

  16. Lung Cancer and Hispanics: Know the Facts

    MedlinePlus

    Lung Cancer and Hispanics: Know the Facts By the National Cancer Institute First, the good news: the number of lung cancer cases diagnosed in ... myth from fact when it comes to lung cancer. So what are the facts?  Smoking is the primary cause of lung cancer. ...

  17. Second lung cancers in patients successfully treated for lung cancer.

    PubMed

    Johnson, B E; Cortazar, P; Chute, J P

    1997-08-01

    The rate of developing second lung cancers and other aerodigestive tumors in patients who have been treated for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) is approximately 10-fold higher than other adult smokers. The risk of second lung cancers in patients surviving resection of NSCLC is approximately 1% to 2% per year. The series reported show that the patients who develop second NSCLCs tend to have early-stage NSCLC (predominantly stage I and II). The survival of patients after the second resection of lung cancer is similar to that of patients presenting with initial NSCLC. The risk of second lung cancers in patients surviving SCLC is 2% to 14% per patient per year and increases two- to seven-fold with the passage of time from 2 to 10 years. The risk of second lung cancers in patients treated for SCLC appears to be higher than that found in patients with NSCLC who were treated only with surgical resection. In addition, the chances of successful resection of second primary NSCLCs in patients who were treated for SCLC is much less than that for patients with metachronous lung cancers after an initial NSCLC. Patients treated for SCLC who continue to smoke cigarettes increase their rate of developing second lung cancers. The contribution of chest radiation and chemotherapy administration to the risk of developing second lung tumors remain to be defined but may be responsible for some of the increased risk in patients treated for SCLC compared to patients undergoing a surgical resection for NSCLC.

  18. Polonium and Lung Cancer

    PubMed Central

    Zagà, Vincenzo; Lygidakis, Charilaos; Chaouachi, Kamal; Gattavecchia, Enrico

    2011-01-01

    The alpha-radioactive polonium 210 (Po-210) is one of the most powerful carcinogenic agents of tobacco smoke and is responsible for the histotype shift of lung cancer from squamous cell type to adenocarcinoma. According to several studies, the principal source of Po-210 is the fertilizers used in tobacco plants, which are rich in polyphosphates containing radio (Ra-226) and its decay products, lead 210 (Pb-210) and Po-210. Tobacco leaves accumulate Pb-210 and Po-210 through their trichomes, and Pb-210 decays into Po-210 over time. With the combustion of the cigarette smoke becomes radioactive and Pb-210 and Po-210 reach the bronchopulmonary apparatus, especially in bifurcations of segmental bronchi. In this place, combined with other agents, it will manifest its carcinogenic activity, especially in patients with compromised mucous-ciliary clearance. Various studies have confirmed that the radiological risk from Po-210 in a smoker of 20 cigarettes per day for a year is equivalent to the one deriving from 300 chest X-rays, with an autonomous oncogenic capability of 4 lung cancers per 10000 smokers. Po-210 can also be found in passive smoke, since part of Po-210 spreads in the surrounding environment during tobacco combustion. Tobacco manufacturers have been aware of the alpha-radioactivity presence in tobacco smoke since the sixties. PMID:21772848

  19. Synthetic progestins induce growth and metastasis of BT-474 human breast cancer xenografts in nude mice

    PubMed Central

    Liang, Yayun; Benakanakere, Indira; Besch-Williford, Cynthia; Hyder, Ryyan S; Ellersieck, Mark R.; Hyder, Salman M

    2010-01-01

    Objective Previous studies showed that sequential exposure to estrogen and progesterone or medroxyprogesterone acetate (MPA) stimulates vascularization and promotes the progression of BT-474 and T47-D human breast cancer cell xenografts in nude mice (Liang et al, Cancer Res 2007, 67:9929). In this follow-up study, the effects of progesterone, MPA, norgestrel (N-EL) and norethindrone (N-ONE) on BT-474 xenograft tumors were compared in the context of several different hormonal environments. N-EL and N-ONE were included in the study since synthetic progestins vary considerably in their biological effects and the effects of these two progestins on the growth of human tumor xenografts are not known. Methods Estradiol-supplemented intact and ovariectomized Immunodeficient mice were implanted with BT-474 cells. Progestin pellets were implanted either simultaneously with estradiol pellets 2-days prior to tumor cell injection (i.e. combined), or 5-days following tumor cell injections (i.e. sequentially). Results Progestins stimulated the growth of BT-474 xenograft tumors independent of exposure timing and protocol, MPA stimulated the growth of BT-474 xenograft tumors in ovariectomized mice and progestins stimulated VEGF elaboration and increased tumor vascularity. Progestins also increased lymph node metastasis of BT-474 cells. Therefore, progestins, including N-EL and N-ONE, induce the progression of breast cancer xenografts in nude mice and promote tumor metastasis. Conclusions These observations suggests that women who ingest progestins for HT or oral contraception could be more at risk for developing breast cancer as a result of proliferation of existing latent tumor cells. Such risks should be considered in the clinical setting. PMID:20461021

  20. Meta-analysis of the independent and cumulative effects of multiple genetic modifications on pig lung xenograft performance during ex vivo perfusion with human blood.

    PubMed

    Harris, Donald G; Quinn, Kevin J; French, Beth M; Schwartz, Evan; Kang, Elizabeth; Dahi, Siamak; Phelps, Carol J; Ayares, David L; Burdorf, Lars; Azimzadeh, Agnes M; Pierson, Richard N

    2015-01-01

    Genetically modified pigs are a promising potential source of lung xenografts. Ex vivo xenoperfusion is an effective platform for testing the effect of new modifications, but typical experiments are limited by testing of a single genetic intervention and small sample sizes. The purpose of this study was to analyze the individual and aggregate effects of donor genetic modifications on porcine lung xenograft survival and injury in an extensive pig lung xenoperfusion series. Data from 157 porcine lung xenoperfusion experiments using otherwise unmodified heparinized human blood were aggregated as either continuous or dichotomous variables. Lungs were wild type in 17 perfusions (11% of the study group), while 31 lungs (20% of the study group) had one genetic modification, 40 lungs (39%) had 2, and 47 lungs (30%) had 3 or more modifications. The primary endpoint was functional lung survival to 4 h of perfusion. Secondary analyses evaluated previously identified markers associated with known lung xenograft injury mechanisms. In addition to comparison among all xenografts grouped by survival status, a subgroup analysis was performed of lungs incorporating the GalTKO.hCD46 genotype. Each increase in the number of genetic modifications was associated with additional prolongation of lung xenograft survival. Lungs that exhibited survival to 4 h generally had reduced platelet activation and thrombin generation. GalTKO and the expression of hCD46, HO-1, hCD55, or hEPCR were associated with improved survival. hTBM, HLA-E, and hCD39 were associated with no significant effect on the primary outcome. This meta-analysis of an extensive lung xenotransplantation series demonstrates that increasing the number of genetic modifications targeting known xenogeneic lung injury mechanisms is associated with incremental improvements in lung survival. While more detailed mechanistic studies are needed to explore the relationship between gene expression and pathway-specific injury and explore

  1. The inhibitory efficacy of methylseleninic acid against colon cancer xenografts in C57BL/6 mice

    USDA-ARS?s Scientific Manuscript database

    Data indicate that methylselenol is a critical selenium (Se) metabolite for anticancer activity in vivo. We tested the hypoththesis that oral dosing methylseleninic acid (MSeA), a methylselenol precursor, inhibits the growth of colon cancer xenografts in C57BL/6 mice fed a Se adequate diet. In this...

  2. Lung cancer among Chinese women.

    PubMed

    Gao, Y T; Blot, W J; Zheng, W; Ershow, A G; Hsu, C W; Levin, L I; Zhang, R; Fraumeni, J F

    1987-11-15

    A case-control study involving interviews with 672 female lung cancer patients and 735 population-based controls was conducted to investigate the high rates of lung cancer, notably adenocarcinoma, among women in Shanghai. Cigarette smoking was a strong risk factor, but accounted for only about one-fourth of all newly diagnosed cases of lung cancer. Most patients, particularly with adenocarcinoma, were life-long non-smokers. The risks of lung cancer were higher among women reporting tuberculosis and other pre-existing lung diseases. Hormonal factors were suggested by an increased risk associated with late menopause and by a gradient in the risk of adenocarcinoma with decreasing menstrual cycle length, with a 3-fold excess among women who had shorter cycles. Perhaps most intriguing were associations found between lung cancer and measures of exposure to cooking oil vapors. Risks increased with the numbers of meals cooked by either stir frying, deep frying or boiling; with the frequency of smokiness during cooking; and with the frequency of eye irritation during cooking. Use of rapeseed oil, whose volatiles following high-temperature cooking may be mutagenic, was also reported more often by the cancer patients. The findings thus confirm that factors other than smoking are responsible for the high risk of lung cancer among Chinese women and provide clues for further research, including the assessment of cooking practices.

  3. Expression Profiling and Proteomic Analysis of JIN Chinese Herbal Formula in Lung Carcinoma H460 Xenografts

    PubMed Central

    Zheng, Luyu; Zhang, Weiyi; Jiang, Miao; Zhang, Huarong; Xiong, Fei; Yu, Yang; Chen, Meijuan; Zhou, Jing; Dai, Xiaoming; Jiang, Ming; Wang, Mingyan; Cheng, Ge; Duan, Jinao; Yu, Wei; Lin, Biaoyang; Fu, Haian; Zhang, Xu

    2013-01-01

    Many traditional Chinese medicine (TCM) formulae have been used in cancer therapy. The JIN formula is an ancient herbal formula recorded in the classic TCM book Jin Kui Yao Lue (Golden Chamber). The JIN formula significantly delayed the growth of subcutaneous human H460 xenografted tumors in vivo compared with the growth of mock controls. Gene array analysis of signal transduction in cancer showed that the JIN formula acted on multiple targets such as the mitogen-activated protein kinase, hedgehog, and Wnt signaling pathways. The coformula treatment of JIN and diamminedichloroplatinum (DDP) affected the stress/heat shock pathway. Proteomic analysis showed 36 and 84 differentially expressed proteins between the mock and DDP groups and between the mock and JIN groups, respectively. GoMiner analysis revealed that the differentially expressed proteins between the JIN and mock groups were enriched during cellular metabolic processes, and so forth. The ones between the DDP and mock groups were enriched during protein-DNA complex assembly, and so forth. Most downregulated proteins in the JIN group were heat shock proteins (HSPs) such as HSP90AA1 and HSPA1B, which could be used as markers to monitor responses to the JIN formula therapy. The mechanism of action of the JIN formula on HSP proteins warrants further investigation. PMID:24066008

  4. Protease inhibitor nafamostat mesilate attenuates complement activation and improves function of xenografts in a discordant lung perfusion model.

    PubMed

    Tagawa, Tsutomu

    2011-01-01

    Anti-complement activity of nafamostat mesilate (FUT-175) is strong including its variety of pharmacological effects. The effect of FUT-175 for xenografts in an ex vivo guinea pig-to-rat lung perfusion model was evaluated. Heparinized Lewis rat blood was used to perfuse the lungs in three groups (n = 6 each). Group I used Lewis rat left lung for donor, Group X used guinea pig left lung for donor, and Group XF used guinea pig left lung for donor, which was perfused with Lewis rat blood with 0.2 mg/ml of FUT-175. Complement activity causing 50% hemolysis (CH50) in the perfusion blood and pulmonary function either before or during perfusion were serially measured. Pathological assessments of the lungs were also carried out after perfusion. The duration of satisfactory pulmonary function was significantly increased in Group XF. Complement activity causing 50% hemolysis in Group XF decreased more significantly compared to Group X. FUT-175 suppressed both the increase in pulmonary arterial pressure and airway resistance, and the decrease in dynamic lung compliance. In Group X, pathology showed intra-alveolar hemorrhage, perivascular edema, and medial thickening with endothelial swelling of the pulmonary arteries. In Group XF, less changes were observed compared to Group X. Group X showed deposition of IgM, IgG, and C3 at the endothelium of arteries, which was fewer in Group XF, and even fewer in Group I. This study suggests that FUT-175 inhibited complement activation and improved lung xenograft function. FUT-175 ameliorates hyperacute rejection in a guinea pig-to-rat ex vivo xenogeneic lung perfusion model. © 2011 John Wiley & Sons A/S.

  5. Occupational exposure and lung cancer

    PubMed Central

    Spyratos, Dionysios; Porpodis, Konstantinos; Tsakiridis, Kosmas; Machairiotis, Nikolaos; Katsikogiannis, Nikolaos; Kougioumtzi, Ioanna; Dryllis, Georgios; Kallianos, Anastasios; Rapti, Aggeliki; Li, Chen; Zarogoulidis, Konstantinos

    2013-01-01

    Lung cancer is the leading cause of cancer death for male and the second most usual cancer for women after breast cancer. Currently there are available several non-specific cytotoxic agents and several targeted agents for lung cancer therapy. However; early stage diagnosis is still unavailable and several efforts are being made towards this direction. Novel biomarkers are being investigated along with new biopsy techniques. The occupational and environmental exposure to carcinogenic agents is an everyday phenomenon. Therefore until efficient early diagnosis is available, avoidance of exposure to carcinogenic agents is necessary. In the current mini-review occupational and environmental carcinogenic agents will be presented. PMID:24102018

  6. Therapeutic Electromagnetic Field (TEMF) and gamma irradiation on human breast cancer xenograft growth, angiogenesis and metastasis

    PubMed Central

    Cameron, Ivan L; Sun, Lu-Zhe; Short, Nicholas; Hardman, W Elaine; Williams, C Douglas

    2005-01-01

    Background The effects of a rectified semi-sinewave signal (15 mT amplitude, 120 pulses per second, EMF Therapeutics, Inc.) (TEMF) alone and in combination with gamma irradiation (IR) therapy in nude mice bearing a human MDA MB231 breast cancer xenograft were tested. Green fluorescence protein transfected cancer cells were injected into the mammary fat pad of young female mice. Six weeks later, mice were randomly divided into four treatment groups: untreated controls; 10 minute daily TEMF; 200 cGy of IR every other day (total 800 cGy); IR plus daily TEMF. Some mice in each group were euthanized 24 hours after the end of IR. TEMF treatment continued for 3 additional weeks. Tumor sections were stained for: endothelial cells with CD31 and PAS or hypoxia inducible factor 1α (HIF). Results Most tumors <35 mm3 were white but tumors >35 mm3 were pink and had a vascularized capsule. The cortex within 100 microns of the capsule had little vascularization. Blood vessels, capillaries, and endothelial pseudopods were found at >100 microns from the capsule (subcortex). Tumors >35 mm3 treated with IR 24 hours previously or with TEMF had decreased blood vessels in the subcortex and more endothelial pseudopods projecting into hypoxic, HIF positive areas than tumors from the control group. Mice that received either IR or TEMF had significantly fewer lung metastatic sites and slower tumor growth than did untreated mice. No harmful side effects were attributed to TEMF. Conclusion TEMF therapy provided a safe means for retarding tumor vascularization, growth and metastasis. PMID:16045802

  7. [Lung cancer and epigenetic modifications].

    PubMed

    Darılmaz Yüce, Gülbahar; Ortaç Ersoy, Ebru

    2016-06-01

    Epigenetic alterations, including DNA methylation, histone modifications, and noncoding RNA expression, have been reported to play a major role in the genesis of lung cancer. DNA methylation, histone modifications, and RNA expression are epigenetic markers in assesment of early detection, prognosis and evaluation of treatment of lung cancer. In this rewiev we summarize the common epigenetic changes associated with lung cancer to give some clarity to its etiology, and to provide an overview of the potential translational applications of these changes, including applications for early detection, diagnosis, prognostication, and therapeutics.

  8. Comprehensive characterization of chemotherapeutic efficacy on metastases in the established gastric neuroendocrine cancer patient derived xenograft model

    PubMed Central

    Chen, Dawei; Pang, Liang; Guo, Sheng; Cai, Jie; Wery, Jean-Pierre; Li, Linda; Li, Henry Qixiang; Lin, Peter Ping

    2015-01-01

    The HuPrime® human gastric neuroendocrine carcinoma derived xenograft model GA0087 was established in this study. GA0087 PDX model showed high gene expression of vascular endothelial growth factors (VEGF)-A and B, and high potential of lung metastasis. Circulating tumor cells (CTCs) with either large or small size, circulating tumor microemboli (CTM) and lung metastatic lesions were detected in GA0087 PDX mice. The number of CTC correlated to the number of metastatic nodules in lung. Both primary tumor growth and metastasis in terms of the number of dynamically monitored CTCs and metastatic nodules were effectively suppressed by Cisplatin. Diverse subtypes of CTCs in the context of sensitivity to Cisplatin were specifically identified by subtraction enrichment (SE) integrated with in situ Phenotyping of cytokeratin 18 (CK18) and Karyotyping of chromosome 8 (in situ PK CTC by CK-iFISH). All the CK18-/diploid and majority of CK18+/diploid CTC subtypes were chemosensitive, whereas a higher percentage of CK18+/multiploid subtype of CTC were Cisplatin-insensitive. Combined histopathological examination of metastatic lesion and in situ PK CTC in a metastatic PDX (mPDX) tumor model are of particular significance, and may provide an unique and robust platform for cancer research as well as pre-clinical evaluation of therapeutic efficacy of new anti-cancer drugs. PMID:25909226

  9. Genome remodelling in a basal-like breast cancer metastasis and xenograft.

    PubMed

    Ding, Li; Ellis, Matthew J; Li, Shunqiang; Larson, David E; Chen, Ken; Wallis, John W; Harris, Christopher C; McLellan, Michael D; Fulton, Robert S; Fulton, Lucinda L; Abbott, Rachel M; Hoog, Jeremy; Dooling, David J; Koboldt, Daniel C; Schmidt, Heather; Kalicki, Joelle; Zhang, Qunyuan; Chen, Lei; Lin, Ling; Wendl, Michael C; McMichael, Joshua F; Magrini, Vincent J; Cook, Lisa; McGrath, Sean D; Vickery, Tammi L; Appelbaum, Elizabeth; Deschryver, Katherine; Davies, Sherri; Guintoli, Therese; Lin, Li; Crowder, Robert; Tao, Yu; Snider, Jacqueline E; Smith, Scott M; Dukes, Adam F; Sanderson, Gabriel E; Pohl, Craig S; Delehaunty, Kim D; Fronick, Catrina C; Pape, Kimberley A; Reed, Jerry S; Robinson, Jody S; Hodges, Jennifer S; Schierding, William; Dees, Nathan D; Shen, Dong; Locke, Devin P; Wiechert, Madeline E; Eldred, James M; Peck, Josh B; Oberkfell, Benjamin J; Lolofie, Justin T; Du, Feiyu; Hawkins, Amy E; O'Laughlin, Michelle D; Bernard, Kelly E; Cunningham, Mark; Elliott, Glendoria; Mason, Mark D; Thompson, Dominic M; Ivanovich, Jennifer L; Goodfellow, Paul J; Perou, Charles M; Weinstock, George M; Aft, Rebecca; Watson, Mark; Ley, Timothy J; Wilson, Richard K; Mardis, Elaine R

    2010-04-15

    Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumour progression. Here we describe the genomic analyses of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The metastasis contained two de novo mutations and a large deletion not present in the primary tumour, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumour mutations and displayed a mutation enrichment pattern that resembled the metastasis. Two overlapping large deletions, encompassing CTNNA1, were present in all three tumour samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared with the primary tumour indicate that secondary tumours may arise from a minority of cells within the primary tumour.

  10. Exosomal Secretion of Cytoplasmic Prostate Cancer Xenograft-derived Proteins *S⃞

    PubMed Central

    Jansen, Flip H.; Krijgsveld, Jeroen; van Rijswijk, Angelique; van den Bemd, Gert-Jan; van den Berg, Mirella S.; van Weerden, Wytske M.; Willemsen, Rob; Dekker, Lennard J.; Luider, Theo M.; Jenster, Guido

    2009-01-01

    Novel markers for prostate cancer (PCa) are needed because current established markers such as prostate-specific antigen lack diagnostic specificity and prognostic value. Proteomics analysis of serum from mice grafted with human PCa xenografts resulted in the identification of 44 tumor-derived proteins. Besides secreted proteins we identified several cytoplasmic proteins, among which were most subunits of the proteasome. Native gel electrophoresis and sandwich ELISA showed that these subunits are present as proteasome complexes in the serum from xenograft-bearing mice. We hypothesized that the presence of proteasome subunits and other cytoplasmic proteins in serum of xenografted mice could be explained by the secretion of small vesicles by cancer cells, so-called exosomes. Therefore, mass spectrometry and Western blotting analyses of the protein content of exosomes isolated from PCa cell lines was performed. This resulted in the identification of mainly cytoplasmic proteins of which several had previously been identified in the serum of xenografted mice, including proteasome subunits. The isolated exosomes also contained RNA, including the gene fusion TMPRSS2-ERG product. These observations suggest that although their function is not clearly defined cancer-derived exosomes offer possibilities for the identification of novel biomarkers for PCa. PMID:19204029

  11. Activation and Molecular Targets of Peroxisome Proliferator-Activated Receptor-γ Ligands in Lung Cancer

    PubMed Central

    Nemenoff, Raphael A.; Weiser-Evans, Mary; Winn, Robert A.

    2008-01-01

    Lung cancer is the leading cause of cancer death, and five-year survival remains poor, raising the urgency for new treatment strategies. Activation of PPARγ represents a potential target for both the treatment and prevention of lung cancer. Numerous studies have examined the effect of thiazolidinediones such as rosiglitazone and pioglitazone on lung cancer cells in vitro and in xenograft models. These studies indicate that activation of PPARγ inhibits cancer cell proliferation as well as invasiveness and metastasis. While activation of PPARγ can occur by direct binding of pharmacological ligands to the molecule, emerging data indicate that PPARγ activation can occur through engagement of other signal transduction pathways, including Wnt signaling and prostaglandin production. Data, both from preclinical models and retrospective clinical studies, indicate that activation of PPARγ may represent an attractive chemopreventive strategy. This article reviews the existing biological and mechanistic experiments focusing on the role of PPARγ in lung cancer, focusing specifically on nonsmall cell lung cancer. PMID:18509496

  12. Metastatic cancer to the lung

    MedlinePlus

    ... lungs may include: Fluid between the lung and chest wall (pleural effusion), which can cause shortness of breath or pain when taking a deep breath Further spread of the cancer Side effects of chemotherapy or radiation therapy When to Contact a Medical Professional Call ...

  13. Lung cancer and tobacco smoking.

    PubMed

    Boyle, P; Maisonneuve, P

    1995-06-01

    The dominant role of tobacco smoking in the causation of lung cancer has been repeatedly demonstrated over the past 50 years. Current lung cancer rates reflect cigarette smoking habits of men and women in the past decades, but not necessarily current smoking patterns, since there is an interval of several decades between the change in smoking habits in a population and its consequences on lung cancer rates. Over 90% of lung cancer may be avoidable simply through avoidance of cigarette smoking. There is at present a huge premature loss of life world-wide caused by smoking. Rates of lung cancer present in central and eastern Europe at the present time are higher than those ever before recorded elsewhere; lung cancer has increased 10-fold in men and eightfold in women in Japan since 1950. There is a world-wide epidemic of smoking among young women which will be translated into increasing rates of tobacco-related disease, including cancer, in the coming decades. There is another epidemic of lung cancer and tobacco-related deaths building up in China as the cohorts of men in whom tobacco smoking became popular reach ages where cancer is an important hazard. Many solutions have been attempted to reduce cigarette smoking and increasingly many countries are enacting legislation to curb this habit. Cigarette smoking remains the number one target for Public Health action aimed at reducing cancer risk in the general population. General practitioners, hospital physicians and everyone working in oncology have a particularly important exemplary role to play in this process.

  14. Research Resource: Diagnostic and Therapeutic Potential of Nuclear Receptor Expression in Lung Cancer

    PubMed Central

    Xie, Yang; Lee, Woochang; Bookout, Angie L.; Girard, Luc; Raso, Gabriela; Behrens, Carmen; Wistuba, Ignacio I.; Gadzar, Adi F.; Minna, John D.; Mangelsdorf, David J.

    2012-01-01

    Lung cancer is the leading cause of cancer-related death. Despite a number of studies that have provided prognostic biomarkers for lung cancer, a paucity of reliable markers and therapeutic targets exist to diagnose and treat this aggressive disease. In this study we investigated the potential of nuclear receptors (NRs), many of which are well-established drug targets, as therapeutic markers in lung cancer. Using quantitative real-time PCR, we analyzed the expression of the 48 members of the NR superfamily in a human panel of 55 normal and lung cancer cell lines. Unsupervised cluster analysis of the NR expression profile segregated normal from tumor cell lines and grouped lung cancers according to type (i.e. small vs. non-small cell lung cancers). Moreover, we found that the NR signature was 79% accurate in diagnosing lung cancer incidence in smokers (n = 129). Finally, the evaluation of a subset of NRs (androgen receptor, estrogen receptor, vitamin D receptor, and peroxisome proliferator-activated receptor-γ) demonstrated the therapeutic potential of using NR expression to predict ligand-dependent growth responses in individual lung cancer cells. Preclinical evaluation of one of these receptors (peroxisome proliferator activated receptor-γ) in mouse xenografts confirmed that ligand-dependent inhibitory growth responses in lung cancer can be predicted based on a tumor's receptor expression status. Taken together, this study establishes NRs as theragnostic markers for predicting lung cancer incidence and further strengthens their potential as therapeutic targets for individualized treatment. PMID:22700587

  15. Global metabolite profiling of human colorectal cancer xenografts in mice using HPLC-MS/MS.

    PubMed

    Loftus, Neil J; Lai, Lindsay; Wilkinson, Robert W; Odedra, Rajesh; Wilson, Ian D; Barnes, Alan J

    2013-06-07

    Reversed-phase gradient LC-MS was used to perform untargeted metabonomic analysis on extracts of human colorectal cancer (CRC) cell lines (COLO 205, HT-29, HCT 116 and SW620) subcutaneously implanted into age-matched athymic nude male mice to study small molecule metabolic profiles and examine possible correlations with human cancer biopsies. Following high mass accuracy data analysis using MS and MS/MS, metabolites were identified by searching against major metabolite databases including METLIN, MASSBANK, The Human Metabolome Database, PubChem, Biospider, LipidMaps and KEGG. HT-29 and COLO 205 tumor xenografts showed a distribution of metabolites that differed from SW620 and HCT 116 xenografts (predominantly on the basis of relative differences in the amounts of amino acids and lipids detected). This finding is consistent with NMR-based analysis of human colorectal tissue, where the metabolite profiles of HT-29 tumors exhibit the greatest similarity to human rectal cancer tissue with respect to changes in the relative amounts of lipids and choline-containing compounds. As the metabolic signatures of cancer cells result from oncogene-directed metabolic reprogramming, the HT-29 xenografts in mice may prove to be a useful model to further study the tumor microenvironment and cancer biology.

  16. The natural compound sulforaphene, as a novel anticancer reagent, targeting PI3K-AKT signaling pathway in lung cancer

    PubMed Central

    Liu, Weilin; Kuang, Pengqun; Liang, Hao; Yuan, Qipeng

    2016-01-01

    Lung cancer is one of the leading causes of cancer death worldwide. Isothiocyanates from cruciferous vegetables been shown to possess anticarcinogenic activities in lung malignances. We previously found sulforaphene (4-methylsufinyl-3-butenyl isothiocyanate, SFE), one new kind of isothiocyanates, existing in a relative high abundance in radish seeds. An efficient methodology based on macroporous resin and preparative high-performance liquid chromatography was developed to isolate SFE in reasonably large quantities, high purity and low cost. However, it is still largely unclear whether SFE could function as an antineoplastic compound, especially in lung cancer. In this study, we systematically investigated the anti-cancer effects of SFE in vitro as well as its possible underling molecular mechanisms in lung cancer. The acute toxicity tests and pharmacokinetics tests for SFE were performed to evaluate its drugability in mice. Also, we evaluated the in vivo anti-cancer effects of SFE using nude Balb/C mice with lung cancer xenograft. SFE can induce apoptosis of multiple lung cancer celllines and, thus, inhibited cancer cell proliferation. Lung cancer cells treated with SFE exhibit significant inhibition of the PI3K-AKT signaling pathway, including depressed PTEN expression and inhibition of AKT phosphoralation. At well-tolerated doses, administration of SFE to mice bearing lung cancer xenografts leads to significant inhibitions of tumor growth. In summary, our work identifies SFE as a novel natural broad-spectrum small molecule inhibitor for lung cancer. PMID:27765931

  17. Anticancer effect of silibinin on the xenograft model using MDA-MB-468 breast cancer cells.

    PubMed

    Kil, Won Ho; Kim, Sang Min; Lee, Jeong Eon; Park, Kyoung Sik; Nam, Seok Jin

    2014-10-01

    The aim of this study is to know whether silibinin has an anticancer effect on triple negative breast cancer xenograft model using MDA-MB-468 cells. To establish the xenograft model, we injected the MDA-MB-468 cells into female Balb/c-nude mice. After establishing a xenograft model, oral silibinin was administered to the tested mice in the way of 200 mg/kg for 45 days. The difference of mean tumor volume between silibinin fed mice and control mice was analyzed. The epidermal growth factor receptor (EGFR) phosphorylation in MDA-MB-468 cells was analyzed by Western blotting. The expression of VEGF, COX-2, and MMP-9 genes in tumor tissue was analyzed by real-time polymerase chain reaction (PCR). In the xenograft model using MDA-MB-468 cells, we found that oral administration of silibinin significantly suppressed the tumor volume (silibinin treated mice vs. control mice; 230.3 ± 61.6 mm(3) vs. 435.7 ± 93.5 mm(3), P < 0.001). The phosphorylation of EGFR in MDA-MB-468 cells was inhibited by treatment with 50 µg/mL of silibinin. In real time-PCR analysis of tumor tissue obtained from sacrificed mice, the gene expression of MMP-9, VEGF, and COX-2 was 51.8%-80% smaller in silibinin group than that of control group and we can also verify the similar result using Western blotting analysis. We verified that silibinin had anticancer effect on xenograft model of MDA-MB-468 cells in the way of preventing the phosphorylation of EGFR and eventually suppressed the production of COX-2, VEGF, and MMP-9 expression. Finally, the tumor volume of xenograft models was decreased after administration of Silibinin.

  18. Anticancer effect of silibinin on the xenograft model using MDA-MB-468 breast cancer cells

    PubMed Central

    Kim, Sang Min; Lee, Jeong Eon; Park, Kyoung Sik; Nam, Seok Jin

    2014-01-01

    Purpose The aim of this study is to know whether silibinin has an anticancer effect on triple negative breast cancer xenograft model using MDA-MB-468 cells. Methods To establish the xenograft model, we injected the MDA-MB-468 cells into female Balb/c-nude mice. After establishing a xenograft model, oral silibinin was administered to the tested mice in the way of 200 mg/kg for 45 days. The difference of mean tumor volume between silibinin fed mice and control mice was analyzed. The epidermal growth factor receptor (EGFR) phosphorylation in MDA-MB-468 cells was analyzed by Western blotting. The expression of VEGF, COX-2, and MMP-9 genes in tumor tissue was analyzed by real-time polymerase chain reaction (PCR). Results In the xenograft model using MDA-MB-468 cells, we found that oral administration of silibinin significantly suppressed the tumor volume (silibinin treated mice vs. control mice; 230.3 ± 61.6 mm3 vs. 435.7 ± 93.5 mm3, P < 0.001). The phosphorylation of EGFR in MDA-MB-468 cells was inhibited by treatment with 50 µg/mL of silibinin. In real time-PCR analysis of tumor tissue obtained from sacrificed mice, the gene expression of MMP-9, VEGF, and COX-2 was 51.8%-80% smaller in silibinin group than that of control group and we can also verify the similar result using Western blotting analysis. Conclusion We verified that silibinin had anticancer effect on xenograft model of MDA-MB-468 cells in the way of preventing the phosphorylation of EGFR and eventually suppressed the production of COX-2, VEGF, and MMP-9 expression. Finally, the tumor volume of xenograft models was decreased after administration of Silibinin. PMID:25317410

  19. Early detection of lung cancer

    PubMed Central

    Midthun, David E.

    2016-01-01

    Most patients with lung cancer are diagnosed when they present with symptoms, they have advanced stage disease, and curative treatment is no longer an option. An effective screening test has long been desired for early detection with the goal of reducing mortality from lung cancer. Sputum cytology, chest radiography, and computed tomography (CT) scan have been studied as potential screening tests. The National Lung Screening Trial (NLST) demonstrated a 20% reduction in mortality with low-dose CT (LDCT) screening, and guidelines now endorse annual LDCT for those at high risk. Implementation of screening is underway with the desire that the benefits be seen in clinical practice outside of a research study format. Concerns include management of false positives, cost, incidental findings, radiation exposure, and overdiagnosis. Studies continue to evaluate LDCT screening and use of biomarkers in risk assessment and diagnosis in attempt to further improve outcomes for patients with lung cancer. PMID:27158468

  20. Lung Cancer Risk Prediction Models

    Cancer.gov

    Developing statistical models that estimate the probability of developing lung cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  1. Carotenoids and lung cancer prevention

    USDA-ARS?s Scientific Manuscript database

    Understanding the molecular actions of carotenoids is critical for human studies involving carotenoids for prevention of lung cancer and cancers at other tissue sites. While the original hypothesis prompting the beta-carotene intervention trials was that beta-carotene exerts beneficial effects thro...

  2. Cigarette smoke and lung cancer

    SciTech Connect

    Martonen, T.B.; Hofmann, W.; Lowe, J.E.

    1987-01-01

    Cigarette smoke has been implicated in a causal relationship with carcinoma of the lung. An intriguing feature of the disease is the site-selectivity with which bronchogenic cancer manifests itself; most cancers are detected in the main, lobar and segmental bronchi, perhaps specifically at airway bifurcations. The elevated risk of lung cancer to smokers may result from a complex interplay between smoking and exposure to ambient Rn progeny, including the promotional-effect role (as opposed to being the initiating event) of cigarette smoke in tumor development. It has been determined that smokers exposed to average indoor Rn progency levels receive surprisingly high doses at hot spots within bronchial bifurcations.

  3. Monitoring Serial Changes in Circulating Human Breast Cancer Cells in Mruine Xenograft Models

    PubMed Central

    Eliane, Jean-Pierre; Repollet, Madeline; Luker, Kathryn E.; Brown, Martha; Rae, James M.; Dontu, Gabriela; Schott, Anne F.; Wicha, Max; Doyle, Gerald V.; Hayes, Daniel F.; Luker, Gary D.

    2009-01-01

    Circulating tumor cells (CTC) are emerging as a powerful prognostic and predictive biomarker in several types of cancer, including breast, colon, and prostate. Studies of CTC in metastasis and further development of CTC as a biomarker in cancer have been limited by the inability to repetitively monitor CTC in mouse models of cancer. We have validated a method to enumerate CTC in blood samples obtained from living mice using a modified version of an in vitro diagnostic system for quantifying CTC in patients. Different routes of blood collection were tested to identify a method to reproducibly recover CTC from tumor-bearing mice without interference from contaminating normal murine epithelial cells. CTC are present in blood samples from mice bearing orthotopic xenografts of several different breast cancer cell lines and primary breast cancer cells from patient biopsies. We also show that this technology can be used for serial monitoring of CTC in mouse xenograft models of human breast cancer. These results establish a new method for studying CTC in mouse models of epithelial cancer, providing the foundation for studies of molecular regulation of CTC in cancer and CTC as biomarker for therapeutic efficacy. PMID:18632603

  4. Functional imaging in lung cancer

    PubMed Central

    Harders, S W; Balyasnikowa, S; Fischer, B M

    2014-01-01

    Lung cancer represents an increasingly frequent cancer diagnosis worldwide. An increasing awareness on smoking cessation as an important mean to reduce lung cancer incidence and mortality, an increasing number of therapy options and a steady focus on early diagnosis and adequate staging have resulted in a modestly improved survival. For early diagnosis and precise staging, imaging, especially positron emission tomography combined with CT (PET/CT), plays an important role. Other functional imaging modalities such as dynamic contrast-enhanced CT (DCE-CT) and diffusion-weighted MR imaging (DW-MRI) have demonstrated promising results within this field. The purpose of this review is to provide the reader with a brief and balanced introduction to these three functional imaging modalities and their current or potential application in the care of patients with lung cancer. PMID:24289258

  5. Combined Therapy of Oncolytic Adenovirus and Temozolomide Enhances Lung Cancer Virotherapy In Vitro and In Vivo

    PubMed Central

    Gomez-Gutierrez, Jorge G.; Nitz, Jonathan; Sharma, Rajesh; Wechman, Stephen L.; Riedinger, Eric; Martinez-Jaramillo, Elvis; Zhou, Heshan Sam; McMasters, Kelly M.

    2015-01-01

    Oncolytic adenoviruses (OAds) are very promising for the treatment of lung cancer. However, OAd-based monotherapeutics have not been effective during clinical trials. Therefore, the effectiveness of virotherapy must be enhanced by combining OAds with other therapies. In this study, the therapeutic potential of OAd in combination with temozolomide (TMZ) was evaluated in lung cancer cells in vitro and in vivo. The combination of OAd and TMZ therapy synergistically enhanced cancer cell death; this enhanced cancer cell death may be explained via three related mechanisms: apoptosis, virus replication, and autophagy. Autophagy inhibition partially protected cancer cells from this combined therapy. This combination significantly suppressed the growth of subcutaneous H441 lung cancer xenograft tumors in athymic nude mice. In this study, we have provided an experimental rationale to test OAds in combination with TMZ in a lung cancer clinical trial. PMID:26561948

  6. Frizzled-8 as a putative therapeutic target in human lung cancer

    SciTech Connect

    Wang, Hua-qing; Xu, Mei-lin; Ma, Jie; Zhang, Yi; Xie, Cong-hua

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Fzd-8 is over-expressed in human lung cancer. Black-Right-Pointing-Pointer shRNA knock-down of Fzd-8 inhibits proliferation and Wnt pathway in lung cancer cells. Black-Right-Pointing-Pointer shRNA knock-down of Fzd-8 suppresses tumor growth in vivo. Black-Right-Pointing-Pointer shRNA knock-down Fzd-8 sensitizes lung cancer cells to chemotherapy Taxotere. -- Abstract: Lung cancer is the leading cause of cancer related deaths worldwide. It is necessary to better understand the molecular mechanisms involved in lung cancer in order to develop more effective therapeutics for the treatment of this disease. Recent reports have shown that Wnt signaling pathway is important in a number of cancer types including lung cancer. However, the role of Frizzled-8 (Fzd-8), one of the Frizzled family of receptors for the Wnt ligands, in lung cancer still remains to be elucidated. Here in this study we showed that Fzd-8 was over-expressed in human lung cancer tissue samples and cell lines. To investigate the functional importance of the Fzd-8 over-expression in lung cancer, we used shRNA to knock down Fzd-8 mRNA in lung cancer cells expressing the gene. We observed that Fzd-8 shRNA inhibited cell proliferation along with decreased activity of Wnt pathway in vitro, and also significantly suppressed A549 xenograft model in vivo (p < 0.05). Furthermore, we found that knocking down Fzd-8 by shRNA sensitized the lung cancer cells to chemotherapy Taxotere. These data suggest that Fzd-8 is a putative therapeutic target for human lung cancer and over-expression of Fzd-8 may be important for aberrant Wnt activation in lung cancer.

  7. A Real-Time Non-invasive Auto-bioluminescent Urinary Bladder Cancer Xenograft Model.

    PubMed

    John, Bincy Anu; Xu, Tingting; Ripp, Steven; Wang, Hwa-Chain Robert

    2017-02-01

    The study was to develop an auto-bioluminescent urinary bladder cancer (UBC) xenograft animal model for pre-clinical research. The study used a humanized, bacteria-originated lux reporter system consisting of six (luxCDABEfrp) genes to express components required for producing bioluminescent signals in human UBC J82, J82-Ras, and SW780 cells without exogenous substrates. Immune-deficient nude mice were inoculated with Lux-expressing UBC cells to develop auto-bioluminescent xenograft tumors that were monitored by imaging and physical examination. Lux-expressing auto-bioluminescent J82-Lux, J82-Ras-Lux, and SW780-Lux cell lines were established. Xenograft tumors derived from tumorigenic Lux-expressing auto-bioluminescent J82-Ras-Lux cells allowed a serial, non-invasive, real-time monitoring by imaging of tumor development prior to the presence of palpable tumors in animals. Using Lux-expressing auto-bioluminescent tumorigenic cells enabled us to monitor the entire course of xenograft tumor development through tumor cell implantation, adaptation, and growth to visible/palpable tumors in animals.

  8. Quality of Life in Patients Undergoing Radiation Therapy for Primary Lung Cancer, Head and Neck Cancer, or Gastrointestinal Cancer

    ClinicalTrials.gov

    2017-05-23

    Anal Cancer; Colorectal Cancer; Esophageal Cancer; Extrahepatic Bile Duct Cancer; Gallbladder Cancer; Gastric Cancer; Head and Neck Cancer; Liver Cancer; Lung Cancer; Pancreatic Cancer; Small Intestine Cancer

  9. Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer

    SciTech Connect

    Staquicini, Fernanda I.; Qian, Ming D.; Salameh, Ahmad; Dobroff, Andrey S.; Edwards, Julianna K.; Cimino, Daniel F.; Moeller, Benjamin J.; Kelly, Patrick; Nunez, Maria I.; Tang, Ximing; Liu, Diane D.; Lee, J. Jack; Hong, Waun Ki; Ferrara, Fortunato; Bradbury, Andrew R. M.; Lobb, Roy R.; Edelman, Martin J.; Sidman, Richard L.; Wistuba, Ignacio I.; Arap, Wadih; Pasqualini, Renata

    2015-03-20

    Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G1/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. In conclusion, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lung cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications.

  10. Targeted Therapies for Lung Cancer

    PubMed Central

    Larsen, Jill E.; Cascone, Tina; Gerber, David E.; Heymach, John V.; Minna, John D.

    2012-01-01

    Although lung cancer remains the leading cancer killer in the United States, recently a number of developments indicate future clinical benefit. These include evidence that computed tomography–based screening decreases lung cancer mortality, the use of stereotactic radiation for early-stage tumors, the development of molecular methods to predict chemotherapy sensitivity, and genome-wide expression and mutation analysis data that have uncovered oncogene “addictions” as important therapeutic targets. Perhaps the most significant advance in the treatment of this challenging disease is the introduction of molecularly targeted therapies, a term that currently includes monoclonal antibodies and small-molecule tyrosine kinase inhibitors. The development of effective targeted therapeutics requires knowledge of the genes and pathways involved and how they relate to the biologic behavior of lung cancer. Drugs targeting the epidermal growth factor receptor, anaplastic lymphoma kinase, and vascular endothelial growth factor are now U.S. Food and Drug Administration approved for the treatment of advanced non-small cell lung cancer. These agents are generally better tolerated than conventional chemotherapy and show dramatic efficacy when their use is coupled with a clear understanding of clinical data, mechanism, patient selection, drug interactions, and toxicities. Integrating genome-wide tumor analysis with drug- and targeted agent-responsive phenotypes will provide a wealth of new possibilities for lung cancer–targeted therapeutics. Ongoing research efforts in these areas as well as a discussion of emerging targeted agents being evaluated in clinical trials are the subjects of this review. PMID:22157296

  11. Impacts of Exercise on Prognostic Biomarkers in Lung Cancer Patients

    ClinicalTrials.gov

    2016-02-18

    Extensive Stage Small Cell Lung Cancer; Healthy, no Evidence of Disease; Limited Stage Small Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Recurrent Small Cell Lung Cancer; Stage IA Non-small Cell Lung Cancer; Stage IB 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

  12. Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models.

    PubMed

    Desnoyers, L R; Pai, R; Ferrando, R E; Hötzel, K; Le, T; Ross, J; Carano, R; D'Souza, A; Qing, J; Mohtashemi, I; Ashkenazi, A; French, D M

    2008-01-03

    Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice its involvement in human cancer is not well characterized. Here we report that FGF19 and its cognate receptor FGF receptor 4 (FGFR4) are coexpressed in primary human liver, lung and colon tumors and in a subset of human colon cancer cell lines. To test the importance of FGF19 for tumor growth, we developed an anti-FGF19 monoclonal antibody that selectively blocks the interaction of FGF19 with FGFR4. This antibody abolished FGF19-mediated activity in vitro and inhibited growth of colon tumor xenografts in vivo and effectively prevented hepatocellular carcinomas in FGF19 transgenic mice. The efficacy of the antibody in these models was linked to inhibition of FGF19-dependent activation of FGFR4, FRS2, ERK and beta-catenin. These findings suggest that the inactivation of FGF19 could be beneficial for the treatment of colon cancer, liver cancer and other malignancies involving interaction of FGF19 and FGFR4.

  13. A zebrafish xenograft model for studying human cancer stem cells in distant metastasis and therapy response.

    PubMed

    Chen, L; Groenewoud, A; Tulotta, C; Zoni, E; Kruithof-de Julio, M; van der Horst, G; van der Pluijm, G; Ewa Snaar-Jagalska, B

    2017-01-01

    Lethal and incurable bone metastasis is one of the main causes of death in multiple types of cancer. A small subpopulation of cancer stem/progenitor-like cells (CSCs), also known as tumor-initiating cells from heterogenetic cancer is considered to mediate bone metastasis. Although over the past decades numerous studies have been performed in different types of cancer, it is still difficult to track small numbers of CSCs during the onset of metastasis. With use of noninvasive high-resolution imaging, transparent zebrafish embryos can be employed to dynamically visualize cancer progression and reciprocal interaction with stroma in a living organism. Recently we established a zebrafish CSC-xenograft model to visually and functionally analyze the role of CSCs and their interactions with the microenvironment at the onset of metastasis. Given the highly conserved human and zebrafish genome, transplanted human cancer cells are able to respond to zebrafish cytokines, modulate the zebrafish microenvironment, and take advantage of the zebrafish stroma during cancer progression. This chapter delineates the zebrafish CSC-xenograft model as a useful tool for both CSC biological study and anticancer drug screening. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Inhibition of histone deacetylases by trans-cinnamic acid and its antitumor effect against colon cancer xenografts in athymic mice

    PubMed Central

    ZHU, BINGYAN; SHANG, BOYANG; LI, YI; ZHEN, YONGSU

    2016-01-01

    Previous studies have shown that trans-cinnamic acid (tCA) has a broad spectrum of biological activities, and exhibits antioxidant, anti-inflammatory and anticancer properties. In addition, tCA and a variety of its analogs have been detected as gut microbe-derived metabolites exerting various biological effects in the colon. The aim of this study was to assess the antitumor activity of tCA in vitro and in vivo, in particular its therapeutic efficacy against colon cancer xenografts in athymic mice. Furthermore, it aimed to examine the effects of tCA on histone deacetylases (HDACs) and to identify the underlying molecular mechanisms. Using an MTT assay, tCA was observed to inhibit the proliferation of several cancer cell lines, and the half maximal inhibitory concentration (IC50) in HT29 colon carcinoma cells was ~1 mM. Western blot analysis demonstrated that tCA upregulated the expression of acetyl-H3 and acetyl-H4 proteins, which was consistent with the effects of the HDAC inhibitor, trichostatin A (TSA). Furthermore, expression of Bcl-2 (a marker of cell proliferation) was reduced, and apoptosis was induced. Apoptosis was shown by the activation of cleavage of poly ADP ribose polymerase and the increased expression of Bax. Apoptosis was also confirmed using APC Annexin V and SYTOX Green Nucleic Acid Stain. In addition, the tCA-induced inhibition of the expression of HDAC markers and activation of apoptosis in tumor tissues were further confirmed by immunohistochemistry. Intragastric administration of tCA at doses of 1.0 and 1.5 mmol/kg body weight suppressed the growth of HT29 human colon carcinoma xenografts in athymic mice at well-tolerated doses. No toxic changes were found in the heart, lung, liver, kidney, colon or bone marrow following histopathological examination. This study indicated that tCA is effective against colon cancer xenograft in nude mice. The antitumor mechanism of tCA was mediated, at least in part, by inhibition of HDACs in cancer cells. As

  15. Transforming growth factor-β signalling controls human breast cancer metastasis in a zebrafish xenograft model.

    PubMed

    Drabsch, Yvette; He, Shuning; Zhang, Long; Snaar-Jagalska, B Ewa; ten Dijke, Peter

    2013-11-07

    The transforming growth factor beta (TGF-β) signalling pathway is known to control human breast cancer invasion and metastasis. We demonstrate that the zebrafish xenograft assay is a robust and dependable animal model for examining the role of pharmacological modulators and genetic perturbation of TGF-β signalling in human breast tumour cells. We injected cancer cells into the embryonic circulation (duct of cuvier) and examined their invasion and metastasis into the avascular collagenous tail. Various aspects of the TGF-β signalling pathway were blocked by chemical inhibition, small interfering RNA (siRNA), or small hairpin RNA (shRNA). Analysis was conducted using fluorescent microscopy. Breast cancer cells with different levels of malignancy, according to in vitro and in vivo mouse studies, demonstrated invasive and metastatic properties within the embryonic zebrafish model that nicely correlated with their differential tumourigenicity in mouse models. Interestingly, MCF10A M2 and M4 cells invaded into the caudal hematopoietic tissue and were visible as a cluster of cells, whereas MDA MB 231 cells invaded into the tail fin and were visible as individual cells. Pharmacological inhibition with TGF-β receptor kinase inhibitors or tumour specific Smad4 knockdown disturbed invasion and metastasis in the zebrafish xenograft model and closely mimicked the results we obtained with these cells in a mouse metastasis model. Inhibition of matrix metallo proteinases, which are induced by TGF-β in breast cancer cells, blocked invasion and metastasis of breast cancer cells. The zebrafish-embryonic breast cancer xenograft model is applicable for the mechanistic understanding, screening and development of anti-TGF-β drugs for the treatment of metastatic breast cancer in a timely and cost-effective manner.

  16. Lung Cancer Epidemiology in Korea.

    PubMed

    Shin, Aesun; Oh, Chang-Mo; Kim, Byung-Woo; Woo, Hyeongtaek; Won, Young-Joo; Lee, Jin-Soo

    2017-07-01

    The current study was undertaken to examine the trends in the lung cancer incidence, mortality, and survival after a diagnosis in Korea. Lung cancer incidence data according to the histologic type and mortality data were obtained from the Korea Central Cancer Registry and the Statistics Korea, respectively. The age-standardized incidence and mortality rates were calculated, and the Joinpoint model and age-period-cohort analyses were used to describe the trends in the rates. The 5-year relative survival rates of lung cancer were also calculated. Although the number of new lung cancer cases increased between 1999 and 2012, the age-standardized incidence rate decreased by 0.9% per year in men, whereas the incidence in women increased by 1.7% per year over the same time. Until 2010, the most common histologic type in men was squamous cell carcinoma, then adenocarcinoma prevailed thereafter. Since 1999, the most frequent histological type in women was adenocarcinoma. The lung cancer mortality started to decrease in 2002, with a more apparent decline for the younger age groups in both men and women. Overall, the 5-year relative survival rates have improved significantly from 11.2% for men and 14.7% for women among patients diagnosed between 1993 and 1997 to 19.3% for men and 28.2% for women among patients diagnosed between 2008 and 2012, respectively. An improvement in survival rate was observed for all major histology groups. The epidemiology of lung cancer in Korea has changed over a short time span, with decreasing mortality and improving survival rates. Further study is warranted to determine the cause of these changes.

  17. A natural small molecule, catechol, induces c-Myc degradation by directly targeting ERK2 in lung cancer.

    PubMed

    Lim, Do Young; Shin, Seung Ho; Lee, Mee-Hyun; Malakhova, Margarita; Kurinov, Igor; Wu, Qiong; Xu, Jinglong; Jiang, Yanan; Dong, Ziming; Liu, Kangdong; Lee, Kun Yeong; Bae, Ki Beom; Choi, Bu Young; Deng, Yibin; Bode, Ann; Dong, Zigang

    2016-06-07

    Various carcinogens induce EGFR/RAS/MAPK signaling, which is critical in the development of lung cancer. In particular, constitutive activation of extracellular signal-regulated kinase 2 (ERK2) is observed in many lung cancer patients, and therefore developing compounds capable of targeting ERK2 in lung carcinogenesis could be beneficial. We examined the therapeutic effect of catechol in lung cancer treatment. Catechol suppressed anchorage-independent growth of murine KP2 and human H460 lung cancer cell lines in a dose-dependent manner. Catechol inhibited ERK2 kinase activity in vitro, and its direct binding to the ERK2 active site was confirmed by X-ray crystallography. Phosphorylation of c-Myc, a substrate of ERK2, was decreased in catechol-treated lung cancer cells and resulted in reduced protein stability and subsequent down-regulation of total c-Myc. Treatment with catechol induced G1 phase arrest in lung cancer cells and decreased protein expression related to G1-S progression. In addition, we showed that catechol inhibited the growth of both allograft and xenograft lung cancer tumors in vivo. In summary, catechol exerted inhibitory effects on the ERK2/c-Myc signaling axis to reduce lung cancer tumor growth in vitro and in vivo, including a preclinical patient-derived xenograft (PDX) model. These findings suggest that catechol, a natural small molecule, possesses potential as a novel therapeutic agent against lung carcinogenesis in future clinical approaches.

  18. A natural small molecule, catechol, induces c-Myc degradation by directly targeting ERK2 in lung cancer

    PubMed Central

    Lim, Do Young; Shin, Seung Ho; Lee, Mee-Hyun; Malakhova, Margarita; Kurinov, Igor; Wu, Qiong; Xu, Jinglong; Jiang, Yanan; Dong, Ziming; Liu, Kangdong; Lee, Kun Yeong; Bae, Ki Beom; Choi, Bu Young; Deng, Yibin; Bode, Ann; Dong, Zigang

    2016-01-01

    Various carcinogens induce EGFR/RAS/MAPK signaling, which is critical in the development of lung cancer. In particular, constitutive activation of extracellular signal-regulated kinase 2 (ERK2) is observed in many lung cancer patients, and therefore developing compounds capable of targeting ERK2 in lung carcinogenesis could be beneficial. We examined the therapeutic effect of catechol in lung cancer treatment. Catechol suppressed anchorage-independent growth of murine KP2 and human H460 lung cancer cell lines in a dose-dependent manner. Catechol inhibited ERK2 kinase activity in vitro, and its direct binding to the ERK2 active site was confirmed by X-ray crystallography. Phosphorylation of c-Myc, a substrate of ERK2, was decreased in catechol-treated lung cancer cells and resulted in reduced protein stability and subsequent down-regulation of total c-Myc. Treatment with catechol induced G1 phase arrest in lung cancer cells and decreased protein expression related to G1-S progression. In addition, we showed that catechol inhibited the growth of both allograft and xenograft lung cancer tumors in vivo. In summary, catechol exerted inhibitory effects on the ERK2/c-Myc signaling axis to reduce lung cancer tumor growth in vitro and in vivo, including a preclinical patient-derived xenograft (PDX) model. These findings suggest that catechol, a natural small molecule, possesses potential as a novel therapeutic agent against lung carcinogenesis in future clinical approaches. PMID:27167001

  19. Cancer initiating-cells are enriched in the CA9 positive fraction of primary cervix cancer xenografts

    PubMed Central

    Marie-Egyptienne, Delphine Tamara; Chaudary, Naz; Kalliomäki, Tuula; Hedley, David William; Hill, Richard Peter

    2017-01-01

    Numerous studies have suggested that Cancer Initiating Cells (CIC) can be identified/enriched in cell populations obtained from solid tumors based on the expression of cell surface marker proteins. We used early passage primary cervix cancer xenografts to sort cells based on the expression of the intrinsic hypoxia marker Carbonic Anhydrase 9 (CA9) and tested their cancer initiation potential by limiting dilution assay. We demonstrated that CICs are significantly enriched in the CA9+ fraction in 5/6 models studied. Analyses of the expression of the stem cell markers Oct4, Notch1, Sca-1 & Bmi1 showed a trend toward an increase in the CA9+ populations, albeit not significant. We present evidence that enhanced autophagy does not play a role in the enhanced growth of the CA9+ cells. Our study suggests a direct in vivo functional link between hypoxic cells and CICs in primary cervix cancer xenografts. PMID:27901496

  20. Molecular biology of lung cancer.

    PubMed

    Cooper, Wendy A; Lam, David C L; O'Toole, Sandra A; Minna, John D

    2013-10-01

    Lung cancers are characterised by abundant genetic diversity with relatively few recurrent mutations occurring at high frequency. However, the genetic alterations often affect a common group of oncogenic signalling pathways. There have been vast improvements in our understanding of the molecular biology that underpins lung cancer in recent years and this has led to a revolution in the diagnosis and treatment of lung adenocarcinomas (ADC) based on the genotype of an individual's tumour. New technologies are identifying key and potentially targetable genetic aberrations not only in adenocarcinoma but also in squamous cell carcinoma (SCC) of the lung. Lung cancer mutations have been identified in v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), BRAF and the parallel phosphatidylinositol 3-kinase (PI3K) pathway oncogenes and more recently in MEK and HER2 while structural rearrangements in ALK, ROS1 and possibly rearranged during transfection (RET) provide new therapeutic targets. Amplification is another mechanism of activation of oncogenes such as MET in adenocarcinoma, fibroblastgrowth factor receptor 1 (FGFR1) and discoidin domain receptor 2 (DDR2) in SCC. Intriguingly, many of these genetic alternations are associated with smoking status and with particular racial and gender differences, which may provide insight into the mechanisms of carcinogenesis and role of host factors in lung cancer development and progression. The role of tumour suppressor genes is increasingly recognised with aberrations reported in TP53, PTEN, RB1, LKB11 and p16/CDKN2A. Identification of biologically significant genetic alterations in lung cancer that lead to activation of oncogenes and inactivation of tumour suppressor genes has the potential to provide further therapeutic opportunities. It is hoped that these discoveries may make a major contribution to improving outcome for patients with this poor prognosis disease.

  1. Tobacco Smoking and Lung Cancer

    PubMed Central

    Furrukh, Muhammad

    2013-01-01

    Tobacco smoking remains the most established cause of lung carcinogenesis and other disease processes. Over the last 50 years, tobacco refinement and the introduction of filters have brought a change in histology, and now adenocarcinoma has become the most prevalent subtype. Over the last decade, smoking also has emerged as a strong prognostic and predictive patient characteristic along with other variables. This article briefly reviews scientific facts about tobacco, and the process and molecular pathways involved in lung carcinogenesis in smokers and never-smokers. The evidence from randomised trials about tobacco smoking’s impact on lung cancer outcomes is also reviewed. PMID:23984018

  2. Risk Profiling May Improve Lung Cancer Screening

    Cancer.gov

    A new modeling study suggests that individualized, risk-based selection of ever-smokers for lung cancer screening may prevent more lung cancer deaths and improve the effectiveness and efficiency of screening compared with current screening recommendations

  3. Suicide Risk Quadruples After Lung Cancer Diagnosis

    MedlinePlus

    ... news/fullstory_165864.html Suicide Risk Quadruples After Lung Cancer Diagnosis Doctors, loved ones need to be on ... TUESDAY, May 23, 2017 (HealthDay News) -- People with lung cancer have a strikingly higher-than-normal risk of ...

  4. The effects of a picosecond pulsed electric field on angiogenesis in the cervical cancer xenograft models.

    PubMed

    Wu, Limei; Yao, Chenguo; Xiong, Zhengai; Zhang, Ruizhe; Wang, Zhiliang; Wu, Yutong; Qin, Qin; Hua, Yuanyuan

    2016-04-01

    The application of picosecond pulsed electric field (psPEF) is a new biomedical engineering technique used in cancer therapy. However, its effects on cervical cancer angiogenesis are not clear. Therefore, the aim of the present study is to investigate the effects of psPEF on angiogenesis in cervical cancer xenograft models. Xenograft tumors were created by subcutaneously inoculating nude mice (athymic BALB/c nu/nu mice) with HeLa cells, then were placed closely between tweezer-type plate electrodes and subjected to psPEF with a gradually increased electric field intensity (0kV/cm, 50kV/cm, 60kV/cm, 70kV/cm). The direct effect on tumor tissue was observed by hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM). The changes of blood vessels and oxygen saturation (sO2) of tumors were monitored in vivo by photoacoustic tomography (PAT). The microvessel density (MVD), vascular endothelial growth factor (VEGF) and hypoxia-inducible transcription factors (HIF-1α and HIF-2α) were detected by immunohistochemical technique (IHC). Their protein expressions and gene transcription levels were evaluated using western blot (WB) and quantitative reverse transcription and polymerase chain reaction (RT-PCR). PsPEF induced obvious necrosis of cervical cancer tissue; with the increasing of electric field intensity, the MVD, vascular PA signal and sO2 values declined significantly. The protein expression and gene transcription levels of VEGF, HIF1α and HIF2α were significantly decreased at the same time. PsPEF exhibited dramatic anti-tumor and anti-angiogenesis effects in cervical cancer xenograft models by exerting direct effect on cancer cells and vascular endothelial cells and indirect effect on tumor angiogenesis-related factors. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Lung Cancer and Eye Metastases

    PubMed Central

    Lampaki, Sofia; Kioumis, Ioannis; Pitsiou, Georgia; Lazaridis, George; Syrigos, Konstantinos; Trakada, Georgia; Kakolyris, Stylianos; Zarogoulidis, Konstantinos; Mpoukovinas, Ioannis; Rapti, Aggeliki; Zarogoulidis, Paul

    2014-01-01

    It has been observed that lung cancer either non-small cell or small cell is responsible for eye metastases. This form of metastases in several cases was the first manifestation of the disease and further investigation led to the diagnosis of the underlying malignancy. Both types of lung cancer are equally responsible for this demonstration. Furthermore; both chemotherapy and tyrosine kinase inhibitors have shown equal positive results in treating the exophalmos manifestation. Up to date information will be presented in our current work. PMID:25738158

  6. Primary esophageal and gastro-esophageal junction cancer xenograft models: clinicopathological features and engraftment.

    PubMed

    Dodbiba, Lorin; Teichman, Jennifer; Fleet, Andrew; Thai, Henry; Sun, Bin; Panchal, Devang; Patel, Devalben; Tse, Alvina; Chen, Zhuo; Faluyi, Olusola O; Renouf, Daniel J; Girgis, Hala; Bandarchi, Bizhan; Schwock, Joerg; Xu, Wei; Bristow, Robert G; Tsao, Ming-Sound; Darling, Gail E; Ailles, Laurie E; El-Zimaity, Hala; Liu, Geoffrey

    2013-04-01

    There are very few xenograft models available for the study of esophageal (E) and gastro-esophageal junction (GEJ) cancer. Using a NOD/SCID model, we implanted 90 primary E and GEJ tumors resected from patients and six endoscopic biopsy specimens. Of 69 resected tumors with histologically confirmed viable adenocarcinoma or squamous cell carcinoma, 22 (32%) was engrafted. One of 11 tumors, considered to have had a complete pathological response to neo-adjuvant chemo-radiation, also engrafted. Of the 23 patients whose tumors were engrafted, 65% were male; 30% were early stage while 70% were late stage; 22% received neo-adjuvant chemo-radiation; 61% were GEJ cancers. Engraftment occurred in 18/54 (33%) adenocarcinomas and 5/16 (31%) squamous cell carcinomas. Small endoscopic biopsy tissue had a 50% (3/6) engraftment rate. Of the factors analyzed, pretreatment with chemo-radiation and well/moderate differentiation showed significantly lower correlation with engraftment (P<0.05). In the subset of patients who did not receive neo-adjuvant chemo-radiation, 18/41 (44%) engrafted compared with those with pretreatment where 5/29 (17%, P=0.02) engrafted. Primary xenograft lines may be continued through 4-12 passages. Xenografts maintained similar histology and morphological characteristics with only minor variations even after multiple passaging in most instances.

  7. Science, medicine, and the future. Lung cancer.

    PubMed Central

    Sethi, T.

    1997-01-01

    Lung cancer, the most prevalent cancer in the Western world, is mainly caused by smoking. Nevertheless, only 20% of smokers develop lung cancer and while prevention is important, environmental factors are expected to contribute to the predicted rise in the incidence of lung cancer in the next 25 years. Survival of lung cancer is still poor, and new treatments are urgently needed. This review examines potential new therapeutic developments which have arisen from a greater understanding of the molecular and cellular biology of lung cancers. PMID:9066480

  8. Human Adipose Tissue-Derived Stromal/Stem Cells Promote Migration and Early Metastasis of Triple Negative Breast Cancer Xenografts

    PubMed Central

    Rowan, Brian G.; Gimble, Jeffrey M.; Sheng, Mei; Anbalagan, Muralidharan; Jones, Ryan K.; Frazier, Trivia P.; Asher, Majdouline; Lacayo, Eduardo A.; Friedlander, Paul L.; Kutner, Robert; Chiu, Ernest S.

    2014-01-01

    Background Fat grafting is used to restore breast defects after surgical resection of breast tumors. Supplementing fat grafts with adipose tissue-derived stromal/stem cells (ASCs) is proposed to improve the regenerative/restorative ability of the graft and retention. However, long term safety for ASC grafting in proximity of residual breast cancer cells is unknown. The objective of this study was to determine the impact of human ASCs derived from abdominal lipoaspirates of three donors, on a human breast cancer model that exhibits early metastasis. Methodology/Principal Findings Human MDA-MB-231 breast cancer cells represents “triple negative” breast cancer that exhibits early micrometastasis to multiple mouse organs [1]. Human ASCs were derived from abdominal adipose tissue from three healthy female donors. Indirect co-culture of MDA-MB-231 cells with ASCs, as well as direct co-culture demonstrated that ASCs had no effect on MDA-MB-231 growth. Indirect co-culture, and ASC conditioned medium (CM) stimulated migration of MDA-MB-231 cells. ASC/RFP cells from two donors co-injected with MDA-MB-231/GFP cells exhibited a donor effect for stimulation of primary tumor xenografts. Both ASC donors stimulated metastasis. ASC/RFP cells were viable, and integrated with MDA-MB-231/GFP cells in the tumor. Tumors from the co-injection group of one ASC donor exhibited elevated vimentin, matrix metalloproteinase-9 (MMP-9), IL-8, VEGF and microvessel density. The co-injection group exhibited visible metastases to the lung/liver and enlarged spleen not evident in mice injected with MDA-MB-231/GFP alone. Quantitation of the total area of GFP fluorescence and human chromosome 17 DNA in mouse organs, H&E stained paraffin sections and fluorescent microscopy confirmed multi-focal metastases to lung/liver/spleen in the co-injection group without evidence of ASC/RFP cells. Conclusions Human ASCs derived from abdominal lipoaspirates of two donors stimulated metastasis of MDA-MB-231

  9. Electrochemical treatment of lung cancer

    SciTech Connect

    Xin, Y.L.; Xue, F.Z.; Ge, B.S.; Zhao, F.R.; Shi, B.; Zhang, W.

    1997-03-01

    A pilot study of electrochemical treatment (ECT) as a therapy for 386 patients with nonsmall cell lung cancer was undertaken. There were 103 stage 2 cases, 89 stage 3a cases, 122 stage 3b cases, and 72 stage 4 cases. Two ECT methods were used. For peripherally located lung cancer, platinum electrodes were inserted transcutaneously into the tumor under x-ray or CT guidance. For central type lung cancer or for those inoperable during thoracotomy, electrodes were inserted intraoperatively directly into the cancer. Voltage was 6--8 V, current was 40--100 mA, and electric charge was 100 coulombs per cm of tumor diameter. The number of electrodes was determined from the size of cancer mass, because the diameter of effective area around each electrode is approximately 3 cm. The short-term (6 months after ECT) results of the 386 lung cancer cases were: complete response (CR), 25.6% (99/386); partial response (PR), 46.4% (179/386); no change (NC), 15.3% (59/386); and progressive disease (PD), 12.7% (49/386). The total effective rate (CR + PR) was 72% (278/386). The 1, 3, and 5 year overall survival rates were 86.3% (333/386), 58.8% (227/386), and 29.5% (114/386), respectively. The main complication was traumatic pneumothorax, with an incidence rate of 14.8% (57/386). These clinical results show that ECT is simple, safe, effective, and minimally traumatic. ECT provides an alternative method for treating lung cancers that are conventionally inoperable, that are not responsive to chemotherapy or radiotherapy, or that cannot be resected after thoracotomy. Long-term survival rates suggest that ECT warrants further investigation.

  10. DNA Topoisomerase I-Targeted Chemotherapy of Human Colon Cancer in Xenografts

    NASA Astrophysics Data System (ADS)

    Giovanella, Beppino C.; Stehlin, John S.; Wall, Monroe E.; Wani, Mansukh C.; Nicholas, Allan W.; Liu, Leroy F.; Silber, Robert; Potmesil, Milan

    1989-11-01

    Drug development is needed to improve chemotherapy of patients with locally advanced or metastatic colon carcinoma, who otherwise have an unfavorable prognosis. DNA topoisomerase I, a nuclear enzyme important for solving topological problems arising during DNA replication and for other cellular functions, has been identified as a principal target of a plant alkaloid 20 (S)-camptothecin. Significantly increased concentrations of this enzyme, compared to that in normal colonic mucosa, were found in advanced stages of human colon adenocarcinoma and in xenografts of colon cancer carried by immunodeficient mice. Several synthetic analogs of camptothecin, selected by tests with the purified enzyme and tissue-culture screens, were evaluated in the xenograft model. Unlike other anticancer drugs tested, 20(RS)-9-amino-camptothecin (9-AC) induced disease-free remissions. The overall drug toxicity was low and allowed for repeated courses of treatment.

  11. Cetuximab Inhibits T790M-Mediated Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in a Lung Adenocarcinoma Patient-Derived Xenograft Mouse Model.

    PubMed

    Martin, Petra; Stewart, Erin; Pham, Nhu-An; Mascaux, Celine; Panchal, Devang; Li, Ming; Kim, Lucia; Sakashita, Shingo; Wang, Dennis; Sykes, Jenna; Friess, Thomas; Shepherd, Frances A; Liu, Geoffrey; Tsao, Ming-Sound

    2016-09-01

    The epidermal growth factor receptor (EGFR) kinase domain T790M (amino acid substitution at position 790 in EGFR from threonine [T] to methionine [M]) mutation in non-small-cell lung cancer (NSCLC) results in resistance to EGFR tyrosine kinase inhibitors (TKIs). We used a patient-derived tumor xenograft (PDX) model containing an EGFR exon 19 deletion/T790M mutation to assess response to the EGFR-directed antibody cetuximab. Changes in the EGFR signaling pathway and ligand expression after treatment were investigated. PDX were randomized into control and treatment arms. Pharmacodynamic studies were performed at 2 and 24 hours and at 4 days after a single administration of cetuximab, erlotinib, or dacomitinib. Changes in the EGFR signaling pathway were assessed using Western blot analysis, and baseline mRNA expression of EGFR ligands using microarray analysis. Relative changes after treatment were assessed using quantitative polymerase chain reaction. The xenograft showed a dramatic response to cetuximab. A complete reduction of total EGFR and phosphorylated EGFR occurred after cetuximab treatment. The PDX had increased baseline levels of heparin-binding epidermal growth factor-like growth factor (HB-EGF) compared with other PDX models with or without EGFR mutations. Amphiregulin was significantly reduced 2 hours after treatment with cetuximab. Compared with control mice, cetuximab- and EGFR-TKI-treated mice had significantly reduced HB-EGF gene expression at 2 hours, however, by day 4 the level of HB-EGF expression was higher. The effect of cetuximab compared with EGFR TKI on HB-EGF gene expression levels differed significantly at 2 and 24 hours but not at 4 days. We showed a dramatic tumor response with cetuximab in an exon 19 deletion/T790M EGFR mutant lung adenocarcinoma PDX model, which suggests a role for the autocrine feedback loop in the mutant EGFR signaling pathway. Further investigation using cetuximab in NSCLC with T790M mutation is warranted. Copyright

  12. GPR171 expression enhances proliferation and metastasis of lung cancer cells.

    PubMed

    Dho, So Hee; Lee, Kwang-Pyo; Jeong, Dongjun; Kim, Chang-Jin; Chung, Kyung-Sook; Kim, Ji Young; Park, Bum-Chan; Park, Sung Sup; Kim, Seon-Young; Kwon, Ki-Sun

    2016-02-16

    G protein-coupled receptors (GPCRs) are among the most significant therapeutic targets and some of them promote the growth and metastasis of cancer. Here, we show that an increase in the levels of GPR171 is crucial for lung cancer tumor progression in vitro and in vivo. Immunostaining of clinical samples indicated that GPR171 was overexpressed in 46.8% of lung carcinoma tissues. Depletion of GPR171 with an anti-GPR171 antibody decreased proliferation of lung carcinoma cells and attenuated tumor progression in a mouse xenograft model. Knockdown of GPR171 also inhibited migration and invasion of the lung cancer cell lines. Notably, inhibition of GPR171 synergistically enhanced the tumoricidal activity of an epidermal growth factor receptor (EGFR) inhibitor in lung cancer cells. These results indicate that GPR171 blockade is a promising antineoplastic strategy and provide a preclinical rationale for combined inhibition of GPR171 and EGFR.

  13. Immunomodulatory action of the DNA methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts.

    PubMed

    Srivastava, Pragya; Paluch, Benjamin E; Matsuzaki, Junko; James, Smitha R; Collamat-Lai, Golda; Taverna, Pietro; Karpf, Adam R; Griffiths, Elizabeth A

    2015-01-01

    We aimed to determine the effect of SGI-110 on methylation and expression of the cancer testis antigens (CTAs) NY-ESO-1 and MAGE-A in epithelial ovarian cancer (EOC) cells in vitro and in vivo and to establish the impact of SGI-110 on expression of major histocompatibility (MHC) class I and Intracellular Adhesion Molecule 1 (ICAM-1) on EOC cells, and on recognition of EOC cells by NY-ESO-1-specific CD8+ T-cells. We also tested the impact of combined SGI-110 and NY-ESO-1-specific CD8+ T-cells on tumor growth and/or murine survival in a xenograft setting. EOC cells were treated with SGI-110 in vitro at various concentrations and as tumor xenografts with 3 distinct dose schedules. Effects on global methylation (using LINE-1), NY-ESO-1 and MAGE-A methylation, mRNA, and protein expression were determined and compared to controls. SGI-110 treated EOC cells were evaluated for expression of immune-modulatory genes using flow cytometry, and were co-cultured with NY-ESO-1 specific T-cell clones to determine immune recognition. In vivo administration of SGI-110 and CD8+ T-cells was performed to determine anti-tumor effects on EOC xenografts. SGI-110 treatment induced hypomethylation and CTA gene expression in a dose dependent manner both in vitro and in vivo, at levels generally superior to azacitidine or decitabine. SGI-110 enhanced the expression of MHC I and ICAM-1, and enhanced recognition of EOC cells by NY-ESO-1-specific CD8+ T-cells. Sequential SGI-110 and antigen-specific CD8+ cell treatment restricted EOC tumor growth and enhanced survival in a xenograft setting. SGI-110 is an effective hypomethylating agent and immune modulator and, thus, an attractive candidate for combination with CTA-directed vaccines in EOC.

  14. Immunomodulatory action of the DNA methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts

    PubMed Central

    Srivastava, Pragya; Paluch, Benjamin E; Matsuzaki, Junko; James, Smitha R; Collamat-Lai, Golda; Taverna, Pietro; Karpf, Adam R; Griffiths, Elizabeth A

    2015-01-01

    We aimed to determine the effect of SGI-110 on methylation and expression of the cancer testis antigens (CTAs) NY-ESO-1 and MAGE-A in epithelial ovarian cancer (EOC) cells in vitro and in vivo and to establish the impact of SGI-110 on expression of major histocompatibility (MHC) class I and Intracellular Adhesion Molecule 1 (ICAM-1) on EOC cells, and on recognition of EOC cells by NY-ESO-1-specific CD8+ T-cells. We also tested the impact of combined SGI-110 and NY-ESO-1-specific CD8+ T-cells on tumor growth and/or murine survival in a xenograft setting. EOC cells were treated with SGI-110 in vitro at various concentrations and as tumor xenografts with 3 distinct dose schedules. Effects on global methylation (using LINE-1), NY-ESO-1 and MAGE-A methylation, mRNA, and protein expression were determined and compared to controls. SGI-110 treated EOC cells were evaluated for expression of immune-modulatory genes using flow cytometry, and were co-cultured with NY-ESO-1 specific T-cell clones to determine immune recognition. In vivo administration of SGI-110 and CD8+ T-cells was performed to determine anti-tumor effects on EOC xenografts. SGI-110 treatment induced hypomethylation and CTA gene expression in a dose dependent manner both in vitro and in vivo, at levels generally superior to azacitidine or decitabine. SGI-110 enhanced the expression of MHC I and ICAM-1, and enhanced recognition of EOC cells by NY-ESO-1-specific CD8+ T-cells. Sequential SGI-110 and antigen-specific CD8+ cell treatment restricted EOC tumor growth and enhanced survival in a xenograft setting. SGI-110 is an effective hypomethylating agent and immune modulator and, thus, an attractive candidate for combination with CTA-directed vaccines in EOC. PMID:25793777

  15. Cytogenetic and molecular aspects of lung cancer.

    PubMed

    Panani, Anna D; Roussos, Charis

    2006-07-28

    Lung cancer is one of the most common cancers worldwide and its pathogenesis is closely associated with tobacco smoking. Continuous exposure of smoking carcinogens results in the accumulation of several alterations of tumorigenesis related genes leading to neoplastic bronchial lesions. Lung cancer is divided in two main histological groups, non-small cell lung carcinomas (NSCLCs) and small cell lung carcinomas (SCLCs). It seems that lung tumorigenesis is a multistep process in which a number of genetic events including alterations of oncogenes and tumor suppressor genes have been occurred. Cytogenetic abnormalities in lung cancer are very complex. However, a number of recurrent cytogenetic abnormalities have been identified. Many of these changes are common in both major histological groups of lung cancer while certain chromosomal abnormalities have been correlated with the stage or the grade of the tumors. In addition, several molecular alterations have been constantly found. Some of them are common in different histological subtypes of lung cancer and they appear to play an important role in the pathogenesis of lung cancer. A good understanding of the underlying genetic changes of lung tumorigenesis will provide new perspectives for early diagnosis and screening of high-risk individuals. In addition, a number of genetical prognostic factors have been identified as possibly helpful parameters in the evaluation of lung cancer patients. Further research is required in order to systematically investigate genetical alterations in lung cancer contributing to improvement of lung cancer classification and staging and to development of new molecular targeted therapies.

  16. Effects of Cancer-Associated EPHA3 Mutations on Lung Cancer

    PubMed Central

    2012-01-01

    Background Cancer genome sequencing efforts recently identified EPHA3, which encodes the EPHA3 receptor tyrosine kinase, as one of the most frequently mutated genes in lung cancer. Although receptor tyrosine kinase mutations often drive oncogenic conversion and tumorigenesis, the oncogenic potential of the EPHA3 mutations in lung cancer remains unknown. Methods We used immunoprecipitation, western blotting, and kinase assays to determine the activity and signaling of mutant EPHA3 receptors. A mutation-associated gene signature was generated from one large dataset, mapped to another training dataset with survival information, and tested in a third independent dataset. EPHA3 expression levels were determined by quantitative reverse transcription-polymerase chain reaction in paired normal-tumor clinical specimens and by immunohistochemistry in human lung cancer tissue microarrays. We assessed tumor growth in vivo using A549 and H1299 human lung carcinoma cell xenografts in mice (n = 7–8 mice per group). Tumor cell proliferation was measured by bromodeoxyuridine incorporation and apoptosis by multiple assays. All P values are from two-sided tests. Results At least two cancer-associated EPHA3 somatic mutations functioned as dominant inhibitors of the normal (wild type) EPHA3 protein. An EPHA3 mutation–associated gene signature that was associated with poor patient survival was identified. Moreover, EPHA3 gene copy numbers and/or expression levels were decreased in tumors from large cohorts of patients with lung cancer (eg, the gene was deleted in 157 of 371 [42%] primary lung adenocarcinomas). Reexpression of wild-type EPHA3 in human lung cancer lines increased apoptosis by suppression of AKT activation in vitro and inhibited the growth of tumor xenografts (eg, for H1299 cells, mean tumor volume with wild-type EPHA3 = 437.4mm3 vs control = 774.7mm3, P < .001). Tumor-suppressive effects of wild-type EPHA3 could be overridden in trans by dominant negative EPHA3

  17. Lung cancer in elderly patients

    PubMed Central

    Diso, Daniele; Onorati, Ilaria; Anile, Marco; Mantovani, Sara; Rendina, Erino A.

    2016-01-01

    There is a worldwide-accepted evidence of a population shift toward older ages. This shift favors an increased risk of developing lung cancer that is primarily a disease of older populations. Decision making is extremely difficult in elderly patients, since this group is under-represented in clinical trials with only 25% of them historically opening to patients older than 65 years. For all these reasons, a “customized” preoperative assessment to identify physiological or pathological frailty should be encouraged since standard tools may be less reliable. The work already done to improve patient selection for lung surgery in the elderly population clearly shows that surgical resection seems the treatment of choice for early stage lung cancer. Further studies are required to improve outcome by reducing postoperative morbidity and mortality. PMID:27942414

  18. Molecular Epidemiology of Female Lung Cancer

    PubMed Central

    Yim, Seon-Hee; Chung, Yeun-Jun

    2011-01-01

    Lung cancer is still a leading cause of cancer mortality in the world. The incidence of lung cancer in developed countries started to decrease mainly due to global anti-smoking campaigns. However, the incidence of lung cancer in women has been increasing in recent decades for various reasons. Furthermore, since the screening of lung cancer is not as yet very effective, clinically applicable molecular markers for early diagnosis are much required. Lung cancer in women appears to have differences compared with that in men, in terms of histologic types and susceptibility to environmental risk factors. This suggests that female lung cancer can be derived by carcinogenic mechanisms different from those involved in male lung cancer. Among female lung cancer patients, many are non-smokers, which could be studied to identify alternative carcinogenic mechanisms independent from smoking-related ones. In this paper, we reviewed molecular susceptibility markers and genetic changes in lung cancer tissues observed in female lung cancer patients, which have been validated by various studies and will be helpful to understand the tumorigenesis of lung cancer. PMID:24212786

  19. Lung Cancer Staging and Prognosis.

    PubMed

    Woodard, Gavitt A; Jones, Kirk D; Jablons, David M

    The seventh edition of the non-small cell lung cancer (NSCLC) TNM staging system was developed by the International Association for the Staging of Lung Cancer (IASLC) Lung Cancer Staging Project by a coordinated international effort to develop data-derived TNM classifications with significant survival differences. Based on these TNM groupings, current 5-year survival estimates in NSLCC range from 73 % in stage IA disease to 13 % in stage IV disease. TNM stage remains the most important prognostic factor in predicting recurrence rates and survival times, followed by tumor histologic grade, and patient sex, age, and performance status. Molecular prognostication in lung cancer is an exploding area of research where interest has moved beyond TNM stage and into individualized genetic tumor analysis with immunohistochemistry, microarray, and mutation profiles. However, despite intense research efforts and countless publications, no molecular prognostic marker has been adopted into clinical use since most fail in subsequent cross-validation with few exceptions. The recent interest in immunotherapy for NSCLC has identified new biomarkers with early evidence that suggests that PD-L1 is a predictive marker of a good response to new immunotherapy drugs but a poor prognostic indicator of overall survival. Future prognostication of outcomes in NSCLC will likely be based on a combination of TNM stage and molecular tumor profiling and yield more precise, individualized survival estimates and treatment algorithms.

  20. Inhibition of human breast cancer xenograft growth by cruciferous vegetable constituent benzyl isothiocyanate.

    PubMed

    Warin, Renaud; Xiao, Dong; Arlotti, Julie A; Bommareddy, Ajay; Singh, Shivendra V

    2010-05-01

    Benzyl isothiocyanate (BITC), a constituent of cruciferous vegetables such as garden cress, inhibits growth of human breast cancer cell lines in culture. The present study was undertaken to determine in vivo efficacy of BITC against MDA-MB-231 human breast cancer xenografts. The BITC administration retarded growth of MDA-MB-231 cells subcutaneously implanted in female nude mice without causing weight loss or any other side effects. The BITC-mediated suppression of MDA-MB-231 xenograft growth correlated with reduced cell proliferation as revealed by immunohistochemical analysis for Ki-67 expression. Analysis of the vasculature in the tumors from BITC-treated mice indicated smaller vessel area compared with control tumors based on immunohistochemistry for angiogenesis marker CD31. The BITC-mediated inhibition of angiogenesis in vivo correlated with downregulation of vascular endothelial growth factor (VEGF) receptor 2 protein levels in the tumor. Consistent with these results, BITC treatment suppressed VEGF secretion and VEGF receptor 2 protein levels in cultured MDA-MB-231 cells. Moreover, the BITC-treated MDA-MB-231 cells exhibited reduced capacity for migration compared with vehicle-treated control cells. In contrast to cellular data, BITC administration failed to elicit apoptotic response as judged by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. In conclusion, the present study demonstrates in vivo anti-cancer efficacy of BITC against MDA-MB-231 xenografts in association with reduced cell proliferation and suppression of neovascularization. These preclinical observations merit clinical investigation to determine efficacy of BITC against human breast cancers. (c) 2010 Wiley-Liss, Inc.

  1. Synergistic antitumor efficiency of docetaxel and curcumin against lung cancer.

    PubMed

    Yin, Haitao; Guo, Rui; Xu, Yong; Zheng, Yulong; Hou, Zhibo; Dai, Xinzheng; Zhang, Zhengdong; Zheng, Donghui; Xu, Hua'e

    2012-02-01

    Curcumin (Cum), the principal polyphenolic curcuminoid, obtained from the turmeric rhizome Curcuma longa, is recently reported to have potential antitumor effects in vitro and in vivo. Docetaxel (Doc) is considered as first-line chemotherapy for the treatment of non-small cell lung cancer. Here we report for the first time that Cum could synergistically enhance the in vitro and in vivo antitumor efficacy of Doc against lung cancer. In the current study, combination index (CI) is calculated in both in vitro and in vivo studies to determine the interaction between Cum and Doc. In the in vitro cytotoxicity test, media-effect analysis clearly indicated a synergistic interaction between Cum and Doc in certain concentrations. Moreover, in vivo evaluation further demonstrated the superior anticancer efficacy of Cum + Doc compared with Doc alone by intravenous delivery in an established A549 transplanted xenograft model. Results showed that Cum synergistically increased the efficacy of Doc immediately after 4 days of the initial treatment. Additionally, simultaneous administration of Cum and Doc showed little toxicity to normal tissues including bone marrow and liver at the therapeutic doses. Therefore, in vitro and in vivo evaluations demonstrated the satisfying synergistic antitumor efficacy of Cum and Doc against lung cancer and the introduction of Cum in traditional chemotherapy is a most promising way to counter the spread of non-small cell lung cancer.

  2. Establishment of patient-derived cancer xenografts in immunodeficient NOG mice.

    PubMed

    Chijiwa, Tsuyoshi; Kawai, Kenji; Noguchi, Akira; Sato, Hidemitsu; Hayashi, Akimune; Cho, Haruhiko; Shiozawa, Manabu; Kishida, Takeshi; Morinaga, Soichiro; Yokose, Tomoyuki; Katayama, Makoto; Takenaka, Nobuo; Suemizu, Hiroshi; Yamada, Roppei; Nakamura, Yoshiyasu; Ohtsu, Takashi; Takano, Yasuo; Imai, Kohzoh; Miyagi, Yohei; Nakamura, Masato

    2015-07-01

    Viable and stable human cancer cell lines and animal models combined with adequate clinical information are essential for future advances in cancer research and patient care. Conventional in vitro cancer cell lines are commonly available; however, they lack detailed information on the patient from which they originate, including disease phenotype and drug sensitivity. Patient-derived xenografts (PDX) with clinical information (so-called 'cancer xenopatients') are a promising advance that may accelerate the development of anticancer therapies. We established 61 PDX lines from 116 surgically removed tumor tissues inoculated subcutaneously into NOG mice (53% success rate). PDX lines were established from various types of epithelial tumors and also from sarcomas, including gastrointestinal stromal tumors and Ewing/PNET sarcomas. The metastatic tumors yielded PDX lines more effectively (65%) than the primary tumors (27%, P<0.001). In our PDX models, morphological characteristics, gene expression profiles, and genetic alteration patterns were all well preserved. In eight cases (7%), the transplantable xenografts for several generations were composed of large monotonous nonepithelial cells of human origin, revealed to be Epstein-Barr virus infection-associated lympho-proliferative lesions. Despite this, PDX linked with clinical information offer many advantages for preclinical studies investigating new anticancer drugs. The fast and efficient establishment of individual PDX may also contribute to future personalized anticancer therapies.

  3. Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer

    DOE PAGES

    Staquicini, Fernanda I.; Qian, Ming D.; Salameh, Ahmad; ...

    2015-03-20

    Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G1/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. In conclusion, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lungmore » cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications.« less

  4. Knockdown of cullin 4A inhibits growth and increases chemosensitivity in lung cancer cells.

    PubMed

    Hung, Ming-Szu; Chen, I-Chuan; You, Liang; Jablons, David M; Li, Ya-Chin; Mao, Jian-Hua; Xu, Zhidong; Lung, Jr-Hau; Yang, Cheng-Ta; Liu, Shih-Tung

    2016-07-01

    Cullin 4A (Cul4A) has been observed to be overexpressed in various cancers. In this study, the role of Cul4A in the growth and chemosensitivity in lung cancer cells were studied. We showed that Cul4A is overexpressed in lung cancer cells and tissues. Knockdown of the Cul4A expression by shRNA in lung cancer cells resulted in decreased cellular proliferation and growth in lung cancer cells. Increased sensitivity to gemcitabine, a chemotherapy drug, was also noted in those Cul4A knockdown lung cancer cells. Moreover, increased expression of p21, transforming growth factor (TGF)-β inducible early gene-1 (TIEG1) and TGF beta-induced (TGFBI) was observed in lung cancer cells after Cul4A knockdown, which may be partially related to increased chemosensitivity to gemcitabine. G0/G1 cell cycle arrest was also noted after Cul4A knockdown. Notably, decreased tumour growth and increased chemosensitivity to gemcitabine were also noted after Cul4A knockdown in lung cancer xenograft nude mice models. In summary, our study showed that targeting Cul4A with RNAi or other techniques may provide a possible insight to the development of lung cancer therapy in the future.

  5. Curcumin-ER Prolonged Subcutaneous Delivery for the Treatment of Non-Small Cell Lung Cancer.

    PubMed

    Ranjan, Amalendu P; Mukerjee, Anindita; Gdowski, Andrew; Helson, Lawrence; Bouchard, Annie; Majeed, Muhammed; Vishwanatha, Jamboor K

    2016-04-01

    Non-small-cell lung cancer therapy is a challenge due to poor prognosis and low survival rate. There is an acute need for advanced therapies having higher drug efficacy, low immunogenicity and fewer side effects which will markedly improve patient compliance and quality of life of cancer patients. The purpose of this study was to develop a novel hybrid curcumin nanoformulation (Curcumin-ER) and evaluate the therapeutic efficacy of this formulation on a non-small cell lung cancer xenograft model. Use of curcumin, a natural anticancer agent, is majorly limited due to its poor aqueous solubility and hence it's low systemic bioavailability. In this paper, we carried out the nanoformulation of Curcumin-ER, optimized the formulation process and determined the anticancer effects of Curcumin-ER against human A549 non-small cell lung cancer using in vitro and in vivo studies. Xenograft tumors in nude mice were treated with 20 mg/kg subcutaneous injection of Curcumin-ER and liposomal curcumin (Lipocurc) twice a week for seven weeks. Results showed that tumor growth was suppressed by 52.1% by Curcumin-ER treatment and only 32.2% by Lipocurc compared to controls. Tumor sections were isolated from murine xenografts and histology and immunohistochemistry was performed. A decrease in expression of NFκB-p65 subunit and proliferation marker, Ki-67 was observed in treated tumors. In addition, a potent anti-angiogenic effect, characterized by reduced expression of annexin A2 protein, was observed in treated tumors. These results establish the effectiveness of Curcumin-ER in regressing human non-small cell lung cancer growth in the xenograft model using subcutaneous route of administration. The therapeutic efficacy of Curcumin-ER highlights the potential of this hybrid nanoformulation in treating patients with non-small cell lung cancer.

  6. Curcumin enhances the lung cancer chemopreventive efficacy of phospho-sulindac by improving its pharmacokinetics

    PubMed Central

    CHENG, KA-WING; WONG, CHI C.; MATTHEOLABAKIS, GEORGE; XIE, GANG; HUANG, LIQUN; RIGAS, BASIL

    2013-01-01

    Phospho-sulindac (PS) is a safe sulindac derivative with promising anticancer efficacy in colon cancer. We evaluated whether its combination with curcumin could enhance the efficacy in the treatment of lung cancer. Curcumin, the principal bioactive component in turmeric, has demonstrated versatile capabilities to modify the therapeutic efficacy of a wide range of anticancer agents. Here, we evaluated the effect of co-administration of curcumin on the anticancer activity of PS in a mouse xenograft model of human lung cancer. Curcumin enhanced the cellular uptake of PS in human lung and colon cancer cell lines. To assess the potential synergism between curcumin and PS in vivo, curcumin was suspended in 10% Tween-80 or formulated in micellar nanoparticles and given to mice by oral gavage prior to the administration of PS. Both formulations of curcumin significantly improved the pharmacokinetic profiles of PS, with the 10% Tween-80 suspension being much more effective than the nanoparticle formation. However, curcumin did not exhibit any significant modification of the metabolite profile of PS. Furthermore, in a mouse subcutaneous xenograft model of human lung cancer, PS (200 mg/kg) in combination with curcumin (500 mg/kg) suspended in 10% Tween-80 (51% inhibition, p<0.05) was significantly more efficacious than PS plus micelle curcumin (30%) or PS (25%) or curcumin alone (no effect). Consistent with the improved pharmacokinetics, the combination treatment group had higher levels of PS and its metabolites in the xenografts compared to PS alone. Our results show that curcumin substantially improves the pharmacokinetics of PS leading to synergistic inhibition of the growth of human lung cancer xenografts, representing a promising drug combination. PMID:23807084

  7. Curcumin enhances the lung cancer chemopreventive efficacy of phospho-sulindac by improving its pharmacokinetics.

    PubMed

    Cheng, Ka-Wing; Wong, Chi C; Mattheolabakis, George; Xie, Gang; Huang, Liqun; Rigas, Basil

    2013-09-01

    Phospho-sulindac (PS) is a safe sulindac derivative with promising anticancer efficacy in colon cancer. We evaluated whether its combination with curcumin could enhance the efficacy in the treatment of lung cancer. Curcumin, the principal bioactive component in turmeric, has demonstrated versatile capabilities to modify the therapeutic efficacy of a wide range of anticancer agents. Here, we evaluated the effect of co-administration of curcumin on the anticancer activity of PS in a mouse xenograft model of human lung cancer. Curcumin enhanced the cellular uptake of PS in human lung and colon cancer cell lines. To assess the potential synergism between curcumin and PS in vivo, curcumin was suspended in 10% Tween-80 or formulated in micellar nanoparticles and given to mice by oral gavage prior to the administration of PS. Both formulations of curcumin significantly improved the pharmacokinetic profiles of PS, with the 10% Tween-80 suspension being much more effective than the nanoparticle formation. However, curcumin did not exhibit any significant modification of the metabolite profile of PS. Furthermore, in a mouse subcutaneous xenograft model of human lung cancer, PS (200 mg/kg) in combination with curcumin (500 mg/kg) suspended in 10% Tween-80 (51% inhibition, p<0.05) was significantly more efficacious than PS plus micelle curcumin (30%) or PS (25%) or curcumin alone (no effect). Consistent with the improved pharmacokinetics, the combination treatment group had higher levels of PS and its metabolites in the xenografts compared to PS alone. Our results show that curcumin substantially improves the pharmacokinetics of PS leading to synergistic inhibition of the growth of human lung cancer xenografts, representing a promising drug combination.

  8. Metabolic response to everolimus in patient-derived triple negative breast cancer xenografts.

    PubMed

    Euceda, Leslie R; Hill, Deborah K; Stokke, Endre; Hatem, Rana; Botty, Rania El; Bièche, Ivan; Marangoni, Elisabetta; Bathen, Tone F; Moestue, Siver A

    2017-03-14

    Patients with triple negative breast cancer (TNBC) are unresponsive to endocrine and anti-HER2 pharmacotherapy, limiting their therapeutic options to chemotherapy. TNBC is frequently associated with abnormalities in the PI3K/AKT/mTOR signaling pathway; drugs targeting this pathway are currently being evaluated in these patients. However, response is variable, partly due to heterogeneity within TNBC, conferring a need to identify biomarkers predicting response and resistance to targeted therapy. In this study, we used a metabolomics approach to assess response to the mTOR inhibitor everolimus in a panel of TNBC patient-derived xenografts (PDX) (n=103 animals). Tumor metabolic profiles were acquired using high-resolution magic angle spinning magnetic resonance spectroscopy. Partial least squares-discriminant analysis on relative metabolite concentrations discriminated treated xenografts from untreated controls with an accuracy of 67% (p=0.003). Multilevel linear mixed-effects models (LMM) indicated reduced glycolytic lactate production and glutaminolysis after treatment, consistent with PI3K/AKT/mTOR pathway inhibition. Although inherent metabolic heterogeneity between different PDX models seemed to hinder prediction of treatment response, the metabolic effects following treatment were more pronounced in responding xenografts compared to non-responders. Additionally, the metabolic information predicted p53 mutation status, which may provide complimentary insight into the interplay between PI3K signaling and other drivers of disease progression.

  9. Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR

    PubMed Central

    Schayowitz, A; Sabnis, G; Goloubeva, O; Njar, V C O; Brodie, A M H

    2010-01-01

    Background: To determine the mechanisms associated with loss of androgen dependency and disease progression in prostate cancer (PCa), we investigated the relationship between the androgen receptor (AR) and mTOR pathways and the impact of inhibiting both pathways in androgen-dependent and castration-resistant PCa models. Experimental design: Androgen-dependent (LNCaP) and castration-resistant PCa (HP-LNCaP) cells were grown as tumours in SCID mice. Once tumours reached 500 mm3, animals were grouped and injected subcutaneous with vehicle, our novel anti-androgen/androgen synthesis inhibitor, VN/124-1, bicalutamide, and everolimus. Tumour volumes were measured biweekly. The PSA and protein analyses were performed after completion of the treatment. Results: The addition of everolimus to bicalutamide treatment of resistant tumours significantly reduced tumour growth rates and tumour volumes. Anti-androgen treatment also increased protein expression of multiple signal transduction pathways earlier than vehicle-treated control xenografts. VN/124-1 plus everolimus acted in concert to reduce tumour growth rates in our castration-resistant xenograft model. Conclusions: This study suggests that dual inhibition of AR and mTOR in castration-resistant xenograft models can restore sensitivity of tumours to anti-androgen therapy. Furthermore, after bicalutamide failure, dual inhibition with VN/124-1 and everolimus was the most effective treatment. PMID:20842117

  10. Patient-derived xenografts of gastrointestinal cancers are susceptible to rapid and delayed B-lymphoproliferation.

    PubMed

    Dieter, Sebastian M; Giessler, Klara M; Kriegsmann, Mark; Dubash, Taronish D; Möhrmann, Lino; Schulz, Erik R; Siegl, Christine; Weber, Sarah; Strakerjahn, Hendrik; Oberlack, Ava; Heger, Ulrike; Gao, Jianpeng; Hartinger, Eva-Maria; Oppel, Felix; Hoffmann, Christopher M; Ha, Nati; Brors, Benedikt; Lasitschka, Felix; Ulrich, Alexis; Strobel, Oliver; Schmidt, Manfred; von Kalle, Christof; Schneider, Martin; Weichert, Wilko; Ehrenberg, K Roland; Glimm, Hanno; Ball, Claudia R

    2017-03-15

    Patient-derived cancer xenografts (PDX) are widely used to identify and evaluate novel therapeutic targets, and to test therapeutic approaches in preclinical mouse avatar trials. Despite their widespread use, potential caveats of PDX models remain considerably underappreciated. Here, we demonstrate that EBV-associated B-lymphoproliferations frequently develop following xenotransplantation of human colorectal and pancreatic carcinomas in highly immunodeficient NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl) /SzJ (NSG) mice (18/47 and 4/37 mice, respectively), and in derived cell cultures in vitro. Strikingly, even PDX with carcinoma histology can host scarce EBV-infected B-lymphocytes that can fully overgrow carcinoma cells during serial passaging in vitro and in vivo. As serial xenografting is crucial to expand primary tumor tissue for biobanks and cohorts for preclinical mouse avatar trials, the emerging dominance of B-lymphoproliferations in serial PDX represents a serious confounding factor in these models. Consequently, repeated phenotypic assessments of serial PDX are mandatory at each expansion step to verify "bona fide" carcinoma xenografts.

  11. Women and lung cancer: waiting to exhale.

    PubMed

    Baldini, E H; Strauss, G M

    1997-10-01

    Lung cancer is now the leading cause of cancer deaths among women. In the United States, 64,300 women are expected to die of lung cancer in 1996. Smoking is responsible for about 80% of lung cancer cases. Unfortunately, the prevalence of smoking among women remains unacceptably high at about 22% and is expected to surpass the rate in men by the year 2000. Smoking rates are highest among young girls and the less educated. Whether lung cancer represents a different disease in women than in men is unclear. Data are conflicting regarding the magnitude of the relative risk of developing lung cancer due to smoking between the genders. There appears to be a difference in the relative distribution of lung cancer histologic features between men and women that is not explained entirely by differences in smoking patterns. Women who smoke appear to be at higher risk of developing small cell lung cancer than squamous cell lung cancer, whereas men who smoke have a similar risk for the two histologic conditions. Furthermore, women smokers are more likely to develop adenocarcinoma of the lung, and estrogens may play a causative role in this phenomenon. Data are unclear regarding whether the outcome of lung cancer treatment differs between genders. Solutions to the lung cancer epidemic among US women include (1) prevention of the disease by reducing smoking rates, (2) improving early detection methods, and (3) exploring new therapeutic strategies.

  12. Thromboprophylaxis in ambulatory lung cancer treatment.

    PubMed

    Cavaliere, Loretta

    2013-02-01

    Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, are common problems experienced by patients with lung cancer that can impact treatment plans, prognoses, and survival. Patients with lung cancer are at greatest risk for development of VTE in the ambulatory care treatment setting. Literature does exist on VTE management for medical and surgical oncology inpatients, as well as clinical guidelines for inpatient prophylaxis; however, published evidence is lacking on outpatient risk and thromboprophylaxis in medical oncology outpatients, particularly patients with lung cancer. Because patients with lung cancer treated in the ambulatory setting have established risks for VTE, they may benefit from thromboprophylaxis. Clinical guidelines for outpatient thromboprophylaxis direct the clinical practice for thromboprophylaxis in lung cancer treatment. The purpose of the current article is to explore the VTE risks associated with ambulatory lung cancer treatment and to review the recommended guidelines for thromboprophylaxis to guide clinical decision making for patients with lung cancer.

  13. Guidance molecules in lung cancer

    PubMed Central

    Nasarre, Patrick; Potiron, Vincent; Drabkin, Harry

    2010-01-01

    Guidance molecules were first described in the nervous system to control axon outgrowth direction. They are also widely expressed outside the nervous system where they control cell migration, tissue development and establishment of the vascular network. In addition, they are involved in cancer development, tumor angiogenesis and metastasis. This review is primarily focused on their functions in lung cancer and their involvement in lung development is also presented. Five guidance molecule families and their corresponding receptors are described, including the semaphorins/neuropilins/plexins, ephrins and Eph receptors, netrin/DCC/UNC5, Slit/Robo and Notch/Delta. In addition, the possibility to target these molecules as a therapeutic approach in cancer is discussed. PMID:20139699

  14. [Inhibition Function of Dominant-negative Mutant Gene Survivin-D53A to SPC-A1 Lung Adenocarcinoma Xenograft in Nude Mice Models].

    PubMed

    Yu, Min; Peng, Xingchen; Lu, You; Huang, Meijuan

    2015-06-01

    Survivin-D53A (SVV-D53A) is a dominant-negative mutant survivin, which represents a potential promising target for cancer gene therapy. The present study was designed to determine whether SVV-D53A plasmid encapsuled by DOTAP: Chol liposome would have the anti-tumor activity against SPC-A1 lung adenocarcinoma, and to detect the possible mechanisms. In our experiment, SPC-A1 cells were transfected in vitro with SVV-D53A plasmid and examined for protein expression by Western blot, then flow cytometric analysis was used to detect apoptosis. SPC-A1 lung adenocarcinoma xenografts were established in vivo in the nude mice, which received the i. v. administrations of SVV-D53A plasmid/liposome complexes. After mice were sacrificed, the paraffin-embedded tumor tissue sections were used for proliferating cell nuclear antigen (PCNA) expression and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Compared with the control group, the mice treated with SVV-D53A plasmid had an obviously reduced tumor volume, with high level of apoptosis and decreased cell proliferation in tumor tissue. The research results proved that the administration of SVV-D53A plasmid resulted in significant inhibition of SPC-A1 cells both in vitro and in vivo. The functional mechanism is that the anti-tumor response causes and induces tumor cell apoptosis.

  15. Resveratrol Enhances Antitumor Activity of TRAIL in Prostate Cancer Xenografts through Activation of FOXO Transcription Factor

    PubMed Central

    Ganapathy, Suthakar; Chen, Qinghe; Singh, Karan P.; Shankar, Sharmila; Srivastava, Rakesh K.

    2010-01-01

    Background Resveratrol (3, 4′, 5 tri-hydroxystilbene), a naturally occurring polyphenol, exhibits anti-inflammatory, antioxidant, cardioprotective and antitumor activities. We have recently shown that resveratrol can enhance the apoptosis-inducing potential of TRAIL in prostate cancer cells through multiple mechanisms in vitro. Therefore, the present study was designed to validate whether resveratrol can enhance the apoptosis-inducing potential of TRAIL in a xenograft model of prostate cancer. Methodology/Principal Findings Resveratrol and TRAIL alone inhibited growth of PC-3 xenografts in nude mice by inhibiting tumor cell proliferation (PCNA and Ki67 staining) and inducing apoptosis (TUNEL staining). The combination of resveratrol and TRAIL was more effective in inhibiting tumor growth than single agent alone. In xenografted tumors, resveratrol upregulated the expressions of TRAIL-R1/DR4, TRAIL-R2/DR5, Bax and p27/K IP1, and inhibited the expression of Bcl-2 and cyclin D1. Treatment of mice with resveratrol and TRAIL alone inhibited angiogenesis (as demonstrated by reduced number of blood vessels, and VEGF and VEGFR2 positive cells) and markers of metastasis (MMP-2 and MMP-9). The combination of resveratrol with TRAIL further inhibited number of blood vessels in tumors, and circulating endothelial growth factor receptor 2-positive endothelial cells than single agent alone. Furthermore, resveratrol inhibited the cytoplasmic phosphorylation of FKHRL1 resulting in its enhanced activation as demonstrated by increased DNA binding activity. Conclusions/Significance These data suggest that resveratrol can enhance the apoptosis-inducing potential of TRAIL by activating FKHRL1 and its target genes. The ability of resveratrol to inhibit tumor growth, metastasis and angiogenesis, and enhance the therapeutic potential of TRAIL suggests that resveratrol alone or in combination with TRAIL can be used for the management of prostate cancer. PMID:21209944

  16. Danshensu, a major water-soluble component of Salvia miltiorrhiza, enhances the radioresponse for Lewis Lung Carcinoma xenografts in mice

    PubMed Central

    Cao, Hong-Ying; Ding, Rui-Lin; Li, Meng; Yang, Mao-Nan; Yang, Ling-Lin; Wu, Jing-Bo; Yang, Bo; Wang, Jing; Luo, Cui-Lian; Wen, Qing-Lian

    2017-01-01

    The molecule 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoic acid (danshensu), a herbal preparation used in traditional Chinese medicine, has been found to possess potential antitumor and anti-angiogenesis effects. The aim of the present study was to investigate the efficacy of the combination of radiation therapy (RT) with danshensu in the treatment of Lewis lung carcinoma (LLC) xenografts, whilst exploring and evaluating the mechanism involved. In total, 8-week old female C57BL/6J mice were randomly assigned into 3 groups to receive: RT, RT + cisplatin and RT + danshensu, respectively, when LLC reached 100–150 mm3. Each group was divided into 7 subgroups according to the different irradiation doses that were administered. Tumor growth curves were created and the sensitization enhancement ratios of the drugs were calculated. The experiment was then repeated, and the 4 groups of tumor-bearing mice were treated with natural saline, danshensu, RT + danshensu and RT, respectively. The mice were sacrificed on day 7, and tumor tissue and blood were collected to determine microvessel density, the expression of proangiogenic factors, and the levels of blood thromboxane B2 and 6-keto-prostaglandin-F1α. Tumor hypoxia was also detected using in vivo fluorescence imaging. With respect to LLC xenografts, treatment with danshensu + RT significantly enhanced the effects of tumor growth inhibition (P<0.05). Furthermore, tumor vasculature was remodeled and microcirculation was improved, which significantly reduced tumor hypoxia (P<0.05). The present study demonstrated that danshensu significantly enhanced the radioresponse of LLC xenografts in mice. The mechanism involved may be associated with the alleviation of tumor cell hypoxia following treatment with danshensu + RT, caused by the improvement of tumor microcirculation and the remodeling of tumor vasculature. PMID:28356936

  17. The p44/wdr77-dependent cellular proliferation process during lung development is re-activated in lung cancer

    PubMed Central

    Gu, Zhongping; Zhang, Fahao; Wang, Zhi-Qiang; Ma, Wencai; Davis, Richard E.; Wang, Zhengxin

    2014-01-01

    During lung development, cells proliferate for a defined length of time before they begin to differentiate. Factors that control this proliferative process and how this growth process is related to lung cancer are currently unknown. Here, we found that the WD40-containing protein (p44/wdr77) was expressed in growing epithelial cells at the early stages of lung development. In contrast, p44/wdr77 expression was diminished in fully differentiated epithelial cells in the adult lung. Loss of p44/wdr77 gene expression led to cell growth arrest and differentiation. Re-expression of p44/wdr77 caused terminally differentiated cells to re-enter the cell cycle. Our findings suggest that p44/wdr77 is essential and sufficient for proliferation of lung epithelial cells. P44/Wdr77 was re-expressed in lung cancer, and silencing p44/wdr77 expression strongly inhibited growth of lung adenocarcinoma cells in tissue culture and abolished growth of lung adenocarcinoma tumor xenografts in mice. The growth arrest induced by loss of p44/wdr77 expression was partially through the p21-Rb signaling. Our results suggest that p44/wdr77 controls cellular proliferation during lung development and this growth process is re-activated during lung tumorigenesis. PMID:22665061

  18. Patient Derived Xenograft Models: An Emerging Platform for Translational Cancer Research

    PubMed Central

    Hidalgo, Manuel; Amant, Frederic; Biankin, Andrew V.; Budinská, Eva; Byrne, Annette T.; Caldas, Carlos; Clarke, Robert B.; de Jong, Steven; Jonkers, Jos; Mælandsmo, Gunhild Mari; Roman-Roman, Sergio; Seoane, Joan; Trusolino, Livio; Villanueva, Alberto

    2014-01-01

    Recently, there has been increasing interest in the development and characterization of patient derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal histological and genetic characteristics of their donor tumor and remain stable across passages. These models have been shown to be predictive of clinical outcomes and are being used for preclinical drug evaluation, biomarker identification, biological studies, and personalized medicine strategies. This paper summarizes the current state of the art in this field including methodological issues, available collections, practical applications, challenges and shortcoming, and future directions, and introduces a European consortium of PDX models. PMID:25185190

  19. Lung Cancer: Glossary

    MedlinePlus

    ... used to fight cancer Chromosome: A strand of DNA and related proteins that carries the genes and ... structure, function and pathology ^ back to top D DNA (deoxyribonucleic acid): The part of the cell that ...

  20. Epidermal Growth Factor Receptor Mutation Enhances Expression of Cadherin-5 in Lung Cancer Cells.

    PubMed

    Hung, Ming-Szu; Chen, I-Chuan; Lung, Jr-Hau; Lin, Paul-Yann; Li, Ya-Chin; Tsai, Ying-Huang

    2016-01-01

    Epidermal growth factor receptor (EGFR) activation has been shown to play a critical role in tumor angiogenesis. In this study, we investigate the correlation between EGFR mutations and cadherin-5 (CDH5), which is an angiogenic factor, in lung cancer cells. Increased expression CDH5 is observed in lung cancer cells with EGFR mutations. Stable lung cancer cell lines expressing mutant (exon 19 deletion E746-A750, and exon 21 missense mutation L858R) and wild type EGFR genes are established. A significantly higher expression of CDH5 is observed in exon 19 deletion stable lung cancer cells and mouse xenografts. Further studies show that expression of CDH5 is decreased after the inhibition of EGFR and downstream Akt pathways in lung cancer cells with EGFR mutation. In addition, mutant EGFR genes potentiates angiogenesis in lung cancer cells, which is inhibited by CDH5 siRNA, and potentiates migration and invasion in lung cancer cells. Our study shows that mutant EGFR genes are associated with overexpression of CDH5 through increased phosphorylation of EGFR and downstream Akt pathways. Our result may provide an insight into the association of mutant EGFR and CDH5 expression in lung cancer and aid further development of target therapy for NSCLC in the future.

  1. Epidermal Growth Factor Receptor Mutation Enhances Expression of Cadherin-5 in Lung Cancer Cells

    PubMed Central

    Hung, Ming-Szu; Chen, I-Chuan; Lung, Jr-Hau; Lin, Paul-Yann; Li, Ya-Chin; Tsai, Ying-Huang

    2016-01-01

    Epidermal growth factor receptor (EGFR) activation has been shown to play a critical role in tumor angiogenesis. In this study, we investigate the correlation between EGFR mutations and cadherin-5 (CDH5), which is an angiogenic factor, in lung cancer cells. Increased expression CDH5 is observed in lung cancer cells with EGFR mutations. Stable lung cancer cell lines expressing mutant (exon 19 deletion E746-A750, and exon 21 missense mutation L858R) and wild type EGFR genes are established. A significantly higher expression of CDH5 is observed in exon 19 deletion stable lung cancer cells and mouse xenografts. Further studies show that expression of CDH5 is decreased after the inhibition of EGFR and downstream Akt pathways in lung cancer cells with EGFR mutation. In addition, mutant EGFR genes potentiates angiogenesis in lung cancer cells, which is inhibited by CDH5 siRNA, and potentiates migration and invasion in lung cancer cells. Our study shows that mutant EGFR genes are associated with overexpression of CDH5 through increased phosphorylation of EGFR and downstream Akt pathways. Our result may provide an insight into the association of mutant EGFR and CDH5 expression in lung cancer and aid further development of target therapy for NSCLC in the future. PMID:27362942

  2. Vasculogenic mimicry in small cell lung cancer.

    PubMed

    Williamson, Stuart C; Metcalf, Robert L; Trapani, Francesca; Mohan, Sumitra; Antonello, Jenny; Abbott, Benjamin; Leong, Hui Sun; Chester, Christopher P E; Simms, Nicole; Polanski, Radoslaw; Nonaka, Daisuke; Priest, Lynsey; Fusi, Alberto; Carlsson, Fredrika; Carlsson, Anders; Hendrix, Mary J C; Seftor, Richard E B; Seftor, Elisabeth A; Rothwell, Dominic G; Hughes, Andrew; Hicks, James; Miller, Crispin; Kuhn, Peter; Brady, Ged; Simpson, Kathryn L; Blackhall, Fiona H; Dive, Caroline

    2016-11-09

    Small cell lung cancer (SCLC) is characterized by prevalent circulating tumour cells (CTCs), early metastasis and poor prognosis. We show that SCLC patients (37/38) have rare CTC subpopulations co-expressing vascular endothelial-cadherin (VE-cadherin) and cytokeratins consistent with vasculogenic mimicry (VM), a process whereby tumour cells form 'endothelial-like' vessels. Single-cell genomic analysis reveals characteristic SCLC genomic changes in both VE-cadherin-positive and -negative CTCs. Higher levels of VM are associated with worse overall survival in 41 limited-stage patients' biopsies (P<0.025). VM vessels are also observed in 9/10 CTC patient-derived explants (CDX), where molecular analysis of fractionated VE-cadherin-positive cells uncovered copy-number alterations and mutated TP53, confirming human tumour origin. VE-cadherin is required for VM in NCI-H446 SCLC xenografts, where VM decreases tumour latency and, despite increased cisplatin intra-tumour delivery, decreases cisplatin efficacy. The functional significance of VM in SCLC suggests VM regulation may provide new targets for therapeutic intervention.

  3. Vasculogenic mimicry in small cell lung cancer

    PubMed Central

    Williamson, Stuart C.; Metcalf, Robert L.; Trapani, Francesca; Mohan, Sumitra; Antonello, Jenny; Abbott, Benjamin; Leong, Hui Sun; Chester, Christopher P. E.; Simms, Nicole; Polanski, Radoslaw; Nonaka, Daisuke; Priest, Lynsey; Fusi, Alberto; Carlsson, Fredrika; Carlsson, Anders; Hendrix, Mary J. C.; Seftor, Richard E. B.; Seftor, Elisabeth A.; Rothwell, Dominic G.; Hughes, Andrew; Hicks, James; Miller, Crispin; Kuhn, Peter; Brady, Ged; Simpson, Kathryn L.; Blackhall, Fiona H.; Dive, Caroline

    2016-01-01

    Small cell lung cancer (SCLC) is characterized by prevalent circulating tumour cells (CTCs), early metastasis and poor prognosis. We show that SCLC patients (37/38) have rare CTC subpopulations co-expressing vascular endothelial-cadherin (VE-cadherin) and cytokeratins consistent with vasculogenic mimicry (VM), a process whereby tumour cells form ‘endothelial-like' vessels. Single-cell genomic analysis reveals characteristic SCLC genomic changes in both VE-cadherin-positive and -negative CTCs. Higher levels of VM are associated with worse overall survival in 41 limited-stage patients' biopsies (P<0.025). VM vessels are also observed in 9/10 CTC patient-derived explants (CDX), where molecular analysis of fractionated VE-cadherin-positive cells uncovered copy-number alterations and mutated TP53, confirming human tumour origin. VE-cadherin is required for VM in NCI-H446 SCLC xenografts, where VM decreases tumour latency and, despite increased cisplatin intra-tumour delivery, decreases cisplatin efficacy. The functional significance of VM in SCLC suggests VM regulation may provide new targets for therapeutic intervention. PMID:27827359

  4. Alpha-carotene inhibits metastasis in Lewis lung carcinoma in vitro, and suppresses lung metastasis and tumor growth in combination with taxol in tumor xenografted C57BL/6 mice.

    PubMed

    Liu, Yi-Zhen; Yang, Chih-Min; Chen, Jen-Yin; Liao, Junn-Wang; Hu, Miao-Lin

    2015-06-01

    This study aimed to investigate the anti-metastatic activity of α-carotene (AC) in Lewis lung carcinoma (LLC) and in combination with taxol in LLC-xenografted C57BL/6 mice. Cell culture studies reveal that AC significantly inhibited invasion, migration and activities of matrix metalloproteinase (MMP)-2, -9 and urokinase plasminogen activator but increased protein expression of tissue inhibitor of MMP (TIMP)-1, -2 and plasminogen activator inhibitor (PAI)-1. These effects of AC are similar to those of β-carotene at the same concentration (2.5 μM). AC (2.5 μM) also significantly inhibited integrin β1-mediated phosphorylation of focal adhesion kinase (FAK) which then decreased the phosphorylation of MAPK family. Findings from the animal model reveal that AC treatment (5m g/kg) alone significantly decreased lung metastasis without affecting primary tumor growth, whereas taxol treatment (6 mg/kg) alone exhibited significant inhibition on both actions, as compared to tumor control group. AC treatment alone significantly decreased protein expression of integrin β1 but increased protein expression of TIMP-1 and PAI-1 without affecting protein expression of TIMP-2 and phosphorylation of FAK in lung tissues, whereas taxol treatment alone significantly increased protein expression of TIMP-1, PAI-1 and TIMP-2 but decreased protein expression of integrin β1 and phosphorylation of FAK. The combined treatment produced stronger actions on lung metastasis and lung tissues protein expression of TIMP-1, TIMP-2 and PAI-1. Overall, we demonstrate that AC effectively inhibits LLC metastasis and suppresses lung metastasis in combination with taxol in LLC-bearing mice, suggesting that AC could be used as an anti-metastatic agent or as an adjuvant for anti-cancer drugs. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Treatment Options by Stage (Small Cell Lung Cancer)

    MedlinePlus

    ... 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 ...

  6. Clinical and experimental pathology of lung cancer

    SciTech Connect

    McVie, J.G.; Bakker, W.; Wagenaar, S.C.; Carney, D.

    1986-01-01

    This book contains 17 selections. Some of the titles are: Flow cytometric DNA analysis in the study of small cell carcinoma of the lung; Mechanisms of oncogenesis; Adhesion mechanisms in liver metastasis; Current concepts in the therapy of small cell lung cancer; Application of monoclonal antibodies in imaging and therapy; and Clinical applications of the biologic properties of small cell lung cancer.

  7. Imaging of insulinlike growth factor type 1 receptor in prostate cancer xenografts using the affibody molecule 111In-DOTA-ZIGF1R:4551.

    PubMed

    Tolmachev, Vladimir; Malmberg, Jennie; Hofström, Camilla; Abrahmsén, Lars; Bergman, Thomas; Sjöberg, Anna; Sandström, Mattias; Gräslund, Torbjörn; Orlova, Anna

    2012-01-01

    One of the pathways leading to androgen independence in prostate cancer involves upregulation of insulinlike growth factor type 1 receptor (IGF-1R). Radionuclide imaging of IGF-1R in tumors might be used for selection of patients who would most likely benefit from IGF-1R-targeted therapy. The goal of this study was to evaluate the feasibility of in vivo radionuclide imaging of IGF-1R expression in prostate cancer xenografts using a small nonimmunoglobulin-derived binding protein called an Affibody molecule. The IGF-1R-binding Z(IGF1R:4551) Affibody molecule was site-specifically conjugated with a maleimido derivative of DOTA and labeled with (111)In. The binding of radiolabeled Z(IGF1R:4551) to IGF-1R-expressing cells was evaluated in vitro and in vivo. DOTA-Z(IGF1R:4551) can be stably labeled with (111)In with preserved specific binding to IGF-1R-expressing cells in vitro. In mice, (111)In-DOTA-Z(IGF1R:4551) accumulated in IGF-1R-expressing organs (pancreas, stomach, lung, and salivary gland). Receptor saturation experiments demonstrated that targeting of DU-145 prostate cancer xenografts in NMRI nu/nu mice was IGF-1R-specific. The tumor uptake was 1.1 ± 0.3 percentage injected dose per gram, and the tumor-to-blood ratio was 3.2 ± 0.2 at 8 h after injection. This study demonstrates the feasibility of in vivo targeting of IGF-1R-expressing prostate cancer xenografts using an Affibody molecule. Further development of radiolabeled Affibody molecules might provide a useful clinical tool for stratification of patients with prostate cancer for IGF-1R-targeting therapy.

  8. Lung cancer screening and management.

    PubMed

    Jones, G S; Baldwin, D R

    2015-12-01

    Deaths from lung cancer are greater than for any other type of malignancy. Many people present with advanced stage cancer at diagnosis and survival is limited. Low radiation dose CT (LDCT) screening appears to offer part of the solution to this. The US National Lung Screening Trial (NLST) showed a 20% reduction in cancer related mortality and a 6.7% reduction in all cause mortality in patients who had LDCT compared to chest X-ray. Lung Cancer screening is now being implemented in the US using the NLST screening criteria but many questions remain about the details of the methodology of screening and its cost effectiveness. Many of these questions are being answered by ongoing European trials that are reporting their findings. In this review we objectively analyse current research evidence and explore the issues that need to be resolved before implementation, including technical considerations, selection criteria and effective nodule management protocols. We discuss the potential barriers that will be faced when beginning a national screening programme and possible solutions to them.

  9. Pleural involvement in lung cancer.

    PubMed

    Agalioti, Theodora; Giannou, Anastasios D; Stathopoulos, Georgios T

    2015-06-01

    The pleural space, a sterile secluded environment in the thoracic cavity, represents an attractive metastatic site for various cancers of lung, breast and gastrointestinal origins. Whereas lung and breast adenocarcinomas could invade the pleural space because of their anatomic proximity, "distant" cancers like ovarian or gastrointestinal tract adenocarcinomas may employ more active mechanisms to the same end. A pleural metastasis is often accompanied by a malignant pleural effusion (MPE), an unfavorable complication that severely restricts the quality of life and expectancy of the cancer patient. MPE is the net "product" of three different processes, namely inflammation, enhanced angiogenesis and vascular leakage. Current efforts are focusing on the identification of cancer cell autocrine (specific mutation spectra and biochemical pathways) and paracrine (cytokine and chemokine signals) characteristics as well as host features (immunological or other) that underlie the MPE phenotype. Herein we examine the pleural histology, cytology and molecular characteristics that make the pleural cavity an attractive metastasis destination for lung adenocarcinoma. Mesothelial and tumor features that may account for the tumor's ability to invade the pleural space are highlighted. Finally, possible therapeutic interventions specifically targeting MPE are discussed.

  10. Pleural involvement in lung cancer

    PubMed Central

    Giannou, Anastasios D.; Stathopoulos, Georgios T.

    2015-01-01

    The pleural space, a sterile secluded environment in the thoracic cavity, represents an attractive metastatic site for various cancers of lung, breast and gastrointestinal origins. Whereas lung and breast adenocarcinomas could invade the pleural space because of their anatomic proximity, “distant” cancers like ovarian or gastrointestinal tract adenocarcinomas may employ more active mechanisms to the same end. A pleural metastasis is often accompanied by a malignant pleural effusion (MPE), an unfavorable complication that severely restricts the quality of life and expectancy of the cancer patient. MPE is the net “product” of three different processes, namely inflammation, enhanced angiogenesis and vascular leakage. Current efforts are focusing on the identification of cancer cell autocrine (specific mutation spectra and biochemical pathways) and paracrine (cytokine and chemokine signals) characteristics as well as host features (immunological or other) that underlie the MPE phenotype. Herein we examine the pleural histology, cytology and molecular characteristics that make the pleural cavity an attractive metastasis destination for lung adenocarcinoma. Mesothelial and tumor features that may account for the tumor’s ability to invade the pleural space are highlighted. Finally, possible therapeutic interventions specifically targeting MPE are discussed. PMID:26150915

  11. CysLT(1)R antagonists inhibit tumor growth in a xenograft model of colon cancer.

    PubMed

    Savari, Sayeh; Liu, Minghui; Zhang, Yuan; Sime, Wondossen; Sjölander, Anita

    2013-01-01

    The expression of the inflammatory G-protein coupled receptor CysLT1R has been shown to be upregulated in colon cancer patients and associated with poor prognosis. The present study investigated the correlation between CysLT1R and colon cancer development in vivo using CysLT1R antagonists (ZM198,615 or Montelukast) and the nude mouse xenograft model. Two drug administration regimens were established. The first regimen was established to investigate the importance of CysLT1R in tumor initiation. Nude mice were inoculated with 50 µM CysLT1R antagonist-pretreated HCT-116 colon cancer cells and received continued treatment (5 mg/kg/day, intraperitoneally). The second regimen aimed to address the role of CysLT1R in tumor progression. Nude mice were inoculated with non-pretreated HCT-116 cells and did not receive CysLT1R antagonist treatment until recordable tumor appearance. Both regimens resulted in significantly reduced tumor size, attributed to changes in proliferation and apoptosis as determined by reduced Ki-67 levels and increased levels of p21(WAF/Cip1) (P<0.01), cleaved caspase 3, and the caspase-cleaved product of cytokeratin 18. Decreased levels of VEGF (P<0.01) and reduced vessel size (P<0.05) were also observed, the latter only in the ZM198,615-pretreatment group. Furthermore, we performed a series of in vitro studies using the colon cancer cell line HCT-116 and CysLT1R antagonists. In addition to significant reductions in cell proliferation, adhesion and colony formation, we observed induction of cell cycle arrest and apoptosis in a dose-dependent manner. The ability of Montelukast to inhibit growth of human colon cancer xenograft was further validated by using two additional colon cancer cell lines, SW-480 and HT-29. Our results demonstrate that CysLT1R antagonists inhibit growth of colon cancer xenografts primarily by reducing proliferation and inducing apoptosis of the tumor cells.

  12. CysLT1R Antagonists Inhibit Tumor Growth in a Xenograft Model of Colon Cancer

    PubMed Central

    Savari, Sayeh; Liu, Minghui; Zhang, Yuan; Sime, Wondossen; Sjölander, Anita

    2013-01-01

    The expression of the inflammatory G-protein coupled receptor CysLT1R has been shown to be upregulated in colon cancer patients and associated with poor prognosis. The present study investigated the correlation between CysLT1R and colon cancer development in vivo using CysLT1R antagonists (ZM198,615 or Montelukast) and the nude mouse xenograft model. Two drug administration regimens were established. The first regimen was established to investigate the importance of CysLT1R in tumor initiation. Nude mice were inoculated with 50 µM CysLT1R antagonist-pretreated HCT-116 colon cancer cells and received continued treatment (5 mg/kg/day, intraperitoneally). The second regimen aimed to address the role of CysLT1R in tumor progression. Nude mice were inoculated with non-pretreated HCT-116 cells and did not receive CysLT1R antagonist treatment until recordable tumor appearance. Both regimens resulted in significantly reduced tumor size, attributed to changes in proliferation and apoptosis as determined by reduced Ki-67 levels and increased levels of p21WAF/Cip1 (P<0.01), cleaved caspase 3, and the caspase-cleaved product of cytokeratin 18. Decreased levels of VEGF (P<0.01) and reduced vessel size (P<0.05) were also observed, the latter only in the ZM198,615-pretreatment group. Furthermore, we performed a series of in vitro studies using the colon cancer cell line HCT-116 and CysLT1R antagonists. In addition to significant reductions in cell proliferation, adhesion and colony formation, we observed induction of cell cycle arrest and apoptosis in a dose-dependent manner. The ability of Montelukast to inhibit growth of human colon cancer xenograft was further validated by using two additional colon cancer cell lines, SW-480 and HT-29. Our results demonstrate that CysLT1R antagonists inhibit growth of colon cancer xenografts primarily by reducing proliferation and inducing apoptosis of the tumor cells. PMID:24039952

  13. Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft.

    PubMed

    Govek, Steven P; Nagasawa, Johnny Y; Douglas, Karensa L; Lai, Andiliy G; Kahraman, Mehmet; Bonnefous, Celine; Aparicio, Anna M; Darimont, Beatrice D; Grillot, Katherine L; Joseph, James D; Kaufman, Joshua A; Lee, Kyoung-Jin; Lu, Nhin; Moon, Michael J; Prudente, Rene Y; Sensintaffar, John; Rix, Peter J; Hager, Jeffrey H; Smith, Nicholas D

    2015-11-15

    Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of indazoles 47 and 56, which induce tumor regression in a tamoxifen-resistant breast cancer xenograft.

  14. DHEA increases epithelial markers and decreases mesenchymal proteins in breast cancer cells and reduces xenograft growth.

    PubMed

    Colín-Val, Zaira; González-Puertos, Viridiana Yazmín; Mendoza-Milla, Criselda; Gómez, Erika Olivia; Huesca-Gómez, Claudia; López-Marure, Rebeca

    2017-10-15

    Breast cancer is one of the most common neoplasias and the leading cause of cancer death in women worldwide. Its high mortality rate is linked to a great metastatic capacity associated with the epithelial-mesenchymal transition (EMT). During this process, a decrease in epithelial proteins expression and an increase of mesenchymal proteins are observed. On the other hand, it has been shown that dehydroepiandrosterone (DHEA), the most abundant steroid in human plasma, inhibits migration of breast cancer cells; however, the underlying mechanisms have not been elucidated. In this study, the in vitro effect of DHEA on the expression pattern of some EMT-related proteins, such as E-cadherin (epithelial), N-cadherin, vimentin and Snail (mesenchymal) was measured by Western blot and immunofluorescence in MDA-MB-231 breast cancer cells with invasive, metastatic and mesenchymal phenotype. Also, the in vivo effect of DHEA on xenograft tumor growth in nude mice (nu(-)/nu(-)) and on expression of the same epithelial and mesenchymal proteins in generated tumors was evaluated. We found that DHEA increased expression of E-cadherin and decreased N-cadherin, vimentin and Snail expression both in MD-MB-231 cells and in the formed tumors, possibly by DHEA-induced reversion of mesenchymal phenotype. These results were correlated with a tumor size reduction in mouse xenografts following DHEA administration either a week earlier or concurrent with breast cancer cells inoculation. In conclusion, DHEA could be useful in the treatment of breast cancer with mesenchymal phenotype. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models.

    PubMed

    Leu, Jyh-Der; Wang, Bo-Shen; Chiu, Shu-Jun; Chang, Chun-Yuan; Chen, Chien-Chih; Chen, Fu-Du; Avirmed, Shiirevnyamba; Lee, Yi-Jang

    2016-12-01

    Fisetin (3,7,3',4'-tetrahydroxyflavone), which belongs to the flavonoid group of polyphenols and is found in a wide range of plants, has been reported to exhibit a number of biological activities in human cancer cells, including antioxidant, anti-inflammatory, antiangiogenic, anti-invasive and antiproliferative effects. Although previous in vitro studies have shown that fisetin treatment increases the apoptotic rate and enhances the radiosensitivity of human colorectal cancer cells, the in vivo effects of fisetin on tumor growth remain unclear. In the present study a murine xenograft tumor model was employed to investigate the therapeutic effects of fisetin in combination with radiation on CT-26 colon cancer cells and human HCT116 colorectal cancer cells. This revealed that intratumoral injection of fisetin significantly suppressed the growth of CT-26 tumors compared with the untreated control group, but had little effect on the growth of HCT116 tumors. However, fisetin in combination with 2-Gy radiation enhanced tumor suppressor activity in murine colon and human colorectal xenograft tumors, as compared with 2-Gy fractionated radiation administered alone for 5 days and fisetin alone. Interestingly, fisetin downregulated the expression of the oncoprotein securin in a p53-independent manner. However, securin-null HCT116 tumors showed only moderate sensitivity to fisetin treatment, and the combination of fisetin and radiation did not significantly suppress securin-null HCT116 tumor growth compared with normal HCT116 tumors. Therefore, the role of securin in mediating the effect of fisetin on colorectal cancer growth warrants further investigation. In conclusion, the results of the current study provide important preclinical data for evaluating the efficacy of fisetin and radiation combination treatment as an adjuvant chemoradiotherapy for human colorectal cancers.

  16. Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models

    PubMed Central

    Leu, Jyh-Der; Wang, Bo-Shen; Chiu, Shu-Jun; Chang, Chun-Yuan; Chen, Chien-Chih; Chen, Fu-Du; Avirmed, Shiirevnyamba; Lee, Yi-Jang

    2016-01-01

    Fisetin (3,7,3′,4′-tetrahydroxyflavone), which belongs to the flavonoid group of polyphenols and is found in a wide range of plants, has been reported to exhibit a number of biological activities in human cancer cells, including antioxidant, anti-inflammatory, antiangiogenic, anti-invasive and antiproliferative effects. Although previous in vitro studies have shown that fisetin treatment increases the apoptotic rate and enhances the radiosensitivity of human colorectal cancer cells, the in vivo effects of fisetin on tumor growth remain unclear. In the present study a murine xenograft tumor model was employed to investigate the therapeutic effects of fisetin in combination with radiation on CT-26 colon cancer cells and human HCT116 colorectal cancer cells. This revealed that intratumoral injection of fisetin significantly suppressed the growth of CT-26 tumors compared with the untreated control group, but had little effect on the growth of HCT116 tumors. However, fisetin in combination with 2-Gy radiation enhanced tumor suppressor activity in murine colon and human colorectal xenograft tumors, as compared with 2-Gy fractionated radiation administered alone for 5 days and fisetin alone. Interestingly, fisetin downregulated the expression of the oncoprotein securin in a p53-independent manner. However, securin-null HCT116 tumors showed only moderate sensitivity to fisetin treatment, and the combination of fisetin and radiation did not significantly suppress securin-null HCT116 tumor growth compared with normal HCT116 tumors. Therefore, the role of securin in mediating the effect of fisetin on colorectal cancer growth warrants further investigation. In conclusion, the results of the current study provide important preclinical data for evaluating the efficacy of fisetin and radiation combination treatment as an adjuvant chemoradiotherapy for human colorectal cancers. PMID:28105204

  17. Cryotherapy in Treating Patients With Lung Cancer That Has Spread to the Other Lung or Parts of the Body

    ClinicalTrials.gov

    2017-01-17

    Advanced Malignant Mesothelioma; Extensive Stage Small Cell Lung Cancer; Lung Metastases; Recurrent Malignant Mesothelioma; Recurrent Non-small Cell Lung Cancer; Recurrent Small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  18. Bortezomib in Treating Patients With Stage IIIB or Stage IV Lung Cancer

    ClinicalTrials.gov

    2014-08-04

    Adenocarcinoma of the Lung; Bronchoalveolar Cell Lung Cancer; Non-small Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  19. Midazolam Induces Cellular Apoptosis in Human Cancer Cells and Inhibits Tumor Growth in Xenograft Mice

    PubMed Central

    Mishra, Siddhartha Kumar; Kang, Ju-Hee; Lee, Chang Woo; Oh, Seung Hyun; Ryu, Jun Sun; Bae, Yun Soo; Kim, Hwan Mook

    2013-01-01

    Midazolam is a widely used anesthetic of the benzodiazepine class that has shown cytotoxicity and apoptosis-inducing activity in neuronal cells and lymphocytes. This study aims to evaluate the effect of midazolam on growth of K562 human leukemia cells and HT29 colon cancer cells. The in vivo effect of midazolam was investigated in BALB/c-nu mice bearing K562 and HT29 cells human tumor xenografts. The results show that midazolam decreased the viability of K562 and HT29 cells by inducing apoptosis and S phase cell-cycle arrest in a concentration-dependent manner. Midazolam activated caspase-9, capspase-3 and PARP indicating induction of the mitochondrial intrinsic pathway of apoptosis. Midazolam lowered mitochondrial membrane potential and increased apoptotic DNA fragmentation. Midazolam showed reactive oxygen species (ROS) scavenging activity through inhibition of NADPH oxidase 2 (Nox2) enzyme activity in K562 cells. Midazolam caused inhibition of pERK1/2 signaling which led to inhibition of the anti-apoptotic proteins Bcl-XL and XIAP and phosphorylation activation of the pro-apoptotic protein Bid. Midazolam inhibited growth of HT29 tumors in xenograft mice. Collectively our results demonstrate that midazolam caused growth inhibition of cancer cells via activation of the mitochondrial intrinsic pathway of apoptosis and inhibited HT29 tumor growth in xenograft mice. The mechanism underlying these effects of midazolam might be suppression of ROS production leading to modulation of apoptosis and growth regulatory proteins. These findings present possible clinical implications of midazolam as an anesthetic to relieve pain during in vivo anticancer drug delivery and to enhance anticancer efficacy through its ROS-scavenging and pro-apoptotic properties. PMID:24008365

  20. Cyclophilin A Enhances Cell Proliferation and Xenografted Tumor Growth of Early Gastric Cancer.

    PubMed

    Feng, Wenhua; Xin, Yan; Xiao, Yuping; Li, Wenhui; Sun, Dan

    2015-09-01

    Recently Cyclophilin A (CypA) was identified as a candidate target protein in gastric carcinoma. However, the role of CypA in gastric cancer (GC) has not been investigated extensively so far. The purpose of this study was to determine the expression pattern of CypA in human GC, and to explore the effects of suppressed CypA expression on cell proliferation and xenografted tumor growth of gastric cancer. In the present study, we detected the expression pattern of CypA in human GC by immunohistochemistry analysis. Further, the RNAi method was used to silence CypA, and colony formation assay, growth curves, cell cycle and mouse xenograft were analysed. An elevated expression of CypA in GC tissues compared with normal gastric mucosa was observed, especially in TNM stage-I and intestinal type of tumor. CypA was overexpressed in most GC cell lines and endogenous expression of CypA correlated with cell growth phenotypes. Transient suppression of CypA reduced the proliferation of BGC-823 and SGC-7901 GC cell lines. Exogenous CypA promoted the proliferation of NCI-N87 GC cells in a concentration dependent manner. Further study revealed that stable CypA silencing inhibited the proliferation, prevented cell cycle and reduced autophagy of BGC-823 GC cells in vitro through suppressing the ERK1/2 signal pathway. Stable CypA silencing also inhibited the growth of xenografted tumor of BGC-823 GC cell in nude mice. These results indicate a special function mode for CypA of playing more important roles in the early stage of gastric tumorigenesis and suggest CypA as a new molecular target of diagnosis and treatment for GC patients.

  1. Lung cancer: biology and treatment options

    PubMed Central

    Hassan, Omer; Yang, Yi-Wei; Buchanan, Petra

    2015-01-01

    Lung cancer remains the leading cause of cancer mortality in men and women in the U.S. and worldwide. About 90% of lung cancer cases are caused by smoking and the use of tobacco products. However, other factors such as radon gas, asbestos, air pollution exposures, and chronic infections can contribute to lung carcinogenesis. In addition, multiple inherited and acquired mechanisms of susceptibility to lung cancer have been proposed. Lung cancer is divided into two broad histologic classes, which grow and spread differently: small-cell lung carcinomas (SCLC) and non-small cell lung carcinomas (NSCLC). Treatment options for lung cancer include surgery, radiation therapy, chemotherapy, and targeted therapy. Therapeutic-modalities recommendations depend on several factors, including the type and stage of cancer. Despite the improvements in diagnosis and therapy made during the past 25 years, the prognosis for patients with lung cancer is still unsatisfactory. The responses to current standard therapies are poor except for the most localized cancers. However, a better understanding of the biology pertinent to these challenging malignancies, might lead to the development of more efficacious and perhaps more specific drugs. The purpose of this review is to summarize the recent developments in lung cancer biology and its therapeutic strategies, and discuss the latest treatment advances including therapies currently under clinical investigation. PMID:26297204

  2. Lung cancer: Biology and treatment options.

    PubMed

    Lemjabbar-Alaoui, Hassan; Hassan, Omer Ui; Yang, Yi-Wei; Buchanan, Petra

    2015-12-01

    Lung cancer remains the leading cause of cancer mortality in men and women in the U.S. and worldwide. About 90% of lung cancer cases are caused by smoking and the use of tobacco products. However, other factors such as radon gas, asbestos, air pollution exposures, and chronic infections can contribute to lung carcinogenesis. In addition, multiple inherited and acquired mechanisms of susceptibility to lung cancer have been proposed. Lung cancer is divided into two broad histologic classes, which grow and spread differently: small-cell lung carcinomas (SCLCs) and non-small cell lung carcinomas (NSCLCs). Treatment options for lung cancer include surgery, radiation therapy, chemotherapy, and targeted therapy. Therapeutic-modalities recommendations depend on several factors, including the type and stage of cancer. Despite the improvements in diagnosis and therapy made during the past 25 years, the prognosis for patients with lung cancer is still unsatisfactory. The responses to current standard therapies are poor except for the most localized cancers. However, a better understanding of the biology pertinent to these challenging malignancies, might lead to the development of more efficacious and perhaps more specific drugs. The purpose of this review is to summarize the recent developments in lung cancer biology and its therapeutic strategies, and discuss the latest treatment advances including therapies currently under clinical investigation.

  3. Lung cancer stem cells—characteristics, phenotype

    PubMed Central

    George, Rachel; Sethi, Tariq

    2016-01-01

    Lung cancer remains a major cause of cancer-related deaths worldwide with unfavourable prognosis mainly due to the late stage of disease at presentation. High incidence and disease recurrence rates are a fact despite advances in treatment. Ongoing experimental and clinical observations suggest that the malignant phenotype in lung cancer is sustained by lung cancer stem cells (CSCs) which are putative stem cells situated throughout the airways that have the potential of initiating lung cancer formation. These cells share the common characteristic of increased proliferation and differentiation, long life span and resistance to chemotherapy and radiation therapy. This review summarises the current knowledge on their characteristics and phenotype. PMID:27413709

  4. Adaptive Radiation for Lung Cancer

    PubMed Central

    Gomez, Daniel R.; Chang, Joe Y.

    2011-01-01

    The challenges of lung cancer radiotherapy are intra/inter-fraction tumor/organ anatomy/motion changes and the need to spare surrounding critical structures. Evolving radiotherapy technologies, such as four-dimensional (4D) image-based motion management, daily on-board imaging and adaptive radiotherapy based on volumetric images over the course of radiotherapy, have enabled us to deliver higher dose to target while minimizing normal tissue toxicities. The image-guided radiotherapy adapted to changes of motion and anatomy has made the radiotherapy more precise and allowed ablative dose delivered to the target using novel treatment approaches such as intensity-modulated radiation therapy, stereotactic body radiation therapy, and proton therapy in lung cancer, techniques used to be considered very sensitive to motion change. Future clinical trials using real time tracking and biological adaptive radiotherapy based on functional images are proposed. PMID:20814539

  5. [Cannabis smoking and lung cancer].

    PubMed

    Underner, M; Urban, T; Perriot, J; de Chazeron, I; Meurice, J-C

    2014-06-01

    Cannabis is the most commonly smoked illicit substance in the world. It can be smoked alone in plant form (marijuana) but it is mainly smoked mixed with tobacco. The combined smoking of cannabis and tobacco is a common-place phenomenon in our society. However, its use is responsible for severe pulmonary consequences. The specific impact of smoking cannabis is difficult to assess precisely and to distinguish from the effect of tobacco. Marijuana smoke contains polycyclic aromatic hydrocarbons and carcinogens at higher concentration than tobacco smoke. Cellular, tissue, animal and human studies, and also epidemiological studies, show that marijuana smoke is a risk factor for lung cancer. Cannabis exposure doubles the risk of developing lung cancer. This should encourage clinicians to identify cannabis use and to offer patients support in quitting.

  6. CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to Erlotinib via transcriptional regulation of EGFR

    SciTech Connect

    Wang, Yunshan; Zhang, Pengju; Liu, Ziming; Wang, Qin; Wen, Mingxin; Wang, Yuli; Yuan, Hongtu; Mao, Jian-Hua; Wei, Guangwei

    2014-11-21

    CUL4A has been proposed as oncogene in several types of human cancer, but its clinical significance and functional role in human non-small cell lung cancer (NSCLC) remain unclear. Expression level of CUL4A was examined by RT-PCR and Western blot. Forced expression of CUL4A was mediated by retroviruses, and CUL4A silencing by shRNAs expressing lentiviruses. Growth capacity of lung cancer cells was measured by MTT in vitro and tumorigenesis in vivo, respectively. We found that CUL4A was highly expressed in human lung cancer tissues and lung cancer cell lines, and this elevated expression positively correlated with disease progression and prognosis. Overexpression of CUL4A in human lung cancer cell lines increased cell proliferation, inhibited apoptosis, and subsequently conferred resistance to chemotherapy. On other hand, silencing CUL4A expression in NSCLC cells reduced proliferation, promoted apoptosis and resulted in tumor growth inhibition in cancer xenograft model. Mechanistically, we revealed CUL4A regulated EGFR transcriptional expression and activation, and subsequently activated AKT. Targeted inhibition of EGFR activity blocked these CUL4A induced oncogenic activities. In conclusion, our results highlight the significance of CUL4A in NSCLC and suggest that CUL4A could be a promising therapy target and a potential biomarker for prognosis and EGFR target therapy in NSCLC patients.

  7. CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to Erlotinib via transcriptional regulation of EGFR

    DOE PAGES

    Wang, Yunshan; Zhang, Pengju; Liu, Ziming; ...

    2014-11-21

    CUL4A has been proposed as oncogene in several types of human cancer, but its clinical significance and functional role in human non-small cell lung cancer (NSCLC) remain unclear. Expression level of CUL4A was examined by RT-PCR and Western blot. Forced expression of CUL4A was mediated by retroviruses, and CUL4A silencing by shRNAs expressing lentiviruses. Growth capacity of lung cancer cells was measured by MTT in vitro and tumorigenesis in vivo, respectively. We found that CUL4A was highly expressed in human lung cancer tissues and lung cancer cell lines, and this elevated expression positively correlated with disease progression and prognosis. Overexpressionmore » of CUL4A in human lung cancer cell lines increased cell proliferation, inhibited apoptosis, and subsequently conferred resistance to chemotherapy. On other hand, silencing CUL4A expression in NSCLC cells reduced proliferation, promoted apoptosis and resulted in tumor growth inhibition in cancer xenograft model. Mechanistically, we revealed CUL4A regulated EGFR transcriptional expression and activation, and subsequently activated AKT. Targeted inhibition of EGFR activity blocked these CUL4A induced oncogenic activities. In conclusion, our results highlight the significance of CUL4A in NSCLC and suggest that CUL4A could be a promising therapy target and a potential biomarker for prognosis and EGFR target therapy in NSCLC patients.« less

  8. Lung Cancer Awareness Week

    ERIC Educational Resources Information Center

    Glennon, Catherine; Laczko, Lori

    2003-01-01

    Smoking is the most preventable cause of death in our society. Tobacco use is responsible for nearly one in five deaths in the United States and the cause of premature death of approximately 2 million individuals in developed countries. Smoking accounts for at least 30% of all cancer deaths and is a major cause of heart disease, cerebrovascular…

  9. Lung Cancer Awareness Week

    ERIC Educational Resources Information Center

    Glennon, Catherine; Laczko, Lori

    2003-01-01

    Smoking is the most preventable cause of death in our society. Tobacco use is responsible for nearly one in five deaths in the United States and the cause of premature death of approximately 2 million individuals in developed countries. Smoking accounts for at least 30% of all cancer deaths and is a major cause of heart disease, cerebrovascular…

  10. Vaccine Therapy and Sargramostim With or Without Docetaxel in Treating Patients With Metastatic Lung Cancer or Metastatic Colorectal Cancer

    ClinicalTrials.gov

    2014-03-28

    Extensive Stage Small Cell Lung Cancer; Recurrent Colon Cancer; Recurrent Non-small Cell Lung Cancer; Recurrent Rectal Cancer; Recurrent Small Cell Lung Cancer; Stage IV Colon Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Rectal Cancer

  11. beta 1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts

    SciTech Connect

    Park, Catherine C.; Park, Catherine C.; Zhang, Hui J.; Yao, Evelyn S.; Park, Chong J.; Bissell, Mina J.

    2008-06-02

    {beta}1 integrin signaling has been shown to mediate cellular resistance to apoptosis after exposure to ionizing radiation (IR). Other signaling molecules that increase resistance include Akt, which promotes cell survival downstream of {beta}1 integrin signaling. We showed previously that {beta}1 integrin inhibitory antibodies, AIIB2, enhance apoptosis and decrease growth in human breast cancer cells in 3 dimensional laminin-rich extracellular matrix (3D lrECM) cultures and in vivo. Here we asked whether AIIB2 could synergize with IR to modify Akt-mediated IR resistance. We used 3D lrECM cultures to test the optimal combination of AIIB2 with IR treatment of two breast cancer cell lines, MCF-7 and HMT3522-T4-2, as well as T4-2 myr-Akt breast cancer colonies or HMT3522-S-1, which form normal organotypic structures in 3D lrECM. Colonies were assayed for apoptosis and {beta}1 integrin/Akt signaling pathways were evaluated using western blot. In addition, mice bearing MCF-7 xenografts were used to validate the findings in 3D lrECM. We report that AIIB2 increased apoptosis optimally post-IR by down regulating Akt in breast cancer colonies in 3D lrECM. In vivo, addition of AIIB2 after IR significantly enhanced tumor growth inhibition and apoptosis compared to either treatment alone. Remarkably, the degree of tumor growth inhibition using AIIB2 plus 2 Gy radiation was similar to that of 8 Gy alone. We showed previously that AIIB2 had no discernible toxicity in mice; here, its addition allowed for a significant reduction in the IR dose that was necessary to achieve comparable growth inhibition and apoptosis in breast cancer xenografts in vivo.

  12. Survivin Antisense Oligonucleotides Effectively Radiosensitize Colorectal Cancer Cells in Both Tissue Culture and Murine Xenograft Models

    SciTech Connect

    Roedel, Franz; Capalbo, Gianni; Weiss, Christian; Roedel, Claus

    2008-05-01

    Purpose: Survivin shows a radiation resistance factor in colorectal cancer. In the present study, we determined whether survivin messenger RNA levels in patients with rectal cancer predict tumor response after neoadjuvant radiochemotherapy and whether inhibition of survivin by the use of antisense oligonucleotides (ASOs) enhances radiation responses. Methods and Materials: SW480 colorectal carcinoma cells were transfected with survivin ASO (LY2181308) and irradiated with doses ranging from 0-8 Gy. Survivin expression, cell-cycle distribution, {gamma}H2AX fluorescence, and induction of apoptosis were monitored by means of immunoblotting, flow cytometry, and caspase 3/7 activity. Clonogenic survival was determined by using a colony-forming assay. An SW480 xenograft model was used to investigate the effect of survivin attenuation and irradiation on tumor growth. Furthermore, survivin messenger RNA levels were studied in patient biopsy specimens by using Affymetrix microarray analysis. Results: In the translational study of 20 patients with rectal cancer, increased survivin levels were associated with significantly greater risk of local tumor recurrence (p = 0.009). Treatment of SW480 cells with survivin ASOs and irradiation resulted in an increased percentage of apoptotic cells, caspase 3/7 activity, fraction of cells in the G{sub 2}/M phase, and H2AX phosphorylation. Clonogenic survival decreased compared with control-treated cells. Furthermore, treatment of SW480 xenografts with survivin ASOs and irradiation resulted in a significant delay in tumor growth. Conclusion: Survivin appears to be a molecular biomarker in patients with rectal cancer. Furthermore, in vitro and in vivo data suggest a potential role of survivin as a molecular target to improve treatment response to radiotherapy in patients with rectal cancer.

  13. PPMP, a novel tubulin-depolymerizing agent against esophageal cancer in patient-derived tumor xenografts

    PubMed Central

    Oi, Naomi; Chen, Hanyong; Reddy, Kanamata; Jiang, Yanan; Yao, Ke; Li, Haitao; Li, Wei; Zhang, Yi; Saleem, Mohammad; Ma, Wei-Ya; Bode, Ann M.; Dong, Ziming; Dong, Zigang

    2016-01-01

    Esophageal cancer is one of the least studied and deadliest cancers worldwide with a poor prognosis due to limited options for treatment. Chemotherapy agents such as the microtubule-targeting compounds are the mainstay of palliation for advanced esophageal cancer treatment. However, the toxicity and side effects of tubulin-binding agents (TBAs) have promoted the development of novel, more potent but less toxic TBAs. Herein, we identified 2-[4-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazol-5-yl]-5-[(2-methylprop-2-en-1-yl)oxy] phenol (PPMP) as a novel TBA for esophageal cancer treatment. PPMP markedly inhibited tubulin polymerization, and decreased viability and anchorage-independent growth of esophageal cancer cell lines, effects that were accompanied by G2/M arrest and apoptosis. Importantly, we produced patient-derived esophageal cancer xenografts to evaluate the therapeutic effect of PPMP in a setting that best mimics the clinical context in patients with esophageal cancer. Overall, we identified PPMP as a novel microtubule-destabilizing compound and as a new therapeutic agent against esophageal carcinoma. PMID:27129160

  14. Experimental investigation of the penetration of ultrasound nanobubbles in a gastric cancer xenograft

    NASA Astrophysics Data System (ADS)

    Fan, Xiaozhou; Wang, Luofu; Guo, Yanli; Tong, Haipeng; Li, Lang; Ding, Jun; Huang, Haiyun

    2013-08-01

    Nanobubbles as a type of ultrasound contrast agent have attracted much interest in recent years due to their many advantages, such as strong penetrating power and high stability. However, there is still insufficient morphological evidence concerning gas-filled nanobubbles in tumor tissue spaces and tumor angiogenesis. We used a gastric cancer xenograft as an example to study this question. Nanobubbles with a particle size of 435.2 ± 60.53 nm were prepared and compared with SonoVue® microbubbles in vitro and in vivo, and they exhibited a superior contrast imaging effect. After excluding the impact of the nanobubbles in blood vessels through saline flush, we used an ultrasound burst and frozen sectioning to investigate the distribution of nanobubbles in the gastric cancer xenografts and confirmed this by transmission electron microscopy. Preliminary results showed that the nanobubbles were able to pass through the gaps between the endothelial cells in the tumor vascular system to enter the tissue space. These findings could provide morphological evidence for extravascular ultrasound imaging of tumors and serve as a foundation for the application of nanobubbles in extravascular tumor-targeted ultrasonic diagnostics and therapy.

  15. LUCIS: lung cancer imaging studies.

    PubMed

    Harders, Stefan Walbom

    2012-11-01

    Pulmonary nodules are of high clinical importance, as they may prove to be an early manifestation of lung cancer. Pulmonary nodules are small, focal opacities that may be solitary or multiple. A solitary pulmonary nodule (SPN) is a single, small (= 30 mm in diameter) radiographic opacity. Larger opacities are called masses and are often malignant. As imaging techniques improve and more nodules are detected, the optimal management of SPNs remains unclear. Current strategies include tissue sampling or CT follow-up. The aim of this PhD was to examine current non-invasive methods used to characterise pulmonary nodules and masses in patients with suspected lung cancer and to stage NSCLC. In doing so, this PhD helps to validate the existing methods used to diagnose and stage lung cancer correctly and, hopefully, aids in the development of new methods. In the first study, 213 participants with pulmonary nodules on CT were examined with an additional HRCT. In this study, it was concluded that HRCT of a solitary pulmonary nodule, assessed using attenuation and morphological criteria is a fast, widely available and effective method for diagnosing lung cancer correctly, and especially for ruling out cancer. In the second study, 168 patients with pulmonary lesions on CT were examined with an additional F-18-FDG PET/CT. It was concluded that when used early in the work-up of the lesions, CT raised the prevalence of lung cancer in the population to the point at which further diagnostic imaging examination could be considered redundant. Standard contrast-enhanced CT seems better suited to identify patients with lung cancer than to rule out cancer. Finally, the overall diagnostic accuracy as well as the classification probabilities and predictive values of the two modalities were not significantly different. The reproducibility of the above results was substantial. In the third study, 59 patients with pulmonary nodules or masses on chest radiography were examined with an

  16. Hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers.

    PubMed

    Kohnoh, Takashi; Hashimoto, Naozumi; Ando, Akira; Sakamoto, Koji; Miyazaki, Shinichi; Aoyama, Daisuke; Kusunose, Masaaki; Kimura, Motohiro; Omote, Norihito; Imaizumi, Kazuyoshi; Kawabe, Tsutomu; Hasegawa, Yoshinori

    2016-01-01

    Persistent hypoxia stimulation, one of the most critical microenvironmental factors, accelerates the acquisition of epithelial-mesenchymal transition (EMT) phenotypes in lung cancer cells. Loss of phosphatase and tensin homologue deleted from chromosome 10 (PTEN) expression might accelerate the development of lung cancer in vivo. Recent studies suggest that tumor microenvironmental factors might modulate the PTEN activity though a decrease in total PTEN expression and an increase in phosphorylation of the PTEN C-terminus (p-PTEN), resulting in the acquisition of the EMT phenotypes. Nevertheless, it is not known whether persistent hypoxia can modulate PTEN phosphatase activity or whether hypoxia-induced EMT phenotypes are negatively regulated by the PTEN phosphatase activity. We aimed to investigate hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers. Western blotting was performed in five lung cancer cell lines to evaluate total PTEN expression levels and the PTEN activation. In a xenograft model of lung cancer cells with endogenous PTEN expression, the PTEN expression was evaluated by immunohistochemistry. To examine the effect of hypoxia on phenotypic alterations in lung cancer cells in vitro, the cells were cultured under hypoxia. The effect of unphosphorylated PTEN (PTEN4A) induction on hypoxia-induced EMT phenotypes was evaluated, by using a Dox-dependent gene expression system. Lung cancer cells involving the EMT phenotypes showed a decrease in total PTEN expression and an increase in p-PTEN. In a xenograft model, loss of PTEN expression was observed in the tumor lesions showing tissue hypoxia. Persistent hypoxia yielded an approximately eight-fold increase in the p-PTEN/PTEN ratio in vitro. PTEN4A did not affect stabilization of hypoxia-inducible factor 1α. PTEN4A blunted hypoxia-induced EMT via inhibition of β-catenin translocation into the cytoplasm and nucleus. Our study strengthens the therapeutic possibility that

  17. Lung Cancer and Interstitial Lung Diseases: A Systematic Review

    PubMed Central

    Archontogeorgis, Kostas; Steiropoulos, Paschalis; Tzouvelekis, Argyris; Nena, Evangelia; Bouros, Demosthenes

    2012-01-01

    Interstitial lung diseases (ILDs) represent a heterogeneous group of more than two hundred diseases of either known or unknown etiology with different pathogenesis and prognosis. Lung cancer, which is the major cause of cancer death in the developed countries, is mainly attributed to cigarette smoking and exposure to inhaled carcinogens. Different studies suggest a link between ILDs and lung cancer, through different pathogenetic mechanisms, such as inflammation, coagulation, dysregulated apoptosis, focal hypoxia, activation, and accumulation of myofibroblasts as well as extracellular matrix accumulation. This paper reviews current evidence on the association between lung cancer and interstitial lung diseases such as idiopathic pulmonary fibrosis, sarcoidosis, systemic sclerosis, dermatomyositis/polymyositis, rheumatoid arthritis, systemic lupus erythematosus, and pneumoconiosis. PMID:22900168

  18. The efficacy of the anthracycline prodrug daunorubicin-GA3 in human ovarian cancer xenografts.

    PubMed

    Houba, P H; Boven, E; Erkelens, C A; Leenders, R G; Scheeren, J W; Pinedo, H M; Haisma, H J

    1998-12-01

    The prodrug N-[4-(daunorubicin-N-carbonyl-oxymethyl)phenyl] O-beta-glucuronyl carbamate (DNR-GA3) was synthesized for specific activation by human beta-glucuronidase, released in necrotic areas of tumour lesions. In vitro, DNR-GA3 was 18 times less toxic than daunorubicin (DNR) and the prodrug was completely activated to the parent drug by human beta-glucuronidase. The maximum tolerated dose of DNR-GA3 in nude mice bearing s.c. human ovarian cancer xenografts was 6-10 times higher than that of DNR. The prodrug was cleared more rapidly from the circulation (elimination t1/2 = 20 min) than the parent drug (elimination t1/2 = 720 min). The anti-tumour effects of DNR-GA3 and DNR were investigated in four different human ovarian cancer xenografts OVCAR-3, FMa, A2780 and MRI-H-207 at a mean tumour size between 100 and 200 mm3. In three out of four of these tumour lines, the prodrug given i.v. at the maximum tolerated dose ranging from 150 to 250 mg kg(-1) resulted in a maximum tumour growth inhibition from 82% to 95%. The standard treatment with DNR at a dose of 8 mg kg(-1) given i.v. weekly x 2 resulted only in a maximum tumour growth inhibition from 40% to 47%. Tumour line FMa did not respond to DNR, nor to DNR-GA3. Treatment with DNR-GA3 was also given to mice with larger tumours that would contain more necrosis (mean size 300-950 mm3). The specific growth delay by DNR-GA3 was extended from 2.1 to 4.4 in OVCAR-3 xenografts and from 4.4 to 6.0 in MRI-H-207 xenografts. Our data indicate that DNR-GA3 is more effective than DNR and may be especially of use for treatment of tumours with areas of necrosis.

  19. Interrogating open issues in cancer precision medicine with patient-derived xenografts.

    PubMed

    Byrne, Annette T; Alférez, Denis G; Amant, Frédéric; Annibali, Daniela; Arribas, Joaquín; Biankin, Andrew V; Bruna, Alejandra; Budinská, Eva; Caldas, Carlos; Chang, David K; Clarke, Robert B; Clevers, Hans; Coukos, George; Dangles-Marie, Virginie; Eckhardt, S Gail; Gonzalez-Suarez, Eva; Hermans, Els; Hidalgo, Manuel; Jarzabek, Monika A; de Jong, Steven; Jonkers, Jos; Kemper, Kristel; Lanfrancone, Luisa; Mælandsmo, Gunhild Mari; Marangoni, Elisabetta; Marine, Jean-Christophe; Medico, Enzo; Norum, Jens Henrik; Palmer, Héctor G; Peeper, Daniel S; Pelicci, Pier Giuseppe; Piris-Gimenez, Alejandro; Roman-Roman, Sergio; Rueda, Oscar M; Seoane, Joan; Serra, Violeta; Soucek, Laura; Vanhecke, Dominique; Villanueva, Alberto; Vinolo, Emilie; Bertotti, Andrea; Trusolino, Livio

    2017-04-01

    Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and the implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions. This Opinion article discusses aspects of PDX modelling that are relevant to these questions and highlights the merits of shared PDX resources to advance cancer medicine from the perspective of EurOPDX, an international initiative devoted to PDX-based research.

  20. Lung and Upper Aerodigestive Cancer | Division of Cancer Prevention

    Cancer.gov

    [[{"fid":"180","view_mode":"default","fields":{"format":"default","field_file_image_alt_text[und][0][value]":"Lung and Upper Aerodigestive Cancer Research Group Homepage Logo","field_file_image_title_text[und][0][value]":"Lung and Upper Aerodigestive Cancer Research Group Homepage Logo","field_folder[und]":"15"},"type":"media","attributes":{"alt":"Lung and Upper Aerodigestive Cancer Research Group Homepage Logo","title":"Lung and Upper Aerodigestive Cancer Research Group Homepage Logo","heigh | Conducts and supports research on the prevention and early detection of lung and head and neck cancers.

  1. A longitudinal MRI study on lymph nodes histiocytosis of a xenograft cancer model

    PubMed Central

    Jiménez-González, María; Plaza-García, Sandra; Arizeta, Janire; Bianchessi, Silvia; Trigueros, César; Reese, Torsten

    2017-01-01

    Background Efforts are continuously made to detect and investigate the pivotal processes and interplay between the response of sentinel lymph node and malignant cells from a primary tumor. Conversely, some frequently used tumor animal models, such as human cancer xenografts, rarely feature metastasis. Therefore, lymph node alterations are seldom assessed. We consider that studying lymph node response could contribute to the understanding of host reaction to cancer. In the present study, we explored the presence of regional lymph node alterations in parallel with tumor growth using a pancreatic tumor xenograft model which does not develop metastasis. Methods and findings We established an animal cancer model by the subcutaneous inoculation of PANC-1 (a metastatic human pancreatic cancer cell line) in the left upper flank of athymic nude mice. Tumor animals, along with controls (n = 7 / group) were subjected to Magnetic Resonance Imaging (MRI) in order to follow tumor growth and brachial and axillary lymph nodes alterations over several weeks. Further histological analyses were performed at the end of the study. The individual average of the different lymph nodes sizes was 15–40% larger in the tumor animals compared to control animals at week 8 to week 20. The tumor size and lymph node size were not correlated. Histological analysis of the lymph nodes showed paracortical histiocytosis. No metastasis to lymph nodes could be detected by histology. In tumor bearing animals, histiocytosis was associated with isolated apoptotic bodies and migration of human tumoral cells was confirmed by specific immunostaining of human origin markers. Conclusions The lack of metastasis as well as the pathological manifestation of the lymph node alteration in this pre-clinical model established here parallels findings in patients with sinus histiocytosis that is correlated with improved survival. PMID:28704462

  2. Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer

    PubMed Central

    Kalari, Krishna R.; Suman, Vera J.; Moyer, Ann M.; Yu, Jia; Visscher, Daniel W.; Dockter, Travis J.; Vedell, Peter T.; Sinnwell, Jason P.; Tang, Xiaojia; Thompson, Kevin J.; McLaughlin, Sarah A.; Moreno-Aspitia, Alvaro; Copland, John A; Northfelt, Donald W.; Gray, Richard J.; Hunt, Katie; Conners, Amy; Weinshilboum, Richard; Wang, Liewei; Boughey, Judy C.

    2017-01-01

    Background: Breast cancer patients with residual disease after neoadjuvant chemotherapy (NAC) have increased recurrence risk. Molecular characterization, knowledge of NAC response, and simultaneous generation of patient-derived xenografts (PDXs) may accelerate drug development. However, the feasibility of this approach is unknown. Methods: We conducted a prospective study of 140 breast cancer patients treated with NAC and performed tumor and germline sequencing and generated patient-derived xenografts (PDXs) using core needle biopsies. Chemotherapy response was assessed at surgery. Results: Recurrent “targetable” alterations were not enriched in patients without pathologic complete response (pCR); however, upregulation of steroid receptor signaling and lower pCR rates (16.7%, 1/6) were observed in triple-negative breast cancer (TNBC) patients with luminal androgen receptor (LAR) vs basal subtypes (60.0%, 21/35). Within TNBC, TP53 mutation frequency (75.6%, 31/41) did not differ comparing basal (74.3%, 26/35) and LAR (83.3%, 5/6); however, TP53 stop-gain mutations were more common in basal (22.9%, 8/35) vs LAR (0.0%, 0/6), which was confirmed in The Cancer Genome Atlas and British Columbia data sets. In luminal B tumors, Ki-67 responses were observed in tumors that harbored mutations conferring endocrine resistance (p53, AKT, and IKBKE). PDX take rate (27.4%, 31/113) varied according to tumor subtype, and in a patient with progression on NAC, sequencing data informed drug selection (olaparib) with in vivo antitumor activity observed in the primary and resistant (postchemotherapy) PDXs. Conclusions: In this study, we demonstrate the feasibility of tumor sequencing and PDX generation in the NAC setting. “Targetable” alterations were not enriched in chemotherapy-resistant tumors; however, prioritization of drug testing based on sequence data may accelerate drug development. PMID:28376176

  3. Curbing the burden of lung cancer.

    PubMed

    Urman, Alexandra; Hosgood, H Dean

    2016-06-01

    Lung cancer contributes substantially to the global burden of disease and healthcare costs. New screening modalities using low-dose computerized tomography are promising tools for early detection leading to curative surgery. However, the screening and follow-up diagnostic procedures of these techniques may be costly. Focusing on prevention is an important factor to reduce the burden of screening, treatment, and lung cancer deaths. The International Agency for Research on Cancer has identified several lung carcinogens, which we believe can be considered actionable when developing prevention strategies. To curb the societal burden of lung cancer, healthcare resources need to be focused on early detection and screening and on mitigating exposure(s) of a person to known lung carcinogens, such as active tobacco smoking, household air pollution (HAP), and outdoor air pollution. Evidence has also suggested that these known lung carcinogens may be associated with genetic predispositions, supporting the hypothesis that lung cancers attributed to differing exposures may have developed from unique underlying genetic mechanisms attributed to the exposure of interest. For instance, smokingattributed lung cancer involves novel genetic markers of risk compared with HAP-attributed lung cancer. Therefore, genetic risk markers may be used in risk stratification to identify subpopulations that are at a higher risk for developing lung cancer attributed to a given exposure. Such targeted prevention strategies suggest that precision prevention strategies may be possible in the future; however, much work is needed to determine whether these strategies will be viable.

  4. Prognosis of Lung Cancer: Heredity or Environment

    DTIC Science & Technology

    2015-06-01

    AWARD NUMBER: W81XWH-12-1-0547 TITLE: Prognosis of Lung Cancer: Heredity or Environment? PRINCIPAL INVESTIGATOR: Melinda Aldrich...0547 Prognosis of Lung Cancer: Heredity or Environment? 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Aldrich...DISTRIBUTION / AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Lung cancer is the

  5. Attitudes and Stereotypes in Lung Cancer versus Breast Cancer

    PubMed Central

    Sriram, N.

    2015-01-01

    Societal perceptions may factor into the high rates of nontreatment in patients with lung cancer. To determine whether bias exists toward lung cancer, a study using the Implicit Association Test method of inferring subconscious attitudes and stereotypes from participant reaction times to visual cues was initiated. Participants were primarily recruited from an online survey panel based on US census data. Explicit attitudes regarding lung and breast cancer were derived from participants’ ratings (n = 1778) regarding what they thought patients experienced in terms of guilt, shame, and hope (descriptive statements) and from participants’ opinions regarding whether patients ought to experience such feelings (normative statements). Participants’ responses to descriptive and normative statements about lung cancer were compared with responses to statements about breast cancer. Analyses of responses revealed that the participants were more likely to agree with negative descriptive and normative statements about lung cancer than breast cancer (P<0.001). Furthermore, participants had significantly stronger implicit negative associations with lung cancer compared with breast cancer; mean response times in the lung cancer/negative conditions were significantly shorter than in the lung cancer/positive conditions (P<0.001). Patients, caregivers, healthcare providers, and members of the general public had comparable levels of negative implicit attitudes toward lung cancer. These results show that lung cancer was stigmatized by patients, caregivers, healthcare professionals, and the general public. Further research is needed to investigate whether implicit and explicit attitudes and stereotypes affect patient care. PMID:26698307

  6. Attitudes and Stereotypes in Lung Cancer versus Breast Cancer.

    PubMed

    Sriram, N; Mills, Jennifer; Lang, Edward; Dickson, Holli K; Hamann, Heidi A; Nosek, Brian A; Schiller, Joan H

    2015-01-01

    Societal perceptions may factor into the high rates of nontreatment in patients with lung cancer. To determine whether bias exists toward lung cancer, a study using the Implicit Association Test method of inferring subconscious attitudes and stereotypes from participant reaction times to visual cues was initiated. Participants were primarily recruited from an online survey panel based on US census data. Explicit attitudes regarding lung and breast cancer were derived from participants' ratings (n = 1778) regarding what they thought patients experienced in terms of guilt, shame, and hope (descriptive statements) and from participants' opinions regarding whether patients ought to experience such feelings (normative statements). Participants' responses to descriptive and normative statements about lung cancer were compared with responses to statements about breast cancer. Analyses of responses revealed that the participants were more likely to agree with negative descriptive and normative statements about lung cancer than breast cancer (P<0.001). Furthermore, participants had significantly stronger implicit negative associations with lung cancer compared with breast cancer; mean response times in the lung cancer/negative conditions were significantly shorter than in the lung cancer/positive conditions (P<0.001). Patients, caregivers, healthcare providers, and members of the general public had comparable levels of negative implicit attitudes toward lung cancer. These results show that lung cancer was stigmatized by patients, caregivers, healthcare professionals, and the general public. Further research is needed to investigate whether implicit and explicit attitudes and stereotypes affect patient care.

  7. Hiwi knockdown inhibits the growth of lung cancer in nude mice.

    PubMed

    Liang, Dong; Dong, Min; Hu, Lin-Jie; Fang, Ze-Hui; Xu, Xia; Shi, En-Hui; Yang, Yi-Ju

    2013-01-01

    Hiwi, a human homologue of the Piwi family, plays an important role in stem cell self-renewal and is overexpressed in various human tumors. This study aimed to determine whether an RNA interference-based strategy to suppress Hiwi expression could inhibit tumor growth in a xenograft mouse model. A rare population of SSCloAldebr cells was isolated and identified as lung cancer stem cells in our previous study. Plasmids containing U6 promoter-driven shRNAs against Hiwi or control plasmids were successfully established. The xenograft tumor model was generated by subcutaneously inoculating with lung cancer stem cell SSCloAldebr cells. After the tumor size reached about 8 mm in diameter, shRNA plasmids were injected into the mice via the tail vein three times a week for two weeks, then xenograft tumor growth was assessed. In nude mice, intravenously delivery of Hiwi shRNA plasmids significantly inhibited tumor growth compared to treatment with control scrambled shRNA plasmids or the vehicle PBS. No mice died during the experiment and no adverse events were observed in mice administered the plasmids. Moreover, delivery of Hiwi shRNA plasmids resulted in a significant suppressed expression of Hiwi and ALDH-1 in xenograft tumor samples, based on immunohistochemical analysis. Thus, shRNA-mediated Hiwi gene silencing in lung cancer stem cells by an effective in vivo gene delivery strategy appeared to be an effective therapeutic approach for lung cancer, and may provide some useful clues for RNAi gene therapy in solid cancers.

  8. Assessment of Tumor Stiffness With Shear Wave Elastography in a Human Prostate Cancer Xenograft Implantation Model.

    PubMed

    Wang, Yiru; Yao, Binwei; Li, Hongfei; Zhang, Yan; Gao, Hanjing; Gao, Yabin; Peng, Ruiyun; Tang, Jie

    2017-05-01

    To investigate the stiffness of human prostate cancer in a xenograft implantation model using shear wave elastography and compare the pathologic features of tumors with varying elasticity. Human prostate cancer DU-145 cells were injected into 24 nude male mice. The mice were divided into 3 groups according to the time of transplantation (6, 8, and 10 weeks). The volume, elasticity, and Young modulus of tumors were recorded by 2-dimensional sonography and shear wave elastography. The tumors were collected for pathologic analyses: hematoxylin-eosin staining, Ponceau S, and aniline staining were used to stain collagen and elastic fibers, and picric acid-sirius red staining was used to indicate type I and III collagen. The area ratios of collagen I/III were calculated. The correlation between the Young modulus of the tumor and area ratio of collagen I/III were evaluated. Immunohistochemistry of vimentin and α-smooth muscle actin was performed. Nineteen tumors in 3 groups were collected. The volume and mean Young modulus increased with the time of transplantation. There were more collagen fibers in the stiff tumors, and there were significant differences in the area ratios of collagen I/III between groups 1 (mean ± SD, 0.50 ± 0.17) and 3 (1.97 ± 0.56; P < .01). The Young modulus of the tumors showed a very significant correlation with the area ratios of collagen I/III (r = 0.968; P < .05). The expression level of α-smooth muscle actin protein was higher in group 3 than in the other groups, but differences in vimentin expression were barely seen. Shear wave elastography is a novel useful technology for showing the elasticity of human prostate cancer xenograft implantation tumors. Collagen fibers, especially collagen type I, play a crucial role in the elasticity in the human prostate cancer xenograft implantation model. © 2017 by the American Institute of Ultrasound in Medicine.

  9. Lung cancer: epidemiology, etiology, and prevention.

    PubMed

    Dela Cruz, Charles S; Tanoue, Lynn T; Matthay, Richard A

    2011-12-01

    Lung cancer is the leading cause of cancer death in the United States and around the world. A vast majority of lung cancer deaths are attributable to cigarette smoking, and curbing the rates of cigarette smoking is imperative. Understanding the epidemiology and causal factors of lung cancer can provide additional foundation for disease prevention. This article focuses on modifiable risk factors, including tobacco smoking, occupational carcinogens, diet, and ionizing radiation. It also discusses briefly the molecular and genetic aspects of lung carcinogenesis. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Combination Chemotherapy, Radiation Therapy, and Gefitinib in Treating Patients With Stage III Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-06-04

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Bronchoalveolar Cell Lung Cancer; Large Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  11. [Lung cancer and lymph drainage].

    PubMed

    Riquet, M

    2007-01-01

    Lung cancer is lymphophile and may involve lymph nodes (LN) belonging to lung lymph drainage. LN metastases are figured within stations numbered 1 to 14. These stations are located along lymph vessels. The lymph vessels and the LN are forming together anatomical chains. Lymph vessels are valved and pulsatile and travel to the cervical venous confluence where they pour the lung lymph into the blood circulation. They may be totally or partly nodeless along their travel, anastomose with each other around the trachea, and connect with the thoracic duct within the mediastinum. Within the anatomical LN chains, LN are variable in number and in size from one individual to another. They may be absent from one or several stations of the international mapping. Stations are located along the anatomical chains: pulmonary ligament (9), tracheal bifurcation(8 and 7), right paratracheal (4R, 2R and 1), preaortic (5 and 6), left paratracheal (4L, 2L and 1). Station 3 is located on 2 differents chains (phrenic and right esophagotracheal). Station 10 are located at the beginning of the mediastinal lymph nodes chains. Each chain connects with the blood circulation, anastomoses with he neighbouring chains and behave as an own entity whatever the number of its LN. International station mapping misknowns this anatomy and occults the true pronostic value of lung lymph drainage.

  12. Inhibition of checkpoint kinase 1 sensitizes lung cancer brain metastases to radiotherapy

    SciTech Connect

    Yang, Heekyoung; Yoon, Su Jin; Jin, Juyoun; Choi, Seung Ho; Seol, Ho Jun; Lee, Jung-Il; and others

    2011-03-04

    Research highlights: {yields} The most important therapeutic tool in brain metastasis is radiation therapy. {yields} Radiosensitivity of cancer cells was enhanced with treatment of Chk1 inhibitor. {yields} Depletion of Chk1 in cancer cells showed an enhancement of sensitivity to radiation. {yields} Chk1 can be a good target for enhancement of radiosensitivity. -- Abstract: The most important therapeutic tool in brain metastasis is radiation therapy. However, resistance to radiation is a possible cause of recurrence or treatment failure. Recently, signal pathways about DNA damage checkpoints after irradiation have been noticed. We investigated the radiosensitivity can be enhanced with treatment of Chk1 inhibitor, AZD7762 in lung cancer cell lines and xenograft models of lung cancer brain metastasis. Clonogenic survival assays showed enhancement of radiosensitivity with AZD7762 after irradiation of various doses. AZD7762 increased ATR/ATM-mediated Chk1 phosphorylation and stabilized Cdc25A, suppressed cyclin A expression in lung cancer cell lines. In xenograft models of lung cancer (PC14PE6) brain metastasis, AZD7762 significantly prolonged the median survival time in response to radiation. Depletion of Chk1 using shRNA also showed an enhancement of sensitivity to radiation in PC14PE6 cells. The results of this study support that Chk1 can be a good target for enhancement of radiosensitivity.

  13. Generation and molecular characterization of pancreatic cancer patient-derived xenografts reveals their heterologous nature

    PubMed Central

    Seol, Hyang Sook; Choi, Yeon Sook; Kim, Eunji; Lee, Eun Ji; Rhee, Je-Keun; Singh, Shree Ram; Jun, Eun Sung; Han, Buhm; Hong, Seung Mo; Kim, Song Cheol; Chang, Suhwan

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is the most challenging type of cancer to treat, with a 5-year survival rate of <10%. Furthermore, because of the large portion of the inoperable cases, it is difficult to obtain specimens to study the biology of the tumors. Therefore, a patient-derived xenograft (PDX) model is an attractive option for preserving and expanding these tumors for translational research. Here we report the generation and characterization of 20 PDX models of PDAC. The success rate of the initial graft was 74% and most tumors were re-transplantable. Histological analysis of the PDXs and primary tumors revealed a conserved expression pattern of p53 and SMAD4; an exome single nucleotide polymorphism (SNP) array and Comprehensive Cancer Panel showed that PDXs retained over 94% of cancer-associated variants. In addition, Polyphen2 and the Sorting Intolerant from Tolerant (SIFT) prediction identified 623 variants among the functional SNPs, highlighting the heterologous nature of pancreatic PDXs; an analysis of 409 tumor suppressor genes and oncogenes in Comprehensive Cancer Panel revealed heterologous cancer gene mutation profiles for each PDX-primary tumor pair. Altogether, we expect these PDX models are a promising platform for screening novel therapeutic agents and diagnostic markers for the detection and eradication of PDAC. PMID:27613834

  14. Inhibition of Stromal PlGF Suppresses the Growth of Prostate Cancer Xenografts

    PubMed Central

    Zins, Karin; Thomas, Anita; Lucas, Trevor; Sioud, Mouldy; Aharinejad, Seyedhossein; Abraham, Dietmar

    2013-01-01

    The growth and vascularization of prostate cancer is dependent on interactions between cancer cells and supporting stromal cells. The primary stromal cell type found in prostate tumors is the carcinoma-associated fibroblast, which produces placental growth factor (PlGF). PlGF is a member of the vascular endothelial growth factor (VEGF) family of angiogenic molecules and PlGF mRNA levels increase after androgen deprivation therapy in prostate cancer. In this study, we show that PlGF has a direct dose-dependent proliferative effect on human PC-3 prostate cancer cells in vitro and fibroblast-derived PlGF increases PC-3 proliferation in co-culture. In xenograft tumor models, intratumoral administration of murine PlGF siRNA reduced stromal-derived PlGF expression, reduced tumor burden and decreased the number of Ki-67 positive proliferating cells associated with reduced vascular density. These data show that targeting stromal PlGF expression may represent a therapeutic target for the treatment of prostate cancer. PMID:24005860

  15. FH535, a β-catenin pathway inhibitor, represses pancreatic cancer xenograft growth and angiogenesis

    PubMed Central

    Gong, Fei-Ran; Zhou, Binhua P.; Lian, Lian; Shen, Bairong; Chen, Kai; Duan, Weiming; Wu, Meng-Yao; Tao, Min; Li, Wei

    2016-01-01

    The WNT/β-catenin pathway plays an important role in pancreatic cancer carcinogenesis. We evaluated the correlation between aberrant β-catenin pathway activation and the prognosis pancreatic cancer, and the potential of applying the β-catenin pathway inhibitor FH535 to pancreatic cancer treatment. Meta-analysis and immunohistochemistry showed that abnormal β-catenin pathway activation was associated with unfavorable outcome. FH535 repressed pancreatic cancer xenograft growth in vivo. Gene Ontology (GO) analysis of microarray data indicated that target genes responding to FH535 participated in stemness maintenance. Real-time PCR and flow cytometry confirmed that FH535 downregulated CD24 and CD44, pancreatic cancer stem cell (CSC) markers, suggesting FH535 impairs pancreatic CSC stemness. GO analysis of β-catenin chromatin immunoprecipitation sequencing data identified angiogenesis-related gene regulation. Immunohistochemistry showed that higher microvessel density correlated with elevated nuclear β-catenin expression and unfavorable outcome. FH535 repressed the secretion of the proangiogenic cytokines vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, and tumor necrosis factor-α, and also inhibited angiogenesis in vitro and in vivo. Protein and mRNA microarrays revealed that FH535 downregulated the proangiogenic genes ANGPT2, VEGFR3, IFN-γ, PLAUR, THPO, TIMP1, and VEGF. FH535 not only represses pancreatic CSC stemness in vitro, but also remodels the tumor microenvironment by repressing angiogenesis, warranting further clinical investigation. PMID:27323403

  16. Systematic Repurposing Screening in Xenograft Models Identifies Approved Drugs with Novel Anti-Cancer Activity

    PubMed Central

    Roix, Jeffrey J.; Harrison, S. D.; Rainbolt, Elizabeth A.; Meshaw, Kathryn R.; McMurry, Avery S.; Cheung, Peter; Saha, Saurabh

    2014-01-01

    Approved drugs target approximately 400 different mechanisms of action, of which as few as 60 are currently used as anti-cancer therapies. Given that on average it takes 10–15 years for a new cancer therapeutic to be approved, and the recent success of drug repurposing for agents such as thalidomide, we hypothesized that effective, safe cancer treatments may be found by testing approved drugs in new therapeutic settings. Here, we report in-vivo testing of a broad compound collection in cancer xenograft models. Using 182 compounds that target 125 unique target mechanisms, we identified 3 drugs that displayed reproducible activity in combination with the chemotherapeutic temozolomide. Candidate drugs appear effective at dose equivalents that exceed current prescription levels, suggesting that additional pre-clinical efforts will be needed before these drugs can be tested for efficacy in clinical trials. In total, we suggest drug repurposing is a relatively resource-intensive method that can identify approved medicines with a narrow margin of anti-cancer activity. PMID:25093583

  17. Aminomethylphosphonic acid inhibits growth and metastasis of human prostate cancer in an orthotopic xenograft mouse model

    PubMed Central

    Parajuli, Keshab Raj; Zhang, Qiuyang; Liu, Sen; You, Zongbing

    2016-01-01

    Aminomethylphosphonic acid (AMPA) has been shown to inhibit prostate cancer cell growth in vitro. The purpose of the present study was to determine if AMPA could inhibit growth and metastasis of prostate cancer in vivo. Human prostate cancer PC-3-LacZ-luciferase cells were implanted into the ventral lateral lobes of the prostate in 39 athymic Nu/Nu nude male mice. Seven days later, mice were randomized into the control group (n = 14, treated intraperitoneally with phosphate buffered saline), low dose group (n = 10, treated intraperitoneally with AMPA at 400 mg/kg body weight/day), and high dose group (n = 15, treated intraperitoneally with AMPA at 800 mg/kg body weight/day). Tumor growth and metastasis were examined every 4-7 days by bioluminescence imaging of live mice. We found that AMPA treatment significantly inhibited growth and metastasis of orthotopic xenograft prostate tumors and prolonged the survival time of the mice. AMPA treatment decreased expression of BIRC2 and activated caspase 3, leading to increased apoptosis in the prostate tumors. AMPA treatment decreased expression of cyclin D1. AMPA treatment also reduced angiogenesis in the prostate tumors. Taken together, these results demonstrate that AMPA can inhibit prostate cancer growth and metastasis, suggesting that AMPA may be developed into a therapeutic agent for the treatment of prostate cancer. PMID:26840261

  18. Aminomethylphosphonic acid inhibits growth and metastasis of human prostate cancer in an orthotopic xenograft mouse model.

    PubMed

    Parajuli, Keshab Raj; Zhang, Qiuyang; Liu, Sen; You, Zongbing

    2016-03-01

    Aminomethylphosphonic acid (AMPA) has been shown to inhibit prostate cancer cell growth in vitro. The purpose of the present study was to determine if AMPA could inhibit growth and metastasis of prostate cancer in vivo. Human prostate cancer PC-3-LacZ-luciferase cells were implanted into the ventral lateral lobes of the prostate in 39 athymic Nu/Nu nude male mice. Seven days later, mice were randomized into the control group (n = 14, treated intraperitoneally with phosphate buffered saline), low dose group (n = 10, treated intraperitoneally with AMPA at 400 mg/kg body weight/day), and high dose group (n = 15, treated intraperitoneally with AMPA at 800 mg/kg body weight/day). Tumor growth and metastasis were examined every 4-7 days by bioluminescence imaging of live mice. We found that AMPA treatment significantly inhibited growth and metastasis of orthotopic xenograft prostate tumors and prolonged the survival time of the mice. AMPA treatment decreased expression of BIRC2 and activated caspase 3, leading to increased apoptosis in the prostate tumors. AMPA treatment decreased expression of cyclin D1. AMPA treatment also reduced angiogenesis in the prostate tumors. Taken together, these results demonstrate that AMPA can inhibit prostate cancer growth and metastasis, suggesting that AMPA may be developed into a therapeutic agent for the treatment of prostate cancer.

  19. Patient-derived xenograft (PDX) models in basic and translational breast cancer research.

    PubMed

    Dobrolecki, Lacey E; Airhart, Susie D; Alferez, Denis G; Aparicio, Samuel; Behbod, Fariba; Bentires-Alj, Mohamed; Brisken, Cathrin; Bult, Carol J; Cai, Shirong; Clarke, Robert B; Dowst, Heidi; Ellis, Matthew J; Gonzalez-Suarez, Eva; Iggo, Richard D; Kabos, Peter; Li, Shunqiang; Lindeman, Geoffrey J; Marangoni, Elisabetta; McCoy, Aaron; Meric-Bernstam, Funda; Piwnica-Worms, Helen; Poupon, Marie-France; Reis-Filho, Jorge; Sartorius, Carol A; Scabia, Valentina; Sflomos, George; Tu, Yizheng; Vaillant, François; Visvader, Jane E; Welm, Alana; Wicha, Max S; Lewis, Michael T

    2016-12-01

    Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational preclinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and "Triple-negative" (TNBC)). Many of these models are well-characterized with respect to genomic, transcriptomic, and proteomic features, metastatic behavior, and treatment response to a variety of standard-of-care and experimental therapeutics. These stably transplantable PDX lines are generally available for dissemination to laboratories conducting translational research, and contact information for each collection is provided. This review summarizes current experiences related to PDX generation across participating groups, efforts to develop data standards for annotation and dissemination of patient clinical information that does not compromise patient privacy, efforts to develop complementary data standards for annotation of PDX characteristics and biology, and progress toward "credentialing" of PDX models as surrogates to represent individual patients for use in preclinical and co-clinical translational research. In addition, this review highlights important unresolved questions, as well as current limitations, that have hampered more efficient generation of PDX lines and more rapid adoption of PDX use in translational breast cancer research.

  20. [Development of the lung cancer diagnostic system].

    PubMed

    Lv, You-Jiang; Yu, Shou-Yi

    2009-07-01

    To develop a lung cancer diagnosis system. A retrospective analysis was conducted in 1883 patients with primary lung cancer or benign pulmonary diseases (pneumonia, tuberculosis, or pneumonia pseudotumor). SPSS11.5 software was used for data processing. For the relevant factors, a non-factor Logistic regression analysis was used followed by establishment of the regression model. Microsoft Visual Studio 2005 system development platform and VB.Net corresponding language were used to develop the lung cancer diagnosis system. The non-factor multi-factor regression model showed a goodness-of-fit (R2) of the model of 0.806, with a diagnostic accuracy for benign lung diseases of 92.8%, a diagnostic accuracy for lung cancer of 89.0%, and an overall accuracy of 90.8%. The model system for early clinical diagnosis of lung cancer has been established.

  1. Gallotannin inhibits NFĸB signaling and growth of human colon cancer xenografts.

    PubMed

    Al-Halabi, Racha; Bou Chedid, Mirella; Abou Merhi, Raghida; El-Hajj, Hiba; Zahr, Hind; Schneider-Stock, Regine; Bazarbachi, Ali; Gali-Muhtasib, Hala

    2011-07-01

    Gallotannin (GT), the polyphenolic hydrolyzable tannin, exhibits anti-inflammatory and anticancer activities through mechanisms that are not fully understood. Several effects modulated by GT have been shown to be linked to interference with inflammatory mediators. Considering the central role of nuclear factor kappa B (NF-ĸB) in inflammation and cancer, we investigated the effect of GT on NF-ĸB signaling in HT-29 and HCT-116 human colon cancer cells. DNA binding assays revealed significant suppression of tumor necrosis factor (TNF-α)-induced NFĸB activation which correlated with the inhibition of IĸBα phosphorylation and degradation. Sequentially, p65 nuclear translocation and DNA binding were inhibited. GT also down-regulated the expression of NFĸB-regulated inflammatory cytokines (IL-8, TNF-α, IL-1α) and caused cell cycle arrest and accumulation of cells in pre-G 1 phase. In vivo, GT (25 mg/kg body weight) injected intraperitoneally (i.p.) prior to or after tumor inoculation significantly decreased the volume of human colon cancer xenografts in NOD/SCID mice. GT-treated xenografts showed significantly lower microvessel density (CD31) as well as lower mRNA expression levels of IL-6, TNF-α and IL-1α and of the proliferation (Ki-67) and angiogenesis (VEGFA) proteins, which may explain GTs in vivo anti-tumorigenic effects. Overall, our results indicate that the anti-inflammatory and antitumor activities of GT may be mediated in part through the suppression of NF-ĸB activation.

  2. Increased expression of Beige/Brown adipose markers from host and breast cancer cells influence xenograft formation in mice

    PubMed Central

    Singh, Rajan; Parveen, Meher; Basgen, John M.; Fazel, Sayeda; Meshesha, Meron F.; Thames, Easter C.; Moore, Brandis; Martinez, Luis; Howard, Carolyn B.; Vergnes, Laurent; Reue, Karen; Pervin, Shehla

    2016-01-01

    The initiation and progression of breast cancer is a complex process that is influenced by heterogeneous cell populations within the tumor microenvironment (TME). Although adipocytes have been shown to promote breast cancer development, adipocyte characteristics involved in this process remain poorly understood. In this study, we demonstrate enrichment of beige/brown adipose markers, contributed from the host as well as tumor cells, in the xenografts from breast cancer cell lines. In addition to uncoupling protein-1 (UCP1) that is exclusively expressed in beige/brown adipocytes, gene expression for classical brown (MYF5, EVA1 and OPLAH), as well as beige (CD137/TNFRSF9 and TBX1) adipocyte markers, were also elevated in the xenografts. Enrichment of beige/brown characteristics in the xenografts was independent of the site of implantation of the breast tumor cells. Early stages of xenografts showed an expansion of a subset of mammary cancer stem cells (MCSCs) that expressed PRDM16, a master regulator of brown adipocyte differentiation. Depletion of UCP1+ or Myf5+ cells significantly reduced tumor development. There was increased COX-2 (MT-CO2) expression, which is known to stimulate formation of beige adipocytes in early xenografts and treatment with a COX-2 inhibitor (SC236) reduced tumor growth. By contrast, treatment with factors that induce brown adipocyte differentiation in vitro led to larger tumors in vivo. A panel of xenografts derived from established breast tumor cells as well as patient-tumor tissues were generated that expressed key brown adipose tissue (BAT)-related markers and contained cells that morphologically resembled brown adipocytes. Implications This is the first report demonstrating that beige /brown adipocyte characteristics could play an important role in breast tumor development and suggest a potential target for therapeutic drug design. PMID:26464213

  3. Lung Cancer in Never Smokers

    PubMed Central

    Yang, Ping

    2012-01-01

    Lung cancer in never smokers (LCINS) has lately been recognized as a unique disease based on rapidly gained knowledge from genomic changes to treatment responses. The focus of this article is on current knowledge and challenges with regard to LCINS expanded from recent reviews highlighting five areas: (1) distribution of LCINS by temporal trends, geographic regions, and populations; (2) three well-recognized environmental risk factors; (3) other plausible environmental risk factors; (4) prior chronic lung diseases and infectious diseases as risk factors; and (5) lifestyles as risk or protective factors. This article will also bring attention to recently published literature in two pioneering areas: (1) histological characteristics, clinical features with emerging new effective therapies, and social and psychological stigma; and (2) searching for susceptibility genes using integrated genomic approaches. PMID:21500120

  4. The bisphosphonate zoledronic acid effectively targets lung cancer cells by inhibition of protein prenylation

    SciTech Connect

    Xie, Fan; Li, Pengcheng; Gong, Jianhua; Zhang, Jiahong; Ma, Jingping

    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.

  5. CXCR4 antibody treatment suppresses metastatic spread to the lung of intratibial human osteosarcoma xenografts in mice.

    PubMed

    Brennecke, Patrick; Arlt, Matthias J E; Campanile, Carmen; Husmann, Knut; Gvozdenovic, Ana; Apuzzo, Tiziana; Thelen, Marcus; Born, Walter; Fuchs, Bruno

    2014-03-01

    Current combined surgical and neo-adjuvant chemotherapy of primary metastatic osteosarcoma (OS) is ineffective, reflected by a 5-year survival rate of affected patients of less than 20 %. Studies in experimental OS metastasis models pointed to the CXCR4/CXCL12 homing axis as a novel target for OS metastasis-suppressive treatment. The present study investigated for the first time the CXCR4-blocking principle in a spontaneously metastasizing human 143B OS cell line-derived orthotopic xenograft mouse model. The highly metastatic 143B cells, unlike the parental non-metastatic HOS cells, express functional CXCR4 receptors at the cell surface, as revealed in this study by RT/PCR of gene transcripts, by FACS analysis with the monoclonal anti CXCR4 antibody 12G5 (mAb 12G5) and by CXCL12 time- and dose-dependent stimulation of AKT and ERK phosphorylation. A significantly (p < 0.05) higher CXCL12 dose-dependent chemotactic response of 143B compared to HOS cells in a Boyden chamber trans-well migration assay suggested a crucial role of the CXCL12/CXCR4 homing axis in 143B cell lung metastasis. Repetitive treatment of mice with 143B cell-derived intratibial tumors given intravenous bolus injections of mAb12G5 indeed inhibited significantly (p < 0.01) the number of X-gal-stainable lung micrometastases of lacZ-transduced 143B cells. Antibody treatment had also a mild inhibitory effect on primary tumor growth associated with remarkably less osteolysis, but it did not affect the number of developing lung macrometastases. In conclusion, these results demonstrate considerable potential of high-affinity CXCR4-blocking agents for OS tumor cell homing suppressive treatment in metastasizing OS complementary to current (neo)-adjuvant chemotherapy.

  6. Enhanced Quitline Intervention in Smoking Cessation for Patients With Non-Metastatic Lung Cancer

    ClinicalTrials.gov

    2017-02-20

    Limited Stage Small Cell Lung Cancer; Recurrent Small Cell Lung Cancer; Stage IA Non-small Cell Lung Cancer; Stage IB 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; Tobacco Use Disorder

  7. Screening and early detection of lung cancer.

    PubMed

    Van't Westeinde, Susan C; van Klaveren, Rob J

    2011-01-01

    Lung cancer with an estimated 342,000 deaths in 2008 (20% of total) is the most common cause of death from cancer, followed by colorectal cancer (12%), breast cancer (8%), and stomach cancer (7%) in Europe. In former smokers, the absolute lung cancer risk remains higher than in never-smokers; these data therefore call for effective secondary preventive measures for lung cancer in addition to smoking cessation programs. This review presents and discusses the most recent advances in the early detection and screening of lung cancer.An overview of randomized controlled computerized tomography-screening trials is given, and the role of bronchoscopy and new techniques is discussed. Finally, the approach of (noninvasive) biomarker testing in the blood, exhaled breath, sputum, and bronchoscopic specimen is reviewed.

  8. Synergistic and attenuated effect of HSS in combination treatment with docetaxel plus cisplatin in human non-small-cell lung SPC-A-1 tumor xenograft.

    PubMed

    Jia, Yuping; Zhou, Dongshun; Jia, Qingwen; Ying, Yong; Chen, Shuntai

    2016-04-01

    Platinum based combination regimens are first-line treatment option in treatment of non-small cell lung cancer (NSCLC) but the clinical utility has been limited because of their toxicities. Many reports indicated that patients with tumors can benefit from adjuvant chemotherapy drugs. The aim of this study was to confirm adjuvant chemotherapy of HSS with docetaxel plus cisplatin (DP) against NSCLC by evaluating antitumor activity and attenuated effect. In vivo SPC-A-1 xenograft model was established to evaluate antitumor activity and toxicity of HSS along or combination with DP. Evaluation indexes include the relative tumor proliferation rate, tumor growth inhibition rate, body weight, food consumption, hematological and biochemical analysis. HSS treatment showed inhibited tumor growth and increased tumor inhibition of DP treatment at doses of 250 mg/kg and 500 mg/kg. No significant toxicity was found in HSS-treated mice, but significant toxicity was found in DP-treated mice. HSS combination with DP could reduce toxicity of DP treatment by improving body weight and food consumption, and increasing the number of WBC and PLT, decreasing the level of ALT, AST and BUN. HSS combined with DP treatment has additive effect which contributes to enhance tumor growth inhibition of DP treatment and attenuated effect which contributes to reduce toxicity of DP treatment. These findings indicate potential benefit for use of HSS adjuvant chemotherapy for NSCLC treatment. Copyright © 2016. Published by Elsevier Masson SAS.

  9. MicroRNA-383 is a tumor suppressor in human lung cancer by targeting endothelial PAS domain-containing protein 1.

    PubMed

    Ma, Hongjing; Liu, Bin; Wang, Shuoying; Liu, Jing

    2016-12-01

    Lung cancer is the deadliest of all human cancers worldwide. The role of microRNA (miR)-383 has been controversial in the initiation and progression of different cancers. We aimed to investigate the function of miR-383 in human lung cancer both in vitro and in vivo. MicroRNA-383 levels were analyzed in noncancerous versus cancerous human lung tissues and in normal versus lung cancer cell lines. Effect of miR-383 on cell migration and invasion was examined in vitro and on tumor growth by using a xenograft mouse model in vivo. Potential mRNA target of miR-383 was predicted, and underlying mechanism was explored as well. MicroRNA-383 was downregulated in lung cancer tissue and cell lines. Expression of miR-383 inhibited migration and invasion of human lung cancer cell lines in vitro and tumorigenesis of lung cancer xenografts in vivo. MicroRNA-383 directly targeted 3' untranslated region of endothelial PAS domain-containing protein 1 (EPAS1) messenger RNA and inhibited both its mRNA and protein expressions. Reintroduction of EPAS1 could bypass the inhibition by miR-383 on tumorigenesis of human lung cancer cell lines. MicroRNA-383 is a tumor suppressor in human lung cancer by inhibiting EPAS1, both of which could serve as potential therapeutic targets in the treatment of lung cancer. MicroRNA-383 is a tumor suppressor in human lung cancer, which functions to inhibit tumorigenesis of lung cancer cells both in vitro and in vivo. This inhibitory effect is mediated by direct targeting of EPAS1 mRNA and subsequent repressing of its expression. Both microRNA-383 and EPAS1 could serve as potential therapeutic targets in the treatment of lung cancer. Copyright © 2016 John Wiley & Sons, Ltd.

  10. Lung cancer stem cells: An epigenetic perspective.

    PubMed

    Shukla, Samriddhi; Khan, Sajid; Sinha, Sonam; Meeran, Syed Musthapa

    2017-02-05

    Lung cancer remains the major cause of human mortality among all the cancer types despite the colossal amount of efforts to prevent the cancer onset and to provide the appropriate cure. Recent reports have identified that important contributors of lung cancer-related mortality are the drug resistance and aggressive tumor relapse, the characteristics contributed by the presence of lung cancer stem cells (CSCs). The identification of lung CSCs is inherently complex due to the quiescent nature of lung epithelium, which makes the distinction between the normal lung epithelium and lung CSCs difficult. Recently, multiple researches have helped in the identification of lung CSCs based on the presence or absence of certain specific types of stem cell markers. Maintenance of lung CSCs is chiefly mediated through the epigenetic modifications of their genome. In this review, we will discuss about the origin of lung CSCs and the role of epigenetic modifications in their maintenance. We will also discuss in brief the major lung CSC markers and the therapeutic approaches to selectively target this population of cells.

  11. Transcriptomic alterations in human prostate cancer cell LNCaP tumor xenograft modulated by dietary phenethyl isothiocyanate

    USDA-ARS?s Scientific Manuscript database

    Temporal growth of tumor xenografts in mice on a control diet was compared to mice supplemented daily with 3 µmol/g of the cancer preventive compound phenethyl isothiocyanate. Phenethyl isothiocyanate decreased the rate of tumor growth. The effects of phenethyl isothiocyanate on tumor growth were ex...

  12. Age and cellular context influence rectal prolapse formation in mice with caecal wall colorectal cancer xenografts

    PubMed Central

    Tommelein, Joke; Gremonprez, Félix; Verset, Laurine; De Vlieghere, Elly; Wagemans, Glenn; Gespach, Christian; Boterberg, Tom; Demetter, Pieter; Ceelen, Wim; Bracke, Marc; De Wever, Olivier

    2016-01-01

    In patients with rectal prolapse is the prevalence of colorectal cancer increased, suggesting that a colorectal tumor may induce rectal prolapse. Establishment of tumor xenografts in immunodeficient mice after orthotopic inoculations of human colorectal cancer cells into the caecal wall is a widely used approach for the study of human colorectal cancer progression and preclinical evaluation of therapeutics. Remarkably, 70% of young mice carrying a COLO320DM caecal tumor showed symptoms of intussusception of the large bowel associated with intestinal lumen obstruction and rectal prolapse. The quantity of the COLO320DM bioluminescent signal of the first three weeks post-inoculation predicts prolapse in young mice. Rectal prolapse was not observed in adult mice carrying a COLO320DM caecal tumor or young mice carrying a HT29 caecal tumor. In contrast to HT29 tumors, which showed local invasion and metastasis, COLO320DM tumors demonstrated a non-invasive tumor with pushing borders without presence of metastasis. In conclusion, rectal prolapse can be linked to a non-invasive, space-occupying COLO320DM tumor in the gastrointestinal tract of young immunodeficient mice. These data reveal a model that can clarify the association of patients showing rectal prolapse with colorectal cancer. PMID:27689329

  13. Anti-Cancer Effect of Quercetin in Xenograft Models with EBV-Associated Human Gastric Carcinoma.

    PubMed

    Lee, Hwan Hee; Lee, Seulki; Shin, Yu Su; Cho, Miyeon; Kang, Hyojeung; Cho, Hyosun

    2016-09-26

    Licorice extracts have been widely used in herbal and folk medications. Glycyrrhiza contains diverse range of biological compounds including triterpenes (glycyrrhizin, glycyrrhizic acid) and flavonoids (quercetin, liquiritin, liquiritigenin, glabridin, licoricidin, isoliquiritigenin). The flavonoids in licorice are known to have strong anti-cancer activities. Quercetin, the most abundant flavonoid, has been shown to have anti-ulcer, anti-cancer, antioxidant, and anti-inflammatory properties. Latent Epstein-Barr virus (EBV) infection can lead to serious malignancies, such as, Burkitt's lymphoma, Hodgkin's disease and gastric carcinoma(GC), and (Epstein-Barr virus associated gastric carcinoma) EBVaGC is one of the most common EBV-associated cancers. In this study, the authors first examined the anti-cancer effects of quercetin and isoliquiritigenin in vivo xenograft animal models implanted with EBV(+) human gastric carcinoma (SNU719) or EBV(-) human gastric carcinoma (MKN74), and then explored the molecular mechanisms responsible for their anti-cancer activities. The results obtained showed that anti-cancer effect of quercetin was greater than isoliquiritigenin in mice injected with EBV(+) human gastric carcinoma (SNU719) cells. On the other hand, quercetin and isoliquiritigenin had similar anti-cancer effects in mice injected with EBV(-) human gastric carcinoma (MKN74) cells. Interestingly, quercetin inhibited EBV viral protein expressions, including EBNA-1 and LMP-2 proteins in tumor tissues from mice injected with EBV(+) human gastric carcinoma. Quercetin more effectively induced p53-dependent apoptosis than isoliquiritigenin in EBV(+) human gastric carcinoma, and this induction was correlated with increased expressions of the cleaved forms of caspase-3, -9, and Parp. In EBV(-)human gastric carcinoma (MKN74), both quercetin and isoliquiritigenin induced the expressions of p53, Bax, and Puma and the cleaved forms of caspase-3 and -9 and Parp at similar levels.

  14. The Anti-Proliferative Effect of Boron Neutron Capture Therapy in a Prostate Cancer Xenograft Model

    PubMed Central

    Yoshikawa, Yuki; Takai, Tomoaki; Ibuki, Naokazu; Hirano, Hajime; Nomi, Hayahito; Kawabata, Shinji; Kiyama, Satoshi; Miyatake, Shin-Ichi; Kuroiwa, Toshihiko; Suzuki, Minoru; Kirihata, Mitsunori; Azuma, Haruhito

    2015-01-01

    Purpose Boron neutron capture therapy (BNCT) is a selective radiation treatment for tumors that preferentially accumulate drugs carrying the stable boron isotope, 10B. BNCT has been evaluated clinically as an alternative to conventional radiation therapy for the treatment of brain tumors, and more recently, recurrent advanced head and neck cancer. Here we investigated the effect of BNCT on prostate cancer (PCa) using an in vivo mouse xenograft model that we have developed. Materials and Methods Mice bearing the xenotransplanted androgen-independent human PCa cell line, PC3, were divided into four groups: Group 1: untreated controls; Group 2: Boronophenylalanine (BPA); Group 3: neutron; Group 4: BPA-mediated BNCT. We compared xenograft growth among these groups, and the body weight and any motility disturbance were recorded. Immunohistochemical (IHC) studies of the proliferation marker, Ki-67, and TUNEL staining were performed 9 weeks after treatment. Results The in vivo studies demonstrated that BPA-mediated BNCT significantly delayed tumor growth in comparison with the other groups, without any severe adverse events. There was a significant difference in the rate of freedom from gait abnormalities between the BPA-mediated BNCT group and the other groups. The IHC studies revealed that BNCT treatment significantly reduced the number of Ki-67-positive cells in comparison with the controls (mean±SD 6.9±1.5 vs 12.7±4.0, p<0.05), while there was no difference in the number of apoptotic cells, suggesting that BPA-mediated BNCT reduced PCa progression without affecting apoptosis at 9 weeks post-treatment. Conclusions This study has provided the first preclinical proof-of-principle data to indicate that BPA-mediated BNCT reduces the in vivo growth of PCa. Although further studies will be necessary, BNCT might be a novel potential treatment for PCa. PMID:26325195

  15. The Anti-Proliferative Effect of Boron Neutron Capture Therapy in a Prostate Cancer Xenograft Model.

    PubMed

    Takahara, Kiyoshi; Inamoto, Teruo; Minami, Koichiro; Yoshikawa, Yuki; Takai, Tomoaki; Ibuki, Naokazu; Hirano, Hajime; Nomi, Hayahito; Kawabata, Shinji; Kiyama, Satoshi; Miyatake, Shin-Ichi; Kuroiwa, Toshihiko; Suzuki, Minoru; Kirihata, Mitsunori; Azuma, Haruhito

    2015-01-01

    Boron neutron capture therapy (BNCT) is a selective radiation treatment for tumors that preferentially accumulate drugs carrying the stable boron isotope, 10B. BNCT has been evaluated clinically as an alternative to conventional radiation therapy for the treatment of brain tumors, and more recently, recurrent advanced head and neck cancer. Here we investigated the effect of BNCT on prostate cancer (PCa) using an in vivo mouse xenograft model that we have developed. Mice bearing the xenotransplanted androgen-independent human PCa cell line, PC3, were divided into four groups: Group 1: untreated controls; Group 2: Boronophenylalanine (BPA); Group 3: neutron; Group 4: BPA-mediated BNCT. We compared xenograft growth among these groups, and the body weight and any motility disturbance were recorded. Immunohistochemical (IHC) studies of the proliferation marker, Ki-67, and TUNEL staining were performed 9 weeks after treatment. The in vivo studies demonstrated that BPA-mediated BNCT significantly delayed tumor growth in comparison with the other groups, without any severe adverse events. There was a significant difference in the rate of freedom from gait abnormalities between the BPA-mediated BNCT group and the other groups. The IHC studies revealed that BNCT treatment significantly reduced the number of Ki-67-positive cells in comparison with the controls (mean ± SD 6.9 ± 1.5 vs 12.7 ± 4.0, p<0.05), while there was no difference in the number of apoptotic cells, suggesting that BPA-mediated BNCT reduced PCa progression without affecting apoptosis at 9 weeks post-treatment. This study has provided the first preclinical proof-of-principle data to indicate that BPA-mediated BNCT reduces the in vivo growth of PCa. Although further studies will be necessary, BNCT might be a novel potential treatment for PCa.

  16. Apigenin suppresses the growth of colorectal cancer xenografts via phosphorylation and up-regulated FADD expression.

    PubMed

    Wang, Qi Rui; Yao, Xue Qing; Wen, Ge; Fan, Qin; Li, Ying-Jia; Fu, Xiu Qiong; Li, Chang Ke; Sun, Xue Gang

    2011-01-01

    Apigenin is a flavonoid belonging to the flavone structural class. It has been implicated as a chemopreventive agent against prostate and breast cancers. However, to the best of our knowledge, no published data are available regarding apigenin in colorectal cancer (CRC). The effects and mechanisms of apigenin on CRC may vary significantly. This study aimed to analyze the effects of apigenin on the growth of CRC xenografts in nude mice derived from SW480, as well as to investigate the underlying mechanisms. Whole-body fluorescence imaging is an inexpensive optical system used to visualize gene expression in small mammals using reporter genes, such as eGFP as a reporter. In our study, the expression of eGFP may reflect the size of the tumor. A terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assay showed that apigenin promoted the apoptosis of CRC cells. Furthermore, the expression of five genes related to the proliferation and apoptosis of CRC, i.e., cyclin D1, BAG-1, Bcl-2, yrdC and Fas-associated protein with death domain (FADD), was detected by real-time quantitative RT-PCR. Among these genes, the up-regulated expression of FADD was noted in CRC xenograft tumors treated with apigenin. Immunohistochemistry and Western blotting confirmed the results at the protein level. Furthermore, Western blot analysis showed that apigenin induced the phosphorylation of FADD. Our findings suggest that apigenin enhances the expression of FADD and induces its phosphorylation, which may cause apoptosis of CRC cells and inhibition of tumor growth.

  17. Growth hormone receptor antagonism suppresses tumour regrowth after radiotherapy in an endometrial cancer xenograft model.

    PubMed

    Evans, Angharad; Jamieson, Stephen M F; Liu, Dong-Xu; Wilson, William R; Perry, Jo K

    2016-08-28

    Human GH expression is associated with poor survival outcomes for endometrial cancer patients, enhanced oncogenicity of endometrial cancer cells and reduced sensitivity to ionising radiation in vitro, suggesting that GH is a potential target for anticancer therapy. However, whether GH receptor inhibition sensitises to radiotherapy in vivo has not been tested. In the current study, we evaluated whether the GH receptor antagonist, pegvisomant (Pfizer), sensitises to radiotherapy in vivo in an endometrial tumour xenograft model. Subcutaneous administration of pegvisomant (20 or 100 mg/kg/day, s.c.) reduced serum IGF1 levels by 23% and 68%, respectively, compared to vehicle treated controls. RL95-2 xenografts grown in immunodeficient NIH-III mice were treated with vehicle or pegvisomant (100 mg/kg/day), with or without fractionated gamma radiation (10 × 2.5 Gy over 5 days). When combined with radiation, pegvisomant significantly increased the median time tumours took to reach 3× the pre-radiation treatment volume (49 days versus 72 days; p = 0.001). Immunohistochemistry studies demonstrated that 100 mg/kg pegvisomant every second day was sufficient to abrogate MAP Kinase signalling throughout the tumour. In addition, treatment with pegvisomant increased hypoxic regions in irradiated tumours, as determined by immunohistochemical detection of pimonidazole adducts, and decreased the area of CD31 labelling in unirradiated tumours, suggesting an anti-vascular effect. Pegvisomant did not affect intratumoral staining for HIF1α, VEGF-A, CD11b, or phospho-EGFR. Our results suggest that blockade of the human GH receptor may improve the response of GH and/or IGF1-responsive endometrial tumours to radiation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. Molecular biology of lung cancer: clinical implications.

    PubMed

    Larsen, Jill E; Minna, John D

    2011-12-01

    Lung cancer is a heterogeneous disease clinically, biologically, histologically, and molecularly. Understanding the molecular causes of this heterogeneity, which might reflect changes occurring in different classes of epithelial cells or different molecular changes occurring in the same target lung epithelial cells, is the focus of current research. Identifying the genes and pathways involved, determining how they relate to the biological behavior of lung cancer, and their utility as diagnostic and therapeutic targets are important basic and translational research issues. This article reviews current information on the key molecular steps in lung cancer pathogenesis, their timing, and clinical implications. Published by Elsevier Inc.

  19. Cancer Stem Cells in Lung Tumorigenesis

    PubMed Central

    Kratz, Johannes R.; Yagui-Beltrán, Adam; Jablons, David M.

    2011-01-01

    Although stem cells were discovered more than 50 years ago, we have only recently begun to understand their potential importance in cancer biology. Recent advances in our ability to describe, isolate, and study lung stem cell populations has led to a growing recognition of the central importance cells with stem cell-like properties may have in lung tumorigenesis. This article reviews the major studies supporting the existence and importance of cancer stem cells in lung tumorigenesis. Continued research in the field of lung cancer stem cell biology is vital, as ongoing efforts promise to yield new prognostic and therapeutic targets. PMID:20493987

  20. Establishment of a patient-derived orthotopic Xenograft (PDOX) model of HER-2-positive cervical cancer expressing the clinical metastatic pattern.

    PubMed

    Hiroshima, Yukihiko; Zhang, Yong; Zhang, Nan; Maawy, Ali; Mii, Sumiyuki; Yamamoto, Mako; Uehara, Fuminari; Miwa, Shinji; Yano, Shuya; Murakami, Takashi; Momiyama, Masashi; Chishima, Takashi; Tanaka, Kuniya; Ichikawa, Yasushi; Bouvet, Michael; Murata, Takuya; Endo, Itaru; Hoffman, Robert M

    2015-01-01

    Squamous cell carcinoma of the cervix, highly prevalent in the developing world, is often metastatic and treatment resistant with no standard treatment protocol. Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI). Unlike subcutaneous transplant patient-derived xenograft (PDX) models, PDOX models metastasize. Most importantly, the metastasis pattern correlates to the patient. In the present report, we describe the development of a PDOX model of HER-2-positive cervical cancer. Metastasis after SOI in nude mice included peritoneal dissemination, liver metastasis, lung metastasis as well as lymph node metastasis reflecting the metastatic pattern in the donor patient. Metastasis was detected in 4 of 6 nude mice with primary tumors. Primary tumors and metastases in the nude mice had histological structures similar to the original tumor and were stained by an anti-HER-2 antibody in the same pattern as the patient's cancer. The metastatic pattern, histology and HER-2 tumor expression of the patient were thus preserved in the PDOX model. In contrast, subcutaneous transplantation of the patient's cervical tumors resulted in primary growth but not metastasis.

  1. Establishment of a Patient-Derived Orthotopic Xenograft (PDOX) Model of HER-2-Positive Cervical Cancer Expressing the Clinical Metastatic Pattern

    PubMed Central

    Hiroshima, Yukihiko; Zhang, Yong; Zhang, Nan; Maawy, Ali; Mii, Sumiyuki; Yamamoto, Mako; Uehara, Fuminari; Miwa, Shinji; Yano, Shuya; Murakami, Takashi; Momiyama, Masashi; Chishima, Takashi; Tanaka, Kuniya; Ichikawa, Yasushi; Bouvet, Michael; Murata, Takuya; Endo, Itaru; Hoffman, Robert M.

    2015-01-01

    Squamous cell carcinoma of the cervix, highly prevalent in the developing world, is often metastatic and treatment resistant with no standard treatment protocol. Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI). Unlike subcutaneous transplant patient-derived xenograft (PDX) models, PDOX models metastasize. Most importantly, the metastasis pattern correlates to the patient. In the present report, we describe the development of a PDOX model of HER-2-positive cervical cancer. Metastasis after SOI in nude mice included peritoneal dissemination, liver metastasis, lung metastasis as well as lymph node metastasis reflecting the metastatic pattern in the donor patient. Metastasis was detected in 4 of 6 nude mice with primary tumors. Primary tumors and metastases in the nude mice had histological structures similar to the original tumor and were stained by an anti-HER-2 antibody in the same pattern as the patient’s cancer. The metastatic pattern, histology and HER-2 tumor expression of the patient were thus preserved in the PDOX model. In contrast, subcutaneous transplantation of the patient’s cervical tumors resulted in primary growth but not metastasis. PMID:25689852

  2. Lung Cancer - Multiple Languages: MedlinePlus

    MedlinePlus

    ... Arabic) سرطان الرئة - العربية Bilingual PDF Health Information Translations Bosnian (Bosanski) Lung Cancer Karcinom pluća - Bosanski (Bosnian) Bilingual PDF Health Information Translations Chinese - Simplified (简体中文) Lung Cancer 肺癌 - 简体中文 (Chinese - ...

  3. Lung cancer screening: the way forward

    PubMed Central

    Field, J K; Duffy, S W

    2008-01-01

    To take lung cancer screening into national programmes, we first have to answer the question whether low-dose computed tomography (LDCT) screening and treatment of early lesions will decrease lung cancer mortality compared with a control group, to accurately estimate the balance of benefits and harms, and to determine the cost-effectiveness of the intervention. PMID:18665179

  4. Lung Cancer Clinical Trials: Advances in Immunotherapy

    Cancer.gov

    New treatments for lung cancer and aspects of joining a clinical trial are discussed in this 30-minute Facebook Live event, hosted by NCI’s Dr. Shakun Malik, head of thoracic oncology therapeutics, and Janet Freeman-Daily, lung cancer patient activist and founding member of #LCSM.

  5. Recent advances in lung cancer biology

    SciTech Connect

    Lechner, J.

    1995-12-31

    This paper provides an overview of carcinogenesis, especially as related to lung cancers. Various growth factors and their mutated forms as oncogenes are discussed with respect to gene location and their role in the oncogenic process. Finally the data is related to lung cancer induction in uranium miners and exposure to radon.

  6. Indoor radon and lung cancer in China

    SciTech Connect

    Blot, W.J.; Xu, Z.Y.; Boice, J.D. Jr.; Zhao, D.Z.; Stone, B.J.; Sun, J.; Jing, L.B.; Fraumeni, J.F. Jr. )

    1990-06-20

    Radon has long been known to contribute to risk of lung cancer, especially in undergound miners who are exposed to large amounts of the carcinogen. Recently, however, lower amounts of radon present in living areas have been suggested as an important cause of lung cancer. In an effort to clarify the relationship of low amounts of radon with lung cancer risk, we placed alpha-track radon detectors in the homes of 308 women with newly diagnosed lung cancer and 356 randomly selected female control subjects of similar age. Measurements were taken after 1 year. All study participants were part of the general population of Shenyang, People's Republic of China, an industrial city in the northeast part of the country that has one of the world's highest rates of lung cancer in women. The median time of residence in the homes was 24 years. The median household radon level was 2.3 pCi/L of air; 20% of the levels were greater than 4 pCi/L. Radon levels tended to be higher in single-story houses or on the first floor of multiple-story dwellings, and they were also higher in houses with increased levels of indoor air pollution from coal-burning stoves. However, the levels were not higher in homes of women who developed lung cancer than in homes of controls, nor did lung cancer risk increase with increasing radon level. No association between radon and lung cancer was observed regardless of cigarette-smoking status, except for a nonsignificant trend among heavy smokers. No positive associations of lung cancer cell type with radon were observed, except for a nonsignificant excess risk of small cell cancers among the more heavily exposed residents. Our data suggest that projections from surveys of miners exposed to high radon levels may have overestimated the overall risks of lung cancer associated with levels typically seen in homes in this Chinese city.

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

    ClinicalTrials.gov

    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

  8. The Volume of Three-Dimensional Cultures of Cancer Cells InVitro Influences Transcriptional Profile Differences and Similarities with Monolayer Cultures and Xenografted Tumors.

    PubMed

    Boghaert, Erwin R; Lu, Xin; Hessler, Paul E; McGonigal, Thomas P; Oleksijew, Anatol; Mitten, Michael J; Foster-Duke, Kelly; Hickson, Jonathan A; Santo, Vitor E; Brito, Catarina; Uziel, Tamar; Vaidya, Kedar S

    2017-09-01

    Improving the congruity of preclinical models with cancer as it is manifested in humans is a potential way to mitigate the high attrition rate of new cancer therapies in the clinic. In this regard, three-dimensional (3D) tumor cultures in vitro have recently regained interest as they have been acclaimed to have higher similarity to tumors in vivo than to cells grown in monolayers (2D). To identify cancer functions that are active in 3D rather than in 2D cultures, we compared the transcriptional profiles (TPs) of two non-small cell lung carcinoma cell lines, NCI-H1650 and EBC-1 grown in both conditions to the TP of xenografted tumors. Because confluence, diameter or volume can hypothetically alter TPs, we made intra- and inter-culture comparisons using samples with defined dimensions. As projected by Ingenuity Pathway Analysis (IPA), a limited number of signal transduction pathways operational in vivo were better represented by 3D than by 2D cultures in vitro. Growth of 2D and 3D cultures as well as xenografts induced major changes in the TPs of these 3 modes of culturing. Alterations of transcriptional network activation that were predicted to evolve similarly during progression of 3D cultures and xenografts involved the following functions: hypoxia, proliferation, cell cycle progression, angiogenesis, cell adhesion, and interleukin activation. Direct comparison of TPs of 3D cultures and xenografts to monolayer cultures yielded up-regulation of networks involved in hypoxia, TGF and Wnt signaling as well as regulation of epithelial mesenchymal transition. Differences in TP of 2D and 3D cancer cell cultures are subject to progression of the cultures. The emulation of the predicted cell functions in vivo is therefore not only determined by the type of culture in vitro but also by the confluence or diameter of the 2D or 3D cultures, respectively. Consequently, the successful implementation of 3D models will require phenotypic characterization to verify the relevance of

  9. Analysis of the Lipidome of Xenografts Using MALDI-IMS and UHPLC-ESI-QTOF

    NASA Astrophysics Data System (ADS)

    Fernández, Roberto; Lage, Sergio; Abad-García, Beatriz; Barceló-Coblijn, Gwendolyn; Terés, Silvia; López, Daniel H.; Guardiola-Serrano, Francisca; Martín, M. Laura; Escribá, Pablo V.; Fernández, José A.

    2014-07-01

    Human tumor xenografts in immunodeficient mice are a very popular model to study the development of cancer and to test new drug candidates. Among the parameters analyzed are the variations in the lipid composition, as they are good indicators of changes in the cellular metabolism. Here, we present a study on the distribution of lipids in xenografts of NCI-H1975 human lung cancer cells, using MALDI imaging mass spectrometry and UHPLC-ESI-QTOF. The identification of lipids directly from the tissue by MALDI was aided by the comparison with identification using ESI ionization in lipid extracts from the same xenografts. Lipids belonging to PCs, PIs, SMs, DAG, TAG, PS, PA, and PG classes were identified and their distribution over the xenograft was determined. Three areas were identified in the xenograft, corresponding to cells in different metabolic stages and to a layer of adipose tissue that covers the xenograft.

  10. Analysis of the lipidome of xenografts using MALDI-IMS and UHPLC-ESI-QTOF.

    PubMed

    Fernández, Roberto; Lage, Sergio; Abad-García, Beatriz; Barceló-Coblijn, Gwendolyn; Terés, Silvia; López, Daniel H; Guardiola-Serrano, Francisca; Martín, M Laura; Escribá, Pablo V; Fernández, José A

    2014-07-01

    Human tumor xenografts in immunodeficient mice are a very popular model to study the development of cancer and to test new drug candidates. Among the parameters analyzed are the variations in the lipid composition, as they are good indicators of changes in the cellular metabolism. Here, we present a study on the distribution of lipids in xenografts of NCI-H1975 human lung cancer cells, using MALDI imaging mass spectrometry and UHPLC-ESI-QTOF. The identification of lipids directly from the tissue by MALDI was aided by the comparison with identification using ESI ionization in lipid extracts from the same xenografts. Lipids belonging to PCs, PIs, SMs, DAG, TAG, PS, PA, and PG classes were identified and their distribution over the xenograft was determined. Three areas were identified in the xenograft, corresponding to cells in different metabolic stages and to a layer of adipose tissue that covers the xenograft.

  11. Drug delivery and nanodetection in lung cancer.

    PubMed

    Badrzadeh, Fariba; Rahmati-Yamchi, Mohammad; Badrzadeh, Kazem; Valizadeh, Alireza; Zarghami, Nosratollah; Farkhani, Samad Mussa; Akbarzadeh, Abolfazl

    2016-01-01

    Lung carcinoma is the most widespread type of cancer worldwide, and is responsible for more deaths than other types of cancer. Lung cancer remains the chief cause of cancer-related deaths in both men and women worldwide, and is increasingly common in women. Each year, the number of deaths from lung cancer is greater than the number due to breast and colorectal cancer combined. Lung cancer accounted for 13% (1.6 million) of the total cases and 18% (1.4 million) of the deaths in 2008. In Iran, lung cancer is one of the five leading tumors. Among females, it was the fourth most commonly diagnosed cancer, and the second leading cause of cancer death. Nanotechnology can be defined as the science and engineering involved in the design, characterization, and application of materials and devices whose smallest functional organization in at least one dimension is on the nanometer scale, i.e. one billionth of a meter. It is an exciting multidisciplinary field that involves the design and engineering of nano objects or nanotools with diameters less than 500 nanometers (nm), and it is one of the most interesting fields of the 21st century. Nanotechnology also offers the ability to detect diseases, such as tumors, much earlier than ever imaginable. This article presents nano devices for lung cancer detection and drug delivery systems.

  12. Early diagnosis of lung cancer

    NASA Astrophysics Data System (ADS)

    Saccomanno, Geno; Bechtel, Joel J.

    1991-06-01

    Lung cancer remains the leading cause of death in the United States. Although the incidence of cigarette smoking is decreasing in the United States it appears to be increasing worldwide. The five-year survival rate has not improved in cases with advanced disease, but several articles have indicated that survival can be improved in cases diagnosed early by sputum cytology and chest x-ray. In cases diagnosed while the lesion is in the in-situ stage or measures less than 1 cm in diameter, surgical excision and/or radiation therapy improves survival; therefore, the early diagnosis of high-risk patients should be vigorously pursued. A recent study at a community hospital in Grand Junction, Colorado, presented 45 lung cancer cases diagnosed with positive sputum cytology and negative chest x-ray, and indicates that early diagnosis does improve survival. This study has been conducted during the past six years; 16 cases have survived three years and six cases show five-year survival.

  13. Enhanced cell killing in lewis lung carcinoma and a human pancreatic-carcinoma xenograft by the combination of cytotoxic drugs and misonidazole.

    PubMed

    Stephens, T C; Courtenay, V D; Mills, J; Peacock, J H; Rose, C M; Spooner, D

    1981-04-01

    The "chemosensitizing" properties of the radiosensitizer misonidazole (MISO) were examined in 2 tumour systems, murine Lewis lung carcinoma and human pancreatic adenocarcinoma xenografted into immune-suppressed mice, using a soft-agar colony assay to measure tumour-cell survival. In mice bearing Lewis lung tumour, the administration of MISO simultaneously with melphalan, cyclophosphamide. CCNU, FU or vincristine gave substantial enhancement of cytotoxicity (DEFs from 1.5 to 3.5). However, no enhancement was seen with bleomycin, VP 16-213 or cis-Pt. The same level of enhancement of cyclophosphamide effect (DEF = 2.0) was seen with both cell survival and growth delay end-points effect (DEF = 2.0) was seen with both cell survival and growth delay end-points of tumour response. Enhancement was also seen in the human tumour xenograft with melphalan, cyclophosphamide and MeCCNU, using a cell survival assay, but cis-Pt was again not enhanced.

  14. Potent anti-cancer effects of citrus peel flavonoids in human prostate xenograft tumors.

    PubMed

    Lai, Ching-Shu; Li, Shiming; Miyauchi, Yutaka; Suzawa, Michiko; Ho, Chi-Tang; Pan, Min-Hsiung

    2013-06-01

    Prostate cancer is one of the most prevalent malignancies and is the second leading cause of cancer-related deaths in men. Fruit and vegetable consumption is a novel, non-toxic therapeutic approach that can be used to prevent and treat prostate cancer. Citrus peels and their extracts have been reported to have potent pharmacological activities and health benefits due to the abundance of flavonoids in citrus fruits, particularly in the peels. Our previous studies demonstrated that oral administration of Gold Lotion (GL), an extract of multiple varieties of citrus peels containing abundant flavonoids, including a large percentage of polymethoxyflavones (PMFs), effectively suppressed azoxymethane (AOM)-induced colonic tumorigenesis. However, the efficacy of GL against prostate cancer has not yet been investigated. Here, we explored the anti-tumor effects of GL using a human prostate tumor xenograft mouse model. Our data demonstrated that treatment with GL by both intraperitoneal (i.p.) injection and oral administration dramatically reduced both the weights (57%-100% inhibition) and volumes (78%-94% inhibition) of the tumors without any observed toxicity. These inhibitory effects were accompanied by mechanistic down-regulation of the protein levels of inflammatory enzymes (inducible nitric oxide synthase, iNOS and cyclooxygenase-2, COX-2), metastasis (matrix metallopeptidase-2, MMP-2 and MMP-9), angiogenesis (vascular endothelial growth factor, VEGF), and proliferative molecules, as well as by the induction of apoptosis in prostate tumors. Our findings suggest that GL is an effective anti-cancer agent that may potentially serve as a novel therapeutic option for prostate cancer treatment.

  15. Obesity does not promote tumorigenesis of localized patient-derived prostate cancer xenografts

    PubMed Central

    Ascui, Natasha; Frydenberg, Mark; Risbridger, Gail P.; Taylor, Renea A.; Watt, Matthew J.

    2016-01-01

    There are established epidemiological links between obesity and the severity of prostate cancer. We directly tested this relationship by assessing tumorigenicity of patient-derived xenografts (PDXs) of moderate-grade localized prostate cancer in lean and obese severe combined immunodeficiency (SCID) mice. Mice were rendered obese and insulin resistant by high-fat feeding for 6 weeks prior to transplantation, and PDXs were assessed 10 weeks thereafter. Histological analysis of PDX grafts showed no differences in tumor pathology, prostate-specific antigen, androgen receptor and homeobox protein Nkx-3.1 expression, or proliferation index in lean versus obese mice. Whilst systemic obesity per se did not promote prostate tumorigenicity, we next asked whether the peri-prostatic adipose tissue (PPAT), which covers the prostate anteriorly, plays a role in prostate tumorigenesis. In vitro studies in a cellularized co-culture model of stromal and epithelial cells demonstrated that factors secreted from human PPAT are pro-tumorigenic. Accordingly, we recapitulated the prostate-PPAT spatial relationship by co-grafting human PPAT with prostate cancer in PDX grafts. PDX tissues were harvested 10 weeks after grafting, and histological analysis revealed no evidence of enhanced tumorigenesis with PPAT compared to prostate cancer grafts alone. Altogether, these data demonstrate that prostate cancer tumorigenicity is not accelerated in the setting of diet-induced obesity or in the presence of human PPAT, prompting the need for further work to define the at-risk populations of obesity-driven tumorigenesis and the biological factors linking obesity, adipose tissue and prostate cancer pathogenesis. PMID:27351281

  16. Obesity does not promote tumorigenesis of localized patient-derived prostate cancer xenografts.

    PubMed

    Lo, Jennifer C Y; Clark, Ashlee K; Ascui, Natasha; Frydenberg, Mark; Risbridger, Gail P; Taylor, Renea A; Watt, Matthew J

    2016-07-26

    There are established epidemiological links between obesity and the severity of prostate cancer. We directly tested this relationship by assessing tumorigenicity of patient-derived xenografts (PDXs) of moderate-grade localized prostate cancer in lean and obese severe combined immunodeficiency (SCID) mice. Mice were rendered obese and insulin resistant by high-fat feeding for 6 weeks prior to transplantation, and PDXs were assessed 10 weeks thereafter. Histological analysis of PDX grafts showed no differences in tumor pathology, prostate-specific antigen, androgen receptor and homeobox protein Nkx-3.1 expression, or proliferation index in lean versus obese mice. Whilst systemic obesity per se did not promote prostate tumorigenicity, we next asked whether the peri-prostatic adipose tissue (PPAT), which covers the prostate anteriorly, plays a role in prostate tumorigenesis. In vitro studies in a cellularized co-culture model of stromal and epithelial cells demonstrated that factors secreted from human PPAT are pro-tumorigenic. Accordingly, we recapitulated the prostate-PPAT spatial relationship by co-grafting human PPAT with prostate cancer in PDX grafts. PDX tissues were harvested 10 weeks after grafting, and histological analysis revealed no evidence of enhanced tumorigenesis with PPAT compared to prostate cancer grafts alone. Altogether, these data demonstrate that prostate cancer tumorigenicity is not accelerated in the setting of diet-induced obesity or in the presence of human PPAT, prompting the need for further work to define the at-risk populations of obesity-driven tumorigenesis and the biological factors linking obesity, adipose tissue and prostate cancer pathogenesis.

  17. The Impact of the Cancer Genome Atlas on Lung Cancer

    PubMed Central

    Chang, Jeremy Tzu-Huai; Lee, Yee-Ming; Huang, R. Stephanie

    2015-01-01

    The Cancer Genome Atlas (TCGA) has profiled over 10,000 samples derived from 33 types of cancer to date, with the goal of improving our understanding of the molecular basis of cancer and advancing our ability to diagnose, treat, and prevent cancer. This review focuses on lung cancer as it is the leading cause of cancer-related mortality worldwide in both men and women. Particularly, non-small cell lung cancers (including lung adenocarcinoma and lung squamous cell carcinoma) were evaluated. Our goal is to demonstrate the impact of TCGA on lung cancer research under four themes: namely, diagnostic markers, disease progression markers, novel therapeutic targets, and novel tools. Examples were given related to DNA mutation, copy number variation, mRNA, and microRNA expression along with methylation profiling. PMID:26318634

  18. WWOX gene restoration prevents lung cancer growth in vitro and in vivo.

    PubMed

    Fabbri, Muller; Iliopoulos, Dimitrios; Trapasso, Francesco; Aqeilan, Rami I; Cimmino, Amelia; Zanesi, Nicola; Yendamuri, Sai; Han, Shuang-Yin; Amadori, Dino; Huebner, Kay; Croce, Carlo M

    2005-10-25

    The WWOX (WW domain containing oxidoreductase) gene at the common fragile site, FRA16D, is altered in many types of cancer, including lung cancer. We have examined the tumor suppressor function of WWOX in preclinical lung cancer models. The WWOX gene was expressed in lung cancer cell lines through recombinant adenovirus (Ad) infection (Ad-WWOX), and through a drug [ponasterone A, (ponA)]-inducible system. After WWOX restoration in vitro, endogenous Wwox protein-negative cell lines (A549, H460, and H1299) underwent apoptosis through activation of the intrinsic apoptotic caspase cascade in A549 and H460 cells. Ectopic expression of Wwox caused dramatic suppression of tumorigenicity of A549, H460, and H1299 cells in nude mice after Ad-WWOX infection and after ponA induction of Wwox expression in H1299 lung cancer cells. Tumorigenicity and in vitro growth of U2020 (Wwox-positive) lung cancer cells was unaffected by Wwox overexpression. This study confirms that WWOX is a tumor suppressor gene and is highly effective in preventing growth of lung cancer xenografts, whether introduced through viral infection or by induction of a silent WWOX transgene.

  19. CD44 targeting reduces tumour growth and prevents post-chemotherapy relapse of human breast cancers xenografts

    PubMed Central

    Marangoni, E; Lecomte, N; Durand, L; de Pinieux, G; Decaudin, D; Chomienne, C; Smadja-Joffe, F; Poupon, M-F

    2009-01-01

    CD44 is a marker of tumour-initiating cells and is upregulated in invasive breast carcinoma; however, its role in the cancer progression is unknown. Here, we show that antibody-mediated CD44-targeting in human breast cancer xenografts (HBCx) significantly reduces tumour growth and that this effect is associated to induction of growth-inhibiting factors. Moreover, treatment with this antibody prevents tumour relapse after chemotherapy-induced remission in a basal-like HBCx. PMID:19240712

  20. Study of Ponatinib in Patients With Lung Cancer Preselected Using Different Candidate Predictive Biomarkers

    ClinicalTrials.gov

    2016-11-07

    Adenocarcinoma of the Lung; Extensive Stage Small Cell Lung Cancer; Limited Stage Small Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Recurrent 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

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

    PubMed

    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.

  2. Exosomal formulation enhances therapeutic response of celastrol against lung cancer.

    PubMed

    Aqil, Farrukh; Kausar, Hina; Agrawal, Ashish Kumar; Jeyabalan, Jeyaprakash; Kyakulaga, Al-Hassan; Munagala, Radha; Gupta, Ramesh

    2016-08-01

    Celastrol (CEL), a plant-derived triterpenoid, is a known inhibitor of Hsp90 and NF-κB activation pathways and has recently been suggested to be of therapeutic importance in various cancers. However, the molecular mechanisms of celastrol-mediated effects in lung cancer are not systematically studied. Moreover, it suffers from poor bioavailability and off-site toxicity issues. This study aims to study the effect of celastrol loaded into exosomes against two non-small cell-lung carcinoma (NSCLC) cell lines and explore the molecular mechanisms to determine the proteins governing the cellular responses. We observed that celastrol inhibited the proliferation of A549 and H1299 NSCLC cells in a time- and concentration-dependent manner as indexed by MTT assay. Mechanistically, CEL pre-treatment of H1299 cells completely abrogated TNFα-induced NF-κB activation and upregulated the expression of ER-stress chaperones Grp 94, Grp78, and pPERK. These changes in ER-stress mediators were paralleled by an increase in apoptotic response as evidenced by higher annexin-V/PI positive cells evaluated by FACS and immunoblotting which showed upregulation of the ER stress specific pro-apoptotic transcription factor, GADD153/CHOP and alteration of Bax/Bcl2 levels. Exosomes loaded with CEL exhibited enhanced anti-tumor efficacy as compared to free CEL against lung cancer cell xenograft. CEL did not exhibit any gross or systemic toxicity in wild-type C57BL6 mice as determined by hematological and liver and kidney function test. Together, our data demonstrate the chemotherapeutic potential of CEL in lung cancer and that exosomal formulation enhances its efficacy and reduces dose related toxicity. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Establishment and characterisation of patient-derived xenografts as paraclinical models for gastric cancer

    PubMed Central

    Choi, Yoon Young; Lee, Jae Eun; Kim, Hyunki; Sim, Moon Hee; Kim, Ka-Kyung; Lee, Gunho; Kim, Hyoung-Il; An, Ji Yeong; Hyung, Woo Jin; Kim, Choong-Bai; Noh, Sung Hoon; Kim, Sangwoo; Cheong, Jae-Ho

    2016-01-01

    The patient-derived xenograft (PDX) model is emerging as a promising translational platform to duplicate the characteristics of tumours. However, few studies have reported detailed histological and genomic analyses for model fidelity and for factors affecting successful model establishment of gastric cancer. Here, we generated PDX tumours surgically-derived from 62 gastric cancer patients. Fifteen PDX models were successfully established (24.2%, 15/62) and passaged to maintain tumours in immune-compromised mice. Diffuse type and low tumour cell percentage were negatively correlated with success rates (p = 0.005 and p = 0.025, respectively), while reducing ex vivo and overall procedure times were positively correlated with success rates (p = 0.003 and p = 0.01, respectively). The histology and genetic characteristics of PDX tumour models were stable over subsequent passages. Lymphoma transformation occurred in five cases (33.3%, 5/15), and all were in the NOG mouse, with none in the nude mouse. Together, the present study identified Lauren classification, tumour cell percentages, and ex vivo times along with overall procedure times, as key determinants for successful PDX engraftment. Furthermore, genetic and histological characteristics were highly consistent between primary and PDX tumours, which provide realistic paraclinical models, enabling personalised development of treatment options for gastric cancer. PMID:26926953

  4. New Immunotherapy and Lung Cancer.

    PubMed

    Sánchez de Cos Escuín, Julio

    2017-08-17

    Recent research on the relationship between the immune system and cancer has revealed the molecular mechanisms by which cancer cells co-opt certain T cell receptors which block the cytotoxic response to defend themselves from the antitumor immune attack. These findings have helped identify specific targets (T cell receptors or their corresponding ligands) for the design of monoclonal antibodies that can unlock the immune response. These drugs, known as immune checkpoint inhibitors, have shown efficacy in metastatic melanoma and kidney cancer, and have been successfully tested in non-small cell lung cancer in recent trials. Immune checkpoint inhibitors were included in clinical practice as a second-line option after an initial chemotherapy (CT) regimen, and in the last year positive results have been reported from randomized trials in which they were compared in first line with standard CT. Responses have been surprising and durable, but less than 20%-25% in unselected patients, so it is essential that factors predicting efficacy be identified. One such biomarker is PD-L1, but the different methods used to detect it have produced mixed results. This non-systematic review discusses the results of the latest trials, the possibilities of incorporating these drugs in first-line regimens, the criteria for patient selection, adverse effects, and the prospects of combinations with conventional treatment modalities, such as CT, radiation therapy, and antiangiogenic agents. Copyright © 2017 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

  5. Early Lung Cancer Diagnosis by Biosensors

    PubMed Central

    Zhang, Yuqian; Yang, Dongliang; Weng, Lixing; Wang, Lianhui

    2013-01-01

    Lung cancer causes an extreme threat to human health, and the mortality rate due to lung cancer has not decreased during the last decade. Prognosis or early diagnosis could help reduce the mortality rate. If microRNA and tumor-associated antigens (TAAs), as well as the corresponding autoantibodies, can be detected prior to clinical diagnosis, such high sensitivity of biosensors makes the early diagnosis and prognosis of cancer realizable. This review provides an overview of tumor-associated biomarker identifying methods and the biosensor technology available today. Laboratorial researches utilizing biosensors for early lung cancer diagnosis will be highlighted. PMID:23892596

  6. Proteomic identification of the lactate dehydrogenase A in a radioresistant prostate cancer xenograft mouse model for improving radiotherapy

    PubMed Central

    Hao, Jingli; Graham, Peter; Chang, Lei; Ni, Jie; Wasinger, Valerie; Beretov, Julia; Deng, Junli; Duan, Wei; Bucci, Joseph; Malouf, David; Gillatt, David; Li, Yong

    2016-01-01

    Radioresistance is a major challenge for prostate cancer (CaP) metastasis and recurrence after radiotherapy. This study aimed to identify potential protein markers and signaling pathways associated with radioresistance using a PC-3 radioresistant (RR) subcutaneous xenograft mouse model and verify the radiosensitization effect from a selected potential candidate. PC-3RR and PC-3 xenograft tumors were established and differential protein expression profiles from two groups of xenografts were analyzed using liquid chromatography tandem-mass spectrometry. One selected glycolysis marker, lactate dehydrogenase A (LDHA) was validated, and further investigated for its role in CaP radioresistance. We found that 378 proteins and 51 pathways were significantly differentially expressed between PC-3RR and PC-3 xenograft tumors, and that the glycolysis pathway is closely linked with CaP radioresistance. In addition, we also demonstrated that knock down of LDHA with siRNA or inhibition of LDHA activity with a LDHA specific inhibitor (FX-11), could sensitize PC-3RR cells to radiotherapy with reduced epithelial-mesenchymal transition, hypoxia, DNA repair ability and autophagy, as well as increased DNA double strand breaks and apoptosis. In summary, we identified a list of potential RR protein markers and important signaling pathways from a PC-3RR xenograft mouse model, and demonstrate that targeting LDHA combined with radiotherapy could increase radiosensitivity in RR CaP cells, suggesting that LDHA is an ideal therapeutic target to develop combination therapy for overcoming CaP radioresistance. PMID:27708237

  7. Development of Patient Derived Xenograft Models of Overt Spontaneous Breast Cancer Metastasis: A Cautionary Note

    PubMed Central

    Paez-Ribes, Marta; Man, Shan; Xu, Ping; Kerbel, Robert S.

    2016-01-01

    Several approaches are being evaluated to improve the historically limited value of studying transplanted primary tumors derived by injection of cells from established cell lines for predicting subsequent cancer therapy outcomes in patients and clinical trials. These approaches include use of genetically engineered mouse models (GEMMs) of spontaneous tumors, or patient tumor tissue derived xenografts (PDXs). Almost all such therapy studies utilizing such models involve treatment of established primary tumors. An alternative approach we have developed involves transplanted human tumor xenografts derived from established cell lines to treat mice with overt visceral metastases after primary tumor resection. The rationale is to mimic the more challenging circumstance of treating patients with late stage metastatic disease. These metastatic models entail prior in vivo selection of heritable, phenotypically stable variants with increased aggressiveness for spontaneous metastasis; they were derived by orthotopic injection of tumor cells followed by primary tumor resection and serial selection of distant spontaneous metastases, from which variant cell lines having a more aggressive heritable metastatic phenotype were established. We attempted to adopt this strategy for breast cancer PDXs. We studied five breast cancer PDXs, with the emphasis on two, called HCI-001 and HCI-002, both derived from triple negative breast cancer patients. However significant technical obstacles were encountered. These include the inherent slow growth rates of PDXs, the rarity of overt spontaneous metastases (detected in only 3 of 144 mice), very high rates of tumor regrowths at the primary tumor resection site, the failure of the few human PDX metastases isolated to manifest a more aggressive metastatic phenotype upon re-transplantation into new hosts, and the formation of metastases which were derived from de novo mouse thymomas arising in aged SCID mice that we used for the experiments. We

  8. Nasal Swab Shows Promise in Confirming Lung Cancers

    MedlinePlus

    ... 163805.html Nasal Swab Shows Promise in Confirming Lung Cancers Simple technique is based on cancer DNA ... 27, 2017 MONDAY, Feb. 27, 2017 (HealthDay News) -- Lung cancer remains by far the leading cancer killer ...

  9. Nutritional aspects regarding lung cancer chemoprevention.

    PubMed

    Thanopoulou, E; Baltayiannis, N; Lykogianni, V

    2006-01-01

    Lung cancer is still one of the major causes of cancer-related deaths and its mortality figures argue powerfully for new approaches to control this leading cancer threat. Chemoprevention can be defined as the use of specific agents to reverse, or prevent premalignancy from progressing to invasive cancer. The use of foods and dietary supplements present a safe chemopreventive strategy. Data for this review were identified by searches of PubMed and references from relevant articles. Articles were identified by use of the search terms "lung cancer", "chemoprevention", "carcinogenesis", and "retinoids". Only papers published in English were included. Trials in lung cancer chemoprevention have so far produced either neutral or harmful primary endpoint results, whether in the primary, secondary, or tertiary settings. Lung cancer was not prevented by beta-carotene, alpha-tocopherol, retinol, retinyl palmitate, N-acetylcysteine, or isotretinoin in smokers. Ongoing trials may help define new avenues for chemoprevention. The concept of chemoprevention in lung cancer is still in its infancy, but in the future it may have a significant impact on the incidence and mortality of lung cancer. In addition to epidemiologic studies, basic science research to detect mechanisms and evaluate the chemopreventive potential of food components is necessary. The overwhelming evidence of a major role of nutrition in carcinogenesis, the many leads that nutritional intervention may reduce cancer incidence, and the growth and increasing sophistication of clinical trials networks point to a very promising future for nutritional intervention trials leading to substantial public benefit.

  10. Patient-derived luminal breast cancer xenografts retain hormone receptor heterogeneity and help define unique estrogen-dependent gene signatures.

    PubMed

    Kabos, Peter; Finlay-Schultz, Jessica; Li, Chunling; Kline, Enos; Finlayson, Christina; Wisell, Joshua; Manuel, Christopher A; Edgerton, Susan M; Harrell, J Chuck; Elias, Anthony; Sartorius, Carol A

    2012-09-01

    Bypassing estrogen receptor (ER) signaling during development of endocrine resistance remains the most common cause of disease progression and mortality in breast cancer patients. To date, the majority of molecular research on ER action in breast cancer has occurred in cell line models derived from late stage disease. Here we describe patient-derived ER+ luminal breast tumor models for the study of intratumoral hormone and receptor action. Human breast tumor samples obtained from patients post surgery were immediately transplanted into NOD/SCID or NOD/SCID/ILIIrg(-/-) mice under estrogen supplementation. Five transplantable patient-derived ER+ breast cancer xenografts were established, derived from both primary and metastatic cases. These were assessed for estrogen dependency, steroid receptor expression, cancer stem cell content, and endocrine therapy response. Gene expression patterns were determined in select tumors ±estrogen and ±endocrine therapy. Xenografts morphologically resembled the patient tumors of origin, and expressed similar levels of ER (5-99 %), and progesterone and androgen receptors, over multiple passages. Four of the tumor xenografts were estrogen dependent, and tamoxifen or estrogen withdrawal (EWD) treatment abrogated estrogen-dependent growth and/or tumor morphology. Analysis of the ER transcriptome in select tumors revealed notable differences in ER mechanism of action, and downstream activated signaling networks, in addition to identifying a small set of common estrogen-regulated genes. Treatment of a naïve tumor with tamoxifen or EWD showed similar phenotypic responses, but relatively few similarities in estrogen-dependent transcription, and affected signaling pathways. Several core estrogen centric genes were shared with traditional cell line models. However, novel tumor-specific estrogen-regulated potential target genes, such as cancer/testis antigen 45, were uncovered. These results evoke the importance of mapping both conserved

  11. Genomic heterogeneity of multiple synchronous lung cancer

    PubMed Central

    Liu, Yu; Zhang, Jianjun; Li, Lin; Yin, Guangliang; Zhang, Jianhua; Zheng, Shan; Cheung, Hannah; Wu, Ning; Lu, Ning; Mao, Xizeng; Yang, Longhai; Zhang, Jiexin; Zhang, Li; Seth, Sahil; Chen, Huang; Song, Xingzhi; Liu, Kan; Xie, Yongqiang; Zhou, Lina; Zhao, Chuanduo; Han, Naijun; Chen, Wenting; Zhang, Susu; Chen, Longyun; Cai, Wenjun; Li, Lin; Shen, Miaozhong; Xu, Ningzhi; Cheng, Shujun; Yang, Huanming; Lee, J. Jack; Correa, Arlene; Fujimoto, Junya; Behrens, Carmen; Chow, Chi-Wan; William, William N.; Heymach, John V.; Hong, Waun Ki; Swisher, Stephen; Wistuba, Ignacio I.; Wang, Jun; Lin, Dongmei; Liu, Xiangyang; Futreal, P. Andrew; Gao, Yanning

    2016-01-01

    Multiple synchronous lung cancers (MSLCs) present a clinical dilemma as to whether individual tumours represent intrapulmonary metastases or independent tumours. In this study we analyse genomic profiles of 15 lung adenocarcinomas and one regional lymph node metastasis from 6 patients with MSLC. All 15 lung tumours demonstrate distinct genomic profiles, suggesting all are independent primary tumours, which are consistent with comprehensive histopathological assessment in 5 of the 6 patients. Lung tumours of the same individuals are no more similar to each other than are lung adenocarcinomas of different patients from TCGA cohort matched for tumour size and smoking status. Several known cancer-associated genes have different mutations in different tumours from the same patients. These findings suggest that in the context of identical constitutional genetic background and environmental exposure, different lung cancers in the same individual may have distinct genomic profiles and can be driven by distinct molecular events. PMID:27767028

  12. Dynamics of genomic clones in breast cancer patient xenografts at single cell resolution

    PubMed Central

    Eirew, Peter; Steif, Adi; Khattra, Jaswinder; Ha, Gavin; Yap, Damian; Farahani, Hossein; Gelmon, Karen; Chia, Stephen; Mar, Colin; Wan, Adrian; Laks, Emma; Biele, Justina; Shumansky, Karey; Rosner, Jamie; McPherson, Andrew; Nielsen, Cydney; Roth, Andrew J. L.; Lefebvre, Calvin; Bashashati, Ali; de Souza, Camila; Siu, Celia; Aniba, Radhouane; Brimhall, Jazmine; Oloumi, Arusha; Osako, Tomo; Bruna, Alejandra; Sandoval, Jose; Algara, Teresa; Greenwood, Wendy; Leung, Kaston; Cheng, Hongwei; Xue, Hui; Wang, Yuzhuo; Lin, Dong; Mungall, Andrew J.; Moore, Richard; Zhao, Yongjun; Lorette, Julie; Nguyen, Long; Huntsman, David; Eaves, Connie J.; Hansen, Carl; Marra, Marco A.; Caldas, Carlos; Shah, Sohrab P.; Aparicio, Samuel

    2016-01-01

    Human cancers, including breast cancers, are comprised of clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution1,2, underpinning important emergent features such as drug resistance and metastasis3–7. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours8–10. However the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours has not been systematically examined at single cell resolution. Here we show by both deep genome and single cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all 15 cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (<5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies utilizing patient-derived breast cancer xenoengraftment. PMID:25470049

  13. DMU-212 inhibits tumor growth in xenograft model of human ovarian cancer.

    PubMed

    Piotrowska, Hanna; Myszkowski, Krzysztof; Abraszek, Joanna; Kwiatkowska-Borowczyk, Eliza; Amarowicz, Ryszard; Murias, Marek; Wierzchowski, Marcin; Jodynis-Liebert, Jadwiga

    2014-05-01

    DMU-212 has been shown to evoke a mitochondrial apoptotic pathway in transformed fibroblasts and breast cancer. However, recently published data indicated the ability of DMU-212 to evoke apoptosis in both mitochondria- and receptor-mediated manner in two ovarian cancer cell lines, namely A-2780 and SKOV-3, which showed varied sensitivity to the compound tested. The pronounced cytotoxic effects of DMU-212 observed in A-2780 cells were related to the execution of extracellular apoptosis pathway and cell cycle arrest in G2/M phase. In view of the great anticancer potential of DMU-212 against A-2780 cell line, the aim of the current study was to assess antiproliferative activity of DMU-212 in xenograft model of ovarian cancer. To evaluate in vitro metabolic properties of cells that were to be injected into SCID mice, uptake and decline of DMU-212 in A-2780 ovarian cancer cell line was investigated. It was found that the concentration of the test compound in A-2780 cells was growing within first eight hours, and then the gradual decline was observed. A-2780 cells stably transfected with pcDNA3.1/Zeo(-)-Luc vector were subcutaneously inoculated into the right flanks of SCID mice. After seven days of the treatment with DMU-212 (50mg/kg b.w), tumor growth appeared to be suppressed in the animals treated with the compound tested. At day 14 of the experiment, tumor burden in mice treated with DMU-212 was significantly lower, as compared to untreated controls. Our findings suggest that DMU-212 might be considered as a potential anticancer agent used in ovarian cancer therapy. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  14. Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution.

    PubMed

    Eirew, Peter; Steif, Adi; Khattra, Jaswinder; Ha, Gavin; Yap, Damian; Farahani, Hossein; Gelmon, Karen; Chia, Stephen; Mar, Colin; Wan, Adrian; Laks, Emma; Biele, Justina; Shumansky, Karey; Rosner, Jamie; McPherson, Andrew; Nielsen, Cydney; Roth, Andrew J L; Lefebvre, Calvin; Bashashati, Ali; de Souza, Camila; Siu, Celia; Aniba, Radhouane; Brimhall, Jazmine; Oloumi, Arusha; Osako, Tomo; Bruna, Alejandra; Sandoval, Jose L; Algara, Teresa; Greenwood, Wendy; Leung, Kaston; Cheng, Hongwei; Xue, Hui; Wang, Yuzhuo; Lin, Dong; Mungall, Andrew J; Moore, Richard; Zhao, Yongjun; Lorette, Julie; Nguyen, Long; Huntsman, David; Eaves, Connie J; Hansen, Carl; Marra, Marco A; Caldas, Carlos; Shah, Sohrab P; Aparicio, Samuel

    2015-02-19

    Human cancers, including breast cancers, comprise clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution, underpinning important emergent features such as drug resistance and metastasis. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours. However, the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours have not been systematically examined at single-cell resolution. Here we show, using deep-genome and single-cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all 15 cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (<5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single-cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies using patient-derived breast cancer xenoengraftment.

  15. Patient-Derived Xenograft Models to Improve Targeted Therapy in Epithelial Ovarian Cancer Treatment

    PubMed Central

    Scott, Clare L.; Becker, Marc A.; Haluska, Paul; Samimi, Goli

    2013-01-01

    Despite increasing evidence that precision therapy targeted to the molecular drivers of a cancer has the potential to improve clinical outcomes, high-grade epithelial ovarian cancer (OC) patients are currently treated without consideration of molecular phenotype, and predictive biomarkers that could better inform treatment remain unknown. Delivery of precision therapy requires improved integration of laboratory-based models and cutting-edge clinical research, with pre-clinical models predicting patient subsets that will benefit from a particular targeted therapeutic. Patient-derived xenografts (PDXs) are renewable tumor models engrafted in mice, generated from fresh human tumors without prior in vitro exposure. PDX models allow an invaluable assessment of tumor evolution and adaptive response to therapy. PDX models have been applied to pre-clinical drug testing and biomarker identification in a number of cancers including ovarian, pancreatic, breast, and prostate cancers. These models have been shown to be biologically stable and accurately reflect the patient tumor with regards to histopathology, gene expression, genetic mutations, and therapeutic response. However, pre-clinical analyses of molecularly annotated PDX models derived from high-grade serous ovarian cancer (HG-SOC) remain limited. In vivo response to conventional and/or targeted therapeutics has only been described for very small numbers of individual HG-SOC PDX in conjunction with sparse molecular annotation and patient outcome data. Recently, two consecutive panels of epithelial OC PDX correlate in vivo platinum response with molecular aberrations and source patient clinical outcomes. These studies underpin the value of PDX models to better direct chemotherapy and predict response to targeted therapy. Tumor heterogeneity, before and following treatment, as well as the importance of multiple molecular aberrations per individual tumor underscore some of the important issues addressed in PDX models

  16. Pancratistatin selectively targets cancer cell mitochondria and reduces growth of human colon tumor xenografts.

    PubMed

    Griffin, Carly; Karnik, Aditya; McNulty, James; Pandey, Siyaram

    2011-01-01

    The naturally occurring Amaryllidaceae alkaloid pancratistatin exhibits potent apoptotic activity against a large panel of cancer cells lines and has an insignificant effect on noncancerous cell lines, although with an elusive cellular target. Many current chemotherapeutics induce apoptosis via genotoxic mechanisms and thus have low selectivity. The observed selectivity of pancratistatin for cancer cells promoted us to consider the hypothesis that this alkaloid targets cancer cell mitochondria rather than DNA or its replicative machinery. In this study, we report that pancratistatin decreased mitochondrial membrane potential and induced apoptotic nuclear morphology in p53-mutant (HT-29) and wild-type p53 (HCT116) colorectal carcinoma cell lines, but not in noncancerous colon fibroblast (CCD-18Co) cells. Interestingly, pancratistatin was found to be ineffective against mtDNA-depleted (ρ(0)) cancer cells. Moreover, pancratistatin induced cell death in a manner independent of Bax and caspase activation, and did not alter β-tubulin polymerization rate nor cause double-stranded DNA breaks. For the first time we report the efficacy of pancratistatin in vivo against human colorectal adenocarcinoma xenografts. Intratumor administration of pancratistatin (3 mg/kg) caused significant reduction in the growth of subcutaneous HT-29 tumors in Nu/Nu mice (n = 6), with no apparent toxicity to the liver or kidneys as indicated by histopathologic analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Altogether, this work suggests that pancratistatin may be a novel mitochondria-targeting compound that selectively induces apoptosis in cancer cells and significantly reduces tumor growth.

  17. Effect of Melatonin on Tumor Growth and Angiogenesis in Xenograft Model of Breast Cancer

    PubMed Central

    Jardim-Perassi, Bruna Victorasso; Arbab, Ali S.; Ferreira, Lívia Carvalho; Borin, Thaiz Ferraz; Varma, Nadimpalli R. S.; Iskander, A. S. M.; Shankar, Adarsh; Ali, Meser M.; de Campos Zuccari, Debora Aparecida Pires

    2014-01-01

    As neovascularization is essential for tumor growth and metastasis, controlling angiogenesis is a promising tactic in limiting cancer progression. Melatonin has been studied for their inhibitory properties on angiogenesis in cancer. We performed an in vivo study to evaluate the effects of melatonin treatment on angiogenesis in breast cancer. Cell viability was measured by MTT assay after melatonin treatment in triple-negative breast cancer cells (MDA-MB-231). After, cells were implanted in athymic nude mice and treated with melatonin or vehicle daily, administered intraperitoneally 1 hour before turning the room light off. Volume of the tumors was measured weekly with a digital caliper and at the end of treatments animals underwent single photon emission computed tomography (SPECT) with Technetium-99m tagged vascular endothelial growth factor (VEGF) C to detect in vivo angiogenesis. In addition, expression of pro-angiogenic/growth factors in the tumor extracts was evaluated by membrane antibody array and collected tumor tissues were analyzed with histochemical staining. Melatonin in vitro treatment (1 mM) decreased cell viability (p<0.05). The breast cancer xenografts nude mice treated with melatonin showed reduced tumor size and cell proliferation (Ki-67) compared to control animals after 21 days of treatment (p<0.05). Expression of VEGF receptor 2 decreased significantly in the treated animals compared to that of control when determined by immunohistochemistry (p<0.05) but the changes were not significant on SPECT (p>0.05) images. In addition, there was a decrease of micro-vessel density (Von Willebrand Factor) in melatonin treated mice (p<0.05). However, semiquantitative densitometry analysis of membrane array indicated increased expression of epidermal growth factor receptor and insulin-like growth factor 1 in treated tumors compared to vehicle treated tumors (p<0.05). In conclusion, melatonin treatment showed effectiveness in reducing tumor growth and cell

  18. Patient-derived xenograft models of colorectal cancer in pre-clinical research: a systematic review

    PubMed Central

    Brown, Kai M.; Xue, Aiqun; Mittal, Anubhav; Samra, Jaswinder S.; Smith, Ross; Hugh, Thomas J.

    2016-01-01

    AIMS We sought to objectively assess the internal and external validity of patient-derived xenograft (PDX) models as a platform in pre-clinical research into colorectal cancer (CRC). Metastatic disease is the most common cause of death from CRC, and despite significant research, the results of current combination chemotherapy and targeted therapies have been underwhelming for most of this patient group. One of the key factors limiting the success of translational CRC research is the biologically inaccurate models in which new therapies are developed. METHODS We used the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist and SYRCLE (Systematic Review Centre for Laboratory animal Experimentation) guidelines to search Ovid MEDLINE and Embase databases up to July 2015 to identify studies involving PDX models of CRC where the model had been validated across multiple parameters. Data was extracted including host mouse strain, engraftment rate, site of engraftment, donor tumour source and development of metastases in the model. RESULTS Thirteen articles satisfied the inclusion criteria. There was significant heterogeneity amongst the included studies, but overall the median engraftment rate was high (70%) and PDX models faithfully recapitulated the characteristics of their patient tumours on the microscopic, genetic and functional levels. CONCLUSIONS PDX models of CRC have a reasonable internal validity and a high external validity. Developments in xenografting technology are broadening the applications of the PDX platform. However, the included studies could be improved by standardising reporting standards and closed following the ARRIVE (Animals in Research: Reporting In Vivo Experiments) guidelines. PMID:27517155

  19. Efficacy and Hemotoxicity of Stealth Doxorubicin-Loaded Magnetic Nanovectors on Breast Cancer Xenografts.

    PubMed

    Gautier, J; Allard-Vannier, E; Burlaud-Gaillard, J; Domenech, J; Chourpa, I

    2015-01-01

    In the field of oncology, research is now focused on the development of theranostic nanosystems that combine the functions of drug delivery and imaging for diagnosis/monitoring. In this context, we designed polyethylene glycol (PEG)ylated superparamagnetic iron oxide nanoparticles (SPIONs) for the delivery of doxorubicin (DOX), an antineoplastic agent. These DOX-loaded PEGylated SPIONs, or DLPS, should be useful for the delivery of DOX in vivo, as well as for magnetic drug targeting (MDT) and magnetic resonance imaging (MRI). The aim of this study was to evaluate the potential applications of DLPS in vivo as drug carrier systems for the reduction of xenograft breast tumors induced in nude mice. Prior to the animal model experiments, the main internalization pathways for the nanovectors in MDA-MB435 breast cancer cells were determined to be based on caveolae- and clathrin-mediated endocytosis. The time- and quantity-dependence of the nanoparticle uptake by the cells altered the in vitro cytotoxicity of the DLPS. The in vitro antiproliferative effect of the DLPS was dependent not only on DOX concentration, but also on the efficacy of nanoparticle internalization. Evaluation of the effect of DLPS treatment on xenograft tumors in nude mice showed that DLPS limited tumor growth in a manner comparable to that of free DOX under normal conditions of tumor growth. The application of an external magnetic field on tumors, i.e., MDT, did not improve the efficacy of the DLPS treatment. Nevertheless, the vectorization of DOX with DLPS appears to limit the hematologic side effects usually associated with DOX treatment.

  20. Detection of Lung Cancer with Volatile Organic Biomarkers in Exhaled Breath and Lung Cancer Cells

    NASA Astrophysics Data System (ADS)

    Yu, Jin; Wang, Di; Wang, Le; Wang, Ping; Hu, Yanjie; Ying, Kejing

    2009-05-01

    In patients with lung cancer, volatile organic compounds (VOCs) are excreted in exhaled breath. In this article, exhaled breath of 30 lung cancer paitients and 30 healthy people were collected, preconcentrated by solid-microextraction(SPME) and analyzed with gas chrom-atography and mass spectrometry (GC/MS). A predictive model composed of 5 VOCs out of 16 candidate VOCs detected in the lung cancer patients is constructed by discriminant analysis, with a sensitivity of 76.7% and specificity of 96.7%. We detected exhaled VOCs of 3 different lung cancer cell lines and human bronchial epithelial cell lines. 2-Tridicanone is considered the distinctive marker of lung cancer cells, which is found in lung cancer patients' exhaled breath as well. Compared to healthy people, patients with lung cancer had distinctive VOCs in their exhaled breath. The predictive model can work as diagnosis reference for lung cancer. VOCs found in lung cancer cell line help the cognition of the mechasim VOCs generating in lung cancer patients.

  1. Differential modulation of nicotine-induced gemcitabine resistance by GABA receptor agonists in pancreatic cancer cell xenografts and in vitro.

    PubMed

    Banerjee, Jheelam; Al-Wadei, Hussein An; Al-Wadei, Mohammed H; Dagnon, Koami; Schuller, Hildegard M

    2014-09-27

    Pancreatic cancer is frequently resistant to cancer therapeutics. Smoking and alcoholism are risk factors and pancreatic cancer patients often undergo nicotine replacement therapy (NRT) and treatment for alcohol dependence. Based on our report that low dose nicotine within the range of NRT causes gemcitabine resistance in pancreatic cancer, our current study has tested the hypothesis that GABA or the selective GABA-B-R agonist baclofen used to treat alcohol dependence reverse nicotine-induced gemcitabine resistance in pancreatic cancer. Using mouse xenografts from the gemcitabine--sensitive pancreatic cancer cell line BXPC-3, we tested the effects of GABA and baclofen on nicotine-induced gemcitabine resistance. The levels of cAMP, p-SRC, p-ERK, p-AKT, p-CREB and cleaved caspase-3 in xenograft tissues were determined by ELISA assays. Expression of the two GABA-B receptors, metalloproteinase-2 and 9 and EGR-1 in xenograft tissues was monitored by Western blotting. Mechanistic studies were conducted in vitro, using cell lines BXPC-3 and PANC-1 and included analyses of cAMP production by ELISA assay and Western blots to determine protein expression of GABA-B receptors, metalloproteinase-2 and 9 and EGR-1. Our data show that GABA was as effective as gemcitabine and significantly reversed gemcitabine resistance induced by low dose nicotine in xenografts whereas baclofen did not. These effects of GABA were accompanied by decreases in cAMP, p-CREB, p-AKT, p-Src, p-ERK metalloproteinases-9 and -2 and EGR-1 and increases in cleaved caspase-3 in xenografts whereas baclofen had the opposite effects. In vitro exposure of cells to single doses or seven days of nicotine induced the protein expression of MMP-2, MMP-9 and EGR-1 and these responses were blocked by GABA. Baclofen downregulated the protein expression of GABA-B-Rs in xenograft tissues and in cells exposed to baclofen for seven days in vitro. This response was accompanied by inversed baclofen effects from inhibition of

  2. Targeted delivery of paclitaxel and doxorubicin to cancer xenografts via the nanoparticle of nano-diamino-tetrac.

    PubMed

    Sudha, Thangirala; Bharali, Dhruba J; Yalcin, Murat; Darwish, Noureldien He; Debreli Coskun, Melis; Keating, Kelly A; Lin, Hung-Yun; Davis, Paul J; Mousa, Shaker A

    2017-01-01

    The tetraiodothyroacetic acid (tetrac) component of nano-diamino-tetrac (NDAT) is chemically bonded via a linker to a poly(lactic-co-glycolic acid) nanoparticle that can encapsulate anticancer drugs. Tetrac targets the plasma membrane of cancer cells at a receptor on the extracellular domain of integrin αvβ3. In this study, we evaluate the efficiency of NDAT delivery of paclitaxel and doxorubicin to, respectively, pancreatic and breast cancer orthotopic nude mouse xenografts. Intra-tumoral drug concentrations were 5-fold (paclitaxel; P<0.001) and 2.3-fold (doxorubicin; P<0.01) higher than with conventional systemic drug administration. Tumor volume reductions reflected enhanced xenograft drug uptake. Cell viability was estimated by bioluminescent signaling in pancreatic tumors and confirmed an increased paclitaxel effect with drug delivery by NDAT. NDAT delivery of chemotherapy increases drug delivery to cancers and increases drug efficacy.

  3. Targeted delivery of paclitaxel and doxorubicin to cancer xenografts via the nanoparticle of nano-diamino-tetrac

    PubMed Central

    Sudha, Thangirala; Bharali, Dhruba J; Yalcin, Murat; Darwish, Noureldien HE; Debreli Coskun, Melis; Keating, Kelly A; Lin, Hung-Yun; Davis, Paul J; Mousa, Shaker A

    2017-01-01

    The tetraiodothyroacetic acid (tetrac) component of nano-diamino-tetrac (NDAT) is chemically bonded via a linker to a poly(lactic-co-glycolic acid) nanoparticle that can encapsulate anticancer drugs. Tetrac targets the plasma membrane of cancer cells at a receptor on the extracellular domain of integrin αvβ3. In this study, we evaluate the efficiency of NDAT delivery of paclitaxel and doxorubicin to, respectively, pancreatic and breast cancer orthotopic nude mouse xenografts. Intra-tumoral drug concentrations were 5-fold (paclitaxel; P<0.001) and 2.3-fold (doxorubicin; P<0.01) higher than with conventional systemic drug administration. Tumor volume reductions reflected enhanced xenograft drug uptake. Cell viability was estimated by bioluminescent signaling in pancreatic tumors and confirmed an increased paclitaxel effect with drug delivery by NDAT. NDAT delivery of chemotherapy increases drug delivery to cancers and increases drug efficacy. PMID:28243091

  4. The Involvement of NRF2 in Lung Cancer

    PubMed Central

    Bauer, Alison K.; Hill, Thomas

    2013-01-01

    Nuclear factor, erythroid-derived 2, like 2 (NRF2) is a key regulator of antioxidants and cellular stress responses. The role of NRF2 in pulmonary neoplasia, a diverse disease for which few biomarkers exist, is complicated and appears to depend on several main factors including the existence of activating mutations in NRF2 and/or loss of function mutations in KEAP1 and the stage of carcinogenesis studied, particularly in the mouse models tested. Therapeutic strategies for lung cancer targeting NRF2 have observed mixed results, both anti- and protumorigenic effects; however, these differences seem to reflect the mutation status of NRF2 or KEAP1. In this paper, we will discuss the studies on human NRF2 and the mechanisms proposed, several mouse models using various mice deficient in NRF2, as well as xenograft models, and the chemotherapeutic strategies using the NRF2 pathway. PMID:23577226

  5. Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis.

    PubMed

    Leconet, Wilhem; Chentouf, Myriam; du Manoir, Stanislas; Chevalier, Clément; Sirvent, Audrey; Aït-Arsa, Imade; Busson, Muriel; Jarlier, Marta; Radosevic-Robin, Nina; Theillet, Charles; Chalbos, Dany; Pasquet, Jean-Max; Pèlegrin, André; Larbouret, Christel; Robert, Bruno

    2016-12-06

    Purpose: AXL receptor tyrosine kinase has been described as a relevant molecular marker and a key player in invasiveness, especially in triple-negative breast cancer (TNBC).Experimental Design: We evaluate the antitumor efficacy of the anti-AXL monoclonal antibody 20G7-D9 in several TNBC cell xenografts or patient-derived xenograft (PDX) models and decipher the underlying mechanisms. In a dataset of 254 basal-like breast cancer samples, genes correlated with AXL expression are enriched in EMT, migration, and invasion signaling pathways.Results: Treatment with 20G7-D9 inhibited tumor growth and bone metastasis formation in AXL-positive TNBC cell xenografts or PDX, but not in AXL-negative PDX, highlighting AXL role in cancer growth and invasion. In vitro stimulation of AXL-positive cancer cells by its ligand GAS6 induced the expression of several EMT-associated genes (SNAIL, SLUG, and VIM) through an intracellular signaling implicating the transcription factor FRA-1, important in cell invasion and plasticity, and increased their migration/invasion capacity. 20G7-D9 induced AXL degradation and inhibited all AXL/GAS6-dependent cell signaling implicated in EMT and in cell migration/invasion.Conclusions: The anti-AXL antibody 20G7-D9 represents a promising therapeutic strategy in TNBC with mesenchymal features by inhibiting AXL-dependent EMT, tumor growth, and metastasis formation. Clin Cancer Res; 1-11. ©2016 AACR.

  6. Dissection of stromal and cancer cell-derived signals in melanoma xenografts before and after treatment with DMXAA

    PubMed Central

    Henare, K; Wang, L; Wang, L-Cs; Thomsen, L; Tijono, S; Chen, C-Jj; Winkler, S; Dunbar, P R; Print, C; Ching, L-M

    2012-01-01

    Background: The non-malignant cells of the tumour stroma have a critical role in tumour biology. Studies dissecting the interplay between cancer cells and stromal cells are required to further our understanding of tumour progression and methods of intervention. For proof-of-principle of a multi-modal approach to dissect the differential effects of treatment on cancer cells and stromal cells, we analysed the effects of the stromal-targeting agent 5,6-dimethylxanthenone-4-acetic acid on melanoma xenografts. Methods: Flow cytometry and multi-colour immunofluorescence staining was used to analyse leukocyte numbers in xenografts. Murine-specific and human-specific multiplex cytokine panels were used to quantitate cytokines produced by stromal and melanoma cells, respectively. Human and mouse Affymetrix microarrays were used to separately identify melanoma cell-specific and stromal cell-specific gene expression. Results: 5,6-Dimethylxanthenone-4-acetic acid activated pro-inflammatory signalling pathways and cytokine expression from both stromal and cancer cells, leading to neutrophil accumulation and haemorrhagic necrosis and a delay in tumour re-growth of 26 days in A375 melanoma xenografts. Conclusion: 5,6-Dimethylxanthenone-4-acetic acid and related analogues may potentially have utility in the treatment of melanoma. The experimental platform used allowed distinction between cancer cells and stromal cells and can be applied to investigate other tumour models and anti-cancer agents. PMID:22415295

  7. Retrospective Analysis of Lung Transplant Recipients Found to Have Unexpected Lung Cancer in Explanted Lungs.

    PubMed

    Nakajima, Takahiro; Cypel, Marcelo; de Perrot, Marc; Pierre, Andrew; Waddell, Tom; Singer, Lianne; Roberts, Heidi; Keshavjee, Shaf; Yasufuku, Kazuhiro

    2015-01-01

    Unexpected lung cancer is sometimes found in explanted lungs. The objective of this study was to review these patients and their outcomes to better understand and optimize management protocols for lung transplant candidates with pulmonary nodules. Retrospective analysis of pretransplant imaging and clinicopathologic characteristics of patients who were found to have lung cancer in their explanted lungs was performed. From January 2003 to December 2012, 13 of 853 lung transplant recipients were found to have unexpected lung cancer in their explanted lung (1.52%). Of them, 9 cases were for interstitial lung disease (2.8%; 9/321 recipients) and 4 cases were for chronic obstructive pulmonary disease (1.57%; 4/255 recipients). The median period between computed tomographic scan and lung transplantation was 2.40 months (range: 0.5-19.2). On computed tomographic scan, only 3 cases were shown to possibly have a neoplasm by the radiologist. The staging of these lung cancers was as follows: 3 cases of IA, 1 case of IB, 5 cases of IIA, 1 case of IIIA, and 3 cases of IV. Of 13 cases, 9 died owing to cancer progression. On the contrary, only 1 stage I case with small cell lung cancer showed cancer recurrence. The median survival time was 339 days, and the 3-year survival rate was 11.0%. In conclusion, most of the patients with unexpected lung cancer showed poor prognosis except for the early-stage disease. The establishment of proper protocol for management of such nodules is important to improve the management of candidates who are found to have pulmonary nodules on imaging. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Stanniocalcin-2 (STC2): A potential lung cancer biomarker promotes lung cancer metastasis and progression.

    PubMed

    Na, Sang-su; Aldonza, Mark Borris; Sung, Hye-Jin; Kim, Yong-In; Son, Yeon Sung; Cho, Sukki; Cho, Je-Yoel

    2015-06-01

    The homodimeric glycoprotein, stanniocalcin 2 (STC2) is previously known to be involved in the regulation of calcium and phosphate transport in the kidney and also reported to play multiple roles in several cancers. However, its function and clinical significance in lung cancer have never been reported and still remain uncertain. Here, we investigated the possibility of STC2 as a lung cancer biomarker and identified its potential role in lung cancer cell growth, metastasis and progression. Proteomic analysis of secretome of primary cultured lung cancer cells revealed higher expression of STC2 in cancers compared to that of adjacent normal cells. RT-PCR and Western blot analyses showed higher mRNA and protein expressions of STC2 in lung cancer tissues compared to the adjacent normal tissues. Knockdown of STC2 in H460 lung cancer cells slowed down cell growth progression and colony formation. Further analysis revealed suppression of migration, invasion and delayed G0/G1 cell cycle progression in the STC2 knockdown cells. STC2 knockdown also attenuated the H202-induced oxidative stress on H460 cell viability with a subsequent increase in intracellular ROS levels, which suggest a protective role of STC2 in redox regulatory system of lung cancer. These findings suggest that STC2 can be a potential lung cancer biomarker and plays a positive role in lung cancer metastasis and progression. This article is part of a Special Issue entitled: Medical Proteomics. Copyright © 2015. Published by Elsevier B.V.

  9. Lung Cancer in HIV-Infected Patients.

    PubMed

    Mena, Álvaro; Meijide, Héctor; Marcos, Pedro J

    2016-01-01

    The widespread use of HAART for persons living with HIV since 1996 has resulted in a dramatic decline in AIDS-related mortality. However, other comorbidities are increasing, such as metabolic disturbances or cancers, including solid organ malignancies. Among the latest, lung cancer, especially the adenocarcinoma subtype, is on the rise. HIV infection, even controlling for smoking, is an independent risk factor for developing lung cancer. HIV could promote lung cancers through immunosuppression, chronic inflammation, and a direct oncogenic effect. Smoking, lung infections, and chronic pulmonary diseases are risk factors for lung cancer. All may contribute to the cumulative incidence of lung cancer in persons living with HIV. It is double that in the general population. The role of HAART in lung cancer development in persons living with HIV is not well established. Although data supporting it could be too preliminary, persons living with HIV should be considered within high-risk groups that could benefit from screening strategies with low-dose computed tomography, especially those with airway obstruction and emphysema. Current evidence suggests that quitting smoking strategies in persons living with HIV achieve abstinence rates comparable to those in healthy HIV-negative smokers.

  10. Imaging Tumor Variation in Response to Photodynamic Therapy in Pancreatic Cancer Xenograft Models

    SciTech Connect

    Samkoe, Kimberley S.; Chen, Alina; Rizvi, Imran; O'Hara, Julia A.; Hoopes, P. Jack; Pereira, Stephen P.; Hasan, Tayyaba; Pogue, Brian W.

    2010-01-15

    Purpose: A treatment monitoring study investigated the differential effects of orthotopic pancreatic cancer models in response to interstitial photodynamic therapy (PDT), and the validity of using magnetic resonance imaging as a surrogate measure of response was assessed. Methods and Materials: Different orthotopic pancreatic cancer xenograft models (AsPC-1 and Panc-1) were used to represent the range of pathophysiology observed in human beings. Identical dose escalation studies (10, 20, and 40J/cm) using interstitial verteporfin PDT were performed, and magnetic resonance imaging with T2-weighted and T1-weighted contrast were used to monitor the total tumor volume and the vascular perfusion volume, respectively. Results: There was a significant amount of necrosis in the slower-growing Panc-1 tumor using high light dose, although complete necrosis was not observed. Lower doses were required for the same level of tumor kill in the faster-growing AsPC-1 cell line. Conclusions: The tumor growth rate and vascular pattern of the tumor affect the optimal PDT treatment regimen, with faster-growing tumors being relatively easier to treat. This highlights the fact that therapy in human beings shows a heterogeneous range of outcomes, and suggests a need for careful individualized treatment outcomes assessment in clinical work.

  11. Effects of Tetrahydrocurcumin on Tumor Growth and Cellular Signaling in Cervical Cancer Xenografts in Nude Mice

    PubMed Central

    Yoysungnoen, Bhornprom; Bhattarakosol, Parvapan; Changtam, Chatchawan; Patumraj, Suthiluk

    2016-01-01

    Tetrahydrocurcumin (THC) is a stable metabolite of curcumin (CUR) in physiological systems. The mechanism underlying the anticancer effect of THC is not completely understood. In the present study, we investigated the effects of THC on tumor growth and cellular signaling in cervical cancer xenografts in nude mice. Cervical cancer cells (CaSki) were subcutaneously injected in nude mice to establish tumors. One month after the injection, mice were orally administered vehicle or 100, 300, and 500 mg/kg of THC daily for 30 consecutive days. Relative tumor volume (RTV) was measured every 3-4 days. COX-2, EGFR, p-ERK1&2, p-AKT, and Ki-67 expressions were measured by immunohistochemistry whereas cell apoptosis was detected by TUNELS method. THC treatments at the doses of 100, 300, and 500 mg/kg statistically retarded the RTV by 70.40%, 76.41%, and 77.93%, respectively. The CaSki + vehicle group also showed significantly increased COX-2, EGFR, p-ERK1&2, and p-AKT; however they were attenuated by all treatments with THC. Ki-67 overexpression and a decreasing of cell apoptosis were found in CaSki + vehicle group, but these findings were reversed after the THC treatments. PMID:26881213

  12. Effects of Tetrahydrocurcumin on Tumor Growth and Cellular Signaling in Cervical Cancer Xenografts in Nude Mice.

    PubMed

    Yoysungnoen, Bhornprom; Bhattarakosol, Parvapan; Changtam, Chatchawan; Patumraj, Suthiluk

    2016-01-01

    Tetrahydrocurcumin (THC) is a stable metabolite of curcumin (CUR) in physiological systems. The mechanism underlying the anticancer effect of THC is not completely understood. In the present study, we investigated the effects of THC on tumor growth and cellular signaling in cervical cancer xenografts in nude mice. Cervical cancer cells (CaSki) were subcutaneously injected in nude mice to establish tumors. One month after the injection, mice were orally administered vehicle or 100, 300, and 500 mg/kg of THC daily for 30 consecutive days. Relative tumor volume (RTV) was measured every 3-4 days. COX-2, EGFR, p-ERK1&2, p-AKT, and Ki-67 expressions were measured by immunohistochemistry whereas cell apoptosis was detected by TUNELS method. THC treatments at the doses of 100, 300, and 500 mg/kg statistically retarded the RTV by 70.40%, 76.41%, and 77.93%, respectively. The CaSki + vehicle group also showed significantly increased COX-2, EGFR, p-ERK1&2, and p-AKT; however they were attenuated by all treatments with THC. Ki-67 overexpression and a decreasing of cell apoptosis were found in CaSki + vehicle group, but these findings were reversed after the THC treatments.

  13. Establishment of genetically diverse patient-derived xenografts of colorectal cancer

    PubMed Central

    Burgenske, Danielle M; Monsma, David J; Dylewski, Dawna; Scott, Stephanie B; Sayfie, Aaron D; Kim, Donald G; Luchtefeld, Martin; Martin, Katie R; Stephenson, Paul; Hostetter, Galen; Dujovny, Nadav; MacKeigan, Jeffrey P

    2014-01-01

    Preclinical compounds tested in animal models often show limited efficacy when transitioned into human clinical trials. As a result, many patients are stratified into treatment regimens that have little impact on their disease. In order to create preclinical models that can more accurately predict tumor responses, we established patient-derived xenograft (PDX) models of colorectal cancer (CRC). Surgically resected tumor specimens from colorectal cancer patients were implanted subcutaneously into athymic nude mice. Following successful establishment, fourteen models underwent further evaluation to determine whether these models exhibit heterogeneity, both at the cellular and genetic level. Histological review revealed properties not found in CRC cell lines, most notably in overall architecture (predominantly columnar epithelium with evidence of gland formation) and the presence of mucin-producing cells. Custom CRC gene panels identified somatic driver mutations in each model, and therapeutic efficacy studies in tumor-bearing mice were designed to determine how models with known mutations respond to PI3K, mTOR, or MAPK inhibitors. Interestingly, MAPK pathway inhibition drove tumor responses across most models tested. Noteworthy, the MAPK inhibitor PD0325901 alone did not significantly mediate tumor response in the context of a KRASG12D model, and improved tumor responses resulted when combined with mTOR inhibition. As a result, these genetically diverse models represent a valuable resource for preclinical efficacy and drug discovery studies. PMID:25520871

  14. Cellular therapy in combination with cytokines improves survival in a xenograft mouse model of ovarian cancer.

    PubMed

    Ingersoll, Susan B; Ahmad, Sarfraz; McGann, Hasina C; Banks, Robert K; Stavitzski, Nicole M; Srivastava, Milan; Ali, Ghazanfar; Finkler, Neil J; Edwards, John R; Holloway, Robert W

    2015-09-01

    Studies have shown enhanced survival of ovarian cancer patients in which the tumors are infiltrated with tumor infiltrating lymphocytes and natural killer cells showing the importance of immune surveillance and recognition in ovarian cancer. Therefore, in this study, we tested cellular immunotherapy and varying combinations of cytokines (IL-2 and/or pegylated-IFNα-2b) in a xenograft mouse model of ovarian cancer. SKOV3-AF2 ovarian cancer cells were injected intra-peritoneally (IP) into athymic nude mice. On day 7 post-tumor cell injection, mice were injected IP with peripheral blood mononuclear cells (PBMC; 5 × 10(6) PBMC) and cytokine combinations [IL-2 ± pegylated-IFNα-2b (IFN)]. Cytokine injections were continued weekly for IFN (12,000 U/injection) and thrice weekly for IL-2 (4000 U/injection). Mice were euthanized when they became moribund due to tumor burden at which time tumor and ascitic fluid were measured and collected. Treatment efficacy was measured by improved survival at 8 weeks and overall survival by Kaplan-Meier analysis. We observed that the mice tolerated all treatment combinations without significant weight loss or other apparent illness. Mice receiving PBMC plus IL-2 showed improved median survival (7.3 weeks) compared to mice with no treatment (4.2 weeks), IL-2 (3.5 weeks), PBMC (4.0 weeks), or PBMC plus IL-2 and IFN (4.3 weeks), although PBMC plus IL-2 was not statistically different than PBMC plus IFN (5.5 weeks, p > 0.05). We demonstrate that cytokine-stimulated cellular immune therapy with PBMC and IL-2 was well tolerated and resulted in survival advantage compared to untreated controls and other cytokine combinations in the nude-mouse model.

  15. Lung Cancer:Symptoms, Diagnosis, Treatments & Research | NIH MedlinePlus the Magazine

    MedlinePlus

    ... of this page please turn Javascript on. Feature: Lung Cancer Lung Cancer: Symptoms, Diagnosis, Treatments & Research Past Issues / Winter ... lung cancer are given intravenously or by mouth. Lung Cancer Research The large-scale National Lung Screening ...

  16. Lung cancer disparities and African-Americans.

    PubMed

    Sin, Mo-Kyung

    2017-07-01

    African-Americans, as historically disadvantaged minorities, have more advanced stages of cancer when diagnosed, lower survival rates, and lower rates of accessing timely care than do Caucasians. Lung cancer incidence and mortality, in particular, are high among African-Americans. The U.S. Preventive Services Task Force recently released an evidence-based lung cancer screening technology called low-dose computerized tomography. High-risk African-Americans might benefit greatly from such screening but not many are aware of this technology. Public health nurses can play a key role in increasing awareness of the technology among African-American communities and encouraging qualified African-Americans to obtain screening. This study discusses issues with lung cancer and smoking among African-Americans, a recently released evidence-based lung cancer screening technology, and implications for public health nurses to enhance uptake of the new screening technology among high-risk African-Americans. © 2017 Wiley Periodicals, Inc.

  17. The liquid biopsy in lung cancer.

    PubMed

    Ansari, Junaid; Yun, Jungmi W; Kompelli, Anvesh R; Moufarrej, Youmna E; Alexander, Jonathan S; Herrera, Guillermo A; Shackelford, Rodney E

    2016-11-01

    The incidence of lung cancer has significantly increased over the last century, largely due to smoking, and remains the most common cause of cancer deaths worldwide. This is often due to lung cancer first presenting at late stages and a lack of curative therapeutic options at these later stages. Delayed diagnoses, inadequate tumor sampling, and lung cancer misdiagnoses are also not uncommon due to the limitations of the tissue biopsy. Our better understanding of the tumor microenvironment and the systemic actions of tumors, combined with the recent advent of the liquid biopsy, may allow molecular diagnostics to be done on circulating tumor markers, particularly circulating tumor DNA. Multiple liquid biopsy molecular methods are presently being examined to determine their efficacy as surrogates to the tumor tissue biopsy. This review will focus on new liquid biopsy technologies and how they may assist in lung cancer detection, diagnosis, and treatment.

  18. The liquid biopsy in lung cancer

    PubMed Central

    Ansari, Junaid; Yun, Jungmi W.; Kompelli, Anvesh R.; Moufarrej, Youmna E.; Alexander, Jonathan S.; Herrera, Guillermo A.; Shackelford, Rodney E.

    2016-01-01

    The incidence of lung cancer has significantly increased over the last century, largely due to smoking, and remains the most common cause of cancer deaths worldwide. This is often due to lung cancer first presenting at late stages and a lack of curative therapeutic options at these later stages. Delayed diagnoses, inadequate tumor sampling, and lung cancer misdiagnoses are also not uncommon due to the limitations of the tissue biopsy. Our better understanding of the tumor microenvironment and the systemic actions of tumors, combined with the recent advent of the liquid biopsy, may allow molecular diagnostics to be done on circulating tumor markers, particularly circulating tumor DNA. Multiple liquid biopsy molecular methods are presently being examined to determine their efficacy as surrogates to the tumor tissue biopsy. This review will focus on new liquid biopsy technologies and how they may assist in lung cancer detection, diagnosis, and treatment. PMID:28191282

  19. The Canadian Lung Cancer Conference 2016

    PubMed Central

    Melosky, B.; Ho, C.

    2016-01-01

    Each February, the Canadian Lung Cancer Conference brings together lung cancer researchers, clinicians, and care professionals who are united in their commitment to improve the care of patients with lung cancer. This year’s meeting, held 11–12 February, featured a resident education session, a welcome dinner, networking sessions, lectures, breakout sessions, debates, and a satellite symposium. Key themes from this year’s meeting included innovations across the care spectrum and results of recent clinical trials with targeted agents, immuno-oncology agents, and novel drug combinations.

  20. MicroRNA-490 regulates lung cancer metastasis by targeting poly r(C)-binding protein 1.

    PubMed

    Li, Jindong; Feng, Qingchuan; Wei, Xudong; Yu, Yongkui

    2016-11-01

    Lung cancer remains a leading cause of cancer-related mortality, with metastatic progression remaining the single largest cause of lung cancer mortality. Hence, it is imperative to determine reliable biomarkers of lung cancer prognosis. MicroRNA-490-3p has been previously reported to be a positive prognostic biomarker for hepatocellular cancer. However, its role in human lung cancer has not yet been elucidated. Here, we report that hsa-miR-490-3p expression is significantly higher in human lung cancer tissue specimens and cell line. Gain- and loss-of-function studies of hsa-miR-490-3p showed that it regulates cell proliferation and is required for induction of in vitro migration and invasion-the latter being a hallmark of epithelial to mesenchymal transition. In situ analysis revealed that hsa-miR-490-3p targets poly r(C)-binding protein 1 (PCBP1), which has been previously shown to be a negative regulator of lung cancer metastasis. Reporter assays confirmed PCBP1 as a bona fide target of miR-490-3p, and metagenomic analysis revealed an inverse relation between expression of miR-490-3p and PCBP1 in metastatic lung cancer patients. In fact, PCBP1 expression, as detected by immunohistochemistry, was undetectable in advanced stages of lung cancer patients' brain and lymph node tissues. Xenograft tail vein colonization assays proved that high expression of miR-490-3p is a prerequisite for metastatic progression of lung cancer. Our results suggest that hsa-miR-490-3p might be a potential biomarker for lung cancer prognosis. In addition, we can also conclude that the lung cancer cells have evolved refractory mechanisms to downregulate the expression of the metastatic inhibitor, PCBP1.

  1. SapC-DOPS nanovesicles as targeted therapy for lung cancer.

    PubMed

    Zhao, Shuli; Chu, Zhengtao; Blanco, Victor M; Nie, Yunzhong; Hou, Yayi; Qi, Xiaoyang

    2015-02-01

    Lung cancer is the deadliest type of cancer for both men and women. In this study, we evaluate the in vitro and in vivo efficacy of a biotherapeutic agent composed of a lysosomal protein (Saposin C, SapC) and a phospholipid (dioleoylphosphatidylserine, DOPS), which can be assembled into nanovesicles (SapC-DOPS) with selective antitumor activity. SapC-DOPS targets phosphatidylserine, an anionic phospholipid preferentially exposed in the surface of cancer cells and tumor-associated vasculature. Because binding of SapC to phosphatidylserine is favored at acidic pHs, and the latter characterizes the milieu of many solid tumors, we tested the effect of pH on the binding capacity of SapC-DOPS to lung tumor cells. Results showed that SapC-DOPS binding to cancer cells was more pronounced at low pH. Viability assays on a panel of human lung tumor cells showed that SapC-DOPS cytotoxicity was positively correlated with cell surface phosphatidylserine levels, whereas mitochondrial membrane potential measurements were consistent with apoptosis-related cell death. Using a fluorescence tracking method in live mice, we show that SapC-DOPS specifically targets human lung cancer xenografts, and that systemic therapy with SapC-DOPS induces tumor apoptosis and significantly inhibits tumor growth. These results suggest that SapC-DOPS nanovesicles are a promising treatment option for lung cancer. ©2015 American Association for Cancer Research.

  2. Lung cancer surgery: an up to date

    PubMed Central

    Baltayiannis, Nikolaos; Chandrinos, Michail; Anagnostopoulos, Dimitrios; Tsakiridis, Kosmas; Mpakas, Andreas; Machairiotis, Nikolaos; Katsikogiannis, Nikolaos; Kougioumtzi, Ioanna; Courcoutsakis, Nikolaos; Zarogoulidis, Konstantinos

    2013-01-01

    According to the International Agency for Research on Cancer (IARC) GLOBOCAN World Cancer Report, lung cancer affects more than 1 million people a year worldwide. In Greece according to the 2008 GLOBOCAN report, there were 6,667 cases recorded, 18% of the total incidence of all cancers in the population. Furthermore, there were 6,402 deaths due to lung cancer, 23.5% of all deaths due to cancer. Therefore, in our country, lung cancer is the most common and deadly form of cancer for the male population. The most important prognostic indicator in lung cancer is the extent of disease. The Union Internationale Contre le Cancer (UICC) and the American Joint Committee for Cancer Staging (AJCC) developed the tumour, node, and metastases (TNM) staging system which attempts to define those patients who might be suitable for radical surgery or radical radiotherapy, from the majority, who will only be suitable for palliative measures. Surgery has an important part for the therapy of patients with lung cancer. “Lobectomy is the gold standard treatment”. This statement may be challenged in cases of stage Ia cancer or in patients with limited pulmonary function. In these cases an anatomical segmentectomy with lymph node dissection is an acceptable alternative. Chest wall invasion is not a contraindication to resection. En-bloc rib resection and reconstruction is the treatment of choice. N2 disease represents both a spectrum of disease and the interface between surgical and non-surgical treatment of lung cancer Evidence from trials suggests that multizone or unresectable N2 disease should be treated primarily by chemoradiotherapy. There may be a role for surgery if N2 is downstaged to N0 and lobectomy is possible, but pneumonectomy is avoidable. Small cell lung cancer (SCLC) is considered a systemic disease at diagnosis, because the potential for hematogenous and lymphogenic metastases is very high. The efficacy of surgical intervention for SCLC is not clear. Lung cancer

  3. Enhanced heme function and mitochondrial respiration promote the progression of lung cancer cells.

    PubMed

    Hooda, Jagmohan; Cadinu, Daniela; 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

  4. Exploring a structural protein-drug interactome for new therapeutics in lung cancer.

    PubMed

    Peng, Xiaodong; Wang, Fang; Li, Liwei; Bum-Erdene, Khuchtumur; Xu, David; Wang, Bo; Sinn, Anthony A; Pollok, Karen E; Sandusky, George E; Li, Lang; Turchi, John J; Jalal, Shadia I; Meroueh, Samy O

    2014-03-04

    The pharmacology of drugs is often defined by more than one protein target. This property can be exploited to use approved drugs to uncover new targets and signaling pathways in cancer. Towards enabling a rational approach to uncover new targets, we expand a structural protein-ligand interactome () by scoring the interaction among 1000 FDA-approved drugs docked to 2500 pockets on protein structures of the human genome. This afforded a drug-target network whose properties compared favorably with previous networks constructed using experimental data. Among drugs with the highest degree and betweenness two are cancer drugs and one is currently used for treatment of lung cancer. Comparison of predicted cancer and non-cancer targets reveals that the most cancer-specific compounds were also the most selective compounds. Analysis of compound flexibility, hydrophobicity, and size showed that the most selective compounds were low molecular weight fragment-like heterocycles. We use a previously-developed screening approach using the cancer drug erlotinib as a template to screen other approved drugs that mimic its properties. Among the top 12 ranking candidates, four are cancer drugs, two of them kinase inhibitors (like erlotinib). Cellular studies using non-small cell lung cancer (NSCLC) cells revealed that several drugs inhibited lung cancer cell proliferation. We mined patient records at the Regenstrief Medical Record System to explore the possible association of exposure to three of these drugs with occurrence of lung cancer. Preliminary in vivo studies using the non-small cell lung cancer (NCLSC) xenograft model showed that losartan- and astemizole-treated mice had tumors that weighed 50 (p < 0.01) and 15 (p < 0.01) percent less than the treated controls. These results set the stage for further exploration of these drugs and to uncover new drugs for lung cancer therapy.

  5. Enhanced Heme Function and Mitochondrial Respiration Promote the Progression of Lung Cancer Cells

    PubMed Central

    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

  6. Fei-Liu-Ping ointment inhibits lung cancer growth and invasion by suppressing tumor inflammatory microenvironment

    PubMed Central

    2014-01-01

    Background Lung cancer is one of the leading causes of cancer-related mortality worldwide. Conventional chemotherapy and radiotherapy are the primary therapeutic methods for lung cancer with the use of combination therapies gaining popularity. The frequency and duration of treatment, as well as, managing lung cancer by targeting multiple aspects of cancer biology is often limited by toxicity to the patient. There are many naturally occurring anticancer agents that have a high degree of efficacy and low toxicity, offering a viable and safe approach for the treatment of lung cancer. The herbs traditionally used in Chinese medicine for anticancer treatment offer great potential to enhance the efficacy of conventional therapy. In this study, we evaluated the synergistic effects of Fei-Liu-Ping (FLP) ointment in treating lung cancer; a known anticancer Chinese herbal based formula. Methods In this study, A549 human lung carcinoma cell line and Lewis lung carcinoma xenograft mouse model were used. In addition, we utilized an in vitro co-culture system to simulate the tumor microenvironment in order to evaluate the molecular mechanisms of FLP treatment. Results FLP treatment significantly inhibited tumor growth in the Lewis lung xenograft by 40 percent, compared to that of cyclophosphamide (CTX) of 62.02 percent. Moreover, combining FLP and CTX inhibited tumor growth by 83.23 percent. Upon evaluation, we found that FLP treatment reduced the concentration of serum pro-inflammatory cytokines IL-6, TNF-α, and IL-1β. In addition, we also found an improvement in E-cadherin expression and inhibition of N-cadherin and MMP9. We found similar findings in vitro when we co-cultured A549 cells with macrophages. FLP treatment inhibited A549 cell growth, invasion and metastasis, in part, through the regulation of NF-κB and altering the expression of E-cadherin, N-cadherin, MMP2 and MMP9. Conclusions FLP exerts anti-inflammatory properties in the tumor microenvironment, which may

  7. Other cancers in lung cancer families are overwhelmingly smoking-related cancers.

    PubMed

    Yu, Hongyao; Frank, Christoph; Hemminki, Akseli; Sundquist, Kristina; Hemminki, Kari

    2017-04-01

    Familial risks of lung cancer are well-established, but whether lung cancer clusters with other discordant cancers is less certain, particularly beyond smoking-related sites, which may provide evidence on genetic contributions to lung cancer aetiology. We used a novel approach to search for familial associations in the Swedish Family-Cancer Database. This involved assessment of familial relative risk for cancer X in families with increasing numbers of lung cancer patients and, conversely, relative risks for lung cancer in families with increasing numbers of patients with cancers X. However, we lacked information on smoking. The total number of lung cancers in the database was 125 563. We applied stringent statistical criteria and found that seven discordant cancers were associated with lung cancer among family members, and six of these were known to be connected with smoking: oesophageal, upper aerodigestive tract, liver, cervical, kidney and urinary bladder cancers. A further novel finding was that cancer of unknown primary also associated with lung cancer. We also factored in histological evidence and found that anal and connective tissue cancers could be associated with lung cancer for reasons other than smoking. For endometrial and prostate cancers, suggestive negative associations with lung cancer were found. Although we lacked information on smoking it is prudent to conclude that practically all observed discordant associations of lung cancer were with cancers for which smoking is a risk factor.

  8. Aplidin reduces growth of anaplastic thyroid cancer xenografts and the expression of several angiogenic genes.

    PubMed

    Straight, Ann M; Oakley, Kevin; Moores, Russell; Bauer, Andrew J; Patel, Aneeta; Tuttle, R Michael; Jimeno, J; Francis, Gary L

    2006-01-01

    Anaplastic thyroid cancer (ATC) is one of the most aggressive and highly lethal human cancers. Median survival after diagnosis is 4-6 months despite available radiotherapy and chemotherapy. Additional treatments are needed for ATC. Vascular endothelial growth factor (VEGF) is a potent angiogenic stimulus, which is expressed by ATC. Previously, anti-VEGF antibody was used to block VEGF-dependent angiogenesis in ATC xenografts. This treatment induced partial (56%) but not complete tumor regression. Aplidin (APLD) is a marine derived antitumor agent currently in phase II clinical studies. Multiple activities of this compound have been described which likely contribute to its antiproliferative effect. Notably, APLD has been shown to have antiangiogenic properties which include: inhibition of VEGF secretion, reduction in the synthesis of the VEGF receptor (FLT-1), and blockade of matrix metalloproteinase production by endothelial cells. We hypothesized that Aplidin, with its broad spectrum of action and antiangiogenic properties, would be a potentially effective drug against ATC. Thirty BALB/c nu/nu mice were injected with ATC cells (ARO-81, 1 x 10(6)) and allowed to implant for 3 weeks. Animals were randomized to receive daily intraperitoneal injections of vehicle, low dose (0.5 mg/kg/day), or high dose (1.0 mg/kg/day) APLD. After 3 days, the animals were killed and the tumors were removed, weighed, and divided for RNA and protein analyses. APLD significantly reduced ATC xenograft growth (low dose, 20% reduction, P = 0.01; high dose, 40% reduction, P < 0.001). This was associated with increased levels of apoptosis related proteins polyadenosylribose polymerase 85 (PARP-85, 75% increase, P = 0.024) and caspase 8 (greater than fivefold increase, P = 0.03). APLD treatment was further associated with lost or reduced expression of several genes that support angiogenesis to include: VEGF, hypoxia inducible factor 1(HIF-1), transforming growth factor-beta (TGFbeta), TGFbeta

  9. Missed lung cancer: when, where, and why?

    PubMed Central

    del Ciello, Annemilia; Franchi, Paola; Contegiacomo, Andrea; Cicchetti, Giuseppe; Bonomo, Lorenzo; Larici, Anna Rita

    2017-01-01

    Missed lung cancer is a source of concern among radiologists and an important medicolegal challenge. In 90% of the cases, errors in diagnosis of lung cancer occur on chest radiographs. It may be challenging for radiologists to distinguish a lung lesion from bones, pulmonary vessels, mediastinal structures, and other complex anatomical structures on chest radiographs. Nevertheless, lung cancer can also be overlooked on computed tomography (CT) scans, regardless of the context, either if a clinical or radiologic suspect exists or for other reasons. Awareness of the possible causes of overlooking a pulmonary lesion can give radiologists a chance to reduce the occurrence of this eventuality. Various factors contribute to a misdiagnosis of lung cancer on chest radiographs and on CT, often very similar in nature to each other. Observer error is the most significant one and comprises scanning error, recognition error, decision-making error, and satisfaction of search. Tumor characteristics such as lesion size, conspicuity, and location are also crucial in this context. Even technical aspects can contribute to the probability of skipping lung cancer, including image quality and patient positioning and movement. Albeit it is hard to remove missed lung cancer completely, strategies to reduce observer error and methods to improve technique and automated detection may be valuable in reducing its likelihood. PMID:28206951

  10. Diallyl Trisulfide Inhibits Growth of NCI-H460 in Vitro and in Vivo, and Ameliorates Cisplatin-Induced Oxidative Injury in the Treatment of Lung Carcinoma in Xenograft Mice

    PubMed Central

    Jiang, Xiaoyan; Zhu, Xiaosong; Liu, Na; Xu, Hongya; Zhao, Zhongxi; Li, Siying; Li, Shanzhong; Cai, Jianhua; Cao, Jimin

    2017-01-01

    Diallyl trisulfide (DATS), an organosulfuric component of garlic oil, exhibits potential anticancer and chemopreventive effects. Cisplatin (DDP), a common chemotherapeutic agent, has provided great therapeutic contributions to treating solid tumors, but with serious side effects. Here, we verified the anti-tumor properties of DATS on lung cancer in vitro and in vivo, and evaluated synergistic effects of DATS combined with DDP on the NCI-H460 xenograft model. Significantly decreased cell viabilities, cell cycle G1 arrest, and apoptosis induction were observed in DATS treated NCI-H460 cells (p<0.05). And injection of DATS (30 or 40 mg/kg) to female Balb/c mice significantly inhibited the growth of human NCI-H460 cell tumor xenograft (p<0.001). Moreover, DATS in combination with DDP exhibited enhanced anti-tumor activity via induction of apoptosis. Apoptosis pathways were confirmed by modulation of p53, Bcl-2 family members; induction of active caspase-3/8/9 and activation of JNK- and p38-MAPK pathways. Interestedly, DATS+DDP administration exerted fewer side effects, such as suppressing the weight loss and ameliorating DDP-induced oxidative injury, especially in renal parenchyma. In addition, increased E-cadherin and decreased MMP-9 expression levels were observed in DATS-treated tumor tissues. These studies provide supports that DATS might be a potential candidate for combination with DDP in cancer treatment. PMID:28255269

  11. Diallyl Trisulfide Inhibits Growth of NCI-H460 in Vitro and in Vivo, and Ameliorates Cisplatin-Induced Oxidative Injury in the Treatment of Lung Carcinoma in Xenograft Mice.

    PubMed

    Jiang, Xiaoyan; Zhu, Xiaosong; Liu, Na; Xu, Hongya; Zhao, Zhongxi; Li, Siying; Li, Shanzhong; Cai, Jianhua; Cao, Jimin

    2017-01-01

    Diallyl trisulfide (DATS), an organosulfuric component of garlic oil, exhibits potential anticancer and chemopreventive effects. Cisplatin (DDP), a common chemotherapeutic agent, has provided great therapeutic contributions to treating solid tumors, but with serious side effects. Here, we verified the anti-tumor properties of DATS on lung cancer in vitro and in vivo, and evaluated synergistic effects of DATS combined with DDP on the NCI-H460 xenograft model. Significantly decreased cell viabilities, cell cycle G1 arrest, and apoptosis induction were observed in DATS treated NCI-H460 cells (p<0.05). And injection of DATS (30 or 40 mg/kg) to female Balb/c mice significantly inhibited the growth of human NCI-H460 cell tumor xenograft (p<0.001). Moreover, DATS in combination with DDP exhibited enhanced anti-tumor activity via induction of apoptosis. Apoptosis pathways were confirmed by modulation of p53, Bcl-2 family members; induction of active caspase-3/8/9 and activation of JNK- and p38-MAPK pathways. Interestedly, DATS+DDP administration exerted fewer side effects, such as suppressing the weight loss and ameliorating DDP-induced oxidative injury, especially in renal parenchyma. In addition, increased E-cadherin and decreased MMP-9 expression levels were observed in DATS-treated tumor tissues. These studies provide supports that DATS might be a potential candidate for combination with DDP in cancer treatment.

  12. Mitotane effects in a H295R xenograft model of adjuvant treatment of adrenocortical cancer.

    PubMed

    Lindhe, O; Skogseid, B

    2010-09-01

    Adrenocortical cancer is one of the most aggressive endocrine malignancies. Growth through the capsule or accidental release of cancer cells during surgery frequently results in metastatic disease. We investigated the antitumoral effect of 2 adrenocorticolytic compounds, O, P'-DDD and MeSO2-DDE, in the adrenocortical cell line H295R both in vitro and as a xenograft model in vivo. H295R cells were injected s. c. in nude mice. O, P'-DDD, MeSO2-DDE, or oil (control) was administered i. p., either simultaneously with cell injection at day 0 (mimicking adjuvant treatment), or at day 48 (established tumors). Accumulation of PET tracers [ (11)C]methionine (MET), [ (11)C] metomidate (MTO), 2-deoxy-2-[ (18)F]fluoro-d-glucose (FDG), and [ (18)F]-l-tyrosine (FLT) in the aggregates were assessed +/- drug treatment in vitro. Tumor growth was significantly inhibited when O, P'-DDD was given at the same time as injection of tumor cells. No significant growth inhibition was observed after treatment with O, P'-DDD at day 48. A significant reduction in FLT uptake and an increased FDG uptake, compared to control, were observed following treatment with 15 microM O, P'-DDD (p<0.01) in vitro. MeSO2-DDE (15 microM) treatment gave rise to a reduced MET and an increased FLT uptake (p<0.01). Both compounds reduced the uptake of MTO compared to control (p<0.01). Treatment with O, P'-DDD simultaneously to inoculation of H295R cells in mice, imitating release of cells during surgery, gave a markedly better effect than treatment of established H295R tumors. We suggest that FLT may be a potential PET biomarker when assessing adrenocortical cancer treatment with O,P'-DDD. Further studies in humans are needed to investigate this.

  13. Quercetin inhibits angiogenesis by targeting calcineurin in the xenograft model of human breast cancer.

    PubMed

    Zhao, Xin; Wang, Qiuting; Yang, Shijun; Chen, Chen; Li, Xiaoya; Liu, Jinyu; Zou, Zhongmei; Cai, Dayong

    2016-06-15

    Vascular endothelial growth factor receptor 2 (VEGFR2) mediated calcineurin/nuclear factor of activated T-cells (NFAT) pathway is crucial in the angiogenesis of human breast cancer. Quercetin (Qu), a flavonoid known to possess anti-angiogenesis and antitumor properties, inhibited calcineurin activity in vitro. Herein, we performed a study in vivo to evaluate the effects of Qu on the angiogenesis in breast cancer. Female BALB/c nude mice were injected with MCF-7 cells into the mammary fat and were randomly divided into four groups. The animals were treated with vehicle solution, tamoxifen (TAM, 5.6mg/kg), tacrolimus (FK506, 3mg/kg), or Qu (34mg/kg) for 21 days, respectively. The results showed that, similar to TAM and FK506, Qu decreased tumor growth, limited oncocyte proliferation and promoted tumor necrosis. Anti-angiogenic actions of Qu were demonstrated as decreased serum VEGF (P<0.01), and sparse microvessel density (P<0.05). Qu significantly inhibited tumor calcineurin activities, and the inhibitory rate was 62.73% in Qu treated animals, compared to that was 72.90% in FK506 group (P>0.05). Effects of Qu on calcineurin/NFAT pathway were confirmed as decreased subcellular located levels of VEGF (P<0.05), VEGFR2 (P<0.05) and NFATc3 (P<0.01), downregulated gene expression of VEGF (P<0.05), VEGFR2 (P<0.05) and NFATc3 (P<0.01), reduced protein levels of VEGF (P<0.05), VEGFR2 (P<0.05), and NFATc3 (P<0.01) in tumor tissues. These findings indicate that Qu inhibit angiogenesis of human breast cancer xenograft in nude mice, which was associated with suppressing calcineurin activity and its regulated pathway activation.

  14. Biodistribution of charged F(ab')2 photoimmunoconjugates in a xenograft model of ovarian cancer.

    PubMed

    Duska, L R; Hamblin, M R; Bamberg, M P; Hasan, T

    1997-01-01

    The effect of charge modification of photoimmunoconjugates (PICs) on their biodistribution in a xenograft model of ovarian cancer was investigated. Chlorin(e6)c(e6) was attached site specifically to the F(ab')2 fragment of the murine monoclonal antibody OC125, directed against human ovarian cancer cells, via poly-1-lysine linkers carrying cationic or anionic charges. Preservation of immunoreactivity was checked by enzyme-linked immunosorbent assay (ELISA). PICs were radiolabelled with 125I and compared with non-specific rabbit IgG PICs after intraperitoneal (i.p.) injection into nude mice. Samples were taken from normal organs and tumour at 3 h and 24 h. Tumour to normal 125I ratios showed that the cationic OC125F(ab')2 PIC had the highest tumour selectivity. Ratios for c(e6) were uniformly higher than for 125I, indicating that c(e6) became separated from 125I. OC125F(ab')2 gave highest tissue values of 125I, followed by cationic OC125F(ab')2 PIC; other species were much lower. The amounts of c(e6) delivered per gram of tumour were much higher for cationic OC125F(ab')2 PIC than for other species. The results indicate that cationic charge stimulates the endocytosis and lysosomal degradation of the OC125F(ab')2-pl-c(e6) that has bound to the i.p. tumour. Positively charged PICs may have applications in the i.p. photoimmunotherapy of minimal residual ovarian cancer.

  15. Inhibition of poly(ADP-ribose) polymerase-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft

    PubMed Central

    Senra, Joana M.; Telfer, Brian A.; Cherry, Kim E.; McCrudden, Cian M.; Hirst, David G.; O’Connor, Mark J.; Wedge, Stephen R.; Stratford, Ian J.

    2011-01-01

    Poly(ADP-ribose) polymerase-1 is a critical enzyme in the repair of DNA strand breaks. Inhibition of PARP-1 increases the effectiveness of radiation in killing tumor cells. However, while the mechanism(s) are well understood for these radiosensitizing effects in vitro, the underlying mechanism(s) in vivo are less clear. Nicotinamide, a drug structurally related to the first generation PARP-1 inhibitor, 3-aminobenzamide, reduces tumor hypoxia by preventing transient cessations in tumor blood flow, thus improving tumor oxygenation and sensitivity to radiotherapy. Here we investigate whether olaparib, a potent PARP-1 inhibitor, enhances radiotherapy, not only by inhibiting DNA repair but also by changing tumor vascular haemodynamics in non-small cell lung carcinoma. In irradiated Calu-6 and A549 cells, olaparib enhanced the cytotoxic effects of radiation (SER10=1.5 and 1.3) and DNA double strand breaks persisted for at least 24 h after treatment. Combination treatment of Calu-6 xenografts with olaparib and fractionated radiotherapy caused significant tumor regression (p=0.007) relative to radiotherapy alone. To determine whether this radiosensitisation was due solely to effects on DNA repair we used a dorsal window chamber model to establish the drug/radiation effects on vessel dynamics. Olaparib alone, when given as single or multiple daily doses, or in combination with fractionated radiotherapy, increased the perfusion of tumor blood vessels. Furthermore, an ex vivo assay in phenylephrine pre-constricted arteries confirmed olaparib to have higher vasodilatory properties than nicotinamide. This study suggests that olaparib warrants consideration for further development in combination with radiotherapy in clinical oncology settings such as NSCLC. PMID:21825006

  16. Pharmacoeconomics of systemic therapies for lung cancer.

    PubMed

    Bordeleau, Louise

    2006-01-01

    The purpose of this article is to review the economics of systemic therapies for the treatment of lung cancer. Lung cancer treatment is moderately expensive. The overall cost to society is significant given its high incidence. Most analyses in patients with small cell lung cancer focus on supportive care measures. The economics of chemotherapy in patients with advanced small cell lung cancer, as assessed in one study, shows alternating chemotherapy to be cost effective. Numerous economic analyses of chemotherapy in patients with non-small cell lung cancer (NSCLC) have been completed using varying methodologies in a number of countries. In patients with advanced NSCLC, third generation chemotherapy in the first-line setting can be administered within reasonable incremental cost effectiveness. Single-agent docetaxel chemotherapy in the second-line setting has also been shown to fall within a reasonable cost-effective range. Based on this review, systemic therapies for lung cancer are, for the most part, cost effective. Information on the cost-utility of systemic therapies is more limited. In a population of cancer patients with poor prognosis, the inclusion of quality indicators in the calculation of costs (i.e. cost-utility analyses) will be of great importance to refine our understanding of costs and benefits using a more global approach. Future economic analyses of adjuvant chemotherapy and novel targeted therapies will be of great interest.

  17. Physical activity and lung cancer prevention.

    PubMed

    Emaus, Aina; Thune, Inger

    2011-01-01

    Since lung cancer is among the cancers with the highest incidence and has the highest mortality rate of cancer worldwide, the means of reducing its impact are urgently needed. Emerging evidence shows that physical activity plays an etiological role in lung cancer risk reduction. The majority of studies support the fact that total and recreational physical activity reduces lung cancer risk by 20-30% for women and 20-50% for men, and there is evidence of a dose-response effect. The biological mechanisms operating between physical activity and lung cancer are likely complex and influenced by many factors including inherited or acquired susceptibility genes, gender, smoking, and other environmental factors. Several plausible biological factors and mechanisms have been hypothesized linking physical activity to reduced lung cancer risk including: improved pulmonary function, reduced concentrations of carcinogenic agents in the lungs, enhanced immune function, reduced inflammation, enhanced DNA repair capacity, changes in growth factor levels and possible gene-physical activity interactions. Future research should target the possible subgroup effects and the biologic mechanisms that may be involved.

  18. Plasma immunoreactive calcitonin in lung cancer.

    PubMed

    Roos, B A; Lindall, A W; Baylin, S B; O'Neil, J; Frelinger, A L; Birnbaum, R S; Lambert, P W

    1979-01-01

    We have measured plasma calcitonin in 135 untreated eucalemic men with lung cancer and a control/smoker population. Calcitonin levels were determined by radioimmunoassay and validated by immunoextraction. Plasma immunoreactive calcitonin moieties were purified by immunoadsorbent chromatography, treated with mercaptoethanol and urea, and characterized by gel filtration. Artifacts in human calcitonin radioimmunoassays of cancer-patient plasmas were detected by parallel plasma incubations in a salmon calcitonin radioimmunoassay system which does not detect human calcitonin and by immunoprecipitation of tracer at the end of radioimmunoassay incubations. Heating fresh plasmas to 65 degrees C for 1.5 hours reduced radioimmunoassay artifacts without loss of calcitonin moieties. Such characterization of hypercalcitoninemia in each of the histopathological types of lung cancer has raised some important questions about the interpretation of plasma calcitonin radioimmunoassay measurements in lung cancer. Based on inhibition of tracer-antibody binding, plasma calcitonin seemed to be elevated in 18% (14/80) of basal plasma samples obtained from patients with epidermoid or with anaplastic lung cancer. Unequivocal hypercalcitoninemia (heat stable, causing no inhibition of antibody-tracer binding in the salmon calcitonin radioimmunoassays, and immunoextractable with human calcitonin antibodies) was not found in any of the apparently hypercalcitoninemic plasmas from persons with epidermoid or anaplastic lung cancer. By contrast, unequivocal hypercalcitoninemia was found in 27% (15/55) of plasmas from patients with small cell carcinoma or adenocarcinoma. Most of the immunoreactive calcitonin recovered from small cell and adenocarcinoma lung cancer plasmas with unequivocally elevated calcitonin is much larger than calcitonin monomer.

  19. Suppression of AKT expression by miR-153 produced anti-tumor activity in lung cancer.

    PubMed

    Yuan, Ye; Du, Weijie; Wang, Ying; Xu, Chaoqian; Wang, Jinghao; Zhang, Yang; Wang, Huimin; Ju, Jiaming; Zhao, Liang; Wang, Zhiguo; Lu, Yanjie; Cai, Benzhi; Pan, Zhenwei

    2015-03-15

    Lung cancer is one of the leading causes of cancer death worldwide. microRNAs have been shown to be a novel class of regulators in lung cancer. Here, we explored the role of miR-153 in the pathogenesis of lung cancer and its therapeutic potential. miR-153 was significantly decreased in lung cancer tissues than the adjacent tissues. The protein and mRNA levels of protein kinase B (AKT), which were shown to promote tumor growth, were both increased in lung cancer tissues than adjacent tissues. Overexpression of miR-153 significantly inhibited AKT protein expression, which were abrogated by co-transfection of AMO-153, the specific inhibitor of miR-153. Luciferase assay showed that transfection of miR-153 markedly suppressed the fluorescent intensity of chimeric vectors carrying the 3'UTR of AKT1, while produced no effect on the mutant construct, indicating that AKT is regulated by miR-153. Overexpression of miR-153 significantly inhibited the proliferation and migration, and promoted apoptosis of cultured lung cancer cells in vitro, and suppressed the growth of xenograft tumors in vivo. Interestingly, lung cancer cells with lower endogenous miR-153 expression are more sensitive to ectopic overexpressed miR-153. The IC50 of miR-153 on lung cancer cells is positive correlated with the endogenous miR-153 level, while negative correlated with AKT level. Knockdown of AKT expression suppressed lung cancer cell proliferation. In summary, miR-153 exerted anti-tumor activity in lung cancer by targeting on AKT. The sensitivity of lung cancer cells to miR-153 is determined by its endogenous miR-153 level.

  20. Cigarette smoke radioactivity and lung cancer risk.

    PubMed

    Karagueuzian, Hrayr S; White, Celia; Sayre, James; Norman, Amos

    2012-01-01

    To determine the tobacco industry's policy and action with respect to radioactive polonium 210 ((210)Po) in cigarette smoke and to assess the long-term risk of lung cancer caused by alpha particle deposits in the lungs of regular smokers. Analysis of major tobacco industries' internal secret documents on cigarette radioactivity made available online by the Master Settlement Agreement in 1998. The documents show that the industry was well aware of the presence of a radioactive substance in tobacco as early as 1959. Furthermore, the industry was not only cognizant of the potential "cancerous growth" in the lungs of regular smokers but also did quantitative radiobiological calculations to estimate the long-term (25 years) lung radiation absorption dose (rad) of ionizing alpha particles emitted from the cigarette smoke. Our own calculations of lung rad of alpha particles match closely the rad estimated by the industry. According to the Environmental Protection Agency, the industry's and our estimate of long-term lung rad of alpha particles causes 120-138 lung cancer deaths per year per 1,000 regular smokers. Acid wash was discovered in 1980 to be highly effectively in removing (210)Po from the tobacco leaves; however, the industry avoided its use for concerns that acid media would ionize nicotine converting it into a poorly absorbable form into the brain of smokers thus depriving them of the much sought after instant "nicotine kick" sensation. The evidence of lung cancer risk caused by cigarette smoke radioactivity is compelling enough to warrant its removal.

  1. [Lung cancer screening and management of small pulmonary nodules].

    PubMed

    Schulz, Christian

    2015-03-01

    Worldwide lung cancer is the leading cause of death from cancer. Most lung cancers are diagnosed at an advanced stage, so survival after lung cancer is generally poor. Diagnosis of lung cancer at earlier stages may be associated with an increased survival rate. This indicates that the implementation of lung cancer screening programs at the population level by means of low dose computed tomography might helpful to improve the outcome and mortality of lung cancer patients. By means of rapid advances in imaging technologies over the last decades it became possible to detect small lung nodules as small as a couple of millimeters. This recent developments require management algorithms to guide the clinical management of suspicious and indeterminate lung nodules found in computer tomography during lung cancer screening or by incidental finding.This review will focus on both, the recent advances in lung cancer screening and the guidelines for the management of small pulmonary nodules.

  2. Improved therapeutic effectiveness by combining liposomal honokiol with cisplatin in lung cancer model.

    PubMed

    Jiang, Qi-qi; Fan, Lin-yu; Yang, Guang-li; Guo, Wen-Hao; Hou, Wen-li; Chen, Li-juan; Wei, Yu-quan

    2008-08-16

    Honokiol is a major bioactive compound extracted from Magnolia. The present study was designed to determine whether liposomal honokiol has the antitumor activity against human lung cancer as well as potentiates the antitumor activity of cisplatin in A549 lung cancer xenograft model, if so, to examine the possible mechanism in the phenomenon. human A549 lung cancer-bearing nude mice were treated with liposomal honokiol, liposomal honokiol plus DDP or with control groups. Apoptotic cells and vessels were evaluated by fluorescent in situ TUNEL assay and by immunohistochemistry with an antibody reactive to CD31 respectively. The present study showed that liposomal honokiol alone resulted in effective suppression of the tumor growth, and that the combined treatment with honokiol plus DDP had the enhanced inhibition of the tumor growth and resulted in a significant increase in life span. The more apparent apoptotic cells in the tumors treated with honokiol plus DDP was found in fluorescent in situ TUNEL assay, compared with the treatment with control groups. In addition, the combination of honokiol and DDP apparently reduced the number of vessels by immunolabeling of CD31 in the tissue sections, compared with control groups. In summary, our data suggest that honokiol alone had the antitumor activity against human lung cancer in A549 lung cancer xenograft model, and that the combination of honokiol with DDP can enhance the antitumor activity, and that the enhanced antitumor efficacy in vivo may in part result from the increased induction of the apoptosis and the enhanced inhibition of angiogenesis in the combined treatment. The present findings may be of importance to the further exploration of the potential application of the honokiol alone or the combined approach in the treatment of lung carcinoma.

  3. Improved therapeutic effectiveness by combining liposomal honokiol with cisplatin in lung cancer model

    PubMed Central

    Jiang, Qi-qi; Fan, Lin-yu; Yang, Guang-li; Guo, Wen-Hao; Hou, Wen-li; Chen, Li-juan; Wei, Yu-quan

    2008-01-01

    Background Honokiol is a major bioactive compound extracted from Magnolia. The present study was designed to determine whether liposomal honokiol has the antitumor activity against human lung cancer as well as potentiates the antitumor activity of cisplatin in A549 lung cancer xenograft model, if so, to examine the possible mechanism in the phenomenon. Methods human A549 lung cancer-bearing nude mice were treated with liposomal honokiol, liposomal honokiol plus DDP or with control groups. Apoptotic cells and vessels were evaluated by fluorescent in situ TUNEL assay and by immunohistochemistry with an antibody reactive to CD31 respectively. Results The present study showed that liposomal honokiol alone resulted in effective suppression of the tumor growth, and that the combined treatment with honokiol plus DDP had the enhanced inhibition of the tumor growth and resulted in a significant increase in life span. The more apparent apoptotic cells in the tumors treated with honokiol plus DDP was found in fluorescent in situ TUNEL assay, compared with the treatment with control groups. In addition, the combination of honokiol and DDP apparently reduced the number of vessels by immunolabeling of CD31 in the tissue sections, compared with control groups. Conclusion In summary, our data suggest that honokiol alone had the antitumor activity against human lung cancer in A549 lung cancer xenograft model, and that the combination of honokiol with DDP can enhance the antitumor activity, and that the enhanced antitumor efficacy in vivo may in part result from the increased induction of the apoptosis and the enhanced inhibition of angiogenesis in the combined treatment. The present findings may be of importance to the further exploration of the potential application of the honokiol alone or the combined approach in the treatment of lung carcinoma. PMID:18706101

  4. Exercise therapy across the lung cancer continuum.

    PubMed

    Jones, Lee W; Eves, Neil D; Waner, Emily; Joy, Anil A

    2009-07-01

    A lung cancer diagnosis and associated therapeutic management are associated with unique and varying degrees of adverse physical/functional impairments that dramatically reduce patients' ability to tolerate exercise. Poor exercise capacity predisposes to increased susceptibility to other common age-related diseases, poor quality of life, and likely premature death. This article reviews the literature investigating the role of exercise as an adjunct therapy across the lung cancer continuum (ie, prevention to palliation). The current evidence suggests that exercise training is a safe and feasible adjunct therapy for patients with operable lung cancer both before and after pulmonary resection. Among patients with inoperable disease, feasibility and safety studies of carefully prescribed exercise training are warranted. Preliminary evidence in this area suggests that exercise therapy may be an important consideration in multidisciplinary management of patients diagnosed with lung cancer.

  5. Physical activity and lung cancer survivorship.

    PubMed

    Jones, Lee W

    2011-01-01

    A lung cancer diagnosis and associated therapeutic management is associated with unique and varying degrees of adverse physical/functional impairments that dramatically reduce a patient's ability to tolerate exercise. Poor exercise tolerance predisposes to increased susceptibility to other common age-related diseases, poor quality of life (QOL), and likely premature death. Here we review the putative literature investigating the role of exercise as an adjunct therapy across the lung cancer continuum (i.e., diagnosis to palliation). The current evidence suggests that exercise training is a safe and feasible adjunct therapy for operable lung cancer patients both before and after pulmonary resection. Among patients with inoperable disease, feasibility and safety studies of carefully prescribed exercise training are warranted. Preliminary evidence in this area supports that exercise therapy may be an important consideration in multidisciplinary management of patients diagnosed with lung cancer.

  6. Lung cancer in the Indian subcontinent

    PubMed Central

    Noronha, Vanita; Pinninti, Rakesh; Patil, Vijay M.; Joshi, Amit; Prabhash, Kumar

    2016-01-01

    Smoking tobacco, both cigarettes and beedis, is the principal risk factor for causation of lung cancer in Indian men; however, among Indian women, the association with smoking is not strong, suggesting that there could be other risk factors besides smoking. Despite numerous advances in recent years in terms of diagnostic methods, molecular changes, and therapeutic interventions, the outcomes of the lung cancer patients remain poor; hence, a better understanding of the risk factors may impact the preventive measures to be implemented at the community level. There is a lack of comprehensive data on lung cancer in India. In this review, we attempt to collate the available data on lung cancer from India. PMID:27606290

  7. Dark tobacco and lung cancer in Cuba.

    PubMed

    Joly, O G; Lubin, J H; Caraballoso, M

    1984-01-01

    A retrospective case control study of lung cancer was conducted in Havana, Cuba to investigate whether Cuban high lung cancer mortality rates could be explained by cigarette and cigar consumption habits, including the smoking of dark tobacco cigarettes. The cases were drawn from patients admitted from 1978 to 1980 to the city's 12 main general hospitals with a tentative diagnosis of lung cancer. Only patients whose final diagnosis was confirmed by cytology and/ or histology according to the World Health Organization's Classification of Lung Cancer were included. A hospital control selected from patients with a current admission for a nonsmoking-related disease was matched to each case by sex, age, hospital of admission, and admission date. Data on 826 confirmed lung cancer cases (219 females and 607 males), 979 hospital controls, and 539 neighborhood controls were analyzed with procedures for matched and unmatched studies. Lung cancer patients ranged in age from 23 to 89 years; approximately 1/2 were females and 2/3 of the males were 60 years or older at diagnosis. Education level was similar in all groups. 167 of the 219 female cases (76.3%) and 595 of the 607 male cases (98%) ever smoked regularly, compared with 31% and 80.3%, respectively, of female and male controls. The corresponding proportions for female hospital and neighborhood controls were 30.5 and 31.8%, whereas for males they were 80.5% and 80.1%. The overall relative risk (RR) of lung cancer in cigarette smokers was 7.3 for females and 14.1 for males. Most smokers consumed the local dark tobacco ciagrettes exclusively. There were increased risks of lung cancer in both sexes associated with smoking both tobaccos, but the excess was greater for dark tobacco. The differences were reduced after adjustment for amount smoked. With either dark or light tobacco, the longer the duration of smoking or the greater the total number of cigarettes consumed, the higher the risk, all trends being highly significant

  8. Growth of LAPC4 prostate cancer xenograft tumor is insensitive to 5α-reductase inhibitor dutasteride

    PubMed Central

    Garcia, Raquel Ramos; Masoodi, Khalid Z; Pascal, Laura E; Nelson, Joel B; Wang, Zhou

    2014-01-01

    Intermittent androgen deprivation therapy (IADT) allows prostate cancer patients a break from the side-effects of continuous androgen deprivation therapy (ADT). Although clinical studies suggest that IADT can significantly improve patient quality of life over ADT, it has not been demonstrated to improve patient survival. Recently, increased survival has been demonstrated when 5α-reductase inhibitors have been used during the off-cycle of IADT in animal xenograft tumor models LNCaP and LuCaP35. In the current study, the sensitivity of LAPC4 xenograft tumor regrowth to the 5ARI dutasteride was determined. Tumor regrowth and gene expression changes in LAPC4 tumors were compared to the previously determined response of LNCaP and LuCaP35 xenograft tumors to 5ARI treatment during the off-cycle of IADT, LAPC4, LNCaP and LuCaP35 tumors were sensitive to androgen manipulation. However, in contrast to LNCaP and LuCaP35, dutasteride treatment during testosterone-stimulated prostate regrowth did not affect tumor regrowth or the expression of androgen responsive genes. Tumor response to dutasteride during the off-cycle of IADT is variable in xenograft prostate tumor models. Future studies will be required to elucidate the mechanisms contributing to the dutasteride resistance observed in the LAPC4 model during the off-cycle. PMID:25374909

  9. A patient-derived-xenograft platform to study BRCA-deficient ovarian cancers

    PubMed Central

    George, Erin; Kim, Hyoung; Krepler, Clemens; Wenz, Brandon; Makvandi, Mehran; Tanyi, Janos L.; Brown, Eric; Zhang, Rugang; Brafford, Patricia; Jean, Stephanie; Mach, Robert H.; Lu, Yiling; Herlyn, Meenhard; Morgan, Mark; Zhang, Xiaochen; Soslow, Robert; Johnson, Neil; Zheng, Ying; Cotsarelis, George; Nathanson, Katherine L.

    2017-01-01

    Approximately 50% of high-grade serous ovarian cancers (HGSOCs) have defects in genes involved in homologous recombination (HR) (i.e., BRCA1/2). Preclinical models to optimize therapeutic strategies for HR-deficient (HRD) HGSOC are lacking. We developed a preclinical platform for HRD HGSOCs that includes primary tumor cultures, patient-derived xenografts (PDXs), and molecular imaging. Models were characterized by immunohistochemistry, targeted sequencing, and reverse-phase protein array analysis. We also tested PDX tumor response to PARP, CHK1, and ATR inhibitors. Fourteen orthotopic HGSOC PDX models with BRCA mutations (BRCAMUT) were established with a 93% success rate. The orthotopic PDX model emulates the natural progression of HGSOC, including development of a primary ovarian tumor and metastasis to abdominal viscera. PDX response to standard chemotherapy correlated to that demonstrated in the patient. Pathogenic mutations and HGSOC markers were preserved after multiple mouse passages, indicating retention of underlying molecular mechanisms of carcinogenesis. A BRCA2MUT PDX with high p-CHK1 demonstrated a similar delay of tumor growth in response to PARP, CHK1, and ATR inhibitors. A poly (ADP-ribose) polymerase (PARP) inhibitor radiotracer correlated with PARP1 activity and showed response to PARP inhibition in the BRCA2MUT PDX model. In summary, the orthotopic HGSOC PDX represents a robust and reliable model to optimize therapeutic strategies for BRCAMUT HGSOC. PMID:28097235

  10. The Inhibitory Efficacy of Methylseleninic Acid Against Colon Cancer Xenografts in C57BL/6 Mice.

    PubMed

    Zeng, Huawei; Wu, Min

    2015-01-01

    Data indicate that methylselenol is a critical selenium (Se) metabolite for anticancer activity in vivo. We tested the hypothesis that oral dosing methylseleninic acid (MSeA), a methylselenol precursor, inhibits the growth of colon cancer xenografts in C57BL/6 mice fed a Se adequate diet. In this study, MSeA supplementation was given by an oral dose (0, 1, or 3 mg/kg body weight) regimen. MSeA increased Se content of liver, kidney, muscle, stomach (w/intestine) and plasma, and elevated blood glutathione peroxidase (GPx) activities. However, MSeA did not change lean/fat body composition, food consumption, levels of plasma leptin/adiponectin, and body weight gain. MSeA (3 mg/kg body weight) inhibited tumor growth up to 61% when compared to the control group, and this inhibition was associated with a reduction of plasma tumor necrosis factor (TNFα)/interleukin 6 (IL6) level but elevated blood GPx activities. In addition, MSeA (1 mg/kg body weight) increased the activation of caspase-3, a major apoptotic enzyme, in tumor tissues. Taken together, our MSeA oral dosing regimen was at safe levels; and high blood GPx activities, caspase-3 activities in tumor tissue and a reduction of plasma TNFα/IL6 level, play critical roles in inhibiting colon tumor growth in an immune-competent C57BL/6 mouse model.

  11. Patient-derived bladder cancer xenografts in the preclinical development of novel targeted therapies

    PubMed Central

    Hayashi, Tetsutaro; Janssen, Claudia; Awrey, Shannon; Wyatt, Alexander W.; Anderson, Shawn; Moskalev, Igor; Haegert, Anne; Alshalalfa, Mohammed; Erho, Nicholas; Davicioni, Elai; Fazli, Ladan; Li, Estelle; Collins, Colin; Wang, Yuzhuo; Black, Peter C.

    2015-01-01

    Optimal animal models of muscle invasive bladder cancer (MIBC) are necessary to overcome the current lack of novel targeted therapies for this malignancy. Here we report on the establishment and characterization of patient-derived primary xenografts (PDX). Patient tumors were grafted under the renal capsule of mice and subsequently transplanted over multiple generations. Patient tumor and PDX were processed for analysis of copy number variations by aCGH, gene expression by microarray, and expression of target pathways by immunohistochemistry (IHC). One PDX harbouring an FGFR3 mutation was treated with an inhibitory monoclonal antibody targeting FGFR3. Five PDX were successfully established. Tumor doubling time ranged from 5 to 11 days. Array CGH revealed shared chromosomal aberrations in the patient tumors and PDX. Gene expression microarray and IHC confirmed that PDXs maintain similar patterns to the parental tumors. Tumor growth in the PDX with an FGFR3 mutation was inhibited by the FGFR3 inhibitor. PDXs recapitulate the tumor biology of the patients' primary tumors from which they are derived. Investigations related to tumor biology and drug testing in these models are therefore more likely to be relevant to the disease state in patients. They represent a valuable tool for developing precision therapy in MIBC. PMID:26041878

  12. Calculated Log D is Inversely Correlated with Select Camptothecin Clearance and Efficacy in Colon Cancer Xenografts

    PubMed Central

    Nanavati, Charvi; Mager, Donald E.

    2016-01-01

    Quantitative structure-property relationships (QSPR) are often derived to identify molecular determinants of drug potency and facilitate drug design. However, compound activity is typically based on in vitro bioassays, and the influence of physicochemical properties on pharmacokinetic/pharmacodynamic (PK/PD) behavior is not considered. Here, we integrate PK/PD and QSPR modeling to evaluate the role of lipophilicity in camptothecin anti-tumor responses in colon cancer xenografts. Drug exposure and tumor growth profiles for five camptothecins were extracted from the literature. A PK/PD model with time-dependent transduction was developed, which characterized PK and tumor growth inhibition. Correlations between drug lipophilicity (log D), in vitro potency (IC50), and in vivo efficacy and systemic clearance parameters were tested. Models were qualified using leave-one-out cross-validation. Efficacy and clearance of analogs decreased linearly with increasing log D values; efficacy exhibiting a steeper decline relative to clearance. Cross-validated R2 for predicting in vivo efficacy was 0.55 and 0.18 using log D and in vitro IC50 as the descriptors. Lipophilicity may represent a better predictor of in vivo efficacy than in vitro IC50 measurements for camptothecins. The identified relationships between efficacy, clearance, and lipohilicity may help guide development of new camptothecin analogs and delivery systems with improved pharmacological profiles. PMID:27019967

  13. Eliciting hyperacute xenograft response to treat human cancer: alpha(1,3) galactosyltransferase gene therapy.

    PubMed

    Link, C J; Seregina, T; Atchison, R; Hall, A; Muldoon, R; Levy, J P

    1998-01-01

    Xenograft hyperacute rejection in humans occurs as a secondary response to a cellular glycosylation incompatibility with most non-human mammalian species. A key component of hyperacute rejection, alpha(1,3)galactosyl (agal) epitopes present on the surface of most non-human mammal cells, is bound by host anti-agal IgG antibodies leading to the activation of complement and, cellular lysis (1). The enzyme causing specific glycosylation patterns, alpha(1,3)galactosyltransferase [alpha(1,3)GT], directs the addition of agal to N-acetyl glucosamine residues in the trans Golgi apparatus in most mammalian species including Mus musculus, but not old world primates, apes or humans. In this report, we cloned both a truncated and full length murine alpha(1,3)GT gene into a retroviral vector backbone in order to transfer alpha(1,3)galactosyl epitopes into human A375 melanoma cells. Expression of agal epitopes on A375 cells after alpha(1,3)GT gene transfer was demonstrated using FITC-labeled ligand and FACS analysis. These cells were exposed to human serum for 30 minutes and > 90% of the agal expressing cells were killed by this treatment. These pretreated cells failed to establish tumors after implantation into athymic nude mice. This is the first report of retroviral vector transfer of the alpha(1,3)GT gene into human tumor cells in an attempt to elicit hyperacute rejection as a novel anti-cancer gene therapy strategy.

  14. Antitumor Activity of Garcinol in Human Prostate Cancer Cells and Xenograft Mice.

    PubMed

    Wang, Yu; Tsai, Mei-Ling; Chiou, Li-Yu; Ho, Chi-Tang; Pan, Min-Hsiung

    2015-10-21

    Garcinol, which is isolated from fruit rinds of Garcinia indica, is a polyisoprenylated benzophenone. It has been studied for its antitumor activity by inducing apoptosis and inhibiting autophagy in human prostate cancer cells. The Bax/Bcl-2 ratio increased when garcinol was applied to PC-3 cells indicating a presence of apoptosis. Meanwhile, procaspases-9 and -3 were suppressed with attenuating PARP and DFF-45. Autophagy was inhibited through activating p-mTOR and p-PI3 Kinase/AKT by garcinol, which as a result induced the cells to apoptosis directly. In addition, the apoptosis effect of garcinol in a xenograft mouse model was also tested, suggesting a consistent result with PC-3 cell model. The tumor size was reduced more than 80 percent after the mouse accepted the garcinol treatment. Garcinol was demonstrated to have a strong antitumor activity through inhibiting autophagy and inducing apoptosis, which was discovered for the first time. Based on these findings, our data suggests that garcinol deserves further investigation as a potent chemopreventive agent.

  15. SapC-DOPS Nanovesicles as Targeted Therapy for Lung Cancer

    PubMed Central

    Zhao, Shuli; Chu, Zhengtao; Blanco, Victor M.; Nie, Yunzhong; Hou, Yayi; Qi, Xiaoyang

    2014-01-01

    Lung cancer is the deadliest type of cancer for both men and women. In this study, we evaluate the in vitro and in vivo efficacy of a biotherapeutic agent composed of a lysosomal protein (Saposin C, SapC) and a phospholipid (dioleoylphosphatidylserine, DOPS) which can be assembled into nanovesicles (SapC-DOPS) with selective antitumor activity. SapC-DOPS targets phosphatidylserine, an anionic phospholipid preferentially exposed in the surface of cancer cells and tumor-associated vasculature. Since binding of SapC to phosphatidylserine is favored at acidic pHs, and the latter characterizes the milieu of many solid tumors, we tested the effect of pH on the binding capacity of SapC-DOPS to lung tumor cells. Results showed that SapC-DOPS binding to cancer cells was more pronounced at low pH. Viability assays on a panel of human lung tumor cells showed that SapC-DOPS cytotoxicity was positively correlated with cell surface phosphatidylserine levels, whereas mitochondrial membrane potential measurements were consistent with apoptosis-related cell death. Using a fluorescence tracking method in live mice, we show that SapC-DOPS specifically targets human lung cancer xenografts, and that systemic therapy with SapC-DOPS induces tumor apoptosis and significantly inhibits tumor growth. These results suggest that SapC-DOPS nanovesicles are a promising treatment option for lung cancer. PMID:25670331

  16. The isolation and characterization of renal cancer initiating cells from human Wilms' tumour xenografts unveils new therapeutic targets†

    PubMed Central

    Pode-Shakked, Naomi; Shukrun, Rachel; Mark-Danieli, Michal; Tsvetkov, Peter; Bahar, Sarit; Pri-Chen, Sara; Goldstein, Ronald S; Rom-Gross, Eithan; Mor, Yoram; Fridman, Edward; Meir, Karen; Simon, Amos; Magister, Marcus; Kaminski, Naftali; Goldmacher, Victor S; Harari-Steinberg, Orit; Dekel, Benjamin

    2013-01-01

    There are considerable differences in tumour biology between adult and paediatric cancers. The existence of cancer initiating cells/cancer stem cells (CIC/CSC) in paediatric solid tumours is currently unclear. Here, we show the successful propagation of primary human Wilms' tumour (WT), a common paediatric renal malignancy, in immunodeficient mice, demonstrating the presence of a population of highly proliferative CIC/CSCs capable of serial xenograft initiation. Cell sorting and limiting dilution transplantation analysis of xenograft cells identified WT CSCs that harbour a primitive undifferentiated – NCAM1 expressing – “blastema” phenotype, including a capacity to expand and differentiate into the mature renal-like cell types observed in the primary tumour. WT CSCs, which can be further enriched by aldehyde dehydrogenase activity, overexpressed renal stemness and genes linked to poor patient prognosis, showed preferential protein expression of phosphorylated PKB/Akt and strong reduction of the miR-200 family. Complete eradication of WT in multiple xenograft models was achieved with a human NCAM antibody drug conjugate. The existence of CIC/CSCs in WT provides new therapeutic targets. PMID:23239665

  17. The isolation and characterization of renal cancer initiating cells from human Wilms' tumour xenografts unveils new therapeutic targets.

    PubMed

    Pode-Shakked, Naomi; Shukrun, Rachel; Mark-Danieli, Michal; Tsvetkov, Peter; Bahar, Sarit; Pri-Chen, Sara; Goldstein, Ronald S; Rom-Gross, Eithan; Mor, Yoram; Fridman, Edward; Meir, Karen; Simon, Amos; Magister, Marcus; Kaminski, Naftali; Goldmacher, Victor S; Harari-Steinberg, Orit; Dekel, Benjamin

    2013-01-01

    There are considerable differences in tumour biology between adult and paediatric cancers. The existence of cancer initiating cells/cancer stem cells (CIC/CSC) in paediatric solid tumours is currently unclear. Here, we show the successful propagation of primary human Wilms' tumour (WT), a common paediatric renal malignancy, in immunodeficient mice, demonstrating the presence of a population of highly proliferative CIC/CSCs capable of serial xenograft initiation. Cell sorting and limiting dilution transplantation analysis of xenograft cells identified WT CSCs that harbour a primitive undifferentiated-NCAM1 expressing-"blastema" phenotype, including a capacity to expand and differentiate into the mature renal-like cell types observed in the primary tumour. WT CSCs, which can be further enriched by aldehyde dehydrogenase activity, overexpressed renal stemness and genes linked to poor patient prognosis, showed preferential protein expression of phosphorylated PKB/Akt and strong reduction of the miR-200 family. Complete eradication of WT in multiple xenograft models was achieved with a human NCAM antibody drug conjugate. The existence of CIC/CSCs in WT provides new therapeutic targets.

  18. Development and Characterization of Bladder Cancer Patient-Derived Xenografts for Molecularly Guided Targeted Therapy

    PubMed Central

    Lin, Tzu-yin; Davis, Ryan R.; Keck, James; Ghosh, Paramita M.; Gill, Parkash; Airhart, Susan; Bult, Carol; Gandara, David R.; Liu, Edison; de Vere White, Ralph W.

    2015-01-01

    Background The overarching goal of this project is to establish a patient-derived bladder cancer xenograft (PDX) platform, annotated with deep sequencing and patient clinical information, to accelerate the development of new treatment options for bladder cancer patients. Herein, we describe the creation, initial characterization and use of the platform for this purpose. Methods and Findings Twenty-two PDXs with annotated clinical information were established from uncultured unselected clinical bladder cancer specimens in immunodeficient NSG mice. The morphological fidelity was maintained in PDXs. Whole exome sequencing revealed that PDXs and parental patient cancers shared 92–97% of genetic aberrations, including multiple druggable targets. For drug repurposing, an EGFR/HER2 dual inhibitor lapatinib was effective in PDX BL0440 (progression-free survival or PFS of 25.4 days versus 18.4 days in the control, p = 0.007), but not in PDX BL0269 (12 days versus 13 days in the control, p = 0.16) although both expressed HER2. To screen for the most effective MTT, we evaluated three drugs (lapatinib, ponatinib, and BEZ235) matched with aberrations in PDX BL0269; but only a PIK3CA inhibitor BEZ235 was effective (p<0.0001). To study the mechanisms of secondary resistance, a fibroblast growth factor receptor 3 inhibitor BGJ398 prolonged PFS of PDX BL0293 from 9.5 days of the control to 18.5 days (p<0.0001), and serial biopsies revealed that the MAPK/ERK and PIK3CA-AKT pathways were activated upon resistance. Inhibition of these pathways significantly prolonged PFS from 12 day of the control to 22 days (p = 0.001). To screen for effective chemotherapeutic drugs, four of the first six PDXs were sensitive to the cisplatin/gemcitabine combination, and chemoresistance to one drug could be overcome by the other drug. Conclusion The PDX models described here show good correlation with the patient at the genomic level and known patient response to treatment. This supports further

  19. Association of diet-induced hyperinsulinemia with accelerated growth of prostate cancer (LNCaP) xenografts.

    PubMed

    Venkateswaran, Vasundara; Haddad, Ahmed Q; Fleshner, Neil E; Fan, Rong; Sugar, Linda M; Nam, Rob; Klotz, Laurence H; Pollak, Michael

    2007-12-05

    Prior research suggested that energy balance and fat intake influence prostate cancer progression, but the influence of dietary carbohydrate on prostate cancer progression has not been well characterized. We hypothesized that hyperinsulinemia resulting from high intake of refined carbohydrates would lead to more rapid growth of tumors in the murine LNCaP xenograft model of prostate cancer. Athymic mice were injected subcutaneously with LNCaP human prostate cancer cells and, when tumors were palpable, were randomly assigned (n = 20 per group) to high carbohydrate-high fat or low carbohydrate-high fat diets. Body weight and tumor volume were measured weekly. After 9 weeks, serum levels of insulin and insulin-like growth factor 1 (IGF-1) were measured by enzyme immunoassay. AKT activation and the levels of the insulin receptor in tumor cells were determined by immunoblotting. The in vitro growth response of LNCaP cells to serum from mice in the two treatment groups was measured based on tetrazolium compound reduction. All statistical tests were two-sided. After 9 weeks on the experimental diets, mice on the high carbohydrate-high fat diet were heavier (mean body weight of mice on the high carbohydrate-high fat diet = 34 g versus 29.1 g on the low carbohydrate-high fat diet, difference = 4.9 g, 95% CI = 3.8 to 6.0 g; P = .003), experienced increased tumor growth (mean tumor volume in mice on high carbohydrate-high fat diet = 1695 versus 980 mm3 on low carbohydrate-high fat diet, difference = 715 mm3, 95% CI = 608 to 822 mm3; P<.001), and experienced a statistically significant increase in serum insulin and IGF-1 levels. Tumors from mice on the high carbohydrate-high fat diet had higher levels of activated AKT and modestly higher insulin receptor levels than tumors from mice on the low carbohydrate-high fat diet. Serum from mice on the high carbohydrate-high fat diet was more mitogenic for LNCaP cells in vitro than serum from mice fed the low carbohydrate-high fat diet

  20. Effects of Pre- and Post-Administration of Vitamin A on the Growth of Refractory Cancers in Xenograft Mice.

    PubMed

    Li, Chuan; Imai, Masahiko; Yamasaki, Masahiro; Hasegawa, Shinya; Takahashi, Noriko

    2017-04-01

    Vitamin A is an essential nutrient that is obtained from the daily diet. The major forms of vitamin A in the body consist of retinol, retinal, retinoic acid (RA), and retinyl esters. Retinal is fundamental for vision and RA is used in clinical therapy of human acute promyelocytic leukemia. The actions of retinol and retinyl palmitate (RP) are not known well. Recently, we found that retinol is a potent anti-proliferative agent against human refractory cancers, including gallbladder cancer, being more effective than RA, while RP was inactive. In the current study, we determined serum retinol concentrations in xenograft mice bearing tumors derived from four refractory cancer cell lines. We also examined the effects of vitamin A on proliferation of human gallbladder cancer cells in vivo. Serum retinol concentrations were significantly lower in xenograft mice with tumors derived from various refractory cancer cell lines as compared with control mice. The growth of tumors was inhibited with increasing serum retinol concentrations obtained post-administration of RP. In addition, pre-administration of RP increased serum retinol concentrations and suppressed tumor growth. These results indicate that administration of RP can maintain retinol concentrations in the body and that this might suppress cancer cell growth and attachment. The regulation of vitamin A concentration in the body, which is critical biomarker of health, could be beneficial for cancer prevention and therapy.

  1. Novel peptides functionally targeting in vivo human lung cancer discovered by in vivo peptide displayed phage screening.

    PubMed

    Lee, Kyoung Jin; Lee, Jae Hee; Chung, Hye Kyung; Choi, Jinhyang; Park, Jaesook; Park, Seok Soon; Ju, Eun Jin; Park, Jin; Shin, Seol Hwa; Park, Hye Ji; Ko, Eun Jung; Suh, Nayoung; Kim, InKi; Hwang, Jung Jin; Song, Si Yeol; Jeong, Seong-Yun; Choi, Eun Kyung

    2015-02-01

    Discovery of the cancer-specific peptidic ligands have been emphasized for active targeting drug delivery system and non-invasive imaging. For the discovery of useful and applicable peptidic ligands, in vivo peptide-displayed phage screening has been performed in this study using a xenograft mouse model as a mimic microenvironment to tumor. To seek human lung cancer-specific peptides, M13 phage library displaying 2.9 × 10(9) random peptides was intravenously injected into mouse model bearing A549-derived xenograft tumor through the tail vein. Then the phages emerged from a course of four rounds of biopanning in the xenograft tumor tissue. Novel peptides were categorized into four groups according to a sequence-homology phylogenicity, and in vivo tumor-targeting capacity of these peptides was validated by whole body imaging with Cy5.5-labeled phages in various cancer types. The result revealed that novel peptides accumulated only in adenocarcinoma lung cancer cell-derived xenograft tissue. For further confirmation of the specific targeting ability, in vitro cell-binding assay and immunohistochemistry in vivo tumor tissue were performed with a selected peptide. The peptide was found to bind intensely to lung cancer cells both in vitro and in vivo, which was efficiently compromised with unlabeled phages in an in vitro competition assay. In conclusion, the peptides specifically targeting human lung cancer were discovered in this study, which is warranted to provide substantive feasibilities for drug delivery and imaging in terms of a novel targeted therapeutics and diagnostics.

  2. Exhaled breath analysis for lung cancer.

    PubMed

    Dent, Annette G; Sutedja, Tom G; Zimmerman, Paul V

    2013-10-01

    Early diagnosis of lung cancer results in improved survival compared to diagnosis with more advanced disease. Early disease is not reliably indicated by symptoms. Because investigations such as bronchoscopy and needle biopsy have associated risks and substantial costs, they are not suitable for population screening. Hence new easily applicable tests, which can be used to screen individuals at risk, are required. Biomarker testing in exhaled breath samples is a simple, relatively inexpensive, non-invasive approach. Exhaled breath contains volatile and non-volatile organic compounds produced as end-products of metabolic processes and the composition of such compounds varies between healthy subjects and subjects with lung cancer. Many studies have analysed the patterns of these compounds in exhaled breath. In addition studies have also reported that the exhaled breath condensate (EBC) can reveal gene mutations or DNA abnormalities in patients with lung cancer. This review has summarised the scientific evidence demonstrating that lung cancer has distinct chemical profiles in exhaled breath and characteristic genetic changes in EBC. It is not yet possible to accurately identify individuals with lung cancer in at risk populations by any of these techniques. However, analysis of both volatile organic compounds in exhaled breath and of EBC have great potential to become clinically useful diagnostic and screening tools for early stage lung cancer detection.

  3. Exhaled breath analysis for lung cancer

    PubMed Central

    Sutedja, Tom G.; Zimmerman, Paul V.

    2013-01-01

    Early diagnosis of lung cancer results in improved survival compared to diagnosis with more advanced disease. Early disease is not reliably indicated by symptoms. Because investigations such as bronchoscopy and needle biopsy have associated risks and substantial costs, they are not suitable for population screening. Hence new easily applicable tests, which can be used to screen individuals at risk, are required. Biomarker testing in exhaled breath samples is a simple, relatively inexpensive, non-invasive approach. Exhaled breath contains volatile and non-volatile organic compounds produced as end-products of metabolic processes and the composition of such compounds varies between healthy subjects and subjects with lung cancer. Many studies have analysed the patterns of these compounds in exhaled breath. In addition studies have also reported that the exhaled breath condensate (EBC) can reveal gene mutations or DNA abnormalities in patients with lung cancer. This review has summarised the scientific evidence demonstrating that lung cancer has distinct chemical profiles in exhaled breath and characteristic genetic changes in EBC. It is not yet possible to accurately identify individuals with lung cancer in at risk populations by any of these techniques. However, analysis of both volatile organic compounds in exhaled breath and of EBC have great potential to become clinically useful diagnostic and screening tools for early stage lung cancer detection. PMID:24163746

  4. Lung Cancer Screening with Low Dose CT

    PubMed Central

    Caroline, Chiles

    2014-01-01

    SUMMARY The announcement of the results of the NLST, showing a 20% reduction in lung-cancer specific mortality with LDCT screening in a high risk population, marked a turning point in lung cancer screening. This was the first time that a randomized controlled trial had shown a mortality reduction with an imaging modality aimed at early detection of lung cancer. Current guidelines endorse LDCT screening for smokers and former smokers ages 55 to 74, with at least a 30 pack year smoking history. Adherence to published algorithms for nodule follow-up is strongly encouraged. Future directions for screening research include risk stratification for selection of the screening population, and improvements in the diagnostic follow-up for indeterminate pulmonary nodules. As with screening for other malignancies, screening for lung cancer with LDCT has revealed that there are indolent lung cancers which may not be fatal. More research is necessary if we are to maximize the risk-benefit ratio in lung cancer screening. PMID:24267709

  5. Functional polyesters enable selective siRNA delivery to lung cancer over matched normal cells

    PubMed Central

    Yan, Yunfeng; Liu, Li; Xiong, Hu; Miller, Jason B.; Zhou, Kejin; Kos, Petra; Huffman, Kenneth E.; Elkassih, Sussana; Norman, John W.; Carstens, Ryan; Kim, James; Minna, John D.; Siegwart, Daniel J.

    2016-01-01

    Conventional chemotherapeutics nonselectively kill all rapidly dividing cells, which produces numerous side effects. To address this challenge, we report the discovery of functional polyesters that are capable of delivering siRNA drugs selectively to lung cancer cells and not to normal lung cells. Selective polyplex nanoparticles (NPs) were identified by high-throughput library screening on a unique pair of matched cancer/normal cell lines obtained from a single patient. Selective NPs promoted rapid endocytosis into HCC4017 cancer cells, but were arrested at the membrane of HBEC30-KT normal cells during the initial transfection period. When injected into tumor xenografts in mice, cancer-selective NPs were retained in tumors for over 1 wk, whereas nonselective NPs were cleared within hours. This translated to improved siRNA-mediated cancer cell apoptosis and significant suppression of tumor growth. Selective NPs were also able to mediate gene silencing in xenograft and orthotopic tumors via i.v. injection or aerosol inhalation, respectively. Importantly, this work highlights that different cells respond differentially to the same drug carrier, an important factor that should be considered in the design and evaluation of all NP carriers. Because no targeting ligands are required, these functional polyester NPs provide an exciting alternative approach for selective drug delivery to tumor cells that may improve efficacy and reduce adverse side effects of cancer therapies. PMID:27621434

  6. Functional polyesters enable selective siRNA delivery to lung cancer over matched normal cells.

    PubMed

    Yan, Yunfeng; Liu, Li; Xiong, Hu; Miller, Jason B; Zhou, Kejin; Kos, Petra; Huffman, Kenneth E; Elkassih, Sussana; Norman, John W; Carstens, Ryan; Kim, James; Minna, John D; Siegwart, Daniel J

    2016-09-27

    Conventional chemotherapeutics nonselectively kill all rapidly dividing cells, which produces numerous side effects. To address this challenge, we report the discovery of functional polyesters that are capable of delivering siRNA drugs selectively to lung cancer cells and not to normal lung cells. Selective polyplex nanoparticles (NPs) were identified by high-throughput library screening on a unique pair of matched cancer/normal cell lines obtained from a single patient. Selective NPs promoted rapid endocytosis into HCC4017 cancer cells, but were arrested at the membrane of HBEC30-KT normal cells during the initial transfection period. When injected into tumor xenografts in mice, cancer-selective NPs were retained in tumors for over 1 wk, whereas nonselective NPs were cleared within hours. This translated to improved siRNA-mediated cancer cell apoptosis and significant suppression of tumor growth. Selective NPs were also able to mediate gene silencing in xenograft and orthotopic tumors via i.v. injection or aerosol inhalation, respectively. Importantly, this work highlights that different cells respond differentially to the same drug carrier, an important factor that should be considered in the design and evaluation of all NP carriers. Because no targeting ligands are required, these functional polyester NPs provide an exciting alternative approach for selective drug delivery to tumor cells that may improve efficacy and reduce adverse side effects of cancer therapies.

  7. Carbohydrate restriction and lactate transporter inhibition in a mouse xenograft model of human prostate cancer

    PubMed Central

    Kim, Howard S.; Masko, Elizabeth M.; Poulton, Susan L.; Kennedy, Kelly M.; Pizzo, Salvatore V.; Dewhirst, Mark W.; Freedland, Stephen J.

    2012-01-01

    OBJECTIVES To determine if a no-carbohydrate ketogenic diet (NCKD) and lactate transporter inhibition can exert a synergistic effect on delaying prostate tumour growth in a xenograft mouse model of human prostate cancer. MATERIALS AND METHODS 120 nude athymic male mice (aged 6–8 weeks) were injected s.c. in the flank with 1.0 x 105 LAPC-4 prostate cancer cells. Mice were randomized to one of four treatment groups: Western diet (WD, 35% fat, 16% protein, 49% carbohydrate) and vehicle (Veh) treatment; WD and mono-carboxylate transporter-1 (MCT1) inhibition via α-cyano-4-hydroxycinnamate (CHC) delivered through a mini osmotic pump; NCKD (84% fat, 16% protein, 0% carbohydrate) plus Veh ; or NCKD and MCT1 inhibition. Mice were fed and weighed three times per week and feed was adjusted to maintain similar body weights. Tumour size was measured twice weekly and the combined effect of treatment was tested via Kruskal – Wallis analysis of all four groups. Independent effects of treatment (NCKD vs. WD and CHC vs. Veh) on tumour volume were tested using linear regression analysis. All mice were killed on Day 53 (conclusion of pump ejection), and serum and tumour sections were analysed for various markers. Again, combined and independent effects of treatment were tested using Kruskal – Wallis and linear regression analysis, respectively. RESULTS There were no significant differences in tumour volumes among the four groups (P=0.09). When testing the independent effects of treatment, NCKD was significantly associated with lower tumour volumes at the end of the experiment (P=0.026), while CHC administration was not (P=0.981). However, CHC was associated with increased necrotic fraction (P<0.001). CONCLUSIONS Differences in tumour volumes were observed only in comparisons between mice fed a NCKD and mice fed a WD. MCT1 inhibition did not have a significant effect on tumour volume, although it was associated with increased necrotic fraction. PMID:22394625

  8. Monitoring longitudinal changes in irradiated head and neck cancer xenografts using diffuse reflectance spectroscopy

    NASA Astrophysics Data System (ADS)

    Vishwanath, Karthik; Jiang, Shudong; Gunn, Jason R.; Marra, Kayla; Andreozzi, Jacqueline M.; Pogue, Brian W.

    2016-02-01

    Radiation therapy is often used as the preferred clinical treatment for control of localized head and neck cancer. However, during the course of treatment (6-8 weeks), feedback about functional and/or physiological changes within impacted tissue are not obtained, given the onerous financial and/or logistical burdens of scheduling MRI, PET or CT scans. Diffuse optical sensing is well suited to address this problem since the instrumentation can be made low-cost and portable while still being able to non-invasively provide information about vascular oxygenation in vivo. Here we report results from studies that employed an optical fiber-based portable diffuse reflectance spectroscopy (DRS) system to longitudinally monitor changes in tumor vasculature within two head and neck cancer cell lines (SCC-15 and FaDu) xenografted in the flanks of nude mice, in two separate experiments. Once the tumor volumes were 100mm3, 67% of animals received localized (electron beam) radiation therapy in five fractions (8Gy/day, for 5 days) while 33% of the animals served as controls. DRS measurements were obtained from each animal on each day of treatment and then for two weeks post-treatment. Reflectance spectra were parametrized to extract total hemoglobin concentration and blood oxygen-saturation and the resulting time-trends of optical parameters appear to be dissimilar for the two cell-lines. These findings are also compared to previous animal experiments (using the FaDu line) that were irradiated using a photon beam radiotherapy protocol. These results and implications for the use of fiber-based DRS measurements made at local (irradiated) tumor site as a basis for identifying early radiotherapy-response are presented and discussed.

  9. Indoor radon and lung cancer in China.

    PubMed

    Blot, W J; Xu, Z Y; Boice, J D; Zhao, D Z; Stone, B J; Sun, J; Jing, L B; Fraumeni, J F

    1990-06-20

    Radon has long been known to contribute to risk of lung cancer, especially in undergound miners who are exposed to large amounts of the carcinogen. Recently, however, lower amounts of radon present in living areas have been suggested as an important cause of lung cancer. In an effort to clarify the relationship of low amounts of radon with lung cancer risk, we placed alpha-track radon detectors in the homes of 308 women with newly diagnosed lung cancer and 356 randomly selected female control subjects of similar age. Measurements were taken after 1 year. All study participants were part of the general population of Shenyang, People's Republic of China, an industrial city in the northeast part of the country that has one of the world's highest rates of lung cancer in women. The median time of residence in the homes was 24 years. The median household radon level was 2.3 pCi/L of air; 20% of the levels were greater than 4 pCi/L. Radon levels tended to be higher in single-story houses or on the first floor of multiple-story dwellings, and they were also higher in houses with increased levels of indoor air pollution from coal-burning stoves. However, the levels were not higher in homes of women who developed lung cancer than in homes of controls, nor did lung cancer risk increase with increasing radon level. No association between radon and lung cancer was observed regardless of cigarette-smoking status, except for a nonsignificant trend among heavy smokers. No positive associations of lung cancer cell type with radon were observed, except for a nonsignificant excess risk of small cell cancers among the more heavily exposed residents. Our data suggest that projections from surveys of miners exposed to high radon levels may have overestimated the overall risks of lung cancer associated with levels typically seen in homes in this Chinese city. However, further studies in other population groups are needed to clarify the carcinogenic potential of indoor radon.

  10. Customizing Therapies for Lung Cancer | Center for Cancer Research

    Cancer.gov

    Lung cancer is the leading cause of cancer-related death in both men and women. Although there have been modest improvements in short-term survival over the last few decades, five-year survival rates for lung cancer remain low at only 16 percent. Treatment for lung cancer depends on the stage of the disease at diagnosis, but generally consists of some combination of surgery, chemotherapy, and radiation therapy. Increasing attention has been paid in recent years to customizing therapies based on the molecular characteristics of patients’ tumors. Some of these targeted regimens have already been integrated into the treatment arsenal for lung cancer and others are still being studied in clinical trials, including several being conducted by researchers at NCI’s Center for Cancer Research.

  11. The early diagnosis of lung cancer

    PubMed Central

    Deeley, T. J.

    1972-01-01

    Earlier diagnosis of malignant disease in the lung may bring about improvements in the treatment. This article discusses the effects of early diagnosis on the prognosis. Cancer of the lung may be associated with other lung pathology, thus increasing the problems of diagnosis. Diagnosis depends on radiological examination, cytology of the sputum, radio-isotope lung scanning and mediastinoscopy: an account is given of how these may be used to diagnose the condition whilst it is still at an early stage and suitable for radical treatment. PMID:4552427

  12. Hwanggeumchal sorghum Induces Cell Cycle Arrest, and Suppresses Tumor Growth and Metastasis through Jak2/STAT Pathways in Breast Cancer Xenografts

    PubMed Central

    Lim, Eun Joung; Joung, Youn Hee; Hong, Dae Young; Park, Eui U.; Park, Seung Hwa; Choi, Soo Keun; Moon, Eon-Soo; Cho, Byung Wook; Park, Kyung Do; Lee, Hak Kyo; Kim, Myong-Jo; Park, Dong-Sik; Yang, Young Mok

    2012-01-01

    Background Cancer is one of the highly virulent diseases known to humankind with a high mortality rate. Breast cancer is the most common cancer in women worldwide. Sorghum is a principal cereal food in many parts of the world, and is critical in folk medicine of Asia and Africa. In the present study, we analyzed the effects of HSE in metastatic breast cancer. Methodology/Principal Findings Preliminary studies conducted on MDA-MB 231 and MCF-7 xenograft models showed tumor growth suppression by HSE. Western blotting studies conducted both in vivo and in vitro to check the effect of HSE in Jak/STAT pathways. Anti-metastatic effects of HSE were confirmed using both MDA-MB 231 and MCF-7 metastatic animal models. These studies showed that HSE can modulate Jak/STAT pathways, and it hindered the STAT5b/IGF-1R and STAT3/VEGF pathways not only by down-regulating the expression of these signal molecules and but also by preventing their phosphorylation. The expression of angiogenic factors like VEGF, VEGF-R2 and cell cycle regulators like cyclin D, cyclin E, and pRb were found down-regulated by HSE. In addition, it also targets Brk, p53, and HIF-1α for anti-cancer effects. HSE induced G1 phase arrest and migration inhibition in MDA-MB 231 cells. The metastasis of breast cancer to the lungs also found blocked by HSE in the metastatic animal model. Conclusions/Significance Usage of HS as a dietary supplement is an inexpensive natural cancer therapy, without any side effects. We strongly recommend the use of HS as an edible therapeutic agent as it possesses tumor suppression, migration inhibition, and anti-metastatic effects on breast cancer. PMID:22792362

  13. Mineral particles, mineral fibers, and lung cancer

    SciTech Connect

    Churg, A.; Wiggs, B.

    1985-08-01

    The total fibrous and nonfibrous mineral content of the lung has been analyzed in a series of 14 men with lung cancer but no history of occupational dust exposure, and in a series of 14 control men matched for age, smoking history, and general occupational class. The lung cancer patients had an average of 525 +/- 369 X 10(6) exogenous mineral particles and 17.4 +/- 19.6 X 10(6) exogenous mineral fibers/g dry lung, while the controls had averages of 261 +/- 175 mineral particles and 4.7 +/- 3.2 X 10(6) mineral fibers/g dry lung. These differences are statistically significant for both particles and fibers. Kaolinite, talc, mica, feldspars, and crystalline silica comprised the majority of particles of both groups. Approximately 90% of the particles were smaller than 2 micron in diameter and approximately 60% smaller than 1 micron. In both groups, patients who had smoked more than 35 pack years had greater numbers of particles than patients who had smoked less than 35 pack years. It is concluded that, in this study, lungs from patients with lung cancer had statistically greater numbers of mineral particles and fibers than lungs from controls, and that smoking influences total long-term retention of particles from all sources.

  14. Anti-metastatic effects of liposomal gemcitabine in a human orthotopic LNCaP prostate cancer xenograft model.

    PubMed

    Jantscheff, Peter; Ziroli, Vittorio; Esser, Norbert; Graeser, Ralph; Kluth, Jessica; Sukolinskaya, Alena; Taylor, Lenka A; Unger, Clemens; Massing, Ulrich

    2009-01-01

    Fatal outcomes of prostate carcinoma (PCa) mostly result from metastatic spread rather than from primary tumor burden. Here, we monitored growth and metastatic spread of an orthotopic luciferase/GFP-expressing LNCaP PCa xenograft model in SCID mice by in vivo imaging and in vitro luciferase assay of tissues homogenates. Although the metastatic spread generally shows a significant correlation to primary tumor volumes, the susceptibility of various tissues to metastatic invasion was different in the number of affected animals as well as in absolute metastatic burden in the individual tissues. Using this xenograft model we showed that treatment with liposomal gemcitabine (GemLip) inhibited growth of the primary tumors (83.9 +/- 6.4%; P = 0.009) as well as metastatic burden in lymph nodes (95.6 +/- 24.0%; P = 0.047), lung (86.5 +/- 10.5%; P = 0.015), kidney (88.4 +/- 9.2%; P = 0.045) and stomach (79.5 +/- 6.6%; P = 0.036) already at very low efficient concentrations (8 mg/kg) as compared to conventional gemcitabine (360 mg/kg). Our data show that this orthotopic LNCaP xenograft PCa model seems to reflect the clinical situation characterized by the fact that at time of diagnosis, prostate neoplasms are biologically heterogeneous and thus, it is a useful model to investigate new anti-metastatic therapies.

  15. Lower lung cancer mortality in obesity.

    PubMed

    Leung, Chi C; Lam, Tai H; Yew, Wing W; Chan, Wai M; Law, Wing S; Tam, Cheuk M

    2011-02-01

    Malignancy is the leading cause of death in Hong Kong, and lung cancer tops the list of all cancer deaths. A cohort of clients aged ≥65 years, enrolled at 18 elderly health centres in Hong Kong from 2000 to 2003, was followed up prospectively through linkage with the territory-wide death registry for causes of death until 31 December 2008, using the identity card number as unique identifier. All subjects with suspected cancer, significant weight loss of >5% within past 6 months or obstructive lung disease at the baseline were excluded. After a total of 423 061 person-years of follow-up, 932, 690 and 1433 deaths were caused by lung cancer, other tobacco-related malignancies and non-tobacco-related malignancies, respectively. Body mass index (BMI) was independently (and negatively) associated with death from lung cancer after adjustment for other baseline variables, whereas there was only a minor or no effect for other smoking-related malignancies and non-tobacco-related malignancies. Obesity with BMI ≥30 [adjusted hazard ratio (HR), 0.55, 95% confidence interval (CI) 0.38-0.80] was associated with reduced lung cancer mortality, which was more prominent than the opposing effect of underweight (adjusted HR, 1.38, 95% CI 1.05-1.79). Consistent effects of BMI were observed after stratification into never-smokers and ever-smokers and in sensitivity analysis after excluding deaths within the first 3 years. Obesity was associated with lower lung cancer mortality in this prospective cohort analysis. As the effect was rather specific for lung cancer, further studies are indicated to explore the underlying mechanism.

  16. [The new TNM classification in lung cancer].

    PubMed

    Wrona, Anna; Jassem, Jacek

    2010-01-01

    This paper presents the new TNM classification in lung cancer and its history. Seventh edition of tumor, node, metastasis (TNM) classification in lung cancer has been published by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) at the beginning of 2009. The changes were based upon the results of the international project of the International Association for the Study of Lung Cancer (IASLC). The database included 81.495 patients from the entire world (68.463 with non-small cell lung cancer and 13.032 with small cell lung cancer) treated with various modalities between 1990 and 2000. The collected data were validated internally and externally. The tumor size was considered of prognostic relevance: T1 tumors were subdivided into T1a (≤ 2 cm) and T1b (〉 2 cm - ≤ 3 cm), T2 tumors into T2a (〉 3 cm - ≤ 5 cm) and T2b (〉 5 cm - ≤ 7 cm), and T2 tumors 〉 7 cm were reclassified as T3. Tumors with the additional nodules in the same lobe as the primary tumor were classified as T3, those with additional nodules in another ipsilateral lobe - as T4. There were no changes in N category. In the M category, M1 was subclassified into M1a (contralateral lung nodules and pleural dissemination) and M1b (distant metastasis). Large T2 tumors (T2bN0M0) were upstaged from IB to IIA, small T2 tumors (T2aN1M0) were downstaged from the IIB to IIA and T4N0-N1M0 - from IIIB to IIIA. The TNM classification was also recommended for small cell lung cancer instead of previously used categories of limited and extensive disease.

  17. Activin type IB receptor signaling in prostate cancer cells promotes lymph node metastasis in a xenograft model

    SciTech Connect

    Nomura, Masatoshi; Tanaka, Kimitaka; Wang, Lixiang; Goto, Yutaka; Mukasa, Chizu; Ashida, Kenji; Takayanagi, Ryoichi

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer ActRIB signaling induces Snail and S100A4 expressions in prostate cancer cells. Black-Right-Pointing-Pointer The prostate cancer cell lines expressing an active form of ActRIB were established. Black-Right-Pointing-Pointer ActRIB signaling promotes EMT and lymph node metastasis in xenograft model. -- Abstract: Activin, a member of the transforming growth factor-{beta} family, has been known to be a growth and differentiating factor. Despite its pluripotent effects, the roles of activin signaling in prostate cancer pathogenesis are still unclear. In this study, we established several cell lines that express a constitutive active form of activin type IB receptor (ActRIBCA) in human prostate cancer cells, ALVA41 (ALVA-ActRIBCA). There was no apparent change in the proliferation of ALVA-ActRIBCA cells in vitro; however, their migratory ability was significantly enhanced. In a xenograft model, histological analysis revealed that the expression of Snail, a cell-adhesion-suppressing transcription factor, was dramatically increased in ALVA-ActRIBCA tumors, indicating epithelial mesenchymal transition (EMT). Finally, mice bearing ALVA-ActRIBCA cells developed multiple lymph node metastases. In this study, we demonstrated that ActRIBCA signaling can promote cell migration in prostate cancer cells via a network of signaling molecules that work together to trigger the process of EMT, and thereby aid in the aggressiveness and progression of prostate cancers.

  18. Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models

    PubMed Central

    Bisht, Savita; Karikari, Collins; Garrido-Laguna, Ignacio; Rasheed, Zeshaan; Ottenhof, Niki A; Dadon, Tikva; Alvarez, Hector; Fendrich, Volker; Rajeshkumar, NV; Matsui, William; Brossart, Peter; Hidalgo, Manuel; Bannerji, Rajat

    2011-01-01

    Pancreatic cancer is one of the most lethal of human malignancies, and potent therapeutic options are lacking. Inhibition of cell cycle progression through pharmacological blockade of cyclin-dependent kinases (CDK) has been suggested as a potential treatment option for human cancers with deregulated cell cycle control. Dinaciclib (SCH727965) is a novel small molecule multi-CDK inhibitor with low nanomolar potency against CDK1, CDK2, CDK5 and CDK9 that has shown favorable toxicity and efficacy in preliminary mouse experiments, and has been well tolerated in Phase I clinical trials. In the current study, the therapeutic efficacy of SCH727965 on human pancreatic cancer cells was tested using in vitro and in vivo model systems. Treatment with SCH727965 significantly reduced in vitro cell growth, motility and colony formation in soft agar of MIAPaCa-2 and Pa20C cells. These phenotypic changes were accompanied by marked reduction of phosphorylation of Retinoblastoma (Rb) and reduced activation of RalA. Single agent therapy with SCH727965 (40 mg/kg i.p. twice weekly) for 4 weeks significantly reduced subcutaneous tumor growth in 10/10 (100%) of tested low-passage human pancreatic cancer xenografts. Treatment of low passage pancreatic cancer xenografts with a combination of SCH727965 and gemcitabine was significantly more effective than either agent alone. Gene Set Enrichment Analysis identified overrepresentation of the Notch and Transforming Growth Factor-β (TGFβ) signaling pathways in the xenografts least responsive to SCH727965 treatment. Treatment with the cyclin-dependent kinase inhibitor SCH727965 alone or in combination is a highly promising novel experimental therapeutic strategy against pancreatic cancer. PMID:21768779

  19. Effect of magnetic fluid hyperthermia on lung cancer nodules in a murine model.

    PubMed

    Hu, Runlei; Ma, Shenglin; Li, Hu; Ke, Xianfu; Wang, Guoqing; Wei, Dongshan; Wang, Wei

    2011-11-01

    The purpose of the present study was to investigate the therapeutic effect of magnetic fluid hyperthermia (MFH) induced by an alternating magnetic field (AMF) on human carcinoma A549 xenograft in nude mice. An animal model of human lung cancer was established by subcutaneous injection of human lung cancer A549 cells in BALB/c nude mice. The xenograft mice were randomly divided into four groups and each group was treated with an injection of a different concentration of magnetic fluid: control, low-dose (67.5 mg/ml), medium-dose (90.0 mg/ml) and high-dose group (112.5 mg/ml), respectively. Following the injection (24 h), the tumor was heated in an AMF for 30 min. Tumor volumes were then measured every week. The therapeutic effect was assessed by measuring the tumor volume and weight. Pathological examination was performed with a light and electronic microscope following treatment. The temperature at the surface of the tumor in the low-, medium- and high-dose groups increased to 41.3, 44.5 and 46.8°C, respectively. The tumor grew significantly slower in the medium- and high-dose groups (both p<0.05) compared to the control group. Cytoclasis and apoptosis were detected under light and electron microscopy. In conclusion, MFH induced by AMF inhibited tumor growth and promoted apoptosis of human carcinoma A549 cells in a xenograft mice model.

  20. Gallic acid inhibition of Src-Stat3 signaling overcomes acquired resistance to EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer

    PubMed Central

    Phan, Ai N.H.; Hua, Tuyen N.M.; Kim, Min-Kyu; Vo, Vu T.A.; Choi, Jong-Whan; Kim, Hyun-Won; Rho, Jin Kyung; Kim, Ki Woo; Jeong, Yangsik

    2016-01-01

    Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have clinically benefited to lung cancer patients harboring a subset of activating EGFR mutations. However, even with the remarkable therapeutic response at the initial TKI treatment, most lung cancer patients eventually have relapsed aggressive tumors due to acquired resistance to the TKIs. Here, we report that 3, 4, 5-trihydroxybenzoic acid or gallic acid (GA), a natural polyphenolic compound, shows anti-tumorigenic effects in TKI-resistant non-small cell lung cancer (NSCLC). Using both in vitro growth assay and in vivo xenograft animal model, we demonstrated tumor suppressive effect of GA was more selective for the TKI-resistant cancer compared to the TKI-sensitive one. Mechanistically, GA treatment inhibited Src-Stat3-mediated signaling and decreased the expression of Stat3-regulated tumor promoting genes, subsequently inducing apoptosis and cell cycle arrest in the TKI-resistant lung cancer but not in the TKI-sensitive one. Consistent with the in vitro results, in vivo xenograft experiments showed the TKI-resistant tumor-selective growth inhibition and suppression of Src-Stat3-dependent signaling in the GA-treated tumors isolated from the xenograft model. This finding identified an importance of Src-Stat3 signaling cascade in GA-mediated tumor-suppression activity and, more importantly, provides a novel therapeutic insight of GA for advanced TKI-resistant lung cancer. PMID:27419630

  1. Racial and Ethnic Differences in the Epidemiology of Lung Cancer and the Lung Cancer Genome

    PubMed Central

    Schabath, Matthew B.; Cress, W. Douglas; Muñoz-Antonia, Teresita

    2017-01-01

    Background Globally and in the United States, lung cancer has been the most common cancer for the past several decades. In addition to the well-established geographical- and sex-specific differences in lung cancer incidence, mortality and survival, there is also growing evidence for racial and ethnic differences. Methods Based on available published data, we present a summary of the current knowledge and substantive findings related to racial and ethnic differences in lung cancer. Results Although this report is not a systematic review, we summarized the current knowledge and substantive findings related to racial and ethnic differences in lung cancer with a particular focus on lung cancer statistics(incidence, mortality, and survival), cigarette smoking, prevention and early detection, and the lung cancer genome. Finally, we summarize some the systems-level and provider-related issues that likely contribute to racial and ethnic-specific health disparities and provide some suggestions for future strategies that may reduce the disproportionate burden of lung cancer. Conclusions Although lung carcinogenesis is a multifactorial process driven by exogenous exposures (e.g., cigarette smoking), inherited genetic variations, and an accumulation of somatic genetic events, this multifactorial process appears to have racial and ethnic differences which in turn impacts the observed epidemiologic differences in incidence, mortality, and survival. PMID:27842323

  2. Xenograft Studies of Fatty Acid Synthesis Inhibition as Novel Therapy for Breast Cancer

    DTIC Science & Technology

    2000-08-01

    higher level of malonyl-CoA than liver from tumor bearing mice. Error bars represent standard error of the mean. Xenograft measurements represent...extracted into ether. The organic solution was dried over anhydrous magnesium sulfate and evaporated to a gummy solid, which was dissolved in methylene...individually crystallized from boiling hexanes. 3. Distribution of jH-C75] in MCF7xenograft bearing nude mice. C75 is widely distributed in tumor and

  3. Enantiomeric CopA3 dimer peptide suppresses cell viability and tumor xenograft growth of human gastric cancer cells.

    PubMed

    Lee, Joon Ha; Kim, In-Woo; Shin, Yong Pyo; Park, Ho Jin; Lee, Young Shin; Lee, In Hee; Kim, Mi-Ae; Yun, Eun-Young; Nam, Sung-Hee; Ahn, Mi-Young; Kang, Dongchul; Hwang, Jae Sam

    2016-03-01

    The CopA3 dimer peptide is a coprisin analog that has an anticancer effect against human cancer cells in vitro. In this study, we investigated the anticancer activity of the enantiomeric CopA3 dimer peptide in human gastric cancer cell lines as well as in an in vivo tumor xenograft model. Enantiomeric CopA3 reduced gastric cancer cell viability and exhibited cytotoxicity against cancer cells. Enantiomeric CopA3-induced cell death was mediated by specific interactions with phosphatidylserine and phosphatidylcholine, membrane components that are enriched in cancer cells, in a calcein leakage assay. Moreover, acridine orange/ethidium bromide staining, flow cytometric analysis, and W