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Sample records for cell lung cancer

  1. 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 ...

  2. 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 ...

  3. 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 ...

  4. 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

  5. Nonsmall cell lung cancer.

    PubMed

    Sculier, Jean-Paul

    2013-03-01

    The objective of this review is to report the Clinical Year in Review proceedings in the field of nonsmall cell lung cancer that were presented at the 2012 European Respiratory Society Congress in Vienna, Austria. Various topics were reviewed, including epidemiology, screening, diagnosis, treatment, prognosis, and palliative and end of life care. PMID:23457162

  6. 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 ...

  7. 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 ...

  8. 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 ... day and for how long you have smoked. Being around the smoke ...

  9. General Information about Small Cell Lung Cancer

    MedlinePlus

    ... Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Small Cell Lung Cancer Go to Health ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  10. 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.

  11. [Advances in Lung Stem Cells and Lung Cancer Stem Cells].

    PubMed

    Yin, Huijing; Deng, Jiong

    2015-10-20

    Cancer stem cells (CSCs) are emerging as a hot topic for cancer research. Lung CSCs share many characteristics with normal lung stem cells (SCs), including self-renewal and multi-potency for differentiation. Many molecular markers expressed in various types of CSCs were also found in lung CSCs, such as CD133, CD44, aldehyde dehydrogenase (ALDH) and ATP-binding cassette sub-family G member 2 (ABCG2). Similarly, proliferation and expansion of lung CSCs are regulated not only by signal transduction pathways functioning in normal lung SCs, such as Notch, Hedgehog and Wnt pathways, but also by those acting in tumor cells, such as epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3) and phosphatidylinositol 3 kinase (PI3K) pathways. As CSC plays an critical role in tumor recurrence, metastasis and drug-resistance, understanding the difference between lung CSCs and normal lung SCs, identifying and targeting CSC markers or related signaling pathways may increase the efficacy of therapy on lung cancer and improved survival of lung cancer patients. PMID:26483336

  12. 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 ...

  13. 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

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

    ClinicalTrials.gov

    2015-03-17

    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

  15. Surgery for small cell lung cancer.

    PubMed

    de Hoyos, Alberto; DeCamp, Malcolm M

    2014-11-01

    Small-cell lung cancer (SCLC) comprises approximately 14% of all lung cancer cases. Most patients present with locally advanced or metastatic disease and are therefore treated nonoperatively with chemotherapy, radiotherapy, or both. A small subset of patients with SCLC present with early-stage disease and will benefit from surgical resection plus chemotherapy. The rationale for radiotherapy in these patients remains controversial. PMID:25441133

  16. Transbronchial Dissemination of Squamous Cell Lung Cancer

    PubMed Central

    Tadokoro, Akira; Kanaji, Nobuhiro; Ishii, Tomoya; Watanabe, Naoki; Inoue, Takuya; Kadowaki, Norimitsu; Bandoh, Shuji

    2015-01-01

    We report a case of squamous cell lung cancer with transbronchial dissemination in a 73-year-old man. Bronchoscopic examination revealed multiple bronchial mucosal nodules that existed independently of one another. We reviewed 16 previous cases of endobronchial metastasis in lung cancer. All patients were men. Among the reports that described the smoking history, most patients were smokers (6/7), and the most frequent histological type of cancer was squamous cell carcinoma (11/17). Although hematogenous and lymphogenous routes have been reported as metastatic mechanisms, no previous cases involving transbronchial dissemination have been described. Transbronchial dissemination may be an alternative pathway of endobronchial metastasis. PMID:26672760

  17. Ouabain enhances lung cancer cell detachment.

    PubMed

    Ruanghirun, Thidarat; Pongrakhananon, Varisa; Chanvorachote, Pithi

    2014-05-01

    A human steroid hormone, ouabain, has been shown to play a role in several types of cancer cell behavior; however, its effects on cancer metastasis are largely unknown. Herein, we demonstrate that sub-toxic concentrations of ouabain facilitate cancer cell detachment from the extracellular matrix in human lung cancer cells. Ouabain at concentrations of 0-10 pM significantly enhanced cell detachment in dose- and time- dependent manners, while having minimal effect on cell viability. The detachment-inducing effect of ouabain was found to be mediated through focal-adhesion kinase and ATP-dependent tyrosine kinase pathways. Alpha-5 and beta-1 integrins were found to be down-regulated in response to ouabain treatment. Since detachment of cancer cells is a prerequisite process for metastasis to begin, these insights benefit our understanding over the molecular basis of cancer biology. PMID:24778025

  18. Targeted therapy for squamous cell lung cancer

    PubMed Central

    Liao, Rachel G.; Watanabe, Hideo; Meyerson, Matthew; Hammerman, Peter S.

    2013-01-01

    SUMMARY Lung squamous cell carcinoma (SqCC) is the second most common subtype of non-small-cell lung cancer and leads to 40,000–50,000 deaths per year in the USA. Management of non-small-cell lung cancer has dramatically changed over the past decade with the introduction of targeted therapeutic agents for genotypically selected individuals with lung adenocarcinoma. These agents lead to improved outcomes, and it has now become the standard of care to perform routine molecular genotyping of lung adenocarcinomas. By contrast, progress in lung SqCC has been modest, and there has yet to be a successful demonstration of targeted therapy in this disease. Here, we review exciting work from ongoing genomic characterization and biomarker validation efforts that have nominated several likely therapeutic targets in lung SqCCs. These studies suggest that targeted therapies are likely to be successful in the treatment of lung SqCCs and should be further explored in both preclinical models and in clinical trials. PMID:23956794

  19. Targeting Lung Cancer Stem Cells with Antipsychological Drug Thioridazine

    PubMed Central

    Yue, Haiying; Huang, Dongning; Qin, Li; Zheng, Zhiyong; Hua, Li; Wang, Guodong; Huang, Jian

    2016-01-01

    Lung cancer stem cells are a subpopulation of cells critical for lung cancer progression, metastasis, and drug resistance. Thioridazine, a classical neurological drug, has been reported with anticancer ability. However, whether thioridazine could inhibit lung cancer stem cells has never been studied. In our current work, we used different dosage of thioridazine to test its effect on lung cancer stem cells sphere formation. The response of lung cancer stem cells to chemotherapy drug with thioridazine treatment was measured. The cell cycle distribution of lung cancer stem cells after thioridazine treatment was detected. The in vivo inhibitory effect of thioridazine was also measured. We found that thioridazine could dramatically inhibit sphere formation of lung cancer stem cells. It sensitized the LCSCs to chemotherapeutic drugs 5-FU and cisplatin. Thioridazine altered the cell cycle distribution of LCSCs and decreased the proportion of G0 phase cells in lung cancer stem cells. Thioridazine inhibited lung cancer stem cells initiated tumors growth in vivo. This study showed that thioridazine could inhibit lung cancer stem cells in vitro and in vivo. It provides a potential drug for lung cancer therapy through targeting lung cancer stem cells. PMID:27556038

  20. Combination Chemotherapy, Radiation Therapy, and Bevacizumab in Treating Patients With Newly Diagnosed Stage III Non-Small Cell Lung Cancer That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2016-05-26

    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

  1. Genomics of Squamous Cell Lung Cancer

    PubMed Central

    Rooney, Melissa; Devarakonda, Siddhartha

    2013-01-01

    Approximately 30% of patients with non-small cell lung cancer have the squamous cell carcinoma (SQCC) histological subtype. Although targeted therapies have improved outcomes in patients with adenocarcinoma, no agents are currently approved specifically for use in SQCC. The Cancer Genome Atlas (TCGA) recently published the results of comprehensive genomic analyses of tumor samples from 178 patients with SQCC of the lung. In this review, we briefly discuss key molecular aberrations reported by TCGA and other investigators and their potential therapeutic implications. Carefully designed preclinical and clinical studies based on these large-scale genomic analyses are critical to improve the outcomes of patients with SQCC of lung in the near future. PMID:23728941

  2. General Information about Non-Small Cell Lung Cancer

    MedlinePlus

    ... most patients with non-small cell lung cancer, current treatments do not cure the cancer. If lung ... professional versions have detailed information written in technical language. The patient versions are written in easy-to- ...

  3. Circulating tumor cells in lung cancer.

    PubMed

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

    2012-01-01

    Circulating tumor cells (CTCs) have emerged as potential biomarkers in several cancers such as colon, prostate, and breast carcinomas, with a correlation between CTC number and patient prognosis being established by independent research groups. The detection and enumeration of CTCs, however, is still a developing field, with no universal method of detection suitable for all types of cancer. CTC detection in lung cancer in particular has proven difficult to perform, as CTCs in this type of cancer often present with nonepithelial characteristics. Moreover, as many detection methods rely on the use of epithelial markers to identify CTCs, the loss of these markers during epithelial-to-mesenchymal transition in certain metastatic cancers can render these methods ineffective. The development of personalized medicine has led to an increase in the advancement of molecular characterization of CTCs. The application of techniques such as FISH and RT-PCR to detect EGFR, HER2, and KRAS abnormalities in lung, breast, and colon cancer, for example, could be used to characterize CTCs in real time. The use of CTCs as a 'liquid biopsy' is therefore an exciting possibility providing information on patient prognosis and treatment efficacy. This review summarizes the state of CTC detection today, with particular emphasis on lung cancer, and discusses the future applications of CTCs in helping the clinician to develop new strategies in patient treatment. PMID:23207444

  4. Radiation Therapy, Chemotherapy, and Soy Isoflavones in Treating Patients With Stage IIIA-IIIB Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2016-02-08

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

  5. Low-Dose Acetylsalicylic Acid in Treating Patients With Stage I-III Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2016-06-28

    Adenocarcinoma of the Lung; Recurrent Non-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

  6. Lung cancer

    PubMed Central

    Dong, Jie; Kislinger, Thomas; Jurisica, Igor; Wigle, Dennis A.

    2010-01-01

    High-throughput genomic data for both lung development and lung cancer continue to accumulate. Significant molecular intersection between these two processes has been hypothesized due to overlap in phenotypes and genomic variation. Examining the network biology of both cancer and development of the lung may shed functional light on the individual signaling modules involved. Stem cell biology may explain a portion of this network intersection and consequently studying lung organogenesis may have relevance for understanding lung cancer. This review summarizes our understanding of the potential overlapping mechanisms involved in lung development and lung tumorigenesis. PMID:19202349

  7. Survivorship Care Planning in Patients With Colorectal or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-12-16

    Stage I Colon Cancer; Stage I Rectal Cancer; Stage IA Non-small Cell Lung Cancer; Stage IB Non-small Cell Lung Cancer; Stage IIA Colon Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIA Rectal Cancer; Stage IIB Colon Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIB Rectal Cancer; Stage IIC Colon Cancer; Stage IIC Rectal Cancer; Stage IIIA Colon Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIA Rectal Cancer; Stage IIIB Colon Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IIIB Rectal Cancer; Stage IIIC Colon Cancer; Stage IIIC Rectal Cancer

  8. Cancer stem cells: progress and challenges in lung cancer

    PubMed Central

    Templeton, Amanda K.; Miyamoto, Shinya; Babu, Anish; Munshi, Anupama

    2014-01-01

    The identification of a subpopulation of tumor cells with stem cell-like characteristics first in hematological malignancies and later in solid tumors has emerged into a novel field of cancer research. It has been proposed that this aberrant population of cells now called “cancer stem cells” (CSCs) drives tumor initiation, progression, metastasis, recurrence, and drug resistance. CSCs have been shown to have the capacity of self-renewal and multipotency. Adopting strategies from the field of stem cell research has aided in identification, localization, and targeting of CSCs in many tumors. Despite the huge progress in other solid tumors such as brain, breast, and colon cancers no substantial advancements have been made in lung cancer. This is most likely due to the current rudimentary understanding of lung stem cell hierarchy and heterogeneous nature of lung disease. In this review, we will discuss the most recent findings related to identification of normal lung stem cells and CSCs, pathways involved in regulating the development of CSCs, and the importance of the stem cell niche in development and maintenance of CSCs. Additionally, we will examine the development and feasibility of novel CSC-targeted therapeutic strategies aimed at eradicating lung CSCs.

  9. Pemetrexed (Alimta) in small cell lung cancer.

    PubMed

    Socinski, Mark A

    2005-04-01

    Small cell lung cancer (SCLC) comprises approximately 13% of all lung cancers. In limited stage (LS)-SCLC, combined-modality therapy represents the standard of care. Therapy should be approached curatively in fit patients with a good performance status because 5-year survival rates approach 26% in aggressively treated patients. In contrast, cure is not possible in extensive stage (ES)-SCLC with median 2-year survival rates with current therapy remaining at less than 10%. Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a novel, multi-targeted antifolate that inhibits several folate-dependent enzymes involved in purine and pyrimidine synthesis, and is active as a single-agent or in combination with a platinum in both non-small cell lung cancer and malignant pleural mesothelioma. Pemetrexed/platinum combinations appear active in ES-SCLC based on objective response rates observed in a randomized phase II trial. However, no survival data is yet available from this trial. The toxicity profile of both cisplatin and carboplatin in combination with pemetrexed was extremely favorable, as was the ability to deliver full doses of each of the component drugs. Given the limited options available for patients in the relapsed setting, the activity of single-agent pemetrexed is interesting. Also, preliminary data indicates that full doses of carboplatin/pemetrexed can be administered with thoracic radiation therapy, supporting a future clinical trial initiative in LS-SCLC. PMID:15818532

  10. Cancer stem cells in small cell lung cancer

    PubMed Central

    Verlicchi, Alberto; Rosell, Rafael

    2016-01-01

    Small cell lung cancer (SCLC) is one of the most aggressive lung tumors, with poor survival rates. Although patients may initially respond to treatment, this is followed by rapid development of drug resistance and disease progression. SCLC patients often present with metastasis at time of diagnosis, ruling out surgery as a treatment option. Currently, treatment options for this disease remain limited and platinum-based chemotherapy is the treatment of choice. A better understanding of the biology of SCLC could allow us to identify new therapeutic targets. Cancer stem cell (CSC) theory is currently crucial in cancer research and could provide a viable explanation for the heterogeneity, drug resistance, recurrence and metastasis of several types of tumors. Some characteristics of SCLC, such as aggressiveness, suggest that this kind of tumor could be enriched in CSCs, and drug resistance in SCLC could be attributable to the existence of a CSC subpopulation in SCLC. Herein we summarize current understanding of CSC in SCLC, including the evidence for CSC markers and signaling pathways involved in stemness. We also discuss potential ongoing strategies and areas of active research in SCLC, such as immunotherapy, that focus on inhibition of signaling pathways and targeting molecules driving stemness. Understanding of signaling pathways and the discovery of new therapeutic markers specific to CSCs will lead to new advances in therapy and improvements in prognosis of SCLC patients. Therefore, evaluation of these CSC-specific molecules and pathways may become a routine part of SCLC diagnosis and therapy. PMID:26958490

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

    PubMed Central

    Banat, G-Andre; Tretyn, Aleksandra; Pullamsetti, Soni Savai; Wilhelm, Jochen; Weigert, Andreas; Olesch, Catherine; Ebel, Katharina; Stiewe, Thorsten; Grimminger, Friedrich; Seeger, Werner; Fink, Ludger; Savai, Rajkumar

    2015-01-01

    Recent studies indicate that the abnormal microenvironment of tumors may play a critical role in carcinogenesis, including lung cancer. We comprehensively assessed the number of stromal cells, especially immune/inflammatory cells, in lung cancer and evaluated their infiltration in cancers of different stages, types and metastatic characteristics potential. Immunohistochemical analysis of lung cancer tissue arrays containing normal and lung cancer sections was performed. This analysis was combined with cyto-/histomorphological assessment and quantification of cells to classify/subclassify tumors accurately and to perform a high throughput analysis of stromal cell composition in different types of lung cancer. In human lung cancer sections we observed a significant elevation/infiltration of total-T lymphocytes (CD3+), cytotoxic-T cells (CD8+), T-helper cells (CD4+), B cells (CD20+), macrophages (CD68+), mast cells (CD117+), mononuclear cells (CD11c+), plasma cells, activated-T cells (MUM1+), B cells, myeloid cells (PD1+) and neutrophilic granulocytes (myeloperoxidase+) compared with healthy donor specimens. We observed all of these immune cell markers in different types of lung cancers including squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma, small cell carcinoma, papillary adenocarcinoma, metastatic adenocarcinoma, and bronchioloalveolar carcinoma. The numbers of all tumor-associated immune cells (except MUM1+ cells) in stage III cancer specimens was significantly greater than those in stage I samples. We observed substantial stage-dependent immune cell infiltration in human lung tumors suggesting that the tumor microenvironment plays a critical role during lung carcinogenesis. Strategies for therapeutic interference with lung cancer microenvironment should consider the complexity of its immune cell composition. PMID:26413839

  12. Cisplatin and Etoposide With or Without Veliparib in Treating Patients With Extensive Stage Small Cell Lung Cancer or Metastatic Large Cell Neuroendocrine Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2016-06-01

    Carcinoma of Unknown Primary Origin; Extensive Stage Small Cell Lung Carcinoma; Large Cell Lung Carcinoma; Neuroendocrine Carcinoma; Newly Diagnosed Carcinoma of Unknown Primary Origin; Stage IV Non-Small Cell Lung Cancer

  13. Cloning of human lung cancer cells.

    PubMed Central

    Walls, G. A.; Twentyman, P. R.

    1985-01-01

    We have carried out a comparison of two different methods for cloning human lung cancer cells. The method of Courtenay & Mills (1978) generally gave higher plating efficiencies (PE) than the method of Carney et al. (1980). The number of colonies increased with incubation time in both methods and the weekly medium replenishment in the Courtenay method was advantageous for longer incubation times of several weeks. In the Courtenay method, the use of August rat red blood cells (RBC) and low oxygen tension were both found to be necessary factors for maximum plating efficiency. The usefulness of heavily irradiated feeder cells in improving PE is less certain; each cell type may have its own requirement. PMID:3904799

  14. Lung Cancer Screening

    MedlinePlus

    ... Cancer Treatment Small Cell Lung Cancer Treatment Lung cancer is the leading cause of cancer death in the United States. Lung cancer is ... non- skin cancer in the United States. Lung cancer is the leading cause of cancer death in men and in women. ...

  15. NK Cell Phenotypic Modulation in Lung Cancer Environment

    PubMed Central

    Hao, Jun-Wei; Li, Yang; Liu, Bin; Yu, Yan; Shi, Fu-Dong; Zhou, Qing-Hua

    2014-01-01

    Background Nature killer (NK) cells play an important role in anti-tumor immunotherapy. But it indicated that tumor cells impacted possibly on NK cell normal functions through some molecules mechanisms in tumor microenvironment. Materials and methods Our study analyzed the change about NK cells surface markers (NK cells receptors) through immunofluorescence, flow cytometry and real-time PCR, the killed function from mouse spleen NK cell and human high/low lung cancer cell line by co-culture. Furthermore we certificated the above result on the lung cancer model of SCID mouse. Results We showed that the infiltration of NK cells in tumor periphery was related with lung cancer patients' prognosis. And the number of NK cell infiltrating in lung cancer tissue is closely related to the pathological types, size of the primary cancer, smoking history and prognosis of the patients with lung cancer. The expression of NK cells inhibitor receptors increased remarkably in tumor micro-environment, in opposite, the expression of NK cells activated receptors decrease magnificently. Conclusions The survival time of lung cancer patient was positively related to NK cell infiltration degree in lung cancer. Thus, the down-regulation of NKG2D, Ly49I and the up-regulation of NKG2A may indicate immune tolerance mechanism and facilitate metastasis in tumor environment. Our research will offer more theory for clinical strategy about tumor immunotherapy. PMID:25299645

  16. Treatment of small cell lung cancer patients.

    PubMed

    Zöchbauer-Müller, S; Pirker, R; Huber, H

    1999-01-01

    Small cell lung cancers, comprising approximately 20% of lung cancers, are rapidly growing and disseminating carcinomas which are initially chemosensitive but acquire drug resistance during the course of disease. Thus, outcome is poor with median survival of 10-16 months for patients with limited and 7-11 months for patients with extensive disease. Polychemotherapy with established drugs (platins, etoposide, anthracyclines, cyclophosphamide, ifosfamide and Vinca alkaloids) plays the major role in the treatment of this disease and results in overall response rates between 80%-95% for limited disease and 60%-80% for extensive disease. Dose-intensified chemotherapy and high-dose chemotherapy with peripheral blood progenitor cell support were tested in several trials but their exact impact on outcome remains to be determined. New drugs including the taxanes (paclitaxel, docetaxel), the topoisomerase I inhibitors (topotecan, irinotecan), vinorelbine and gemcitabine are currently evaluated in clinical trials. In limited disease, thoracic radiotherapy improves survival and prophylactic cranial irradiation should be administered to those with a reasonable chance of cure. PMID:10676558

  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. Stereotactic Body Radiation Therapy in Treating Patients With Metastatic Breast Cancer, Non-small Cell Lung Cancer, or Prostate Cancer

    ClinicalTrials.gov

    2016-06-17

    Male Breast Carcinoma; Prostate Adenocarcinoma; Recurrent Breast Carcinoma; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Prostate Carcinoma; Stage IV Breast Cancer; Stage IV Non-Small Cell Lung Cancer; Stage IV Prostate Cancer

  19. Personalized Therapy of Small Cell Lung Cancer.

    PubMed

    Schneider, Bryan J; Kalemkerian, Gregory P

    2016-01-01

    Small cell lung cancer (SCLC) is an aggressive, poorly differentiated neuroendocrine carcinoma with distinct clinical, pathological and molecular characteristics. Despite robust responses to initial chemotherapy and radiation, the prognosis of patients with SCLC remains poor with an overall 5-year survival rate of less than 10 %. Despite the fact that numerous molecularly targeted approaches have thus far failed to demonstrate clinical utility in SCLC, further advances will rely on better definition of the biological pathways that drive survival, proliferation and metastasis. Recent next-generation, molecular profiling studies have identified many new therapeutic targets in SCLC, as well as extreme genomic instability which explains the high degree of resistance. A wide variety of anti-angiogenic agents, growth factor inhibitors, pro-apoptotic agents, and epigenetic modulators have been evaluated in SCLC and many studies of these strategies are on-going. Perhaps the most promising approaches involve agents targeting cancer stem cell pathways and immunomodulatory drugs that interfere with the PD1 and CTLA-4 pathways. SCLC offers many barriers to the development of successful therapy, including limited tumor samples, inadequate preclinical models, high mutational burden, and aggressive tumor growth which impairs functional status and hampers enrollment on clinical trials. PMID:26703804

  20. Inhibition of rhotekin exhibits antitumor effects in lung cancer cells

    PubMed Central

    ZHANG, WEIZHEN; LIANG, ZHENYU; LI, JING

    2016-01-01

    Lung cancer is the leading cause for cancer-related death, however, the pathogenesis mechanism is poorly understood. Although the rhotekin (RTKN) gene has been reported to encode an effector for the Rho protein that has critical roles in regulating cell growth, the role of RTKN in lung cancer has not been investigated. In clinical lung cancer patient tumor samples, we identified that the RTKN gene expression level was significantly higher in tumor tissues compared to that of the adjacent normal tissues. To investigate the molecular mechanisms of RTKN in lung cancer, we established RTKN stable knock-down A549 and SPC-A-1 lung adenocarcinoma cell lines using lentiviral transfection of RTKN shRNA and evaluated the antitumor effects. The results showed that RTKN knock-down inhibited lung adenocarcinoma cell viability, induced S phase arrest and increased cell apoptosis. In addition, RTKN knock-down inhibited lung cancer cell invasion and adhesion. Further analysis showed that the S phase promoting factors cyclindependent kinase (CDK)1 and CDK2 levels were decreased in RTKN knock-down cells, and that the DNA replication initiation complex proteins Minichromosome maintenance protein complex (MCM)2 and MCM6 were decreased as well in RTKN knock-down cells. These results indicated that the RTKN protein was associated with lung cancer in clinic samples and exerted anticancer activity in lung adenocarcinoma cells through inhibiting cell cycle progression and the DNA replication machinery. These findings suggest that RTKN inhibition may be a novel therapeutic strategy for lung adenocarcinoma. PMID:26935528

  1. How to target small cell lung cancer

    PubMed Central

    Hamilton, Gerhard; Rath, Barbara; Ulsperger, Ernst

    2015-01-01

    Small cell lung cancer (SCLC) is a highly malignant disease with dismal prognosis. Although great progress has been made in investigating genetic aberrations and putative drivers of this tumor entity, the mechanisms of rapid dissemination and acquisition of drug resistance are not clear. The majority of SCLC cases are characterized by inactivation of the tumor suppressors p53 and retinoblastoma (Rb) and, therefore, interchangeable drivers will be difficult to target successfully. Access to pure cultures of SCLC circulating tumor cells (CTCs) and study of their tumor biology has revealed a number of new potential targets. Most important, expression of chitinase-3-like-1/YKL-40 (CHI3L1) which controls expression of vascular epithelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP9) was newly described in these cells. The process switching CHI3L1-negative SCLC cells to CHI3L1-positive CTCs seems to be associated with cytokines released by inflammatory immune cells. Furthermore, these CTCs were found to promote monocyte-macrophage differentiation, most likely of the M2 tumor-promoting type, recently described to express PD-1 immune checkpoint antigen in SCLC. In conclusion, dissemination of SCLC seems to be linked to conversion of regular tumor cells to highly invasive CHI3L1-positive CTCs, which are protected by immune system suppression. Besides the classical targets VEGF, MMP-9 and PD-1, CHI3L1 constitutes a new possibly drugable molecule to retard down dissemination of SCLC cells, which may be similarly relevant for glioblastoma and other tumor entities. PMID:26425658

  2. TP53 Mutations in Nonsmall Cell Lung Cancer

    PubMed Central

    Mogi, Akira; Kuwano, Hiroyuki

    2011-01-01

    The tumor suppressor gene TP53 is frequently mutated in human cancers. Abnormality of the TP53 gene is one of the most significant events in lung cancers and plays an important role in the tumorigenesis of lung epithelial cells. Human lung cancers are classified into two major types, small cell lung cancer (SCLC) and nonsmall cell lung cancer (NSCLC). The latter accounts for approximately 80% of all primary lung cancers, and the incidence of NSCLC is increasing yearly. Most clinical studies suggest that NSCLC with TP53 alterations carries a worse prognosis and may be relatively more resistant to chemotherapy and radiation. A deep understanding of the role of TP53 in lung carcinogenesis may lead to a more reasonably targeted clinical approach, which should be exploited to enhance the survival rates of patients with lung cancer. This paper will focus on the role of TP53 in the molecular pathogenesis, epidemiology, and therapeutic strategies of TP53 mutation in NSCLC. PMID:21331359

  3. Novel therapies in small cell lung cancer

    PubMed Central

    Induru, Raghava; Jalal, Shadia I.

    2015-01-01

    Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor of the lung with a tendency to metastasize widely early in the course of the disease. The VA staging system classifies the disease into limited stage (LS) which is confined to one hemithorax and can be included into one radiation field or extensive stage (ES) which extends beyond one hemithorax. Current standard of care is concurrent chemoradiation for LS disease and chemotherapy alone for ES disease. Only a quarter of patients with LS disease will be cured with current standard treatments and majority of the patients ultimately succumb to their disease. A very complex genetic landscape of SCLC accounts for its resistance to conventional therapy and a high recurrence rate, however, at the same time this complexity can form the basis for effective targeted therapy for the disease. In recent years, several different therapeutic strategies and targeted agents have been under investigation for their potential role in SCLC. Several of them including EGFR TKIs, BCR-ABL TKIs, mTOR inhibitors, and VEGF inhibitors have been unsuccessful in showing a survival advantage in this disease. Several others including DNA repair inhibitors, cellular developmental pathway inhibitors, antibody drug conjugates (ADCs), as well as immune therapy with vaccines, immunomodulators, and immune checkpoint inhibitors are being tested. So far, none of these agents are approved for use in SCLC and the majority are in phase I/II clinical trials, with immune checkpoint inhibitors being the most promising therapeutic strategy. In this article, we will discuss these novel therapeutic agents and currently available data in SCLC. PMID:26629422

  4. Nonsmall-cell lung cancer: chemoprevention studies.

    PubMed

    Karp, Daniel D; Tsao, Anne S; Kim, Edward S

    2003-10-01

    Lung cancer is the leading cause of cancer-related death in the world. Tobacco is an addictive agent producing carcinogenic effects that have been extremely difficult to prevent or detect in a curable stage. Important randomized controlled studies have been published in "healthy" smokers (primary prevention); patients with early lesions, such as mucosal dysplasia/metaplasia (secondary prevention); and those who have already had definitive treatment for their first tobacco-related malignancy (tertiary prevention). To date, the results have been generally disappointing. It is critical to remember that lung cancer is usually diagnosed decades after the patient has begun or even stopped smoking. We must intervene with more effective agents or combinations of agents and do it earlier in the process of carcinogenesis. Approximately 10% of patients with lung cancer either never smoked or only were "passive" smokers due to their environment, workplace. These "never-smokers" may actually benefit from retinoids, while current smokers have not benefited from alpha-tocopherol, retinal, N-acetylcysteine, or isotretinoin. Smokers are actually harmed by the concurrent use of beta-carotene. We now have unprecedented knowledge regarding the control of cellular growth and senescence. New diagnostic tools also allow detection of smaller lesions. We must use all our knowledge of the cancer biology, new risk models, more refined intermediate markers, and modern detection tools to focus more clearly on the pathology of lung cancer and design research to ask more probing and relevant questions so we can begin to put an end to the worldwide scourge of this terrible killer. PMID:14710383

  5. Advances in immunotherapy for non-small cell lung cancer.

    PubMed

    Reckamp, Karen L

    2015-12-01

    In most patients, lung cancer presents as advanced disease with metastases to lymph nodes and/or distant organs, and survival is poor. Lung cancer is also a highly immune-suppressing malignancy with numerous methods to evade antitumor immune responses, including deficiencies in antigen processing and presentation, release of immunomodulatory cytokines, and inhibition of T-cell activation. Advances in understanding the complex interactions of the immune system and cancer have led to novel therapies that promote T-cell activation at the tumor site, resulting in prolonged clinical benefit. Immune checkpoint inhibitors, specifically programmed death receptor 1 pathway antibodies, have demonstrated impressively durable responses and improved survival in patients with non-small cell lung cancer. This article will review the recent progress made in immunotherapy for lung cancer with data from trials evaluating programmed death receptor 1 and cytotoxic T-lymphocyte-associated protein 4 monoclonal antibodies in addition to cancer vaccines. The review will focus on studies that have been published and the latest randomized trials exploring immune therapy in lung cancer. These results form the framework for a new direction in the treatment of lung cancer toward immunotherapy. PMID:27058851

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

    NASA Astrophysics Data System (ADS)

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

    2014-05-01

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

  7. Squamous Cell Lung Cancer: From Tumor Genomics to Cancer Therapeutics

    PubMed Central

    Gandara, David R.; Hammerman, Peter S.; Sos, Martin L.; Lara, Primo N.; Hirsch, Fred R.

    2016-01-01

    Squamous cell lung cancer (SCC) represents an area of unmet need in lung cancer research. For the last several years, therapeutic progress in SCC has lagged behind the now more common NSCLC histologic subtype of adenocarcinoma. However, recent efforts to define the complex biology underlying SCC have begun to bear fruit in a multitude of ways, including characterization of previously unknown genomic and signaling pathways, delineation of new potentially actionable molecular targets, and subsequent development of a large number of agents directed against unique SCC-associated molecular abnormalities. For the first time, SCC-specific prognostic gene signatures and predictive biomarkers of new therapeutic agents are emerging. In addition, recent and ongoing clinical trials, including the Lung-MAP master protocol, have been designed to facilitate approval of targeted therapy-biomarker combinations. In this comprehensive review we describe the current status of SCC therapeutics, recent advances in the understanding of SCC biology and prognostic gene signatures, and the development of innovative new clinical trials, all of which offer new hope for patients with advanced SCC. PMID:25979930

  8. Recombinant Interleukin-15 in Treating Patients With Advanced Melanoma, Kidney Cancer, Non-small Cell Lung Cancer, or Squamous Cell Head and Neck Cancer

    ClinicalTrials.gov

    2016-05-05

    Head and Neck Squamous Cell Carcinoma; Recurrent Head and Neck Carcinoma; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Skin Carcinoma; Stage III Renal Cell Cancer; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIA Skin Melanoma; Stage IIIB Non-Small Cell Lung Cancer; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Non-Small Cell Lung Cancer; Stage IV Renal Cell Cancer; Stage IV Skin Melanoma

  9. Taste thresholds in patients with small-cell lung cancer.

    PubMed

    Ovesen, L; Hannibal, J; Sørensen, M

    1991-01-01

    Recognition thresholds for the four basic tastes (salt, sour, sweet and bitter) were tested by the forced-choice technique in 27 patients with small-cell lung cancer, and 22 weight-matched control patients with non-malignant diseases. No significant differences in threshold concentrations could be demonstrated. When patients who were losing weight were compared with weight-stable patients, significantly lower taste thresholds for bitter substances were found in weight losing groups in both cancer and control patients. Small-cell lung cancer patients who responded to therapy had obtained an increased threshold for bitter taste at the time of reevaluation than at the time of diagnosis, an effect that may be explained by the chemotherapeutic regimen. The results suggest that in patients with small-cell lung cancer it is not the cancer disease per se but the weight loss that often accompanies it that causes an increased taste sensitivity for bitter substances. PMID:1847701

  10. Lung Cancer

    MedlinePlus

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

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

    ClinicalTrials.gov

    2012-12-13

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

  12. Personalized Therapy of Non-small Cell Lung Cancer (NSCLC).

    PubMed

    Gadgeel, Shirish M

    2016-01-01

    Lung cancer remains the most common cause of cancer related deaths in both men and women in the United States and non-small cell lung cancer (NSCLC) accounts for over 85 % of all lung cancers. Survival of these patients has not significantly altered in over 30 years. This chapter initially discusses the clinical presentation of lung cancer patients. Most patients diagnosed with lung cancer due to symptoms have advanced stage cancer. Once diagnosed, lung cancer patients need imaging studies to assess the stage of the disease before decisions regarding therapy are finalized. The most important prognostic factors are stage of the disease and performance status and these factors also determine therapy. The chapter subsequently discusses management of each stage of the disease and the impact of several pathologic, clinical factors in personalizing therapy for each individual patient. Transition from chemotherapy for every patient to a more personalized approach based on histology and molecular markers has occurred in the management of advanced stage NSCLC. It is expected that such a personalized approach will extend to all stages of NSCLC and will likely improve the outcomes of all NSCLC patients. PMID:26703806

  13. Gene expression profiles of small-cell lung cancers: molecular signatures of lung cancer.

    PubMed

    Taniwaki, Masaya; Daigo, Yataro; Ishikawa, Nobuhisa; Takano, Atsushi; Tsunoda, Tatsuhiko; Yasui, Wataru; Inai, Kouki; Kohno, Nobuoki; Nakamura, Yusuke

    2006-09-01

    To characterize the molecular mechanisms involved in the carcinogenesis and progression of small-cell lung cancer (SCLC) and identify molecules to be applied as novel diagnostic markers and/or for development of molecular-targeted drugs, we applied cDNA microarray profile analysis coupled with purification of cancer cells by laser-microbeam microdissection (LMM). Expression profiles of 32,256 genes in 15 SCLCs identified 252 genes that were commonly up-regulated and 851 transcripts that were down-regulated in SCLC cells compared with non-cancerous lung tissue cells. An unsupervised clustering algorithm applied to the expression data easily distinguished SCLC from the other major histological type of non-small cell lung cancer (NSCLC) and identified 475 genes that may represent distinct molecular features of each of the two histological types. In particular, SCLC was characterized by altered expression of genes related to neuroendocrine cell differentiation and/or growth such as ASCL1, NRCAM, and INSM1. We also identified 68 genes that were abundantly expressed both in advanced SCLCs and advanced adenocarcinomas (ADCs), both of which had been obtained from patients with extensive chemotherapy treatment. Some of them are known to be transcription factors and/or gene expression regulators such as TAF5L, TFCP2L4, PHF20, LMO4, TCF20, RFX2, and DKFZp547I048 as well as those encoding nucleotide-binding proteins such as C9orf76, EHD3, and GIMAP4. Our data provide valuable information for better understanding of lung carcinogenesis and chemoresistance. PMID:16865272

  14. Image-Guided Hypofractionated Radiation Therapy With Stereotactic Body Radiation Therapy Boost and Combination Chemotherapy in Treating Patients With Stage II-III Non-Small Cell Lung Cancer That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2016-09-07

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Large Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Squamous 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

  15. Genetically Modified T Cells in Treating Patients With Stage III-IV Non-small Cell Lung Cancer or Mesothelioma

    ClinicalTrials.gov

    2016-05-02

    Advanced Pleural Malignant Mesothelioma; HLA-A*0201 Positive Cells Present; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Pleural Malignant Mesothelioma; Stage III Pleural Mesothelioma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer; Stage IV Pleural Mesothelioma

  16. Drugs Approved for Lung Cancer

    MedlinePlus

    ... Professionals Questions to Ask about Your Treatment Research Drugs Approved for Lung Cancer This page lists cancer ... in lung cancer that are not listed here. Drugs Approved for Non-Small Cell Lung Cancer Abitrexate ( ...

  17. Veliparib With or Without Radiation Therapy, Carboplatin, and Paclitaxel in Patients With Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2016-08-31

    Bronchioloalveolar Carcinoma; Large Cell Lung Carcinoma; Lung Adenocarcinoma; Lung Adenocarcinoma, Mixed Subtype; Squamous Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer

  18. Risks of Lung Cancer Screening

    MedlinePlus

    ... Cancer Treatment Small Cell Lung Cancer Treatment Lung cancer is the leading cause of cancer death in the United States. Lung cancer is ... non- skin cancer in the United States. Lung cancer is the leading cause of cancer death in men and in women. ...

  19. Identification of five candidate lung cancer biomarkers by proteomics analysis of conditioned media of four lung cancer cell lines.

    PubMed

    Planque, Chris; Kulasingam, Vathany; Smith, Chris R; Reckamp, Karen; Goodglick, Lee; Diamandis, Eleftherios P

    2009-12-01

    Detection of lung cancer at an early stage is necessary for successful therapy and improved survival rates. We performed a bottom-up proteomics analysis using a two-dimensional LC-MS/MS strategy on the conditioned media of four lung cancer cell lines of different histological backgrounds (non-small cell lung cancer: H23 (adenocarcinoma), H520 (squamous cell carcinoma), and H460 (large cell carcinoma); small cell lung cancer: H1688) to identify secreted or membrane-bound proteins that could be useful as novel lung cancer biomarkers. Proteomics analysis of the four conditioned media allowed identification of 1,830 different proteins (965, 871, 726, and 847 from H1688, H23, H460, and H520, respectively). All proteins were assigned a subcellular localization, and 38% were classified as extracellular or membrane-bound. We successfully identified the internal control proteins (also detected by ELISA), kallikrein-related peptidases 14 and 11, and IGFBP2. We also identified known or putative lung cancer tumor markers such as squamous cell carcinoma antigen, carcinoembryonic antigen, chromogranin A, creatine kinase BB, progastrin-releasing peptide, neural cell adhesion molecule, and tumor M2-PK. To select the most promising candidates for validation, we performed tissue specificity assays, functional classifications, literature searches for association to cancer, and a comparison of our proteome with the proteome of lung-related diseases and serum. Five novel lung cancer candidates, ADAM-17, osteoprotegerin, pentraxin 3, follistatin, and tumor necrosis factor receptor superfamily member 1A were preliminarily validated in the serum of patients with lung cancer and healthy controls. Our results demonstrate the utility of this cell culture proteomics approach to identify secreted and shed proteins that are potentially useful as serological markers for lung cancer. PMID:19776420

  20. Identification of Five Candidate Lung Cancer Biomarkers by Proteomics Analysis of Conditioned Media of Four Lung Cancer Cell Lines*

    PubMed Central

    Planque, Chris; Kulasingam, Vathany; Smith, Chris R.; Reckamp, Karen; Goodglick, Lee; Diamandis, Eleftherios P.

    2009-01-01

    Detection of lung cancer at an early stage is necessary for successful therapy and improved survival rates. We performed a bottom-up proteomics analysis using a two-dimensional LC-MS/MS strategy on the conditioned media of four lung cancer cell lines of different histological backgrounds (non-small cell lung cancer: H23 (adenocarcinoma), H520 (squamous cell carcinoma), and H460 (large cell carcinoma); small cell lung cancer: H1688) to identify secreted or membrane-bound proteins that could be useful as novel lung cancer biomarkers. Proteomics analysis of the four conditioned media allowed identification of 1,830 different proteins (965, 871, 726, and 847 from H1688, H23, H460, and H520, respectively). All proteins were assigned a subcellular localization, and 38% were classified as extracellular or membrane-bound. We successfully identified the internal control proteins (also detected by ELISA), kallikrein-related peptidases 14 and 11, and IGFBP2. We also identified known or putative lung cancer tumor markers such as squamous cell carcinoma antigen, carcinoembryonic antigen, chromogranin A, creatine kinase BB, progastrin-releasing peptide, neural cell adhesion molecule, and tumor M2-PK. To select the most promising candidates for validation, we performed tissue specificity assays, functional classifications, literature searches for association to cancer, and a comparison of our proteome with the proteome of lung-related diseases and serum. Five novel lung cancer candidates, ADAM-17, osteoprotegerin, pentraxin 3, follistatin, and tumor necrosis factor receptor superfamily member 1A were preliminarily validated in the serum of patients with lung cancer and healthy controls. Our results demonstrate the utility of this cell culture proteomics approach to identify secreted and shed proteins that are potentially useful as serological markers for lung cancer. PMID:19776420

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

    ClinicalTrials.gov

    2016-04-06

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

  2. Radiation Therapy and MK-3475 for Patients With Recurrent/Metastatic Head and Neck Cancer, Renal Cell Cancer, Melanoma, and Lung Cancer

    ClinicalTrials.gov

    2016-07-06

    Head and Neck Squamous Cell Carcinoma; Metastatic Renal Cell Cancer; Recurrent Head and Neck Carcinoma; Recurrent Lung Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Skin Carcinoma; Stage III Renal Cell Cancer; Stage IV Lung Cancer; Stage IV Skin Melanoma

  3. Phase 3 Study of Bavituximab Plus Docetaxel Versus Docetaxel Alone in Patients With Late-stage Non-squamous Non-small-cell Lung Cancer

    ClinicalTrials.gov

    2016-02-01

    Non-Small-Cell Lung Cancer Stage IIIB; Non-Small-Cell Lung Cancer Stage IV; Non-Small-Cell Lung Cancer Metastatic; Carcinoma, Non-Small-Cell Lung; Non-Small Cell Lung Cancer; Non-Small-Cell Lung Carcinoma; Nonsmall Cell Lung Cancer

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

    PubMed Central

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

    2016-01-01

    Cancer stem cells (CSCs) play vital role in lung cancer progression, resistance, metastasis and relapse. Identifying lung CSCs makers for lung CSCs targeting researches are critical for lung cancer therapy. In this study, utilizing previous identified lung CSCs as model, we compared the expression of CD24, CD133 and CD44 between CSCs and non-stem cancer cells. Increased ratio of CD24- cells were found in CSCs. CD24- cells were then sorted by flow cytometry and their proliferative ability, chemo-resistance property and in vivo tumor formation abilities were detected. A549 CD24- cells formed smaller colonies, slower proliferated in comparison to A549 CD24+ cells. Besides, A549 CD24- exhibited stronger resistance to chemotherapy drug. However, A549 CD24- didn’t exert any stronger tumor formation ability in vivo, which is the gold standard of CSCs. These results showed that CD24- A549 cells showed some properties of CSCs but not actually CSCs. This study provides evidence that CD24 cannot be considered as lung CSCs marker. PMID:27073722

  5. Thoracoscopic Lobectomy for Non-small Cell Lung Cancer.

    PubMed

    Gaudet, Matthew A; D'Amico, Thomas A

    2016-07-01

    Lobectomy is the gold standard treatment in operable patients with surgically resectable non-small cell lung cancer. Thoracoscopic lobectomy has emerged as an option for surgeons facile with the technique. Video-assisted thoracoscopic surgery (VATS) is used for a variety of indications, but its efficacy as a reliable oncologic procedure makes it appealing in the treatment of non-small cell lung cancer. Fewer postoperative complications and decreased postoperative pain associated with VATS procedures can lead to shorter lengths of stay and lower overall costs. Thoracoscopic surgery continues to evolve, and uniportal, robot-assisted, and awake thoracoscopic procedures have all shown promising results. PMID:27261912

  6. CD133 is a temporary marker of cancer stem cells in small cell lung cancer, but not in non-small cell lung cancer.

    PubMed

    Cui, Fei; Wang, Jian; Chen, Duan; Chen, Yi-Jiang

    2011-03-01

    Lung cancer is the most common cause of cancer-related death worldwide. Current investigations in the field of cancer research have intensively focused on the 'cancer stem cell' or 'tumor-initiating cell'. While CD133 was initially considered as a stem cell marker only in the hematopoietic system and the nervous system, the membrane antigen also identifies tumorigenic cells in certain solid tumors. In this study, we investigated the human lung cancer cell lines A549, H157, H226, Calu-1, H292 and H446. The results of real-time PCR analysis after chemotherapy drug selection and the fluorescence-activated cell sorting analysis showed that CD133 only functioned as a marker in the small cell lung cancer line H446. The sorted CD133+ subset presented stem cell-like features, including self-renewal, differentiation, proliferation and tumorigenic capacity in subsequent assays. Furthermore, a proportion of the CD133+ cells had a tendency to remain stable, which may explain the controversies arising from previous studies. Therefore, the CD133+ subset should provide an enriched source of tumor-initiating cells among H446 cells. Moreover, the antigen could be used as an investigative marker of the tumorigenic process and an effective treatment for small cell lung cancer. PMID:21174061

  7. 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

  8. 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.

  9. Methoxyamine, Pemetrexed Disodium, Cisplatin, and Radiation Therapy in Treating Patients With Stage IIIA-IV Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2016-04-05

    Metastatic Malignant Neoplasm in the Brain; Stage IIIA Large Cell Lung Carcinoma; Stage IIIA Lung Adenocarcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Large Cell Lung Carcinoma; Stage IIIB Lung Adenocarcinoma; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Large Cell Lung Carcinoma; Stage IV Lung Adenocarcinoma; Stage IV Non-Small Cell Lung Cancer

  10. GTI-2040 and Docetaxel in Treating Patients With Recurrent, Metastatic, or Unresectable Locally Advanced Non-Small Cell Lung Cancer, Prostate Cancer, or Other Solid Tumors

    ClinicalTrials.gov

    2013-01-23

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

  11. Immunotherapy for non-small cell lung cancer

    PubMed Central

    Kelly, Ronan J.; Gulley, James L.; Giaccone, Giuseppe

    2012-01-01

    Developing effective immunotherapy for lung cancer is a daunting but hugely attractive challenge. Until recently, non-small cell lung cancer was thought of as a non-immunogenic tumor, but there is now evidence highlighting the integral role played by both inflammatory and immunological responses in lung carcinogenesis. Despite recent encouraging preclinical and phase I/II data, there is a paucity of phase III trials showing a clear clinical benefit for vaccines in lung cancer. There are many difficulties to overcome prior to the development of a successful therapy. Perhaps a measurable immune response may not translate into a clinically meaningful or radiological response. Patient selection may also be a problem for ongoing clinical studies. The majority of trials for lung cancer vaccines are focused on patients with advanced-stage disease, while the ideal candidates may be patients with a lower tumor burden stage I or II disease. Selecting the exact antigens to target is also difficult. It will likely require multiple epitopes of a diverse set of genes restricted to multiple haplotypes to generate a truly effective vaccine that is able to overcome the various immunologic escape mechanisms that tumors employ. This review discusses active immunotherapy employing protein/peptide vaccines, whole cell vaccines, and dendritic cell vaccines and examines the current data on some novel immunomodulating agents. PMID:20630824

  12. Ciprofloxacin mediates cancer stem cell phenotypes in lung cancer cells through caveolin-1-dependent mechanism.

    PubMed

    Phiboonchaiyanan, Preeyaporn Plaimee; Kiratipaiboon, Chayanin; Chanvorachote, Pithi

    2016-04-25

    Cancer stem cells (CSCs), a subpopulation of cancer cells with high aggressive behaviors, have been identified in many types of cancer including lung cancer as one of the key mediators driving cancer progression and metastasis. Here, we have reported for the first time that ciprofloxacin (CIP), a widely used anti-microbial drug, has a potentiating effect on CSC-like features in human non-small cell lung cancer (NSCLC) cells. CIP treatment promoted CSC-like phenotypes, including enhanced anchorage-independent growth and spheroid formation. The known lung CSC markers: CD133, CD44, ABCG2 and ALDH1A1 were found to be significantly increased, while the factors involving in epithelial to mesenchymal transition (EMT): Slug and Snail, were depleted. Also, self-renewal transcription factors Oct-4 and Nanog were found to be up-regulated in CIP-treated cells. The treatment of CIP on CSC-rich populations obtained from secondary spheroids resulted in the further increase of CSC markers. In addition, we have proven that the mechanistic insight of the CIP induced stemness is through Caveolin-1 (Cav-1)-dependent mechanism. The specific suppression of Cav-1 by stably transfected Cav-1 shRNA plasmid dramatically reduced the effect of CIP on CSC markers as well as the CIP-induced spheroid formation ability. Cav-1 was shown to activate protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) pathways in CSC-rich population; however, such an effect was rarely found in the main lung cancer cells population. These findings reveal a novel effect of CIP in positively regulating CSCs in lung cancer cells via the activation of Cav-1, Akt and ERK, and may provoke the awareness of appropriate therapeutic strategy in cancer patients. PMID:26947806

  13. EF5 in Measuring Tumor Hypoxia in Patients With Stage I-III Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2015-04-10

    Stage IA Non-Small Cell Lung Carcinoma; Stage IB Non-Small Cell Lung Carcinoma; Stage IIA Non-Small Cell Lung Carcinoma; Stage IIB Non-Small Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer

  14. A translational approach to lung cancer research: From EGFRs to Wnt and cancer stem cells.

    PubMed

    Yagui-Beltrán, Adam; Jablons, David M

    2009-08-01

    Lung cancer remains the main cause of all cancer deaths in the United States. The prognosis for non-small cell lung cancer, despite advances in current therapies, is disappointing. Fortunately, we are steadily gaining significant insights into the heterogeneous molecular pathogenesis of lung cancer, which seems to occur in a stepwise manner, mainly secondary to tobacco smoking. With the emerging power of gene expression signatures for individual lung tumors and with the advancing field of stem cell biology and the paradigm of cancer stem cells, we are most certainly paving the way to developing novel tools for the early detection, chemoprevention, and treatment of these vastly morbid pathologies with enormous global burden. We will explore some of these issues and highlight how we are starting to translate them into clinically relevant tools for lung cancer patients. PMID:19763051

  15. Murine Lung Cancer Induces Generalized T Cell Exhaustion

    PubMed Central

    Mittal, Rohit; Chen, Ching-Wen; Lyons, John D; Margoles, Lindsay M; Liang, Zhe; Coopersmith, Craig M; Ford, Mandy L

    2015-01-01

    Background Cancer is known to modulate tumor-specific immune responses by establishing a micro-environment that leads to the upregulation of T cell inhibitory receptors, resulting in the progressive loss of function and eventual death of tumor-specific T cells. However, the ability of cancer to impact the functionality of the immune system on a systemic level is much less well characterized. Because cancer is known to predispose patients to infectious complications including sepsis, we hypothesized that the presence of cancer alters pathogen-directed immune responses on a systemic level. Materials and Methods We assessed systemic T cell coinhibitory receptor expression, cytokine production, and apoptosis in mice with established subcutaneous lung cancer tumors and in unmanipulated mice without cancer. Results Results indicated that the frequencies of PD-1+, BTLA+, and 2B4+ cells in both the CD4+ and CD8+ T cell compartments were increased in mice with localized cancer relative to non-cancer controls, and the frequencies of both CD4+ and CD8+ T cells expressing multiple different inhibitory receptors was increased in cancer animals relative to non-cancer controls. Additionally, 2B4+CD8+ T cells in cancer mice exhibited reduced IL-2 and IFN-γ, while BTLA+CD8+ T cells in cancer mice exhibited reduced IL-2 and TNF. Conversely, CD4+ T cells in cancer animals demonstrated an increase in the frequency of Annexin V+ apoptotic cells. Conclusion Taken together, these data suggest that the presence of cancer induces systemic T cell exhaustion and generalized immune suppression. PMID:25748104

  16. 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 ...

  17. 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 ...

  18. Application of proteomics in non-small-cell lung cancer.

    PubMed

    Cho, William C S

    2016-01-01

    Non-small-cell lung cancer (NSCLC) is a heterogeneous disease with diverse pathological features. Clinical proteomics allows the discovery of molecular markers and new therapeutic targets for this most prevalent type of lung cancer. Some of them may be used to detect early lung cancer, while others may serve as predictive markers of resistance to different therapies. Therapeutic targets and prognostic markers in NSCLC have also been discovered. These proteomics biomarkers may help to pair the individual NSCLC patient with the best treatment option. Despite the fact that implementation of these biomarkers in the clinic appears to be scarce, the recently launched Precision Medicine Initiative may encourage their translation into clinical practice. PMID:26577456

  19. Hyponatremia of non-small cell lung cancer: Indian experience

    PubMed Central

    Bose, Chinmoy K.; Dey, Subhashis; Mukhopadhyay, Ashis

    2011-01-01

    Background: Hyponatremia is a hazardous complication of lung cancer and its treatment. It is seen at presentation in approximately 15% of patients with small-cell lung cancer (SCLC) and 1% of patients with non-small cell lung cancer (NSCLC). Platinum compounds used as first-line agents along with taxols frequently cause hyponatremia. Till date there is no data on its prevalence in patients with advanced lung cancer in the Indian subcontinent. Aim: This study was undertaken to find out its incidence before and after institution of chemotherapy and to observe the results of treatment of hyponatremia in a group of lung cancer patient. Materials and Methods: Forty patients with advanced lung cancer (25 patients with stage III disease and 15 with stage IV disease) were included in the study. Variables looked at included, but were not limited to, serum sodium, serum albumin, serum alkaline phosphatase, serum lactate dehydrogenase, and hemoglobin. These variables were measured as per the standard clinical laboratory procedure. No ethics approval was required as these parameters are routinely measured in such patients. Results: In the chemo-naïve state, one out of five cases with SCLC (20%) had hyponatremia at presentation; among the 35 cases of NSCLC, 7 patients (20%) had hyponatremia at presentation, which is in sharp contrast to earlier reports of 1% prevalence of hyponatremia in this group. Among the 27 cases who died within 6 months, 11 had hyponatremia; this finding was statistically highly significant. Conclusion: In India, NSCLC patients are at high risk of having hyponatremia at presentation and this is significantly associated with a worse outcome. PMID:22557779

  20. What Is Lung Cancer?

    MedlinePlus

    ... starts in the lungs, it is called lung cancer. Lung cancer begins in the lungs and may spread ... lung cancer. For more information, visit the National Cancer Institute’s Lung Cancer. Previous Basic Information Basic Information Basic Information ...

  1. [Immune Checkpoint Therapy for Non-Small-Cell Lung Cancer].

    PubMed

    Miyauchi, Eisaku; Inoue, Akira

    2016-06-01

    Nivolumab is an anti-PD-1 antibody that has recently been approved in Japan, and has shown high response rates and more favorable safety profiles in 2 phase III clinical trials. Accordingly, immune checkpoint therapy has now been included as a new standard treatment for non-small-cell lung cancer. These immune checkpoints are receptors expressed on T cells that regulate the immune response. The PD-1/PD-L1 signal inhibits cytotoxic T lymphocyte proliferation and survival, induces apoptosis of infiltrative T cells, and increases the amount of regulatory T cells in the tumor microenvironment. Therefore, severe immune-related adverse event(irAE)have been observed, including enterocolitis, neuropathies, and endocrinopathies. There are different management approaches to irAEs with conventional cytotoxic drugs. This article reviews the available data regarding immune checkpoint therapy for patients with non-small-cell lung cancer. PMID:27306803

  2. EF5 and Motexafin Lutetium in Detecting Tumor Cells in Patients With Abdominal or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-01-15

    Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Fallopian Tube Cancer; Gastrointestinal Stromal Tumor; Localized Extrahepatic Bile Duct Cancer; Localized Gallbladder Cancer; Localized Gastrointestinal Carcinoid Tumor; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Metastatic Gastrointestinal Carcinoid Tumor; Ovarian Sarcoma; Ovarian Stromal Cancer; Primary Peritoneal Cavity Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Adult Soft Tissue Sarcoma; Recurrent Colon Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Recurrent Small Intestine Cancer; Recurrent Uterine Sarcoma; Regional Gastrointestinal Carcinoid Tumor; Small Intestine Adenocarcinoma; Small Intestine Leiomyosarcoma; Small Intestine Lymphoma; Stage 0 Non-small Cell Lung Cancer; Stage I Adult Soft Tissue Sarcoma; Stage I Colon Cancer; Stage I Gastric Cancer; Stage I Non-small Cell Lung Cancer; Stage I Ovarian Epithelial Cancer; Stage I Ovarian Germ Cell Tumor; Stage I Pancreatic Cancer; Stage I Rectal Cancer; Stage I Uterine Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage II Colon Cancer; Stage II Gastric Cancer; Stage II Non-small Cell Lung Cancer; Stage II Ovarian Epithelial Cancer; Stage II Ovarian Germ Cell Tumor; Stage II Pancreatic Cancer; Stage II Rectal Cancer; Stage II Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Colon Cancer; Stage III Gastric Cancer; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage III Pancreatic Cancer; Stage III Rectal Cancer; Stage III Uterine Sarcoma; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Adult Soft Tissue Sarcoma; Stage IV Colon Cancer; Stage

  3. Comprehensive genomic characterization of squamous cell lung cancers

    PubMed Central

    2012-01-01

    Summary Lung squamous cell carcinoma (lung SqCC) is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in lung SqCC have not been comprehensively characterized and no molecularly targeted agents have been developed specifically for its treatment. As part of The Cancer Genome Atlas (TCGA), we profiled 178 lung SqCCs to provide a comprehensive landscape of genomic and epigenomic alterations. Lung SqCC is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumor. We found statistically recurrent mutations in 18 genes in including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations were seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2/KEAP1 in 34%, squamous differentiation genes in 44%, PI3K/AKT in 47%, and CDKN2A/RB1 in 72% of tumors. We identified a potential therapeutic target in the majority of tumors, offering new avenues of investigation for lung SqCC treatment. PMID:22960745

  4. Treatment Option Overview (Non-Small Cell Lung Cancer)

    MedlinePlus

    ... lung cancer include a cough that doesn't go away and shortness of breath. Sometimes lung cancer ... discomfort or pain. A cough that doesn’t go away or gets worse over time. Trouble breathing. ...

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

    MedlinePlus

    ... lung cancer include a cough that doesn't go away and shortness of breath. Sometimes lung cancer ... discomfort or pain. A cough that doesn’t go away or gets worse over time. Trouble breathing. ...

  6. Stages of Non-Small Cell Lung Cancer

    MedlinePlus

    ... lung cancer include a cough that doesn't go away and shortness of breath. Sometimes lung cancer ... discomfort or pain. A cough that doesn’t go away or gets worse over time. Trouble breathing. ...

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

    PubMed Central

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

    2016-01-01

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

  8. Mast cells and histamine enhance the proliferation of non-small cell lung cancer cells.

    PubMed

    Stoyanov, Evgeniy; Uddin, Mohib; Mankuta, David; Dubinett, Steven M; Levi-Schaffer, Francesca

    2012-01-01

    Non-small cell lung cancer (NSCLC) is the most common form of lung cancer with an extremely low survival rate. It is characterized by a chronic inflammatory process with intense mast cell infiltrate that is associated with reduced survival. The aim of this study was to test the hypothesis that mast cells have an enhancing effect on NSCLC proliferation. To assess the tumor-promoting potential of mast cells, we used the human alveolar basal adenocarcinoma (A549) and the mouse Lewis lung carcinoma (LLC) cell lines, umbilical cord blood-derived mast cells (CBMC) and the mast cell-deficient mouse Sash model. The proliferation rate of A549/LLC cells was markedly increased by mast cells and histamine. Histamine proliferating activity was mediated via H(1), H(2) and H(4) receptors and caused ERK phosphorylation. LLC induced in Sash mice or in wild-type mice treated with the mast cell stabilizer nedocromil sodium displayed an accelerated growth (number of metastic colonies in the lungs, total lung area and lung/total mice weight ratio). In summary, we have shown a significant effect of mast cells and histamine in enhancing NSCLC/LLCX growth in vitro, while in a mouse LLC model in vivo we have found that mast cells are important negative regulators of cancer development. Therefore our results would indicate a pro-tumorogenic effect of the mast cells in vitro on established lung tumor cell lines, and anti-tumorogenic effect in mice at lung cancer induction. In conclusion, mast cell/anti-histamine targeted therapies should carefully consider this dual effect. PMID:21733595

  9. Genetic polymorphisms and non-small-cell lung cancer: future paradigms

    PubMed Central

    de Mello, Ramon Andrade Bezerra

    2014-01-01

    This article addresses some current issues about genetic polymorphisms studied in the non-small-cell lung cancer translational field. Furthermore, it discusses about new potential biomarkers regarding lung cancer risk and prognosis. PMID:25628210

  10. RASSF4 is downregulated in nonsmall cell lung cancer and inhibits cancer cell proliferation and invasion.

    PubMed

    Han, Yong; Dong, Qianze; Hao, Jie; Fu, Lin; Han, Xu; Zheng, Xiaoying; Wang, Enhua

    2016-04-01

    RASSF4 has been implicated as a tumor suppressor in several human cancers. Its clinical significance and biological characteristics in human nonsmall cell lung cancer (NSCLC) have not been explored yet. In this study, we explored expression pattern of RASSF4 in 89 NSCLC specimens. The results showed that RASSF4 was downregulated in 36/89 NSCLC tissues compared with normal tissue. RASSF4 downregulation significantly associated with advanced TNM stage, positive nodal status, and poor prognosis. We examined RASSF4 protein expression in normal lung epithelial cell line and lung cancer lines. We found that RASSF4 expression was downregulated in four of seven lung cancer cell lines compared with normal bronchial epithelial cells. RASSF4 plasmid transfection was performed in H460 and A549 cell lines. RASSF4 overexpression inhibited proliferation, colony formation, and invading ability. In addition, we identified that RASSF4 could inhibit cell cycle progression with downregulation of cyclin D1. Expression of invasion-related protein MMP2, MMP9 was also decreased. In conclusion, the present study suggested that RASSF4 serves as an important tumor suppressor in NSCLC. PMID:26526576

  11. Adherence to Survivorship Care Guidelines in Health Care Providers for Non-Small Cell Lung Cancer and Colorectal Cancer Survivor Care

    ClinicalTrials.gov

    2016-03-01

    Adenocarcinoma of the Lung; Mucinous Adenocarcinoma of the Colon; Mucinous Adenocarcinoma of the Rectum; Signet Ring Adenocarcinoma of the Colon; Signet Ring Adenocarcinoma of the Rectum; Squamous Cell Lung Cancer; Stage I Colon Cancer; Stage I Rectal Cancer; Stage IA Non-small Cell Lung Cancer; Stage IB Non-small Cell Lung Cancer; Stage IIA Colon Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIA Rectal Cancer; Stage IIB Colon Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIB Rectal Cancer; Stage IIC Colon Cancer; Stage IIC Rectal Cancer; Stage IIIA Colon Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIA Rectal Cancer; Stage IIIB Colon Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IIIB Rectal Cancer; Stage IIIC Colon Cancer; Stage IIIC Rectal Cancer

  12. Lung cancer in women.

    PubMed

    Coscio, Angela M; Garst, Jennifer

    2006-07-01

    Lung cancer is the most common cancer in both men and women; however, there are some clear gender-based differences. As the incidence of lung cancer is declining in men, the incidence of lung cancer is increasing in women. Women are more likely than men to have adenocarcinoma, a histologic subtype that correlates with worsened prognosis, but women have improved survival compared with men. Genetic predisposition and the presence of estrogen receptors in lung cancer cells may predispose women to developing lung cancer. Further studies are needed to understand the mechanism and significance of these findings. PMID:17254523

  13. Lung cancer stem cells: The root of resistance.

    PubMed

    MacDonagh, Lauren; Gray, Steven G; Breen, Eamon; Cuffe, Sinead; Finn, Stephen P; O'Byrne, Kenneth J; Barr, Martin P

    2016-03-28

    In the absence of specific treatable mutations, platinum-based chemotherapy remains the gold standard of treatment for lung cancer patients. However, 5-year survival rates remain poor due to the development of resistance and eventual relapse. Resistance to conventional cytotoxic therapies presents a significant clinical challenge in the treatment of this disease. The cancer stem cell (CSC) hypothesis suggests that tumors are arranged in a hierarchical structure, with the presence of a small subset of stem-like cells that are responsible for tumor initiation and growth. This CSC population has a number of key properties such as the ability to asymmetrically divide, differentiate and self-renew, in addition to having increased intrinsic resistance to therapy. While cytotoxic chemotherapy kills the bulk of tumor cells, CSCs are spared and have the ability to recapitulate the heterogenic tumor mass. The identification of lung CSCs and their role in tumor biology and treatment resistance may lead to innovative targeted therapies that may ultimately improve clinical outcomes in lung cancer patients. This review will focus on lung CSC markers, their role in resistance and their relevance as targets for future therapies. PMID:26797015

  14. Lung Cancer Cell Lines as Tools for Biomedical Discovery and Research

    PubMed Central

    Girard, Luc; Lockwood, William W.; Lam, Wan L.; Minna, John D.

    2010-01-01

    Lung cancer cell lines have made a substantial contribution to lung cancer translational research and biomedical discovery. A systematic approach to initiating and characterizing cell lines from small cell and non–small cell lung carcinomas has led to the current collection of more than 200 lung cancer cell lines, a number that exceeds those for other common epithelial cancers combined. The ready availability and widespread dissemination of the lines to investigators worldwide have resulted in more than 9000 citations, including multiple examples of important biomedical discoveries. The high (but not perfect) genomic similarities between lung cancer cell lines and the lung tumor type from which they were derived provide evidence of the relevance of their use. However, major problems including misidentification or cell line contamination remain. Ongoing studies and new approaches are expected to reveal the full potential of the lung cancer cell line panel. PMID:20679594

  15. Comparison of Two Therapeutic Strategies in Patients With Non-squamous Non-small Cell Lung Cancer (NSCLC) With Asymptomatic Brain Metastases

    ClinicalTrials.gov

    2015-11-29

    Non-small Cell Lung Cancer Metastatic; Non Epidermoid; Non-small Cell Lung Cancer; Adenocarcinoma of Lung Metastatic to Brain; Cerebral Metastases; Cerebral Radiotherapy; Brain Radiotherapy; Bevacizumab

  16. Targeted therapies in small cell lung cancer: a review

    PubMed Central

    Abidin, Aidalena Z.; Garassino, Marina C.; Califano, Raffaele; Harle, Amelie; Blackhall, Fiona

    2010-01-01

    Small cell lung cancer (SCLC) is an aggressive form of lung cancer that is characterized by a rapid doubling time, early onset of dissemination and high sensitivity to chemotherapy. Despite the potential for cure in patients with limited disease with concurrent chemoradiation and an initial good response to chemotherapy in extensive disease, there is a high chance of disease relapse with an overall poor median survival for both stages. With increasing translational research and a better understanding of the molecular basis of cancer, a number of molecular targets have been identified in various preclinical studies. This review summarizes potentially viable targets and new agents that have been developed and employed in recent, ongoing and future clinical trials to attempt to improve clinical outcomes in this disease. PMID:21789124

  17. [Therapy of Metastatic Non-small Cell Lung Cancer].

    PubMed

    Reinmuth, N; Gröschel, A; Schumann, C; Sebastian, M; Wiewrodt, R; Reck, M

    2016-09-01

    Lung cancer accounts for the leading cause of cancer deaths in Germany and is characterized by early metastasis formation. The majority of patients with non-small cell lung cancer (NSCLC) will receive systemic therapy for treatment of their disease. Importantly together with the identification of targetable oncogenic alterations, systemic treatment of NSCLC has dramatically changed in recent years with the implementation of various new agents such as tyrosine kinase inhibitors, anti angiogenic agents, and immune modulating drugs. However, these new therapeutic options also challenge the treating physician since molecular, histologic, and clinical factors need to be considered for the clinical decision-making. Moreover, supportive therapy including bronchoscopic therapy has evolved. The following therapy recommendations will summarize the up-to date treatment strategies for metastatic NSCLC. PMID:27603945

  18. Inhibitory effect of Disulfiram/copper complex on non-small cell lung cancer cells

    SciTech Connect

    Duan, Lincan; Shen, Hongmei; Zhao, Guangqiang; Yang, Runxiang; Cai, Xinyi; Zhang, Lijuan; Jin, Congguo; Huang, Yunchao

    2014-04-18

    Highlights: • Disulfiram and copper synergistically inhibit lung cancer cell proliferation. • Lung cancer cell colony formation ability is inhibited by Disulfiram/copper. • Disulfiram/copper increases the sensitivity of cisplatin to lung cancer cells. • Lung cancer stem cells are specifically targeted by Disulfiram/copper complex. - Abstract: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related death in both men and women worldwide. Recently, Disulfiram has been reported to be able to inhibit glioblastoma, prostate, or breast cancer cell proliferation. In this study, the synergistic effect of Disulfiram and copper on NSCLC cell growth was investigated. Inhibition of cancer cell proliferation was detected by 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) assay and cell cycle analysis. Liquid colony formation and tumor spheroid formation assays were used to evaluate their effect on cancer cell clonogenicity. Real-time PCR was performed to test the mRNA level of cancer stem cell related genes. We found that Disulfiram or copper alone did not potently inhibit NSCLC cell proliferation in vitro. However, the presence of copper significantly enhanced inhibitory effect of Disulfiram on NSCLC cell growth, indicating a synergistic effect between Disulfiram and copper. Cell cycle analysis showed that Disulfiram/copper complex caused NSCLC cell cycle arrest in G2/M phase. Furthermore, Disulfiram/copper significantly increased the sensitivity of cisplatin in NSCLC cells tested by MTT assay. Liquid colony formation assay revealed that copper dramatically increased the inhibitory effect of Disulfiram on NSCLC cell colony forming ability. Disulfiram combined with copper significantly attenuated NSCLC cell spheroid formation and recuded the mRNA expression of lung cancer stem cell related genes. Our data suggest that Disulfiram/copper complex alone or combined with other chemotherapy is a potential therapeutic strategy for NSCLC patients.

  19. Gigantol Suppresses Cancer Stem Cell-Like Phenotypes in Lung Cancer Cells

    PubMed Central

    Bhummaphan, Narumol; Chanvorachote, Pithi

    2015-01-01

    As cancer stem cells (CSCs) contribute to malignancy, metastasis, and relapse of cancers, potential of compound in inhibition of CSCs has garnered most attention in the cancer research as well as drug development fields recently. Herein, we have demonstrated for the first time that gigantol, a pure compound isolated from Dendrobium draconis, dramatically suppressed stem-like phenotypes of human lung cancer cells. Gigantol at nontoxic concentrations significantly reduced anchorage-independent growth and survival of the cancer cells. Importantly, gigantol significantly reduced the ability of the cancer cells to form tumor spheroids, a critical hallmark of CSCs. Concomitantly, the treatment of the compound was shown to reduce well-known lung CSCs markers, including CD133 and ALDH1A1. Moreover, we revealed that gigantol decreased stemness in the cancer cells by suppressing the activation of protein kinase B (Akt) signal which in turn decreased the cellular levels of pluripotency and self-renewal factors Oct4 and Nanog. In conclusion, gigantol possesses CSCs suppressing activity which may facilitate the development of this compound for therapeutic approaches by targeting CSCs. PMID:26339272

  20. LPP inhibits collective cell migration during lung cancer dissemination.

    PubMed

    Kuriyama, S; Yoshida, M; Yano, S; Aiba, N; Kohno, T; Minamiya, Y; Goto, A; Tanaka, M

    2016-02-25

    Lipoma preferred partner (LPP) is a LIM domain protein, which has multiple functions as an actin-binding protein and a transcriptional coactivator, and it has been suggested that LPP has some roles in cell migration or invasion, however, its role in cancer cells remains to be elucidated. Here, we showed that LPP degraded N-cadherin in lung cancer, PC14PE6 cells via regulating the expression of matrix metalloproteinase 15 (MMP-15), and loss-of-LPP increases collective cell migration (CCM) and dissemination consequently. Knockdown of LPP and its functional partner, Etv5, markedly restores the full-length N-cadherin and increases cell-cell adhesion. We investigated the common target of LPP and Etv5, and found that MMP-15 is transcribed as their direct transcriptional target. Furthermore, MMP-15 could directly digest the N-cadherin extracellular domain. LPP knockdown in PC14PE6 cells increases N-cadherin-dependent CCM in the three-dimensional collagen gel invasion assays, and promoted the dissemination of cancer cells when they were orthotopically implanted in nude mice. Immunohistochemistry of lung adenocarcinoma specimens revealed the heterogeneity of LPP intensity and complementary expression of LPP and N-cadherin in the primary tumors. These findings suggest that loss-of-LPP, Etv5 or MMP-15 can be a prognostic marker of increasing malignancy. PMID:26028032

  1. ALX1 promotes migration and invasion of lung cancer cells through increasing snail expression

    PubMed Central

    Yao, Wei; Liu, Yong; Zhang, Zhuo; Li, Guoquan; Xu, Xiaoying; Zou, Kun; Xu, Yinghui; Zou, Lijuan

    2015-01-01

    Lung cancer is one of the main causes in cancer-related death. Here we reported a novel functional role of Aristaless-like homeobox1 (ALX1) in lung carcinogenesis. Analysis of ALX1 in lung cancer specimens confirms upregulation of ALX1 in lung cancer, especially these with distant metastasis. Moreover, higher level of ALX1 expression is associated with poorer prognosis of lung cancer patients. Ectopic expression of ALX1 significantly promotes lung cancer cell proliferation, migration and invasion, while ALX1 silencing by siRNA significantly inhibits these abilities of lung cancer cells. The functional role of ALX1 is dependent on increasing Snail expression and knockdown of Snail could restrain the role of ALX1. Collectively, we identify critical roles of ALX1 in lung cancer development and progression. These findings may serve as a framework for future investigations designed to more comprehensive determination of ALX1 as a potential therapeutic target. PMID:26722397

  2. Somatostatin Analog Therapy in Small Cell Lung Cancer.

    PubMed

    Tartarone, Alfredo; Lerose, Rosa; Aieta, Michele

    2016-05-01

    Chemotherapy represents the cornerstone of treatment for patients with small cell lung cancer (SCLC); however, standard therapy has reached a plateau in improving patient survival with overall disappointing results. The demonstration that SCLC expresses neuroendocrine markers, such as somatostatin (SST) receptors, has led to use SST analogs or radiolabeled SST analogs in the treatment of SCLC patients. In the current review, we would focus on the possible role of SST analogs in SCLC. PMID:27067504

  3. Mucin 1-mediated chemo-resistance in lung cancer cells

    PubMed Central

    Ham, S Y; Kwon, T; Bak, Y; Yu, J-H; Hong, J; Lee, S K; Yu, D-Y; Yoon, D-Y

    2016-01-01

    Paclitaxel (PTX) is a commonly used drug to treat diverse cancer types. However, its treatment can generate resistance and the mechanisms of PTX-resistance in lung cancers are still unclear. We demonstrated that non-small cell lung cancers (NSCLCs) survive PTX treatment. Compared with the progenitor NSCLC A549 cells, the PTX-resistant A549 cells (A549/PTX) displayed enhanced sphere-formation ability. The proportion of the cancer stem cell marker, aldehyde dehydrogenase-positive cells, and epithelial–mesenchymal transition signaling protein levels were also elevated in A549/PTX. Importantly, the levels of oncoproteins phosphoinositide-3 kinase/Akt, mucin 1 cytoplasmic domain (MUC1-C) and β-catenin were also significantly elevated in A549/PTX. Furthermore, nuclear translocation of MUC1-C and β-catenin increased in A549/PTX. The c-SRC protein, an activator of MUC1-C, was also overexpressed in A549/PTX. These observations led to the hypothesis that enhanced expression of MUC1-C is associated with stemness and PTX resistance in NSCLCs. To test this, we knocked down or overexpressed MUC1-C in A549/PTX and found that inhibition of MUC1-C expression coupled with PTX treatment was sufficient to reduce the sphere-forming ability and survival of A549/PTX. In summary, our in vitro and in vivo studies have revealed a potential mechanism of MUC1-C-mediated PTX resistance and provided insights into a novel therapeutic measure for lung cancers. PMID:26779808

  4. [Advances in Surgical Treatment of Early Stage Non-small Cell Lung Cancer].

    PubMed

    Hu, Jian; Bao, Feichao

    2016-06-20

    Lung cancer is the leading cause of cancer-related deaths worldwide, computed tomography screening has made the disease spectrum of lung cancer shift from the previously predominating central local advanced squamous cell carcinoma to early stage lung adenocarcinoma represented by solitary pulmonary nodule, ground-glass opacity (GGO) and sub-centimeter nodule. This paper reviewed the recent proceeding in the surgical management of early stage lung cancer. PMID:27335305

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  7. Telomerase activity in non-small cell lung cancer

    PubMed Central

    Dobija-Kubica, Katarzyna; Bruliński, Krzysztof; Rogoziński, Paweł; Wiczkowski, Andrzej; Gawrychowska, Agata; Gawrychowski, Jacek

    2016-01-01

    Introduction High telomerase activity has been detected in the majority of malignant neoplasms including lung cancer. The purpose of the study was to attempt to use telomerase activity as a prognostic factor in patients with non-small cell lung cancer (NSCLC). Material and methods Telomerase activity was analyzed in 47 tissue specimens taken from patients with NSCLC. The control group consisted of 30 specimens of non-cancerous lung parenchyma. Telomerase activity was measured by means of the telomeric repeat amplification protocol (TRAP). Results Telomerase activity in the neoplastic tissue was significantly higher than in the lung parenchyma that was free from neoplastic infiltration. There was no significant association between telomerase activity and age, gender, tobacco smoking, histological type of the tumor, or staging (pTNM). No association was found between the level of telomerase activity in NSCLC specimens and the two-year survival rate of patients (p = 0.326). A higher level of telomerase activity in poorly differentiated tumors (G3) as compared to moderately differentiated tumors (G2) was detected (p = 0.008). A positive association was identified between telomerase activity in pulmonary parenchyma free from tumor infiltration and the presence of leukocyte infiltration (p = 0.0001). Conclusions No association was found between the level of telomerase activity in NSCLC specimens and the two-year survival rate of patients. The study has revealed a positive association between telomerase activity and the grade of differentiation (G) in NSCLC. PMID:27212973

  8. Protein Kinase Cα Mediates Erlotinib Resistance in Lung Cancer Cells

    PubMed Central

    Abera, Mahlet B.

    2015-01-01

    Overexpression and mutational activation of the epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of non–small cell lung cancer (NSCLC). EGFR tyrosine-kinase inhibitors (TKIs) are given as a primary therapy for advanced patients with EGFR-activating mutations; however, the majority of these tumors relapse and patients eventually develop resistance to TKIs. To address a potential role of protein kinase C (PKC) isozymes in the resistance to TKIs, we used the isogenic NSCLC H1650 cell line and its erlotinib-resistant derivative H1650-M3, a cell line that displays a mesenchymal-like morphology driven by transforming growth factor-β signaling. We found that H1650-M3 cells display remarkable PKCα upregulation and PKCδ downregulation. Notably, silencing PKCα from H1650-M3 cells using RNA interference caused a significant reduction in the expression of epithelial-to-mesenchymal transition (EMT) markers vimentin, Zeb2, Snail, and Twist. Moreover, pharmacological inhibition or PKCα RNA interference depletion and PKCδ restoring sensitized H1650-M3 cells to erlotinib. Whereas ectopic overexpression of PKCα in parental H1650 cells was not sufficient to alter the expression of EMT genes or to confer resistance to erlotinib, it caused downregulation of PKCδ expression, suggesting a unidirectional crosstalk. Finally, mechanistic studies revealed that PKCα upregulation in H1650-M3 cells is driven by transforming growth factor-β. Our results identified important roles for specific PKC isozymes in erlotinib resistance and EMT in lung cancer cells, and highlight PKCα as a potential target for lung cancer treatment. PMID:25724832

  9. Protein kinase Cα mediates erlotinib resistance in lung cancer cells.

    PubMed

    Abera, Mahlet B; Kazanietz, Marcelo G

    2015-05-01

    Overexpression and mutational activation of the epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of non-small cell lung cancer (NSCLC). EGFR tyrosine-kinase inhibitors (TKIs) are given as a primary therapy for advanced patients with EGFR-activating mutations; however, the majority of these tumors relapse and patients eventually develop resistance to TKIs. To address a potential role of protein kinase C (PKC) isozymes in the resistance to TKIs, we used the isogenic NSCLC H1650 cell line and its erlotinib-resistant derivative H1650-M3, a cell line that displays a mesenchymal-like morphology driven by transforming growth factor-β signaling. We found that H1650-M3 cells display remarkable PKCα upregulation and PKCδ downregulation. Notably, silencing PKCα from H1650-M3 cells using RNA interference caused a significant reduction in the expression of epithelial-to-mesenchymal transition (EMT) markers vimentin, Zeb2, Snail, and Twist. Moreover, pharmacological inhibition or PKCα RNA interference depletion and PKCδ restoring sensitized H1650-M3 cells to erlotinib. Whereas ectopic overexpression of PKCα in parental H1650 cells was not sufficient to alter the expression of EMT genes or to confer resistance to erlotinib, it caused downregulation of PKCδ expression, suggesting a unidirectional crosstalk. Finally, mechanistic studies revealed that PKCα upregulation in H1650-M3 cells is driven by transforming growth factor-β. Our results identified important roles for specific PKC isozymes in erlotinib resistance and EMT in lung cancer cells, and highlight PKCα as a potential target for lung cancer treatment. PMID:25724832

  10. Rnd3 regulates lung cancer cell proliferation through notch signaling.

    PubMed

    Tang, Yongjun; Hu, Chengping; Yang, Huaping; Cao, Liming; Li, Yuanyuan; Deng, Pengbo; Huang, Li

    2014-01-01

    Rnd3/RhoE is a small Rho GTPase involved in the regulation of different cell behaviors. Dysregulation of Rnd3 has been linked to tumorigenesis and metastasis. Lung cancers are the leading cause of cancer-related death in the West and around the world. The expression of Rnd3 and its ectopic role in non-small cell lung cancer (NSCLC) remain to be explored. Here, we reported that Rnd3 was down-regulated in three NSCLC cell lines: H358, H520 and A549. The down-regulation of Rnd3 led to hyper-activation of Rho Kinase and Notch signaling. The reintroduction of Rnd3 or selective inhibition of Notch signaling, but not Rho Kinase signaling, blocked the proliferation of H358 and H520 cells. Mechanistically, Notch intracellular domain (NICD) protein abundance in H358 cells was regulated by Rnd3-mediated NICD proteasome degradation. Rnd3 regulated H358 and H520 cell proliferation through a Notch1/NICD/Hes1 signaling axis independent of Rho Kinase. PMID:25372032

  11. Rnd3 Regulates Lung Cancer Cell Proliferation through Notch Signaling

    PubMed Central

    Tang, Yongjun; Hu, Chengping; Yang, Huaping; Cao, Liming; Li, Yuanyuan; Deng, Pengbo; Huang, Li

    2014-01-01

    Rnd3/RhoE is a small Rho GTPase involved in the regulation of different cell behaviors. Dysregulation of Rnd3 has been linked to tumorigenesis and metastasis. Lung cancers are the leading cause of cancer-related death in the West and around the world. The expression of Rnd3 and its ectopic role in non-small cell lung cancer (NSCLC) remain to be explored. Here, we reported that Rnd3 was down-regulated in three NSCLC cell lines: H358, H520 and A549. The down-regulation of Rnd3 led to hyper-activation of Rho Kinase and Notch signaling. The reintroduction of Rnd3 or selective inhibition of Notch signaling, but not Rho Kinase signaling, blocked the proliferation of H358 and H520 cells. Mechanistically, Notch intracellular domain (NICD) protein abundance in H358 cells was regulated by Rnd3-mediated NICD proteasome degradation. Rnd3 regulated H358 and H520 cell proliferation through a Notch1/NICD/Hes1 signaling axis independent of Rho Kinase. PMID:25372032

  12. Chemotherapy and Radiation Therapy With or Without Metformin Hydrochloride in Treating Patients With Stage III Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2016-06-17

    Adenosquamous Lung Carcinoma; Bronchioloalveolar Carcinoma; Large Cell Lung Carcinoma; Lung Adenocarcinoma; Non-Small Cell Lung Carcinoma; Recurrent Non-Small Cell Lung Carcinoma; Squamous Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer

  13. Differential expression of hypoxia-inducible factor 1α in non-small cell lung cancer and small cell lung cancer

    PubMed Central

    Karetsi, Eleni; Ioannou, Maria G.; Kerenidi, Theodora; Minas, Markos; Molyvdas, Paschalis A.; Gourgoulianis, Konstantinos I.; Paraskeva, Efrosyni

    2012-01-01

    OBJECTIVES: The aim of this study was to compare the expression of hypoxia-inducible factor 1α and vascular endothelial growth factor in small cell lung cancer and subtypes of non-small cell lung cancer and examine their relationships with clinicopathologic factors, response to treatment and survival. METHODS: We examined samples obtained by bronchial endoscopic biopsy from 55 patients with inoperable lung cancer (16 with adenocarcinoma, 17 with squamous cell carcinoma, and 22 with small cell lung cancer). Hypoxia-inducible factor 1α and vascular endothelial growth factor were detected using immunohistochemistry. The diagnosis, treatment, and follow-up of patients were conducted according to the standard practice. RESULTS: A significant difference (p = 0.022) in hypoxia-inducible factor 1α expression was observed between non-small cell lung cancer (75.8% positive) and small cell lung cancer (45.5% positive). The frequency of hypoxia-inducible factor 1α nuclear expression was 88.2% in squamous cell carcinoma, 62.5% in adenocarcinoma, and 45.5% in small cell lung cancer. A significant correlation was observed between hypoxia-inducible factor 1α and vascular endothelial growth factor expression (Fisher's exact test, p = 0.001) when all types of lung cancer were examined, either collectively or separately. CONCLUSIONS: The expression of hypoxia-inducible factor-1α differs significantly between subtypes of lung cancer. These findings could help elucidate the biology of the different types of non-operable lung carcinomas and have implications for the design of new therapeutic approaches for lung cancer. PMID:23295589

  14. Lung cancer.

    PubMed

    Akhurst, Tim; MacManus, Michael; Hicks, Rodney J

    2015-04-01

    (18)F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) plays a key role in the evaluation of undiagnosed lung nodules, when primary lung cancer is strongly suspected, or when it has already been diagnosed by other techniques. Although technical factors may compromise characterization of small or highly mobile lesions, lesions without apparent FDG uptake can generally be safely observed, whereas FDG-avid lung nodules almost always need further evaluation. FDG-PET/CT is now the primary staging imaging modality for patients with lung cancer who are being considered for curative therapy with either surgery or definitive radiation therapy. PMID:25829084

  15. Targeted drugs in small-cell lung cancer

    PubMed Central

    Daffinà, Maria Grazia; Karachaliou, Niki; González-Cao, Maria; Lazzari, Chiara; Altavilla, Giuseppe; Rosell, Rafael

    2016-01-01

    In contrast to non-small-cell lung cancer (NSCLC), few advances have been made in systemic treatment of small-cell lung cancer (SCLC) in recent years. Most patients are diagnosed with extensive stage disease and are commonly treated with platinum-based chemotherapy which, although attaining high initial objective responses, has a limited impact on survival. Due to the dismal prognosis of SCLC, novel and more effective treatment strategies are urgently needed. A deeper characterization of the genomic landscape of SCLC has led to the development of rational and promising targeted agents. However, despite a large number of clinical trials, results have been disappointing and there are still no approved targeted drugs for SCLC. Recent comprehensive genomic studies suggest SCLC is a heterogeneous disease, characterized by genomic alterations targeting a broad variety of genes, including those involved in transcription regulation and chromatin modification which seem to be a hallmark of this specific lung cancer subtype. Current research efforts are focusing on further understanding of the cellular and molecular abnormalities underlying SCLC development, progression and resistance to chemotherapy. Unraveling the genomic complexity of SCLC could be the key to optimize existing treatments, including chemotherapy and radiotherapy, and for identifying those patients most likely to benefit from selected targeted therapeutic approaches. PMID:26958493

  16. Wnt/{beta}-catenin signaling regulates cancer stem cells in lung cancer A549 cells

    SciTech Connect

    Teng, Ying; Wang, Xiuwen; Wang, Yawei; Ma, Daoxin

    2010-02-12

    Wnt/{beta}-catenin signaling plays an important role not only in cancer, but also in cancer stem cells. In this study, we found that {beta}-catenin and OCT-4 was highly expressed in cisplatin (DDP) selected A549 cells. Stimulating A549 cells with lithium chloride (LiCl) resulted in accumulation of {beta}-catenin and up-regulation of a typical Wnt target gene cyclin D1. This stimulation also significantly enhanced proliferation, clone formation, migration and drug resistance abilities in A549 cells. Moreover, the up-regulation of OCT-4, a stem cell marker, was observed through real-time PCR and Western blotting. In a reverse approach, we inhibited Wnt signaling by knocking down the expression of {beta}-catenin using RNA interference technology. This inhibition resulted in down-regulation of the Wnt target gene cyclin D1 as well as the proliferation, clone formation, migration and drug resistance abilities. Meanwhile, the expression of OCT-4 was reduced after the inhibition of Wnt/{beta}-catenin signaling. Taken together, our study provides strong evidence that canonical Wnt signaling plays an important role in lung cancer stem cell properties, and it also regulates OCT-4, a lung cancer stem cell marker.

  17. Mediastinal Staging in Non-Small Cell Lung Cancer.

    PubMed

    Gamliel, Ziv

    2016-07-01

    In the absence of distant metastases, lung cancer treatment is determined by the results of mediastinal lymph node staging. Occult mediastinal lymph node metastases can be missed by radiologic and needle-based staging methods. Aggressive staging of mediastinal lymph nodes improves staging accuracy. Improved accuracy of mediastinal lymph node staging results in more appropriate lung cancer treatment. Improved accuracy of mediastinal lymph node staging can improve stage-specific survival from lung cancer. PMID:27261911

  18. New therapeutic perspectives in CCDC6 deficient lung cancer cells.

    PubMed

    Morra, Francesco; Luise, Chiara; Visconti, Roberta; Staibano, Stefania; Merolla, Francesco; Ilardi, Gennaro; Guggino, Gianluca; Paladino, Simona; Sarnataro, Daniela; Franco, Renato; Monaco, Roberto; Zitomarino, Federica; Pacelli, Roberto; Monaco, Guglielmo; Rocco, Gaetano; Cerrato, Aniello; Linardopoulos, Spiros; Muller, Mark T; Celetti, Angela

    2015-05-01

    Non-small cell lung cancer (NSCLC) is the main cause of cancer-related death worldwide and new therapeutic strategies are urgently needed. In this study, we have characterized a panel of NSC lung cancer cell lines for the expression of coiled-coil-domain containing 6 (CCDC6), a tumor suppressor gene involved in apoptosis and DNA damage response. We show that low CCDC6 protein levels are associated with a weak response to DNA damage and a low number of Rad51 positive foci. Moreover, CCDC6 deficient lung cancer cells show defects in DNA repair via homologous recombination. In accordance with its role in the DNA damage response, CCDC6 attenuation confers resistance to cisplatinum, the current treatment of choice for NSCLC, but sensitizes the cells to olaparib, a small molecule inhibitor of the repair enzymes PARP1/2. Remarkably, the combination of the two drugs is more effective than each agent individually, as demonstrated by a combination index <1. Finally, CCDC6 is expressed at low levels in about 30% of the NSCL tumors we analyzed by TMA immunostaining. The weak CCDC6 protein staining is significatively correlated with the presence of lymph node metastasis (p ≤ 0.02) and negatively correlated to the disease free survival (p ≤ 0.01) and the overall survival (p ≤ 0.05). Collectively, the data indicate that CCDC6 levels provide valuable insight for OS. CCDC6 could represent a predictive biomarker of resistance to conventional single mode therapy and yield insight on tumor sensitivity to PARP inhibitors in NSCLC. PMID:25302833

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

    SciTech Connect

    Maneckjee, R.; Minna, J.D. Uniformed Services Univ. of the Health Sciences, Bethesda, MD )

    1990-05-01

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

  20. 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

  1. Bromodomain and hedgehog pathway targets in small cell lung cancer.

    PubMed

    Kaur, Gurmeet; Reinhart, Russell A; Monks, Anne; Evans, David; Morris, Joel; Polley, Eric; Teicher, Beverly A

    2016-02-28

    Small cell lung cancer (SCLC) is an extremely aggressive cancer that frequently recurs. Twenty-three human SCLC lines were selected representing varied Myc status. Gene expression of lung cancer, stem-like, hedgehog pathway, and notch pathway genes were determined by RT(2)-PCR array and Exon 1.0 ST array. Etoposide and topotecan concentration response was examined. The IC50's for etoposide and topotecan ranged over nearly 3 logs upon 96 hrs exposure to the drugs. Myc status, TOP2A, TOP2B and TOP1 mRNA expression or topoisomerase 1 and topoisomerase 2 protein did not account for the range in the sensitivity to the drugs. γ-secretase inhibitors, RO429097 and PF-03084014, had little activity in the SCLC lines over ranges covering the clinical Cmax concentrations. MYC amplified lines tended to be more sensitive to the bromodomain inhibitor JQ1. The Smo antagonists, erismodegib and vismodegib and the Gli antagonists, HPI1 and SEN-450 had a trend toward greater sensitivity of the MYC amplified line. Recurrent SCLC is among the most recalcitrant cancers and drug development efforts in this cancer are a high priority. PMID:26683772

  2. PET/CT in the Staging of the Non-Small-Cell Lung Cancer

    PubMed Central

    Chao, Fangfang; Zhang, Hong

    2012-01-01

    Lung cancer is a common disease and the leading cause of cancer-related death in many countries. Precise staging of patients with non-small-cell lung cancer plays an important role in determining treatment strategy and prognosis. Positron emission tomography/computed tomography (PET/CT), combining anatomic information of CT and metabolic information of PET, is emerging as a potential diagnosis and staging test in patients with non-small-cell lung cancer (NSCLC). The purpose of this paper is to discuss the value of integrated PET/CT in the staging of the non-small-cell lung cancer and its health economics. PMID:22577296

  3. Myeloid suppressor cells and immune modulation in lung cancer

    PubMed Central

    Srivastava, Minu K.; Andersson, Åsa; Zhu, Li; Harris-White, Marni; Lee, Jay M.; Dubinett, Steven; Sharma, Sherven

    2012-01-01

    Many tumors, including lung cancers, promote immune tolerance to escape host immune surveillance and facilitate tumor growth. Tumors utilize numerous pathways to inhibit immune responses, including the elaboration of immune-suppressive mediators such as PGE2, TGF-β, IL-10, VEGF, GM-CSF, IL-6, S100A8/A9 and SCF, which recruit and/or activate myeloid-derived suppressor cells (MDSCs). MDSCs, a subset of heterogeneous bone marrow-derived hematopoietic cells, are found in the peripheral blood of cancer patients and positively correlate to malignancy. Solid tumors contain MDSCs that maintain an immune-suppressive network in the tumor microenvironment. This review will focus on the interaction of tumors with MDSCs that lead to dysregulation of antigen presentation and T-cell activities in murine tumor models. Specific genetic signatures in lung cancer modulate the activities of MDSCs and impact tumor progression. Targeting MDSCs may have a long-term antitumor benefit and is at the forefront of anticancer therapeutic strategies. PMID:22401635

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

    PubMed Central

    Zhao, Xiaoting; Guo, Yinan; Yue, Wentao; Zhang, Lina; Gu, Meng; Wang, Yue

    2014-01-01

    Background Multidrug resistance protein 4 (MRP4), also known as ATP-cassette binding protein 4 (ABCC4), is a member of the MRP/ABCC subfamily of ATP-binding cassette transporters, which are capable of pumping a wide variety of drugs out of the cell. However, little is known about the function of ABCC4 in the proliferation of lung cancer cells. Methods ABCC4 mRNA and protein levels in lung cancer cell lines were measured by real-time polymerase chain reaction and Western blot, respectively. A lentivirus-mediated RNA interference technique was used to inhibit ABCC4 mRNA expression in A549 and 801D cells. The function of ABCC4 in cell growth was investigated by MTS and colony formation assays. The role of ABCC4 in cell cycle progression was evaluated by flow cytometry and Western blot analysis. ABCC4 mRNA levels in 30 pairs of tumors and corresponding matched adjacent normal tissues from non-small cell lung cancer patients were detected by real-time polymerase chain reaction. Results ABCC4 was highly expressed in lung cancer cell lines. ABCC4 expression was markedly downregulated in A549 and 801D cells using the RNA interference technique. Suppression of ABCC4 expression inhibited cell growth. The percentage of cells in G1 phase was increased when ABCC4 expression was suppressed. Phosphorylation of retinoblastoma protein was weakened, originating in the downregulation of ABCC4. ABCC4 mRNA was highly expressed in lung cancer tissue and lung cancer cell lines. Conclusion ABCC4 may play an important role in the control of A549 and 801D cell growth. ABCC4 is a potential target for lung cancer therapy. PMID:24591841

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

    SciTech Connect

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

    2014-12-12

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

  6. Veliparib, Cisplatin, and Gemcitabine Hydrochloride in Treating Patients With Advanced Biliary, Pancreatic, Urothelial, or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-07-01

    Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Stage III Bladder Cancer; Stage III Pancreatic Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Bladder Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Pancreatic Cancer; Transitional Cell Carcinoma of the Bladder; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  7. S100A4 is frequently overexpressed in lung cancer cells and promotes cell growth and cell motility

    SciTech Connect

    Chen, Na; Sato, Daisuke; Saiki, Yuriko; Sunamura, Makoto; Fukushige, Shinichi; Horii, Akira

    2014-05-09

    Highlights: • We observed frequent overexpression of S100A4 in lung cancer cell lines. • Knockdown of S100A4 suppressed proliferation in lung cancer cells. • Forced expression of S100A4 accelerated cell motility in lung cancer cells. • PRDM2 was found to be one of the downstream suppressed genes of S100A4. - Abstract: S100A4, a small calcium-binding protein belonging to the S100 protein family, is commonly overexpressed in a variety of tumor types and is widely accepted to associate with metastasis by regulating the motility and invasiveness of cancer cells. However, its biological role in lung carcinogenesis is largely unknown. In this study, we found that S100A4 was frequently overexpressed in lung cancer cells, irrespective of histological subtype. Then we performed knockdown and forced expression of S100A4 in lung cancer cell lines and found that specific knockdown of S100A4 effectively suppressed cell proliferation only in lung cancer cells with S100A4-overexpression; forced expression of S100A4 accelerated cell motility only in S100A4 low-expressing lung cancer cells. PRDM2 and VASH1, identified as novel upregulated genes by microarray after specific knockdown of S100A4 in pancreatic cancer, were also analyzed, and we found that PRDM2 was significantly upregulated after S100A4-knockdown in one of two analyzed S100A4-overexpressing lung cancer cells. Our present results suggest that S100A4 plays an important role in lung carcinogenesis by means of cell proliferation and motility by a pathway similar to that in pancreatic cancer.

  8. Resected small cell lung cancer-time for more?

    PubMed

    Marr, Alissa S; Zhang, Chi; Ganti, Apar Kishor

    2016-08-01

    Small cell lung cancer (SCLC) often presents with either regional or systemic metastases, but approximately 4% of patients present with a solitary pulmonary nodule. Surgical resection can be an option for these patients and is endorsed by the National Comprehensive Cancer Network (NCCN) guidelines. There are no prospective randomized clinical trials evaluating the role of adjuvant systemic therapy in these resected SCLC patients. A recent National Cancer Database analysis found that the receipt of adjuvant chemotherapy alone [hazard ratio (HR), 0.78; 95% CI, 0.63-0.95] or with brain radiation (HR, 0.52; 95% CI, 0.36-0.75) was associated with significantly improved survival as compared to surgery alone. As it is unlikely that a randomized prospective clinical trial addressing this question will be completed, these data should assist with decision making in these patients. PMID:27620199

  9. PET-Adjusted Intensity Modulated Radiation Therapy and Combination Chemotherapy in Treating Patients With Stage II-IV Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2016-01-10

    Metastatic Malignant Neoplasm in the Brain; Recurrent Non-Small Cell Lung Carcinoma; Stage IIA Non-Small Cell Lung Carcinoma; Stage IIB Non-Small Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer

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

    SciTech Connect

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

    2009-10-15

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

  11. Computational discovery of pathway-level genetic vulnerabilities in non-small-cell lung cancer | Office of Cancer Genomics

    Cancer.gov

    Novel approaches are needed for discovery of targeted therapies for non-small-cell lung cancer (NSCLC) that are specific to certain patients. Whole genome RNAi screening of lung cancer cell lines provides an ideal source for determining candidate drug targets. Unsupervised learning algorithms uncovered patterns of differential vulnerability across lung cancer cell lines to loss of functionally related genes. Such genetic vulnerabilities represent candidate targets for therapy and are found to be involved in splicing, translation and protein folding.

  12. Neoadjuvant Therapy in Non-Small Cell Lung Cancer.

    PubMed

    Zheng, Yifan; Jaklitsch, Michael T; Bueno, Raphael

    2016-07-01

    Locally advanced (stage IIIA) non-small cell lung cancer (NSCLC) is confined to the chest, but requires more than surgery to maximize cure. Therapy given preoperatively is termed neoadjuvant, whereas postoperative therapy is termed adjuvant. Trimodality therapy (chemotherapy, radiation, and surgery) has become the standard treatment regimen for resectable, locally advanced NSCLC. During the past 2 decades, several prospective, randomized, and nonrandomized studies have explored various regimens for preoperative treatment of NSCLC. The evaluation of potential candidates with NSCLC for neoadjuvant therapy as well as the currently available therapeutic regimens are reviewed. PMID:27261916

  13. 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

  14. Lung cancer.

    PubMed

    Frödin, J E

    1996-01-01

    This synthesis of the literature on radiotherapy for lung cancer is based on 80 scientific articles, including 2 meta-analyses, 29 randomized studies, 19 prospective studies, and 21 retrospective studies. These studies involve 28172 patients. Basic treatment for limited-stage small cell lung cancer (SCLC), is chemotherapy. Addition of radiotherapy to the primary tumor and mediastinum reduces local recurrence, prolongs long-term survival, and is often indicated. Current, and future, studies can be expected to show successive improvements in results for SCLC by optimizing the combination of radiotherapy and chemotherapy. Should these treatments be given simultaneously or sequentially, and in which order? Which fractionation is best? Probably, no change in resource requirements for radiotherapy will be necessary, with the possible exception of changes in fractionation. Surgery constitutes primary treatment for nonsmall cell lung cancer (NSCLC) stages I and II. Radiotherapy may provide an alternative for patients who are inoperable for medical reasons. The value of radiotherapy following radical surgery for NSCLC remains to be shown. It is not indicated based on current knowledge. For NSCLC stage III, radiotherapy shrinks tumors and prolongs survival at 2 and 3 years. Whether it influences long-term survival after 5 years has not been shown. Considering the side effects of treatment, one must question whether limited improvements in survival motivate routine radiotherapy in these patients. Earlier attempts to add chemotherapy to radiotherapy to improve treatment results of NSCLC have not yielded convincing results. Several studies are currently on-going. Prophylactic cranial irradiation (PCI) greatly reduces the risk for brain metastases from SCLC. However, it has little influence on survival. Many treatment centers give PCI to SCLC patients who have achieved complete remission. This practice may be questioned since PCI is associated with serious complications. PCI is

  15. 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

  16. An IMRT/VMAT Technique for Nonsmall Cell Lung Cancer

    PubMed Central

    Zhao, Nan; Yang, Ruijie; Wang, Junjie; Zhang, Xile; Li, Jinna

    2015-01-01

    The study is to investigate a Hybrid IMRT/VMAT technique which combines intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) for the treatment of nonsmall cell lung cancer (NSCLC). Two partial arcs VMAT, 5-field IMRT, and hybrid plans were created for 15 patients with NSCLC. The hybrid plans were combination of 2 partial arcs VMAT and 5-field IMRT. The dose distribution of planning target volume (PTV) and organs at risk (OARs) for hybrid technique was compared with IMRT and VMAT. The monitor units (MUs) and treatment delivery time were also evaluated. Hybrid technique significantly improved the target conformity and homogeneity compared with IMRT and VMAT. The mean delivery time of IMRT, VMAT, and hybrid plans was 280 s, 114 s, and 327 s, respectively. The mean MUs needed for IMRT, VMAT, and hybrid plans were 933, 512, and 737, respectively. Hybrid technique reduced V5, V10, V30, and MLD of normal lung compared with VMAT and spared the OARs better with fewer MUs with the cost of a little higher V5, V10, and mean lung dose (MLD) of normal lung compared with IMRT. Hybrid IMRT/VMAT can be a viable radiotherapy technique with better plan quality. PMID:26539515

  17. An IMRT/VMAT Technique for Nonsmall Cell Lung Cancer.

    PubMed

    Zhao, Nan; Yang, Ruijie; Wang, Junjie; Zhang, Xile; Li, Jinna

    2015-01-01

    The study is to investigate a Hybrid IMRT/VMAT technique which combines intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) for the treatment of nonsmall cell lung cancer (NSCLC). Two partial arcs VMAT, 5-field IMRT, and hybrid plans were created for 15 patients with NSCLC. The hybrid plans were combination of 2 partial arcs VMAT and 5-field IMRT. The dose distribution of planning target volume (PTV) and organs at risk (OARs) for hybrid technique was compared with IMRT and VMAT. The monitor units (MUs) and treatment delivery time were also evaluated. Hybrid technique significantly improved the target conformity and homogeneity compared with IMRT and VMAT. The mean delivery time of IMRT, VMAT, and hybrid plans was 280 s, 114 s, and 327 s, respectively. The mean MUs needed for IMRT, VMAT, and hybrid plans were 933, 512, and 737, respectively. Hybrid technique reduced V5, V10, V30, and MLD of normal lung compared with VMAT and spared the OARs better with fewer MUs with the cost of a little higher V5, V10, and mean lung dose (MLD) of normal lung compared with IMRT. Hybrid IMRT/VMAT can be a viable radiotherapy technique with better plan quality. PMID:26539515

  18. Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells

    SciTech Connect

    Person, Rachel J.; Tokar, Erik J.; Xu, Yuanyuan; Orihuela, Ruben; Ngalame, Ntube N. Olive; Waalkes, Michael P.

    2013-12-01

    Cadmium is a known human lung carcinogen. Here, we attempt to develop an in vitro model of cadmium-induced human lung carcinogenesis by chronically exposing the peripheral lung epithelia cell line, HPL-1D, to a low level of cadmium. Cells were chronically exposed to 5 μM cadmium, a noncytotoxic level, and monitored for acquired cancer characteristics. By 20 weeks of continuous cadmium exposure, these chronic cadmium treated lung (CCT-LC) cells showed marked increases in secreted MMP-2 activity (3.5-fold), invasion (3.4-fold), and colony formation in soft agar (2-fold). CCT-LC cells were hyperproliferative, grew well in serum-free media, and overexpressed cyclin D1. The CCT-LC cells also showed decreased expression of the tumor suppressor genes p16 and SLC38A3 at the protein levels. Also consistent with an acquired cancer cell phenotype, CCT-LC cells showed increased expression of the oncoproteins K-RAS and N-RAS as well as the epithelial-to-mesenchymal transition marker protein Vimentin. Metallothionein (MT) expression is increased by cadmium, and is typically overexpressed in human lung cancers. The major MT isoforms, MT-1A and MT-2A were elevated in CCT-LC cells. Oxidant adaptive response genes HO-1 and HIF-1A were also activated in CCT-LC cells. Expression of the metal transport genes ZNT-1, ZNT-5, and ZIP-8 increased in CCT-LC cells culminating in reduced cadmium accumulation, suggesting adaptation to the metal. Overall, these data suggest that exposure of human lung epithelial cells to cadmium causes acquisition of cancer cell characteristics. Furthermore, transformation occurs despite the cell's ability to adapt to chronic cadmium exposure. - Highlights: • Chronic cadmium exposure induces cancer cell characteristics in human lung cells. • This provides an in vitro model of cadmium-induced human lung cell transformation. • This occurred with general and lung specific changes typical for cancer cells. • These findings add insight to the relationship

  19. Expression of a phosphorylated form of ATF4 in lung and non-small cell lung cancer tissues.

    PubMed

    Fan, Chui-Feng; Miao, Yuan; Lin, Xu-Yong; Zhang, Di; Wang, En-Hua

    2014-01-01

    ATF4 is a member of the cAMP-responsive element-binding protein family of basic zipper-containing proteins, a family of transcription factors phosphorylated at serines residues by protein kinase A. The family has been proved to be able to stimulate the transcription of the genes containing CRE elements. Elevated ATF4 expression was detected in some tumors including breast carcinoma compared to their corresponding nontumor tissues. p-ATF4 (ser 245), a phosphorylated form of ATF4 protein at serine 245 site, was believed to be an active type of this protein. However, its expression and clinical significance in malignant tumors including non-small cell lung cancer were not reported up to date. In the current study, we investigate the expression of p-ATF4 (ser 245) in non-small cell lung cancer using tissue microarray and immunohistochemistry. p-ATF4 (ser 245) immunostaining was detected in nucleus and cytoplasm in cancer cells and normal lung epithelial cells. Compared to bronchial epithelium and submucosal glands (total positive rate, 14.6% (12/82)), there was increased expression of p-ATF4 (ser 245) in non-small cell lung cancer cells (total positive rate, 42.7% (35/82)) (p < 0.05). In addition, increased expression of p-ATF4 (ser 245) was associated with lymph node metastasis and advanced TNM stages (III and IV) in non-small cell lung cancer (p < 0.05). Immunofluorescent staining confirmed nuclear and cytoplasmic expression of p-ATF4 (ser 245) in lung and cancer tissues, and also in non-small cell lung cancer cell lines including NCI-H157 and LTE cells. These results indicate that increased expression of p-ATF4 (ser 245) may contribute to cancer development of non-small cell lung cancer and may be a potential cancer marker. PMID:23975372

  20. Gambogenic Acid Kills Lung Cancer Cells through Aberrant Autophagy

    PubMed Central

    Mei, Wang; Dong, Chen; Hui, Cheng; Bin, Li; Fenggen, Yan; Jingjing, Su; Cheng, Peng; Meiling, Sun; Yawen, Hu; Xiaoshan, Wang; Guanghui, Wang; Zhiwu, Chen; Qinglin, Li

    2014-01-01

    Lung cancer is one of the most common types of cancer and causes 1.38 million deaths annually, as of 2008 worldwide. Identifying natural anti-lung cancer agents has become very important. Gambogenic acid (GNA) is one of the active compounds of Gamboge, a traditional medicine that was used as a drastic purgative, emetic, or vermifuge for treating tapeworm. Recently, increasing evidence has indicated that GNA exerts promising anti-tumor effects; however, the underlying mechanism remains unclear. In the present paper, we found that GNA could induce the formation of vacuoles, which was linked with autophagy in A549 and HeLa cells. Further studies revealed that GNA triggers the initiation of autophagy based on the results of MDC staining, AO staining, accumulation of LC3 II, activation of Beclin 1 and phosphorylation of P70S6K. However, degradation of p62 was disrupted and free GFP could not be released in GNA treated cells, which indicated a block in the autophagy flux. Further studies demonstrated that GNA blocks the fusion between autophagosomes and lysosomes by inhibiting acidification in lysosomes. This dysfunctional autophagy plays a pro-death role in GNA-treated cells by activating p53, Bax and cleaved caspase-3 while decreasing Bcl-2. Beclin 1 knockdown greatly decreased GNA-induced cell death and the effects on p53, Bax, cleaved caspase-3 and Bcl-2. Similar results were obtained using a xenograft model. Our findings show, for the first time, that GNA can cause aberrant autophagy to induce cell death and may suggest the potential application of GNA as a tool or viable drug in anticancer therapies. PMID:24427275

  1. A role for cancer stem cells in drug resistance and metastasis in non-small-cell lung cancer.

    PubMed

    Perona, Rosario; López-Ayllón, Blanca D; de Castro Carpeño, Javier; Belda-Iniesta, Cristóbal

    2011-05-01

    The cancer stem cell (CSC) theory is currently a very important field in cancer research. This theory states that tumours are organised in a hierarchical manner with a subpopulation of limited number called CSCs with the ability to self-renew and undergo asymmetrical divisions, giving rise to a differentiated progeny that represents most of the tumour populations. CSCs are metastatic and chemoresistant, two features that very likely contribute to the poor response of locally advanced lung cancer. CSCs have been identified in non-small-cell lung cancer cell lines as well as those from patient primary samples. A correlation has been found in terms of chemoresistance and bad prognosis in patient-derived samples enriched with CSCs, indicating that these cells are an important target for future therapy combinations. Therefore, understanding the biology and exploring cell markers and signalling pathways specific for CSCs of lung cancer may help in achieving progress in the treatment of the disease. PMID:21596655

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

    ClinicalTrials.gov

    2015-09-28

    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

  3. 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. PMID:27101251

  4. Fas signal promotes lung cancer growth by recruiting myeloid-derived suppressor cells via cancer cell-derived PGE2.

    PubMed

    Zhang, Yongliang; Liu, Qiuyan; Zhang, Minggang; Yu, Yizhi; Liu, Xia; Cao, Xuetao

    2009-03-15

    Fas/FasL system has been extensively investigated with respect to its capacity to induce cellular apoptosis. However, accumulated evidences show that Fas signaling also exhibits nonapoptotic functions, such as induction of cell proliferation and differentiation. Lung cancer is one of cancer's refractory to the immunotherapy, however, the underlying mechanisms remain to be fully understood. In this study, we show that Fas overexpression does not affect in vitro growth of 3LL cells, but promotes lung cancer growth in vivo. However, such tumor-promoting effect is not observed in FasL-deficient (gld) mice, and also not observed in the immune competent mice once inoculation with domain-negative Fas-overexpressing 3LL cells, suggesting the critical role of Fas signal in the promotion of lung cancer growth in vivo. More accumulation of myeloid-derived suppressor cells (MDSC) and Foxp3(+) regulatory T cells is found in tumors formed by inoculation with Fas-overexpressing 3LL cells, but not domain-negative Fas-overexpressing 3LL cells. Accordingly, Fas-ligated 3LL lung cancer cells can chemoattract more MDSC but not regulatory T cells in vitro. Furthermore, Fas ligation induces 3LL lung cancer cells to produce proinflammatory factor PGE(2) by activating p38 pathway, and in turn, 3LL cells-derived PGE(2) contribute to the Fas ligation-induced MDSC chemoattraction. Furthermore, in vivo administration of cyclooxygenase-2 inhibitor can significantly reduce MDSC accumulation in the Fas-overexpressing tumor. Therefore, our results demonstrate that Fas signal can promote lung cancer growth by recruiting MDSC via cancer cell-derived PGE(2), thus providing new mechanistic explanation for the role of inflammation in cancer progression and immune escape. PMID:19265159

  5. Anthropometric measurements in non-small-cell lung cancer.

    PubMed

    Ferrigno, D; Buccheri, G

    2001-10-01

    There is evidence that malnutrition is an important cause of morbidity and mortality in lung cancer patients and may have an impact on the clinical course of disease. The simplest way to assess nutritional status at the patient's bedside remains recourse to anthropometric measurements. This study was carried out in order to assess the clinical and prognostic significance of triceps skinfold thickness (TST), arm circumference (AC), and wrist circumference (WC) in lung cancer. The patient population was a consecutive series of 388 patients seen for a newly diagnosed primary non-small-cell lung cancer during the last 4 years. A set of 22 anthropometric, clinical, physical, laboratory, radiological, and pathological variables was prospectively recorded for all patients. Patients were carefully followed up, and their subsequent clinical course was recorded. The median values of TST, WC and AC were 8 mm (range 2-25 mm), 18 cm (range 10-27 cm), and 25 cm (range 15-35 cm), respectively. In 107 patients (27.6% of the total) TST values were below the reference value, and 37 of these patients also had a pathologically low small circumference. In all, AC was below the normality range in 60 of the 388 subjects (15.5%). Among the three variables, the strongest relationships were those between AC and WC (r(s)=0.541), and between TST and AC (r(s)=0.521). Univariate analyses of survival showed that TST was strongly predictive of a better prognosis (P<0.001), while WC was unrelated to outcome (P=0.101). Patients with higher values of AC had significantly longer survival than patients with lower values (P<0.018). The multivariate model, in contrast, did not confirm the prognostic capability of any of the anthropometric measures. These data indicate that the anthropometric measures may be significant predictors of survival, although not independently of the other prognostic factors. PMID:11680832

  6. Identification and Targeting of Long-Term Tumor-Propagating Cells in Small Cell Lung Cancer.

    PubMed

    Jahchan, Nadine S; Lim, Jing Shan; Bola, Becky; Morris, Karen; Seitz, Garrett; Tran, Kim Q; Xu, Lei; Trapani, Francesca; Morrow, Christopher J; Cristea, Sandra; Coles, Garry L; Yang, Dian; Vaka, Dedeepya; Kareta, Michael S; George, Julie; Mazur, Pawel K; Nguyen, Thuyen; Anderson, Wade C; Dylla, Scott J; Blackhall, Fiona; Peifer, Martin; Dive, Caroline; Sage, Julien

    2016-07-19

    Small cell lung cancer (SCLC) is a neuroendocrine lung cancer characterized by fast growth, early dissemination, and rapid resistance to chemotherapy. We identified a population of long-term tumor-propagating cells (TPCs) in a mouse model of SCLC. This population, marked by high levels of EpCAM and CD24, is also prevalent in human primary SCLC tumors. Murine SCLC TPCs are numerous and highly proliferative but not intrinsically chemoresistant, indicating that not all clinical features of SCLC are linked to TPCs. SCLC TPCs possess a distinct transcriptional profile compared to non-TPCs, including elevated MYC activity. Genetic and pharmacological inhibition of MYC in SCLC cells to non-TPC levels inhibits long-term propagation but not short-term growth. These studies identify a highly tumorigenic population of SCLC cells in mouse models, cell lines, and patient tumors and a means to target them in this most fatal form of lung cancer. PMID:27373157

  7. PDGFR-{beta} expression in small cell lung cancer patients

    SciTech Connect

    Shinohara, Eric T.; Gonzalez, Adriana; Massion, Pierre P.; Olson, Sandra J.; Albert, Jeffrey M.; Shyr, Yu; Carbone, David P.; Johnson, David H.; Hallahan, Dennis E.; Lu Bo . E-mail: bo.lu@vanderbilt.edu

    2007-02-01

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

  8. Targeting Angiogenesis in Squamous Non-small Cell Lung Cancer

    PubMed Central

    Merla, Amartej; Perez-Soler, Roman

    2014-01-01

    Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and can be further classified as nonsquamous carcinoma (including adenocarcinoma, which accounts for 50% of NSCLCs) and squamous NSCLC, which makes up 30% of NSCLC cases. The emergence of inhibitors of epidermal growth factor receptors, anaplastic lymphoma kinase, and vascular endothelial growth factors (VEGF) in the last decade has resulted in steady improvement in clinical outcome for patients with advanced lung adenocarcinoma. However, improvements in the survival of patients with squamous NSCLC have remained elusive, presenting an urgent need for understanding and investigating therapeutically relevant molecular targets specifically in squamous NSCLC. Although anti-VEGF therapy has been studied in squamous NSCLC, progress has been slow, in part due to issues related to pulmonary hemorrhage. In addition to these safety concerns, several phase III trials that initially included patients with squamous NSCLC failed to demonstrate improved overall survival (primary endpoint) with the addition of antiangiogenic therapy to chemotherapy compared with chemotherapy alone. Angiogenesis is an established hallmark of tumor progression and metastasis, and the role of VEGF signaling in angiogenesis is well established. However, some studies suggest that while inhibiting VEGF signaling may be beneficial, prolonged exposure to VEGF/VEGF receptor (VEGFR) inhibitors may allow tumor cells to utilize alternative angiogenic mechanisms and become resistant. As a result, agents that target multiple angiogenic pathways simultaneously are also under evaluation. This review focuses on current and investigational antiangiogenic targets in squamous NSCLC, including VEGF/VEGFRs, fibroblast growth factor receptors, platelet-derived growth factor receptors, and angiopoietin. Additionally, clinical trials investigating VEGF- and multi-targeted antiangiogenic therapies are discussed. PMID:24578213

  9. Erlotinib Hydrochloride With or Without Carboplatin and Paclitaxel in Treating Patients With Stage III-IV Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2016-06-29

    Adenosquamous Lung Carcinoma; Bronchioloalveolar Carcinoma; Lung Adenocarcinoma; Malignant Pericardial Effusion; Malignant Pleural Effusion; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer

  10. Proton Beam Therapy for Non-Small Cell Lung Cancer: Current Clinical Evidence and Future Directions

    PubMed Central

    Berman, Abigail T.; St. James, Sara; Rengan, Ramesh

    2015-01-01

    Lung cancer is the leading cancer cause of death in the United States. Radiotherapy is an essential component of the definitive treatment of early-stage and locally-advanced lung cancer, and the palliative treatment of metastatic lung cancer. Proton beam therapy (PBT), through its characteristic Bragg peak, has the potential to decrease the toxicity of radiotherapy, and, subsequently improve the therapeutic ratio. Herein, we provide a primer on the physics of proton beam therapy for lung cancer, present the existing data in early-stage and locally-advanced non-small cell lung cancer (NSCLC), as well as in special situations such as re-irradiation and post-operative radiation therapy. We then present the technical challenges, such as anatomic changes and motion management, and future directions for PBT in lung cancer, including pencil beam scanning. PMID:26147335

  11. Crizotinib for Advanced Non-Small Cell Lung Cancer

    Cancer.gov

    A summary of results from an international phase III clinical trial that compared crizotinib versus chemotherapy in previously treated patients with advanced lung cancer whose tumors have an EML4-ALK fusion gene.

  12. 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

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

    PubMed

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

    2015-05-01

    Xylitol is a widely used anti-caries agent that has anti-inflammatory effects. We have evaluated the potential of xylitol in cancer treatment. It's effects on cell proliferation and cytotoxicity were measured by MTT assay and LDH assay. Cell morphology and autophagy were examined by immunostaining and immunoblotting. Xylitol inhibited cell proliferation in a dose-dependent manner in these cancer cells: A549, Caki, NCI-H23, HCT-15, HL-60, K562, and SK MEL-2. The IC50 of xylitol in human gingival fibroblast cells was higher than in cancer cells, indicating that it is more specific for cancer cells. Moreover, xylitol induced autophagy in A549 cells that was inhibited by 3-methyladenine, an autophagy inhibitor. These results indicate that xylitol has potential in therapy against lung cancer by inhibiting cell proliferation and inducing autophagy of A549 cells. PMID:25650339

  14. Reversine Induced Multinucleated Cells, Cell Apoptosis and Autophagy in Human Non-Small Cell Lung Cancer Cells

    PubMed Central

    Lin, Ching-Yen; Chen, Yih-Yuan; Chen, Ping-Tzu; Tseng, Ya-Shih

    2016-01-01

    Reversine, an A3 adenosine receptor antagonist, has been shown to induce differentiated myogenic-lineage committed cells to become multipotent mesenchymal progenitor cells. We and others have reported that reversine has an effect on human tumor suppression. This study revealed anti-tumor effects of reversine on proliferation, apoptosis and autophagy induction in human non-small cell lung cancer cells. Treatment of these cells with reversine suppressed cell growth in a time- and dosage-dependent manner. Moreover, polyploidy occurred after reversine treatment. In addition, caspase-dependent apoptosis and activation of autophagy by reversine in a dosage-dependent manner were also observed. We demonstrated in this study that reversine contributes to growth inhibition, apoptosis and autophagy induction in human lung cancer cells. Therefore, reversine used as a potential therapeutic agent for human lung cancer is worthy of further investigation. PMID:27385117

  15. 6 Common Cancers - Lung Cancer

    MedlinePlus

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

  16. 6 Common Cancers - Lung Cancer

    MedlinePlus

    ... Bar 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 next ...

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

    ClinicalTrials.gov

    2012-03-16

    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. The regulation of cancer cell migration by lung cancer cell-derived exosomes through TGF-β and IL-10

    PubMed Central

    WANG, YUZHOU; YI, JUN; CHEN, XINGGUI; ZHANG, YING; XU, MENG; YANG, ZHIXIONG

    2016-01-01

    Tumorigenesis has been considered to be as a result of abnormal cell-cell communication. It has been proposed that exosomes act as communicators between tumors and their microenvironment and have been demonstrated to be involved in tumorigenesis and subsequent metastasis. However, the mechanisms underlying the role of exosomes in these processes remains elusive. The present study sought to determine the underlying mechanisms. Using two lung cancer cell lines, it was demonstrated that exosomes derived from metastatic small cell lung cancer cells (NCI-H1688) have greater effects on cancer cell migration, compared with exosomes derived from primary non-small cell lung cancer cells (NCI-H2228). Further characterization of the contents of the exosomes demonstrated that there were increased levels of TGF-β and IL-10 in exosomes from NCI-H1688 cells compared with exosomes derived from NCI-H2228 cells, in particular under hypoxia. Blockade of TGF-β and IL-10 with antibodies confirmed that these cytokines were essential for the regulation of cancer cell migration. Taken together, the results of the present study indicated that exosomes derived from cancer cells regulated the cellular migration of tumor cells through TGF-β and IL-10, which may provide a novel approach for developing therapeutic methods against cancer. PMID:26893774

  19. Immunotherapy for non-small cell lung cancer: current concepts and clinical trials.

    PubMed

    Mayor, Marissa; Yang, Neng; Sterman, Daniel; Jones, David R; Adusumilli, Prasad S

    2016-05-01

    Recent successes in immunotherapeutic strategies are being investigated to combat cancers that have less than ideal responses to standard of care treatment, such as non-small-cell lung cancer. In this paper, we summarize concepts and the current status of immunotherapy for non-small cell lung cancer, including salient features of the major categories of immunotherapy-monoclonal antibody therapy, immune checkpoint blockade, immunotoxins, anticancer vaccines, and adoptive cell therapy. PMID:26516195

  20. Inhibition of mTOR enhances radiosensitivity of lung cancer cells and protects normal lung cells against radiation.

    PubMed

    Zheng, Hang; Wang, Miao; Wu, Jing; Wang, Zhi-Ming; Nan, Hai-Jun; Sun, He

    2016-06-01

    Radiotherapy has been used for a long time as a standard therapy for cancer; however, there have been no recent research breakthroughs. Radioresistance and various side-effects lead to the unexpected outcomes of radiation therapy. Specific and accurate targeting as well as reduction of radioresistance have been major challenges for irradiation therapy. Recent studies have shown that rapamycin shows promise for inhibiting tumorigenesis by suppressing mammalian target of rapamycin (mTOR). We found that the combination of rapamycin with irradiation significantly diminished cell viability and colony formation, and increased cell apoptosis, as compared with irradiation alone in lung cancer cell line A549, suggesting that rapamycin can enhance the effectiveness of radiation therapy by sensitizing cancer cells to irradiation. Importantly, we observed that the adverse effects of irradiation on a healthy lung cell line (WI-38) were also offset. No enhanced protein expression of mTOR signaling was observed in WI-38 cells, which is normally elevated in lung cancer cells. Moreover, DNA damage was significantly less with the combination therapy than with irradiation therapy alone. Our data suggest that the incorporation of rapamycin during radiation therapy could be a potent way to improve the sensitivity and effectiveness of radiation therapy as well as to protect normal cells from being damaged by irradiation. PMID:26999331

  1. Comprehensive genomic profiles of small cell lung cancer.

    PubMed

    George, Julie; Lim, Jing Shan; Jang, Se Jin; Cun, Yupeng; Ozretić, Luka; Kong, Gu; Leenders, Frauke; Lu, Xin; Fernández-Cuesta, Lynnette; Bosco, Graziella; Müller, Christian; Dahmen, Ilona; Jahchan, Nadine S; Park, Kwon-Sik; Yang, Dian; Karnezis, Anthony N; Vaka, Dedeepya; Torres, Angela; Wang, Maia Segura; Korbel, Jan O; Menon, Roopika; Chun, Sung-Min; Kim, Deokhoon; Wilkerson, Matt; Hayes, Neil; Engelmann, David; Pützer, Brigitte; Bos, Marc; Michels, Sebastian; Vlasic, Ignacija; Seidel, Danila; Pinther, Berit; Schaub, Philipp; Becker, Christian; Altmüller, Janine; Yokota, Jun; Kohno, Takashi; Iwakawa, Reika; Tsuta, Koji; Noguchi, Masayuki; Muley, Thomas; Hoffmann, Hans; Schnabel, Philipp A; Petersen, Iver; Chen, Yuan; Soltermann, Alex; Tischler, Verena; Choi, Chang-min; Kim, Yong-Hee; Massion, Pierre P; Zou, Yong; Jovanovic, Dragana; Kontic, Milica; Wright, Gavin M; Russell, Prudence A; Solomon, Benjamin; Koch, Ina; Lindner, Michael; Muscarella, Lucia A; la Torre, Annamaria; Field, John K; Jakopovic, Marko; Knezevic, Jelena; Castaños-Vélez, Esmeralda; Roz, Luca; Pastorino, Ugo; Brustugun, Odd-Terje; Lund-Iversen, Marius; Thunnissen, Erik; Köhler, Jens; Schuler, Martin; Botling, Johan; Sandelin, Martin; Sanchez-Cespedes, Montserrat; Salvesen, Helga B; Achter, Viktor; Lang, Ulrich; Bogus, Magdalena; Schneider, Peter M; Zander, Thomas; Ansén, Sascha; Hallek, Michael; Wolf, Jürgen; Vingron, Martin; Yatabe, Yasushi; Travis, William D; Nürnberg, Peter; Reinhardt, Christian; Perner, Sven; Heukamp, Lukas; Büttner, Reinhard; Haas, Stefan A; Brambilla, Elisabeth; Peifer, Martin; Sage, Julien; Thomas, Roman K

    2015-08-01

    We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer. PMID:26168399

  2. Comprehensive genomic profiles of small cell lung cancer

    PubMed Central

    George, Julie; Lim, Jing Shan; Jang, Se Jin; Cun, Yupeng; Ozretić, Luka; Kong, Gu; Leenders, Frauke; Lu, Xin; Fernández-Cuesta, Lynnette; Bosco, Graziella; Müller, Christian; Dahmen, Ilona; Jahchan, Nadine S.; Park, Kwon-Sik; Yang, Dian; Karnezis, Anthony N.; Vaka, Dedeepya; Torres, Angela; Wang, Maia Segura; Korbel, Jan O.; Menon, Roopika; Chun, Sung-Min; Kim, Deokhoon; Wilkerson, Matt; Hayes, Neil; Engelmann, David; Pützer, Brigitte; Bos, Marc; Michels, Sebastian; Vlasic, Ignacija; Seidel, Danila; Pinther, Berit; Schaub, Philipp; Becker, Christian; Altmüller, Janine; Yokota, Jun; Kohno, Takashi; Iwakawa, Reika; Tsuta, Koji; Noguchi, Masayuki; Muley, Thomas; Hoffmann, Hans; Schnabel, Philipp A.; Petersen, Iver; Chen, Yuan; Soltermann, Alex; Tischler, Verena; Choi, Chang-min; Kim, Yong-Hee; Massion, Pierre P.; Zou, Yong; Jovanovic, Dragana; Kontic, Milica; Wright, Gavin M.; Russell, Prudence A.; Solomon, Benjamin; Koch, Ina; Lindner, Michael; Muscarella, Lucia A.; la Torre, Annamaria; Field, John K.; Jakopovic, Marko; Knezevic, Jelena; Castaños-Vélez, Esmeralda; Roz, Luca; Pastorino, Ugo; Brustugun, Odd-Terje; Lund-Iversen, Marius; Thunnissen, Erik; Köhler, Jens; Schuler, Martin; Botling, Johan; Sandelin, Martin; Sanchez-Cespedes, Montserrat; Salvesen, Helga B.; Achter, Viktor; Lang, Ulrich; Bogus, Magdalena; Schneider, Peter M.; Zander, Thomas; Ansén, Sascha; Hallek, Michael; Wolf, Jürgen; Vingron, Martin; Yatabe, Yasushi; Travis, William D.; Nürnberg, Peter; Reinhardt, Christian; Perner, Sven; Heukamp, Lukas; Büttner, Reinhard; Haas, Stefan A.; Brambilla, Elisabeth; Peifer, Martin; Sage, Julien; Thomas, Roman K.

    2016-01-01

    We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer. PMID:26168399

  3. Teroxirone inhibited growth of human non-small cell lung cancer cells by activating p53

    SciTech Connect

    Wang, Jing-Ping; Lin, Kai-Han; Liu, Chun-Yen; Yu, Ya-Chu; Wu, Pei-Tsun; Chiu, Chien-Chih; Su, Chun-Li; Chen, Kwun-Min; Fang, Kang

    2013-11-15

    In this work, we demonstrated that the growth of human non-small-cell-lung-cancer cells H460 and A549 cells can be inhibited by low concentrations of an epoxide derivative, teroxirone, in both in vitro and in vivo models. The cytotoxicity was mediated by apoptotic cell death through DNA damage. The onset of ultimate apoptosis is dependent on the status of p53. Teroxirone caused transient elevation of p53 that activates downstream p21 and procaspase-3 cleavage. The presence of caspase-3 inhibitor reverted apoptotic phenotype. Furthermore, we showed the cytotoxicity of teroxirone in H1299 cells with stable ectopic expression of p53, but not those of mutant p53. A siRNA-mediated knockdown of p53 expression attenuated drug sensitivity. The in vivo experiments demonstrated that teroxirone suppressed growth of xenograft tumors in nude mice. Being a potential therapeutic agent by restraining cell growth through apoptotic death at low concentrations, teroxirone provides a feasible perspective in reversing tumorigenic phenotype of human lung cancer cells. - Highlights: • Teroxirone repressed tumor cell growth in nude mice of human lung cancer cells. • The apoptotic cell death reverted by caspase-3 inhibitor is related to p53 status. • Teroxirone provides a good candidate for lung cancer treatment.

  4. Nitric oxide induces cancer stem cell-like phenotypes in human lung cancer cells.

    PubMed

    Yongsanguanchai, Nuttida; Pongrakhananon, Varisa; Mutirangura, Apiwat; Rojanasakul, Yon; Chanvorachote, Pithi

    2015-01-15

    Even though tremendous advances have been made in the treatment of cancers during the past decades, the success rate among patients with cancer is still dismal, largely because of problems associated with chemo/radioresistance and relapse. Emerging evidence has indicated that cancer stem cells (CSCs) are behind the resistance and recurrence problems, but our understanding of their regulation is limited. Rapid reversible changes of CSC-like cells within tumors may result from the effect of biological mediators found in the tumor microenvironment. Here we show how nitric oxide (NO), a key cellular modulator whose level is elevated in many tumors, affects CSC-like phenotypes of human non-small cell lung carcinoma H292 and H460 cells. Exposure of NO gradually altered the cell morphology toward mesenchymal stem-like shape. NO exposure promoted CSC-like phenotype, indicated by increased expression of known CSC markers, CD133 and ALDH1A1, in the exposed cells. These effects of NO on stemness were reversible after cessation of the NO treatment for 7 days. Furthermore, such effect was reproducible using another NO donor, S-nitroso-N-acetylpenicillamine. Importantly, inhibition of NO by the known NO scavenger 2-(4-carboxy-phenyl)-4,4,5,5 tetramethylimidazoline-1-oxy-3-oxide strongly inhibited CSC-like aggressive cellular behavior and marker expression. Last, we unveiled the underlying mechanism of NO action through the activation of caveolin-1 (Cav-1), which is upregulated by NO and is responsible for the aggressive behavior of the cells, including anoikis resistance, anchorage-independent cell growth, and increased cell migration and invasion. These findings indicate a novel role of NO in CSC regulation and its importance in aggressive cancer behaviors through Cav-1 upregulation. PMID:25411331

  5. Integrated molecular portrait of non-small cell lung cancers

    PubMed Central

    2013-01-01

    Background Non-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and candidate-gene full sequencing data to characterize the molecular distinctions between AC and SCC. Methods Comparative genomic hybridization followed by mutational analysis, gene expression and miRNA microarray profiling were performed on 123 paired tumor and non-tumor tissue samples from patients with NSCLC. Results At DNA, mRNA and miRNA levels we could identify molecular markers that discriminated significantly between the various histopathological entities of NSCLC. We identified 34 genomic clusters using aCGH data; several genes exhibited a different profile of aberrations between AC and SCC, including PIK3CA, SOX2, THPO, TP63, PDGFB genes. Gene expression profiling analysis identified SPP1, CTHRC1and GREM1 as potential biomarkers for early diagnosis of the cancer, and SPINK1 and BMP7 to distinguish between AC and SCC in small biopsies or in blood samples. Using integrated genomics approach we found in recurrently altered regions a list of three potential driver genes, MRPS22, NDRG1 and RNF7, which were consistently over-expressed in amplified regions, had wide-spread correlation with an average of ~800 genes throughout the genome and highly associated with histological types. Using a network enrichment analysis, the targets of these potential drivers were seen to be involved in DNA replication, cell cycle, mismatch repair, p53 signalling pathway and other lung cancer related signalling pathways, and many immunological pathways. Furthermore, we also identified one potential driver miRNA hsa-miR-944. Conclusions Integrated molecular characterization of AC and SCC helped identify clinically relevant markers

  6. Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells

    PubMed Central

    Person, Rachel J.; Tokar, Erik J.; Xu, Yuanyuan; Orihuela, Ruben; Olive Ngalame, Ntube N.; Waalkes, Michael P.

    2013-01-01

    Cadmium is a known human lung carcinogen. Here, we attempt to develop an in vitro model of cadmium-induced human lung carcinogenesis by chronically exposing the peripheral lung epithelia cell line, HPL-1D, to a low level of cadmium. Cells were chronically exposed to 5 μM cadmium, a noncytotoxic level, and monitored for acquired cancer characteristics. By 20 weeks of continuous cadmium exposure, these chronic cadmium treated lung (CCT-LC) cells showed marked increases in secreted MMP-2 activity (3.5-fold), invasion (3.4-fold), and colony formation in soft agar (2-fold). CCT-LC cells were hyperproliferative, grew well in serum-free media, and overexpressed cyclin D1. The CCT-LC cells also showed decreased expression of the tumor suppressor genes p16 and SLC38A3 at the protein levels. Also consistent with an acquired cancer cell phenotype, CCT-LC cells showed increased expression of the oncoproteins K-RAS and N-RAS as well as the epithelial-to-mesenchymal transition marker protein Vimentin. Metallothionein (MT) expression is increased by cadmium, and is typically overexpressed in human lung cancers. The major MT isoforms, MT-1A and MT-2A were elevated in CCT-LC cells. Oxidant adaptive response genes HO-1 and HIF-1A were also activated in CCT-LC cells. Expression of the metal transport genes ZNT-1, ZNT-5, and ZIP-8 increased in CCT-LC cells culminating in reduced cadmium accumulation, suggesting adaptation to the metal. Overall, these data suggest that exposure of human lung epithelial cells to cadmium causes acquisition of cancer cell characteristics. Furthermore, transformation occurs despite the cell’s ability to adapt to chronic cadmium exposure. PMID:23811327

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

    PubMed

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

    2016-01-01

    Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis activation in lung cancer cells, which was evidenced by TRAIL/death receptor-5 (DR5) induction and caspase-8 activation. The caspase-8 inhibitor or TRAIL/DR5 siRNA knockdown alleviated ONC201's cytotoxicity against lung cancer cells. Molecularly, ONC201 in-activated Akt-S6K1 and Erk signalings in lung cancer cells, causing Foxo3a nuclear translocation. For the in vivo studies, intraperitoneal injection of ONC201 at well-tolerated doses significantly inhibited xenografted A549 tumor growth in severe combined immunodeficient (SCID) mice. Further, ONC201 administration induced TRAIL/DR5 expression, yet inactivated Akt-S6K1 and Erk in tumor tissues. These results of the study demonstrates the potent anti-lung cancer activity by ONC201. PMID:27626799

  8. Vaccine therapy in non-small-cell lung cancer.

    PubMed

    Albright, Carol; Garst, Jennifer

    2007-07-01

    Lung cancer is the leading cause of death from cancer worldwide. First-line therapy is based on stage at diagnosis and can include chemotherapy, radiation, and surgery. Despite advances, the prognosis for advanced-stage lung cancer is very poor. Vaccines with the capability to activate the host immune system may have a role in second-line therapy. Advances in the understanding of cellular and molecular immunology are forming the basis for improving vaccine therapy. Most trials to date have demonstrated safety but inconsistent efficacy. Further research is needed to enhance this potential. PMID:17588347

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

    PubMed Central

    Ma, Debin; Jia, Hui; Qin, Mengmeng; Dai, Wenjie; Wang, Tao; Liang, Erguang; Dong, Guofu; Wang, Zuojun; Zhang, Zhiyuan; Feng, Fan

    2015-01-01

    MiR-122 is a novel tumor suppresser and its expression induces cell cycle arrest, or apoptosis, and inhibits cell proliferation in multiple cancer cells, including non-small cell lung cancer (NSCLC) cells. Radioresistance of cancer cell leads to the major drawback of radiotherapy for NSCLC and the induction of radiosensitization could be a useful strategy to fix this problem. The present work investigates the function of miR-122 in inducing radiosensitization in A549 cell, a type of NSCLC cells. MiR-122 induces the radiosensitization of A549 cells. MiR-122 also boosts the inhibitory activity of ionizing radiation (IR) on cancer cell anchor-independent growth and invasion. Moreover, miR-122 reduced the expression of its targeted genes related to tumor-survival or cellular stress response. These results indicate that miR-122 would be a novel strategy for NSCLC radiation-therapy. PMID:26389880

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

    PubMed

    Ma, Debin; Jia, Hui; Qin, Mengmeng; Dai, Wenjie; Wang, Tao; Liang, Erguang; Dong, Guofu; Wang, Zuojun; Zhang, Zhiyuan; Feng, Fan

    2015-01-01

    MiR-122 is a novel tumor suppresser and its expression induces cell cycle arrest, or apoptosis, and inhibits cell proliferation in multiple cancer cells, including non-small cell lung cancer (NSCLC) cells. Radioresistance of cancer cell leads to the major drawback of radiotherapy for NSCLC and the induction of radiosensitization could be a useful strategy to fix this problem. The present work investigates the function of miR-122 in inducing radiosensitization in A549 cell, a type of NSCLC cells. MiR-122 induces the radiosensitization of A549 cells. MiR-122 also boosts the inhibitory activity of ionizing radiation (IR) on cancer cell anchor-independent growth and invasion. Moreover, miR-122 reduced the expression of its targeted genes related to tumor-survival or cellular stress response. These results indicate that miR-122 would be a novel strategy for NSCLC radiation-therapy. PMID:26389880

  11. TUBERCULOSIS AND LUNG CANCER.

    PubMed

    Tamura, Atsuhisa

    2016-01-01

    The occurrence of pulmonary tuberculosis (PTB) and lung cancer as comorbidities has been extensively discussed in many studies. In the past, it was well known that lung cancer is a specific epidemiological successor of PTB and that lung cancer often develops in scars caused by PTB. In recent years, the relevance of the two diseases has drawn attention in terms of the close epidemiological connection and chronic inflammation-associated carcinogenesis. In Japanese case series studies, most lung cancer patients with tuberculous sequelae received supportive care alone in the past, but more recently, the use of aggressive lung cancer treatment is increasing. Many studies on PTB and lung cancer as comorbidities have revealed that active PTB is noted in 2-5% of lung cancer cases, whereas lung cancer is noted in 1-2% of active PTB cases. In such instances of comorbidity, many active PTB cases showed Type II (non-extensively cavitary disease) and Spread 2-3 (intermediate-extensive diseases) on chest X-rays, but standard anti-tuberculosis treatment easily eradicates negative conversion of sputum culture for M. tuberculosis; lung cancer cases were often stage III- IV and squamous cell carcinoma predominant, and the administration of aggressive treatment for lung cancer is increasing. The major clinical problems associated with PTB and lung cancer as comorbidities include delay in diagnosis (doctor's delay) and therapeutic limitations. The former involves two factors of radiographic interpretation: the principles of parsimony (Occam's razor) and visual search; the latter involves three factors of lung cancer treatment: infectivity of M.tuberculosis, anatomical limitation due to lung damage by tuberculosis, and drug-drug interactions between rifampicin and anti-cancer drugs, especially molecularly targeted drugs. The comorbidity of these two diseases is an important health-related issue in Japan. In the treatment of PTB, the possibility of concurrent lung cancer should be kept

  12. [Maintenance therapy for advanced non-small-cell lung cancer].

    PubMed

    Saruwatari, Koichi; Yoh, Kiyotaka

    2014-08-01

    Maintenance therapy is a new treatment strategy for advanced non-small-cell lung cancer(NSCLC), and it consists of switch maintenance and continuation maintenance.Switch maintenance is the introduction of a different drug, not included as part of the induction therapy, immediately after completion of 4 cycles of first-line platinum-based chemotherapy.Continuation maintenance is a continuation of at least one of the drugs used in the induction therapy in the absence of disease progression.Several phase III trials have reported survival benefits with continuation maintenance of pemetrexed and switch maintenance of pemetrexed or erlotinib.Therefore, maintenance therapy has become a part of the standard first-line treatment for advanced NSCLC.However, further research is needed to elucidate the selection criteria of patients who may benefit the most from maintenance therapy. PMID:25132023

  13. Pharmacogenomics and targeted therapy of cancer: Focusing on non-small cell lung cancer.

    PubMed

    Haghgoo, Seyyed Mortaza; Allameh, Abdolamir; Mortaz, Esmaeil; Garssen, Johan; Folkerts, Gert; Barnes, Peter J; Adcock, Ian M

    2015-05-01

    Recent studies have been established high degree of genetic diversity in solid organ tumors among individuals and even between individual tumor cells. This intratumor and intertumor genetic diversity results in a heterogeneous tumor with unique characteristics which potentially allows effective drug therapy. The goal of pharmacogenomics is to elucidate the genetic network(s) that underlie drug efficacy and drug resistance. Advances in targeted and personalized therapy play an increasingly important role in many common cancers, notably lung cancer, due to the high incidence, prevalence, mortality and the greater tendency towards drug resistance seen in these patients. Non-small cell lung cancer (NSCLC) is characterized by mutations in the epidermal growth factor receptor (EGFR) and or downstream kinase pathways. This has led to the development of highly selective monoclonal antibodies and EGFR tyrosine kinase inhibitors (EGFR-TKIs) to prevent cancer initiation, proliferation, differentiation, angiogenesis, survival, and invasion. However, resistance to many of these new treatments is induced and further pharmacogenomic analysis has revealed mutations associated with increased or reduced drug efficacy. Combinations of kinase inhibitors or potentially the targeting of cancer stem cells may further increase the success of pharmacogenomics in treating patients with lung cancer. PMID:25725115

  14. Genetic Testing in Screening Patients With Stage IB-IIIA Non-Small Cell Lung Cancer That Has Been or Will Be Removed by Surgery (The ALCHEMIST Screening Trial)

    ClinicalTrials.gov

    2016-08-30

    Large Cell Lung Carcinoma; Lung Adenocarcinoma; Stage IB Non-Small Cell Lung Carcinoma; Stage IB Squamous Cell Lung Carcinoma; Stage IIA Non-Small Cell Lung Carcinoma; Stage IIA Squamous Cell Lung Carcinoma; Stage IIB Non-Small Cell Lung Carcinoma; Stage IIB Squamous Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIA Squamous Cell Lung Carcinoma

  15. CDO, an Hh-Coreceptor, Mediates Lung Cancer Cell Proliferation and Tumorigenicity through Hedgehog Signaling

    PubMed Central

    Leem, Young-Eun; Ha, Hye-Lim; Bae, Ju-Hyeon; Baek, Kwan-Hyuck; Kang, Jong-Sun

    2014-01-01

    Hedgehog (Hh) signaling plays essential roles in various developmental processes, and its aberrant regulation results in genetic disorders or malignancies in various tissues. Hyperactivation of Hh signaling is associated with lung cancer development, and there have been extensive efforts to investigate how to control Hh signaling pathway and regulate cancer cell proliferation. In this study we investigated a role of CDO, an Hh co-receptor, in non-small cell lung cancer (NSCLC). Inhibition of Hh signaling by SANT-1 or siCDO in lung cancer cells reduced proliferation and tumorigenicity, along with the decrease in the expression of the Hh components. Histological analysis with NSCLC mouse tissue demonstrated that CDO was expressed in advanced grade of the cancer, and precisely co-localized with GLI1. These data suggest that CDO is required for proliferation and survival of lung cancer cells via Hh signaling. PMID:25369201

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

    ClinicalTrials.gov

    2016-06-07

    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

  17. Lung cancer in Australia.

    PubMed

    McLennan, G; Roder, D M

    1989-02-20

    Lung cancer is the leading cause of death of cancer in Australian men and the third leading cause in Australian women. Efforts are being made to reduce the incidence of this disease by smoking-cessation programmes and improved industrial hygiene, and these measures need to be encouraged strongly by all sectors of the community. On a population basis, insufficient evidence is available to justify screening procedures for the early detection of lung cancer in "at-risk" groups. Cure is possible by surgical resection in early cases. Improvements in therapeutic results with traditional cancer treatments largely have reached a plateau, but a number of newer therapies, and combinations of standard therapies, currently are being evaluated. Of particular interest is concurrent radiotherapy and chemotherapy in localized non-small-cell lung cancer; laser "debulking" in conjunction with radiotherapy in non-small-cell lung cancer, and biological response-modifying agents in non-small-cell and small-cell lung cancer. It is important that data be collected adequately to define epidemiological changes and to evaluate treatment results (including repeat bronchoscopy, to assess local control of tumour), and that the quality of life is recorded and reported in the evaluation process. Finally, phase-III studies in lung-cancer treatments require adequate numbers of subjects to enable meaningful conclusions to be achieve objectives within a reasonable study period. PMID:2469943

  18. REV3L modulates cisplatin sensitivity of non-small cell lung cancer H1299 cells.

    PubMed

    Wang, Wenjie; Sheng, Wenjiong; Yu, Chenxiao; Cao, Jianping; Zhou, Jundong; Wu, Jinchang; Zhang, Huojun; Zhang, Shuyu

    2015-09-01

    Lung cancer remains the leading cause of cancer-related mortality worldwide and non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all cases of lung cancer. Cisplatin plays a significant role in the management of human lung cancer. Translesion DNA synthesis (TLS) is involved in DNA damage repair. DNA polymerase ζ (Pol ζ) is able to mediate the DNA replication bypass of DNA damage, which is suggested to be involved in chemoresistance. REV3L is the catalytic subunit of Pol ζ. Due to its critical role in translesion DNA synthesis, whether REV3L modulates cisplatin response in NSCLC cells remains unknown. In this study, REV3L overexpression and silencing H1299 cell lines were established. The reports showed that cisplatin induced the expression of REV3L by recruiting Sp1 to its promoter. Similar results were obtained when the ability of the cells to express luciferase from a platinated plasmid was measured. Co-transfection of the reporter with the REV3L overexpression vector or REV3L plus REV7L significantly enhanced the reporter activity. Nuclear condensation and fragmentation of shRNA-REV3L H1299 cells were more pronounced than shRNA-NC H1299 cells after cisplatin exposure, indicating that REV3L overexpression abolished cisplatin-induced DNA damage. Moreover, a forced expression of REV3L conferred the resistance of H1299 cells to cisplatin, whereas the knockdown of REV3L sensitized cisplatin efficacy in H1299 cells. Taken together, we demonstrated that inhibition of REV3L sensitized lung cancer H1299 cells to cisplatin treatment. Thus, REV3L may be a novel target for the chemotherapy of NSCLC. PMID:26165320

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

    DOE PAGESBeta

    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. 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

  20. 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.

  1. ALDH isozymes downregulation affects cell growth, cell motility and gene expression in lung cancer cells

    PubMed Central

    Moreb, Jan S; Baker, Henry V; Chang, Lung-Ji; Amaya, Maria; Lopez, M Cecilia; Ostmark, Blanca; Chou, Wayne

    2008-01-01

    Background Aldehyde dehydrogenase isozymes ALDH1A1 and ALDH3A1 are highly expressed in non small cell lung cancer. Neither the mechanisms nor the biologic significance for such over expression have been studied. Methods We have employed oligonucleotide microarrays to analyze changes in gene profiles in A549 lung cancer cell line in which ALDH activity was reduced by up to 95% using lentiviral mediated expression of siRNA against both isozymes (Lenti 1+3). Stringent analysis methods were used to identify gene expression patterns that are specific to the knock down of ALDH activity and significantly different in comparison to wild type A549 cells (WT) or cells similarly transduced with green fluorescent protein (GFP) siRNA. Results We confirmed significant and specific down regulation of ALDH1A1 and ALDH3A1 in Lenti 1+3 cells and in comparison to 12 other ALDH genes detected. The results of the microarray analysis were validated by real time RT-PCR on RNA obtained from Lenti 1+3 or WT cells treated with ALDH activity inhibitors. Detailed functional analysis was performed on 101 genes that were significantly different (P < 0.001) and their expression changed by ≥ 2 folds in the Lenti 1+3 group versus the control groups. There were 75 down regulated and 26 up regulated genes. Protein binding, organ development, signal transduction, transcription, lipid metabolism, and cell migration and adhesion were among the most affected pathways. Conclusion These molecular effects of the ALDH knock-down are associated with in vitro functional changes in the proliferation and motility of these cells and demonstrate the significance of ALDH enzymes in cell homeostasis with a potentially significant impact on the treatment of lung cancer. PMID:19025616

  2. Toxicity of Cerium Oxide Nanoparticles in Human Lung Cancer Cells

    SciTech Connect

    Weisheng, Lin; Huang, Yue-wern; Zhou, Xiao Dong; Ma, Yinfa

    2006-12-31

    With the fast development of nanotechnology, the nanomaterials start to cause people's attention for potential toxic effect. In this paper, the cytotoxicity and oxidative stress caused by 20-nm cerium oxide (CeO2) nanoparticles in cultured human lung cancer cells was investigated. The sulforhodamine B method was employed to assess cell viability after exposure to 3.5, 10.5, and 23.3 μg/ml of CeO2 nanoparticles for 24, 48, and 72 h. Cell viability decreased significantly as a function of nanoparticle dose and exposure time. Indicators of oxidative stress and cytotoxicity, including total reactive oxygen species, glutathione, malondialdehyde, α-tocopherol, and lactate dehydrogenase, were quantitatively assessed. It is concluded from the results that free radicals generated by exposure to 3.5 to 23.3 μg/ml CeO2 nanoparticles produce significant oxidative stress in the cells, as reflected by reduced glutathione and α-tocopherol levels; the toxic effects of CeO2 nanoparticles are dose dependent and time dependent; elevated oxidative stress increases the production of malondialdehyde and lactate dehydrogenase, which are indicators of lipid peroxidation and cell membrane damage, respectively.

  3. CDDO-Me Protects Normal Lung and Breast Epithelial Cells but Not Cancer Cells from Radiation

    PubMed Central

    El-Ashmawy, Mariam; Delgado, Oliver; Cardentey, Agnelio; Wright, Woodring E.; Shay, Jerry W.

    2014-01-01

    Although radiation therapy is commonly used for treatment for many human diseases including cancer, ionizing radiation produces reactive oxygen species that can damage both cancer and healthy cells. Synthetic triterpenoids, including CDDO-Me, act as anti-inflammatory and antioxidant modulators primarily by inducing the transcription factor Nrf2 to activate downstream genes containing antioxidant response elements (AREs). In the present series of experiments, we determined if CDDO-Me can be used as a radioprotector in normal non-cancerous human lung and breast epithelial cells, in comparison to lung and breast cancer cell lines. A panel of normal non-cancerous, partially cancer progressed, and cancer cell lines from both lung and breast tissue was exposed to gamma radiation with and without pre-treatment with CDDO-Me. CDDO-Me was an effective radioprotector when given ∼18 hours before radiation in epithelial cells (average dose modifying factor (DMF) = 1.3), and Nrf2 function was necessary for CDDO-Me to exert these radioprotective effects. CDDO-Me did not protect cancer lines tested from radiation-induced cytotoxicity, nor did it protect experimentally transformed human bronchial epithelial cells (HBECs) with progressive oncogenic manipulations. CDDO-Me also protected human lymphocytes against radiation-induced DNA damage. A therapeutic window exists in which CDDO-Me protects normal cells from radiation by activating the Nrf2 pathway, but does not protect experimentally transformed or cancer cell lines. This suggests that use of this oral available, non-toxic class of drug can protect non-cancerous healthy cells during radiotherapy, resulting in better outcomes and less toxicity for patients. PMID:25536195

  4. Chemotherapy advances in small-cell lung cancer.

    PubMed

    Chan, Bryan A; Coward, Jermaine I G

    2013-10-01

    Although chemotherapeutic advances have recently been heralded in lung adenocarcinomas, such success with small-cell lung cancer (SCLC) has been ominously absent. Indeed, the dismal outlook of this disease is exemplified by the failure of any significant advances in first line therapy since the introduction of the current standard platinum-etoposide doublet over 30 years ago. Moreover, such sluggish progress is compounded by the dearth of FDA-approved agents for patients with relapsed disease. However, over the past decade, novel formulations of drug classes commonly used in SCLC (e.g. topoisomerase inhibitors, anthracyclines, alkylating and platinum agents) are emerging as potential alternatives that could effectively add to the armamentarium of agents currently at our disposal. This review is introduced with an overview on the historical development of chemotherapeutic regimens used in this disease and followed by the recent encouraging advances witnessed in clinical trials with drugs such as amrubicin and belotecan which are forging new horizons for future treatment algorithms. PMID:24163749

  5. Fractal geometry-based classification approach for the recognition of lung cancer cells

    NASA Astrophysics Data System (ADS)

    Xia, Deshen; Gao, Wenqing; Li, Hua

    1994-05-01

    This paper describes a new fractal geometry based classification approach for the recognition of lung cancer cells, which is used in the health inspection for lung cancers, because cancer cells grow much faster and more irregularly than normal cells do, the shape of the segmented cancer cells is very irregular and considered as a graph without characteristic length. We use Texture Energy Intensity Rn to do fractal preprocessing to segment the cells from the image and to calculate the fractal dimention value for extracting the fractal features, so that we can get the figure characteristics of different cancer cells and normal cells respectively. Fractal geometry gives us a correct description of cancer-cell shapes. Through this method, a good recognition of Adenoma, Squamous, and small cancer cells can be obtained.

  6. Cediranib Maleate and Whole Brain Radiation Therapy in Patients With Brain Metastases From Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-03-07

    Male Breast Cancer; Stage IV Breast Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer; Stage IV Renal Cell Cancer; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer; Tumors Metastatic to Brain

  7. Metformin inhibits lung cancer cells proliferation through repressing microRNA-222.

    PubMed

    Wang, Yuqi; Dai, Weimin; Chu, Xiangyang; Yang, Bo; Zhao, Ming; Sun, Yu'e

    2013-12-01

    Metformin, which is commonly used as an oral anti-hyperglycemic agent of the biguanide family, may reduce cancer risk and improve prognosis. However, the mechanism by which metformin affects various cancers, including lung cancer, remains unknown. MiR-222 induces cell growth and cell cycle progression via direct targeting of p27, p57 and PTEN in cancer cells. In the present study, we used A549 and NCI-H358 human lung cancer cell lines to study the effects and mechanisms of metformin. Metformin treatment reduced expression of miR-222 in these cells (p < 0.05). As a result, protein abundance of p27, p57 and PTEN were increased in cells exposed to metformin. Therefore, these data provide novel evidence for a mechanism that may contribute to the anti-neoplastic effects of metformin suggested by recent population studies and justifying further work to explore potential roles for it in lung cancer treatment. PMID:23974492

  8. Mighty mouse breakthroughs: a Sox2-driven model for squamous cell lung cancer

    PubMed Central

    Mukhopadhyay, Anandaroop; Oliver, Trudy G

    2015-01-01

    Squamous lung cancer is a subtype of non-small cell lung cancer with a poor overall prognosis. We have recently generated a mouse model of squamous lung carcinoma by overexpressing Sex-determining region Y-box 2 (Sox2) and deleting liver kinase B1 (Lkb1) using a lentiviral approach. This model recapitulates the human disease in terms of histopathology, biomarker expression, and signaling pathway activation, making it an excellent model for preclinical studies. PMID:27308419

  9. Small cell lung cancer in never-smokers.

    PubMed

    Torres-Durán, María; Ruano-Ravina, Alberto; Kelsey, Karl T; Parente-Lamelas, Isaura; Provencio, Mariano; Leiro-Fernández, Virginia; Abal-Arca, José; Montero-Martínez, Carmen; Vidal-Garcia, Iria; Pena, Carolina; Castro-Añón, Olalla; Golpe-Gómez, Antonio; Martínez, Cristina; Guzmán-Taveras, Rosirys; Mejuto-Martí, María José; Fernández-Villar, Alberto; Barros-Dios, Juan Miguel

    2016-03-01

    Our aim was to describe the characteristics of a case-series of never-smoker small cell lung cancer (SCLC) cases.Cases of SCLC were selected from a prospective, multicenter, hospital-based case-control study performed in Spain. Participants were never-smokers older than 30 years with an anatomo-pathological confirmation of primary lung cancer. We collected clinical and epidemiological variables according to the study's protocol.We included 19 SCLC cases, 18 females (94.7%), median age 75 years (interquartile range (IQR) 70-80 years). Median residential radon concentration was 195 Bq·m(-3) (IQR 130-229 Bq·m(-3)). 10 patients had limited disease and nine had extended disease. Median survival was 242 days (IQR 94-496 days); 1- and 2-year survival were 36.8% and 17.6%, respectively. Survival was much higher for individuals with limited disease than for those with extended disease (median 336 versus 235 days; 1-year survival 50% versus 22.2% and 2-year survival 27% versus 0%, respectively). Performance status at diagnosis was closely related to survival.SCLC is an infrequent, highly aggressive disease in never-smokers. Survival is poor, even for limited disease. Age at diagnosis in SCLC is higher than that observed for never-smokers with adenocarcinoma. Residential radon exposure is higher than the action levels recommended by the World Health Organization. PMID:26699724

  10. Lung Adenocarcinomas and Lung Cancer Cell Lines Show Association of MMP-1 Expression With STAT3 Activation1

    PubMed Central

    Schütz, Alexander; Röser, Katrin; Klitzsch, Jana; Lieder, Franziska; Aberger, Fritz; Gruber, Wolfgang; Mueller, Kristina M.; Pupyshev, Alexander; Moriggl, Richard; Friedrich, Karlheinz

    2015-01-01

    Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in the majority of lung cancer. This study aims at defining connections between STAT3 function and the malignant properties of non–small cell lung carcinoma (NSCLC) cells. To address possible mechanisms by which STAT3 influences invasiveness, the expression of matrix metalloproteinase-1 (MMP-1) was analyzed and correlated with the STAT3 activity status. Studies on both surgical biopsies and on lung cancer cell lines revealed a coincidence of STAT3 activation and strong expression of MMP-1. MMP-1 and tyrosine-phosphorylated activated STAT3 were found co-localized in cancer tissues, most pronounced in tumor fronts, and in particular in adenocarcinomas. STAT3 activity was constitutive, although to different degrees, in the lung cancer cell lines investigated. Three cell lines (BEN, KNS62, and A549) were identified in which STAT3 activitation was inducible by Interleukin-6 (IL-6). In A549 cells, STAT3 activity enhanced the level of MMP-1 mRNA and stimulated transcription from the MMP-1 promoter in IL-6–stimulated A549 cells. STAT3 specificity of this effect was confirmed by STAT3 knockdown through RNA interference. Our results link aberrant activity of STAT3 in lung cancer cells to malignant tumor progression through up-regulation of expression of invasiveness-associated MMPs. PMID:25926075

  11. CXCR4/CXCL12 in Non-Small-Cell Lung Cancer Metastasis to the Brain

    PubMed Central

    Cavallaro, Sebastiano

    2013-01-01

    Lung cancer represents the leading cause of cancer-related mortality throughout the world. Patients die of local progression, disseminated disease, or both. At least one third of the people with lung cancer develop brain metastases at some point during their disease, even often before the diagnosis of lung cancer is made. The high rate of brain metastasis makes lung cancer the most common type of tumor to spread to the brain. It is critical to understand the biologic basis of brain metastases to develop novel diagnostic and therapeutic approaches. This review will focus on the emerging data supporting the involvement of the chemokine CXCL12 and its receptor CXCR4 in the brain metastatic evolution of non-small-cell lung cancer (NSCLC) and the pharmacological tools that may be used to interfere with this signaling axis. PMID:23322021

  12. Non-small cell lung cancer cell survival crucially depends on functional insulin receptors.

    PubMed

    Frisch, Carolin Maria; Zimmermann, Katrin; Zilleßen, Pia; Pfeifer, Alexander; Racké, Kurt; Mayer, Peter

    2015-08-01

    Insulin plays an important role as a growth factor and its contribution to tumor proliferation is intensely discussed. It acts via the cognate insulin receptor (IR) but can also activate the IGF1 receptor (IGF1R). Apart from increasing proliferation, insulin might have additional effects in lung cancer. Therefore, we investigated insulin action and effects of IR knockdown (KD) in three (NCI-H292, NCI-H226 and NCI-H460) independent non-small cell lung cancer (NSCLC) cell lines. All lung cancer lines studied were found to express IR, albeit with marked differences in the ratio of the two variants IR-A and IR-B. Insulin activated the classical signaling pathway with IR autophosphorylation and Akt phosphorylation. Moreover, activation of MAPK was observed in H292 cells, accompanied by enhanced proliferation. Lentiviral shRNA IR KD caused strong decrease in survival of all three lines, indicating that the effects of insulin in lung cancer go beyond enhancing proliferation. Unspecific effects were ruled out by employing further shRNAs and different insulin-responsive cells (human pre-adipocytes) for comparison. Caspase assays demonstrated that IR KD strongly induced apoptosis in these lung cancer cells, providing the physiological basis of the rapid cell loss. In search for the underlying mechanism, we analyzed alterations in the gene expression profile in response to IR KD. A strong induction of certain cytokines (e.g. IL20 and tumour necrosis factor) became obvious and it turned out that these cytokines trigger apoptosis in the NSCLC cells tested. This indicates a novel role of IR in tumor cell survival via suppression of pro-apoptotic cytokines. PMID:26113601

  13. AKAP4 is a circulating biomarker for non-small cell lung cancer

    PubMed Central

    Gumireddy, Kiranmai; Li, Anping; Chang, David H.; Liu, Qin; Kossenkov, Andrew V.; Yan, Jinchun; Korst, Robert J.; Nam, Brian T.; Xu, Hua; Zhang, Lin; Ganepola, Ganepola A.P.; Showe, Louise C.; Huang, Qihong

    2015-01-01

    Cancer testis antigens (CTAs) are widely expressed in tumor tissues, circulating tumor cells (CTCs) and in cancer derived exosomes that are frequently engulfed by lymphoid cells. To determine whether tumor derived CTA mRNAs could be detected in RNA from purified peripheral blood mononuclear cells (PBMC) of non-small cell lung cancer (NSCLC) patients, we assayed for the expression of 116 CTAs in PBMC RNA in a discovery set and identified AKAP4 as a potential NSCLC biomarker. We validated AKAP4 as a highly accurate biomarker in a cohort of 264 NSCLCs and 135 controls from 2 different sites including a subset of controls with high risk lung nodules. When all (264) lung cancers were compared with all (135) controls the area under the ROC curve (AUC) was 0.9714. When 136 stage I NSCLC lung cancers are compared with all controls the AUC is 0.9795 and when all lung cancer patients were compared to 27 controls with histologically confirmed benign lung nodules, a comparison of significant clinical importance, the AUC was 0.9825. AKAP4 expression increases significantly with tumor stage, but independent of age, gender, smoking history or cancer subtype. Follow-up studies in a small number of resected NSCLC patients revealed a decrease of AKAP4 expression post-surgical resection that remained low in patients in remission and increased with tumor recurrence. AKAP4 is a highly accurate biomarker for the detection of early stage lung cancer. PMID:26160834

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

    PubMed Central

    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

    2016-01-01

    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. PMID:26760963

  15. Limited-disease small-cell lung cancer.

    PubMed

    Zimmermann, Frank B; Bamberg, Michael; Molls, Michael; Jeremic, Branislav

    2003-01-01

    Substantial improvements in treatment outcome for limited-disease small-cell lung cancer (LD SCLC) have been achieved in the last two decades owing to the introduction of chemotherapy (CHT) consisting of cisplatin and etoposide (PE), and the understanding that thoracic radiation therapy (TRT) is an essential component in improving treatment outcome. In addition, a recent metaanalysis confirmed the importance of prophylactic cranial irradiation (PCI) in general treatment plans for patients who show a complete response to treatment. However, numerous questions remain unanswered regarding this disease. While TRT/PE/PCI is considered to be the standard treatment in the majority of centers worldwide, the emergence of new and effective drugs (e.g., topoisomerase I inhibitors and paclitaxel) for the treatment of LD SCLC will likely affect therapy strategies in the near future. Important issues regarding optimal doses and fractionation regimens, as well as the timing of TRT, remain to be resolved. While most centers currently use b.i.d. fractionation as a result of the Intergroup findings, high-dose standard TRT may also be beneficial. TRT volumes are also considered an important issue, since they likely relate to the incidence of both local failure and toxicity. Finally, the optimization of PCI (total dose, fractionation regimen, and timing) is already under way. The value of surgery is limited to peripheral tumors and poorly responding cancer, and to confirm histology or improve local control and survival. PMID:14508848

  16. Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress.

    PubMed

    Lu, Jun; Chen, Jian; Xu, Nianjun; Wu, Jun; Kang, Yani; Shen, Tingting; Kong, Hualei; Ma, Chao; Cheng, Ming; Shao, Zhifeng; Xu, Ling; Zhao, Xiaodong

    2016-09-01

    Application of cisplatin (DDP) for treating lung cancer is restricted due to its toxicity and lung cancer's drug resistance. In this study, we examined the effect of Jinfukang (JFK), an effective herbal medicine against lung cancer, on DDP-induced cytotoxicity in lung cancer cells. Morphologically, we observed that JFK increases DDP-induced pro-apoptosis in A549 cells in a synergistic manner. Transcriptome profiling analysis indicated that the combination of JFK and DDP regulates genes involved in apoptosis-related signaling pathways. Moreover, we found that the combination of JFK and DDP produces synergistic pro-apoptosis effect in other lung cancer cell lines, such as NCI-H1975, NCI-H1650, and NCI-H2228. Particularly, we demonstrated that AIFM2 is activated by the combined treatment of JFK and DDP and partially mediates the synergistic pro-apoptosis effect. Collectively, this study not only offered the first evidence that JFK promotes DDP-induced cytotoxicity, and activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress, but also provided a novel insight for improving cytotoxicity by combining JFK with DDP to treat lung cancer cells. PMID:27392435

  17. Enrichment and characterization of cancer stem cells from a human non-small cell lung cancer cell line.

    PubMed

    Zhao, Changhong; Setrerrahmane, Sarra; Xu, Hanmei

    2015-10-01

    Tumor cells from the same origin comprise different cell populations. Among them, cancer stem cells (CSCs) have higher tumorigenicity. It is necessary to enrich CSCs to determine an effective way to suppress and eliminate them. In the present study, using the non-adhesive culture system, tumor spheres were successfully generated from human A549 non-small cell lung cancer (NSCLC) cell line within 2 weeks. Compared to A549 adherent cells, sphere cells had a higher self-renewal ability and increased resistance to cytotoxic drugs. Sphere cells were more invasive and expressed stem cell markers including octamer‑binding transcription factor 4 (Oct4) and sex-determining region Y-box 2 (Sox2) at high levels. CD133, a disputed marker of lung CSCs, was also upregulated. Tumor sphere cells showed higher tumorigenic ability in vivo, indicating that more CSCs were enriched in the sphere cells. More blood vessels were formed in the tumor generated by sphere cells suggesting the interaction between CSCs and blood vessel. A reliable model of enriching CSCs from the human A549 NSCLC cell line was established that was simple and cost-effective compared to other methods. PMID:26239272

  18. The Role of Cancer Stem Cells in Recurrent and Drug-Resistant Lung Cancer.

    PubMed

    Suresh, Raagini; Ali, Shadan; Ahmad, Aamir; Philip, Philip A; Sarkar, Fazlul H

    2016-01-01

    Lung cancer is the leading cause of cancer-related deaths worldwide with a 5-year overall survival rate of less than 20 %. Considering the treatments currently available, this statistics is shocking. A possible explanation for the disconnect between sophisticated treatments and the survival rate can be related to the post-treatment enrichment of Cancer Stem Cells (CSCs), which is one of a sub-set of drug resistant tumor cells with abilities of self-renewal, cancer initiation, and further maintenance of tumors. Lung CSCs have been associated with resistance to radiation and chemotherapeutic treatments. CSCs have also been implicated in tumor recurrence because CSCs are not typically killed after conventional therapy. Investigation of CSCs in determining their role in tumor recurrence and drug-resistance relied heavily on the use of specific markers present in CSCs, including CD133, ALDH, ABCG2, and Nanog. Yet another cell type that is also associated with increased resistance to treatment is epithelial-to-mesenchymal transition (EMT) phenotypic cells. Through the processes of EMT, epithelial cells lose their epithelial phenotype and gain mesenchymal properties, rendering EMT phenotypic cells acquire drug-resistance. In this chapter, we will further discuss the role of microRNAs (miRNAs) especially because miRNA-based therapies are becoming attractive target with respect to therapeutic resistance and CSCs. Finally, the potential role of the natural agents and synthetic derivatives of natural compounds with anti-cancer activity, e.g. curcumin, CDF, and BR-DIM is highlighted in overcoming therapeutic resistance, suggesting that the above mentioned agents could be important for better treatment of lung cancer in combination therapy. PMID:26703799

  19. S100P interacts with integrin α7 and increases cancer cell migration and invasion in lung cancer.

    PubMed

    Hsu, Ya-Ling; Hung, Jen-Yu; Liang, Yung-Yu; Lin, Yi-Shiuan; Tsai, Ming-Ju; Chou, Shah-Hwa; Lu, Chi-Yu; Kuo, Po-Lin

    2015-10-01

    S100P, a Ca2+ binding protein, has been shown to be overexpressed in various cancers. However, its functional character in lung cancer remains largely unknown. In this study, we show that S100P increases cancer migration, invasion and metastasis in lung cancer cells. Ectopic expression of S100P increases migration, invasion and EMT in less invasive CL1-0 lung cancer cells. Conversely, knockdown of S100P suppressed migration and invasion, and caused a reversion of EMT in highly invasive lung cancer cells. These effects were transduced by increasing the interaction of S100P with integrin α7, which activated focal adhesion kinase (FAK) and AKT. Blocking FAK significantly decreased S100P-induced migration by decreasing Src and AKT activation, whereas inhibiting AKT reduced S100P upregulation on ZEB1 expression. Further study has indicated that S100P knockdown prevents the spread of highly metastatic human lung cancer in animal models. This study therefore suggests that S100P represents a critical activator of lung cancer metastasis. Detection and targeted treatment of S100P-expressing cancer is an attractive therapeutic strategy in treating lung cancer. PMID:26320193

  20. S100P interacts with integrin α7 and increases cancer cell migration and invasion in lung cancer

    PubMed Central

    Hsu, Ya-Ling; Hung, Jen-Yu; Liang, Yung-Yu; Lin, Yi-Shiuan; Tsai, Ming-Ju; Chou, Shah-Hwa; Lu, Chi-Yu; Kuo, Po-Lin

    2015-01-01

    S100P, a Ca2+ binding protein, has been shown to be overexpressed in various cancers. However, its functional character in lung cancer remains largely unknown. In this study, we show that S100P increases cancer migration, invasion and metastasis in lung cancer cells. Ectopic expression of S100P increases migration, invasion and EMT in less invasive CL1-0 lung cancer cells. Conversely, knockdown of S100P suppressed migration and invasion, and caused a reversion of EMT in highly invasive lung cancer cells. These effects were transduced by increasing the interaction of S100P with integrin α7, which activated focal adhesion kinase (FAK) and AKT. Blocking FAK significantly decreased S100P-induced migration by decreasing Src and AKT activation, whereas inhibiting AKT reduced S100P upregulation on ZEB1 expression. Further study has indicated that S100P knockdown prevents the spread of highly metastatic human lung cancer in animal models. This study therefore suggests that S100P represents a critical activator of lung cancer metastasis. Detection and targeted treatment of S100P-expressing cancer is an attractive therapeutic strategy in treating lung cancer. PMID:26320193

  1. Therapeutic vaccines in non-small cell lung cancer

    PubMed Central

    Socola, Francisco; Scherfenberg, Naomi; Raez, Luis E

    2013-01-01

    Non-small cell lung cancer (NSCLC) unfortunately carries a very poor prognosis. Patients usually do not become symptomatic, and therefore do not seek treatment, until the cancer is advanced and it is too late to employ curative treatment options. New therapeutic options are urgently needed for NSCLC, because even current targeted therapies cure very few patients. Active immunotherapy is an option that is gaining more attention. A delicate and complex interplay exists between the tumor and the immune system. Solid tumors utilize a variety of mechanisms to evade immune detection. However, if the immune system can be stimulated to recognize the tumor as foreign, tumor cells can be specifically eliminated with little systemic toxicity. A number of vaccines designed to boost immunity against NSCLC are currently undergoing investigation in phase III clinical trials. Belagenpumatucel-L, an allogeneic cell vaccine that decreases transforming growth factor (TGF-β) in the tumor microenvironment, releases the immune suppression caused by the tumor and it has shown efficacy in a wide array of patients with advanced NSCLC. Melanoma-associated antigen A3 (MAGE-A3), an antigen-based vaccine, has shown promising results in MAGE-A3+ NSCLC patients who have undergone complete surgical resection. L-BLP25 and TG4010 are both antigenic vaccines that target the Mucin-1 protein (MUC-1), a proto-oncogene that is commonly mutated in solid tumors. CIMAVax is a recombinant human epidermal growth factor (EGF) vaccine that induces anti-EGF antibody production and prevents EGF from binding to its receptor. These vaccines may significantly improve survival and quality of life for patients with an otherwise dismal NSCLC prognosis. This review is intended to give an overview of the current data and the most promising studies of active immunotherapy for NSCLC.

  2. T helper 17 cells play a critical pathogenic role in lung cancer

    PubMed Central

    Chang, Seon Hee; Mirabolfathinejad, Seyedeh Golsar; Katta, Harshadadevi; Cumpian, Amber M.; Gong, Lei; Caetano, Mauricio S.; Moghaddam, Seyed Javad; Dong, Chen

    2014-01-01

    Lung cancer development is associated with extensive pulmonary inflammation. In addition, the linkage between chronic obstructive pulmonary disease (COPD) and lung cancer has been demonstrated in population-based studies. IL-17–producing CD4 helper T cells (Th17 cells) play a critical role in promoting chronic tissue inflammation. Although Th17 cells are found in human COPD and lung cancer, their role is not understood. We have thus used a mouse model of lung cancer, in which an oncogenic form of K-ras (K-rasG12D), frequently found in human lung cancer, is restrictedly expressed in lung epithelial cells [via Clara cell secretory protein (CCSPcre)]. In this model, Th17 and Treg but not Th1 cells were found enriched at the tumor tissues. When CCSPcre/K-rasG12D mice were weekly challenged with a lysate of nontypeable Haemophilus influenza (NTHi), which induces COPD-type inflammation and accelerates the tumor growth, they showed greatly enhanced Th17 cell infiltration in the lung tissues. Lack of IL-17, but not IL-17F, resulted in a significant reduction in lung tumor numbers in CCSPcre/K-rasG12D mice and also those treated with NTHi. Absence of IL-17 not only resulted in reduction of tumor cell proliferation and angiogenesis, but also decreased the expression of proinflammatory mediators and reduced recruitment of myeloid cells. Depletion of Gr-1+CD11b+ myeloid cells in CCSPcre/K-rasG12D mice suppressed tumor growth in lung, indicating Gr-1+CD11b+ myeloid cells recruited by IL-17 play a protumor role. Taken together, our data demonstrate a critical role for Th17 cell-mediated inflammation in lung tumorigenesis and suggest a novel way for prevention and treatment of this disease. PMID:24706787

  3. Shorter telomere length of T-cells in peripheral blood of patients with lung cancer

    PubMed Central

    Qian, Yaqin; Ding, Tingting; Wei, Lijuan; Cao, Shui; Yang, Lili

    2016-01-01

    Purpose Telomere shortening occurs in tumor tissues and peripheral blood lymphocytes of many common human malignancies, including lung cancer, but its variation in T-cells has never been investigated. Thus, the aim of this study was to assess telomere length in T-cells and its correlation with the clinical characteristics of patients with lung cancer. Patients and methods A total of 40 patients with lung cancer but without prior cancer history and 25 healthy individuals were selected. T-cells were isolated and their telomere lengths were measured using quantitative real-time polymerase chain reaction methods. Results Telomere length in T-cells was significantly shorter in patients with lung cancer than in controls (P<0.001). Shorter telomere length was significantly associated with increased clinical stage (P=0.008) and distant metastasis (P=0.028). Naïve T-cells from patients with lung cancer had significantly decreased telomere length when compared with those from controls (P=0.012). Conclusion The shortened telomere length in T-cells occurred in naïve T-cells and might be related to lung cancer progression. PMID:27226730

  4. Iron induces cancer stem cells and aggressive phenotypes in human lung cancer cells.

    PubMed

    Chanvorachote, Pithi; Luanpitpong, Sudjit

    2016-05-01

    Evidence has accumulated in support of the critical impact of cancer stem cells (CSCs) behind the chemotherapeutic failure, cancer metastasis, and subsequent disease recurrence and relapse, but knowledge of how CSCs are regulated is still limited. Redox status of the cells has been shown to dramatically influence cell signaling and CSC-like aggressive behaviors. Here, we investigated how subtoxic concentrations of iron, which have been found to specifically induce cellular hydroxyl radical, affected CSC-like subpopulations of human non-small cell lung carcinoma (NSCLC). We reveal for the first time that subchronic iron exposure and higher levels of hydroxyl radical correlated well with increased CSC-like phenotypes. The iron-exposed NSCLC H460 and H292 cells exhibited a remarkable increase in propensities to form CSC spheroids and to proliferate, migrate, and invade in parallel with an increase in level of a well-known CSC marker, ABCG2. We further observed that such phenotypic changes induced by iron were not related to an epithelial-to-mesenchymal transition (EMT). Instead, the sex-determining region Y (SRY)-box 9 protein (SOX9) was substantially linked to iron treatment and hydroxyl radical level. Using gene manipulations, including ectopic SOX9 overexpression and SOX9 short hairpin RNA knockdown, we have verified that SOX9 is responsible for CSC enrichment mediated by iron. These findings indicate a novel role of iron via hydroxyl radical in CSC regulation and its importance in aggressive cancer behaviors and likely metastasis through SOX9 upregulation. PMID:26911281

  5. Polydatin inhibits growth of lung cancer cells by inducing apoptosis and causing cell cycle arrest.

    PubMed

    Zhang, Yusong; Zhuang, Zhixiang; Meng, Qinghui; Jiao, Yang; Xu, Jiaying; Fan, Saijun

    2014-01-01

    Polydatin (PD), a small natural compound from Polygonum cuspidatum, has a number of biological functions. However, the anticancer activity of PD has been poorly investigated. In the present study, thiazolyl blue tetrazolium bromide assay was used to evaluate the inhibitory effect of PD on cell growth. Cell cycle distribution and apoptosis were investigated by flow cytometry. In addition, the expression of several proteins associated with apoptosis and cell cycle were analyzed by western blot analysis. The results demonstrated that PD significantly inhibits the proliferation of A549 and NCI-H1975 lung cancer cell lines and causes dose-dependent apoptosis. Cell cycle analysis revealed that PD induces S phase cell cycle arrest. Western blot analysis showed that the expression of Bcl-2 decreased as that of Bax increased, and the expression of cyclin D1 was also suppressed. The results suggest that PD has potential therapeutic applications in the treatment of lung cancer. PMID:24348867

  6. Infrared spectroscopy characterization of normal and lung cancer cells originated from epithelium

    PubMed Central

    Lee, So Yeong; Yoon, Kyong-Ah; Jang, Soo Hwa; Ganbold, Erdene Ochir; Uuriintuya, Dembereldorj; Shin, Sang-Mo; Ryu, Pan Dong

    2009-01-01

    The vibrational spectral differences of normal and lung cancer cells were studied for the development of effective cancer cell screening by means of attenuated total reflection infrared spectroscopy. The phosphate monoester symmetric stretching νs(PO32-) band intensity at ~970 cm-1 and the phosphodiester symmetric stretching νs(PO2-) band intensity at ~1,085 cm-1 in nucleic acids and phospholipids appeared to be significantly strengthened in lung cancer cells with respect to the other vibrational bands compared to normal cells. This finding suggests that more extensive phosphorylation occur in cancer cells. These results demonstrate that lung cancer cells may be prescreened using infrared spectroscopy tools. PMID:19934594

  7. The antitumor activity study of ginsenosides and metabolites in lung cancer cell

    PubMed Central

    Xu, Feng-Yuan; Shang, Wen-Qing; Yu, Jia-Jun; Sun, Qian; Li, Ming-Qing; Sun, Jian-Song

    2016-01-01

    Ginseng and its components exert various biological effects, including antioxidant, anti-carcinogenic, anti-mutagenic, and antitumor activity. Ginsenosides are the main biological components of ginseng. Protopanaxadiol (PPD) and protopanaxatriol (PPT) are two metabolites of ginsenosides. However, the difference between these compounds in anti-lung cancer is unclear. The present study aimed to evaluate the antitumor activity of PPD, PPT, Ginsenosides-Rg3 (G-Rg3) and Ginsenosides-Rh2 (G-Rh2) in lung cancer cell. After treatment with cisplatin, PPD, PPT, G-Rg3 or G-Rh2, the viability, apoptosis level and invasiveness of lung cell lines (A549 cell, a lung adenocarcinoma cell line and SK-MES-1 cell, a lung squamous cell line) in vitro were analyzed by Cell Counting Kit-8 (CCK8), Annexin V/PI apoptosis and Matrigel invasion assays, respectively. Here we found that all these compounds led to significant decreases of viability and invasiveness and an obvious increase of apoptosis of A549 and SK-MES-1 cells. Among these, the viability of SK-MES-1 cell treated with PPT was decreased to 66.8%, and this effect was closest to Cisplatin. G-Rg3 had the highest stimulatory effect on apoptosis, and PTT had the highest inhibitory effect on cell invasiveness in A549 and SK-MES-1 cells. These results indicate that both ginsenosides and two metabolites have antitumor activity on lung cancer cell in vitro. However, PPT is more powerful for inhibiting the viability and invasiveness of lung cancer cell, especially lung squamous cell. G-Rg3 has the best pro-apoptosis effects. This study provides a scientific basis for potential therapeutic strategies targeted to lung cancer by further structure modification. PMID:27186294

  8. XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

    SciTech Connect

    Wang, Ting; Han, Shuai; Wu, Zhipeng; Han, Zhitao; Yan, Wangjun; Liu, Tielong; Wei, Haifeng; Song, Dianwen; Zhou, Wang Yang, Xinghai Xiao, Jianru

    2015-08-21

    Bone metastasis occurs in approximately 30–40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis. - Highlights: • XCR1 is overexpressed in bone metastasis compared with primary NSCLC. • XCR1 activation by XCL1 promotes lung cancer cell proliferation and migration. • JAK2/STAT3 is a novel potential downstream pathway of XCR1.

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

    PubMed

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

    2015-12-15

    Nonsmall-cell lung cancer (NSCLC) is the leading type of lung cancer and has a poor prognosis. We have shown that chronic stress promoted NSCLC xenografts in mice via stress neurotransmitter-activated cAMP signaling downstream of beta-adrenergic receptors and incidental beta-blocker therapy was reported to improve clinical outcomes in NSCLC patients. These findings suggest that psychological stress promotes NSCLC whereas pharmacologically or psychologically induced decreases in cAMP may inhibit NSCLC. Cancer stem cells are thought to drive the development, progression and resistance to therapy of NSCLC. However, their potential regulation by stress neurotransmitters has not been investigated. In the current study, epinephrine increased the number of cancer stem cell like cells (CSCs) from three NSCLC cell lines in spheroid formation assays while enhancing intracellular cAMP and the stem cell markers sonic hedgehog (SHH), aldehyde dehydrogenase-1 (ALDH-1) and Gli1, effects reversed by GABA or dynorphin B via Gαi -mediated inhibition of cAMP formation. The growth of NSCLC xenografts in a mouse model of stress reduction was significantly reduced as compared with mice maintained under standard conditions. Stress reduction reduced serum levels of corticosterone, norepinephrine and epinephrine while the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and opioid peptides increased. Stress reduction significantly reduced cAMP, VEGF, p-ERK, p-AKT, p-CREB, p-SRc, SHH, ALDH-1 and Gli1 in xenograft tissues whereas cleaved caspase-3 and p53 were induced. We conclude that stress neurotransmitters activate CSCs in NSCLC via multiple cAMP-mediated pathways and that pharmacologically or psychologically induced decreases in cAMP signaling may improve clinical outcomes in NSCLC patients. PMID:26088878

  10. Inhibitor-Sensitive FGFR1 Amplification in Human Non-Small Cell Lung Cancer

    PubMed Central

    Dutt, Amit; Ramos, Alex H.; Hammerman, Peter S.; Mermel, Craig; Cho, Jeonghee; Sharifnia, Tanaz; Chande, Ajit; Tanaka, Kumiko Elisa; Stransky, Nicolas; Greulich, Heidi; Gray, Nathanael S.; Meyerson, Matthew

    2011-01-01

    Background Squamous cell lung carcinomas account for approximately 25% of new lung carcinoma cases and 40,000 deaths per year in the United States. Although there are multiple genomically targeted therapies for lung adenocarcinoma, none has yet been reported in squamous cell lung carcinoma. Methodology/Principal Findings Using SNP array analysis, we found that a region of chromosome segment 8p11-12 containing three genes–WHSC1L1, LETM2, and FGFR1–is amplified in 3% of lung adenocarcinomas and 21% of squamous cell lung carcinomas. Furthermore, we demonstrated that a non-small cell lung carcinoma cell line harboring focal amplification of FGFR1 is dependent on FGFR1 activity for cell growth, as treatment of this cell line either with FGFR1-specific shRNAs or with FGFR small molecule enzymatic inhibitors leads to cell growth inhibition. Conclusions/Significance These studies show that FGFR1 amplification is common in squamous cell lung cancer, and that FGFR1 may represent a promising therapeutic target in non-small cell lung cancer. PMID:21666749

  11. Targeted therapies and immunotherapy in non-small-cell lung cancer

    PubMed Central

    Cortinovis, D; Abbate, M; Bidoli, P; Capici, S; Canova, S

    2016-01-01

    Non-small-cell lung cancer is still considered a difficult disease to manage because of its aggressiveness and resistance to common therapies. Chemotherapy remains the gold standard in nearly 80% of lung cancers, but clinical outcomes are discouraging, and the impact on median overall survival (OS) barely reaches 12 months. At the end of the last century, the discovery of oncogene-driven tumours completely changed the therapeutic landscape in lung cancers, harbouring specific gene mutations/translocations. Epidermal growth factors receptor (EGFR) common mutations first and anaplastic lymphoma kinase (ALK) translocations later led new insights in lung cancer biology knowledge. The use of specific tyrosine kinases inhibitors overturned the biological behaviour of EGFR mutation positive tumours and became a preclinical model to understand the heterogeneity of lung cancers and the mechanisms of drug resistance. In this review, we summarise the employment of targeted agents against the most representative biomolecular alterations and provide some criticisms of the therapeutic strategies. PMID:27433281

  12. Non-small cell lung cancer: current treatment and future advances

    PubMed Central

    Zappa, Cecilia

    2016-01-01

    Lung cancer has a poor prognosis; over half of people diagnosed with lung cancer die within one year of diagnosis and the 5-year survival is less than 18%. Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancer cases. Risk factors for developing NSCLC have been identified, with cigarette smoking being a major factor along with other environmental and genetic risk factors. Depending on the staging of lung cancer, patients are eligible for certain treatments ranging from surgery to radiation to chemotherapy as well as targeted therapy. With the advancement of genetics and biomarkers testing, specific mutations have been identified to better target treatment for individual patients. This review discusses current treatments including surgery, chemotherapy, radiotherapy, and immunotherapy as well as how biomarker testing has helped improve survival in patients with NSCLC. PMID:27413711

  13. Pharmacological Modulation of Cytotoxicity and Cellular Uptake of Anti-cancer Drugs by PDE5 Inhibitors in Lung Cancer Cells

    PubMed Central

    LI, QING; SHU, YAN

    2013-01-01

    Purpose Previous research has led to the recognition of a cGMP signaling pathway governing drug transport. This study is to investigate whether inhibitors of phosphodiesterase type 5 (PDE5), which increase intracellular cGMP levels, modulate the cytotoxicity and uptake of anti-cancer drugs in cancer cells. Methods The experiments were conducted with and without PDE5 inhibitors: dipyridamole, vardenafil, and/or sildenafil. The cytotoxicity of doxorubicin, cisplatin and oxaliplatin was determined in multiple cancer cell lines derived from different tissues. The cellular uptake of structurally diverse compounds was further examined in lung cancer cells with and without various endocytotic inhibitors. The tumor accumulation and the anti-tumor effect of trastuzumab were examined in a lung cancer xenograft mouse model. Results Dipyridamole could modulate the cytotoxicity of doxorubicin, cisplatin, and oxaliplatin in cancer cells. Particularly, PDE5 inhibitors increased cellular uptake of structurally diverse compounds into lung cancer cells both in vitro and in vivo. The effect of vardenafil on drug uptake could be blocked by endocytotic inhibitors. The growth of lung cancer xenograft in nude mice was significantly suppressed by addition of vardenafil to trastuzumab treatment. Conclusion PDE5 inhibitors may increase the efficacy of anti-cancer drugs by increasing endocytosis-mediated cellular drug uptake, and thus serve as adjuvant therapy for certain cancers such as lung cancer. PMID:23884568

  14. Augmented delivery of gemcitabine in lung cancer cells exploring mannose anchored solid lipid nanoparticles.

    PubMed

    Soni, Namrata; Soni, Neetu; Pandey, Himanshu; Maheshwari, Rahul; Kesharwani, Prashant; Tekade, Rakesh Kumar

    2016-11-01

    Gemcitabine (GmcH) is an effective anti-cancer agent used in the chemotherapy of lung cancer. However, the clinical applications of GmcH has been impeded primarily due to its low blood residence time, unfavorable pharmacokinetic and pharmacodynamic (PK/PD) profile, and poor penetration in the complex environment of lung cancer cells. Thus, the present study aims to formulate GmcH loaded mannosylated solid lipid nanoparticles (GmcH-SLNs) for improving its drug uptake into the lung cancer cells. GmcH-SLNs were prepared by emulsification and solvent evaporation process, and surface modification was done with mannose using ring opening technique. The cellular toxicity and cell uptake studies were performed in A549 lung adenocarcinoma cell line. The developed nanoformulation appears to be proficient in targeted delivery of GmcH with improved therapeutic effectiveness and enhanced safety. PMID:27459173

  15. Protein signature for non-small cell lung cancer prognosis

    PubMed Central

    Liu, Wei; Wu, Yong; Wang, Libo; Gao, Ling; Wang, Yingping; Liu, Xiaoliang; Zhang, Kai; Song, Jena; Wang, Hongxia; Bayer, Thomas A; Glaser, Laurel; Sun, Yezhou; Zhang, Weijia; Cutaia, Michael; Zhang, David Y; Ye, Fei

    2014-01-01

    Background: Current histopathological classification and TNM staging have limited accuracy in predicting survival and stratifying patients for appropriate treatment. The goal of the study is to determine whether the expression pattern of functionally important regulatory proteins can add additional values for more accurate classification and prognostication of non-small lung cancer (NSCLC). Methods: The expression of 108 proteins and phosphoproteins in 30 paired NSCLC samples were assessed using Protein Pathway Array (PPA). The differentially expressed proteins were further confirmed using a tissue microarray (TMA) containing 94 NSCLC samples and were correlated with clinical data and survival. Results: Twelve of 108 proteins (p-CREB(Ser133), p-ERK1/2(Thr202/Tyr204), Cyclin B1, p-PDK1(Ser241), CDK4, CDK2, HSP90, CDC2p34, β-catenin, EGFR, XIAP and PCNA) were selected to build the predictor to classify normal and tumor samples with 97% accuracy. Five proteins (CDC2p34, HSP90, XIAP, CDK4 and CREB) were confirmed to be differentially expressed between NSCLC (n=94) and benign lung tumor (n=19). Over-expression of CDK4 and HSP90 in tumors correlated with a favorable overall survival in all NSCLC patients and the over-expression of p-CREB(Ser133) and CREB in NSCLC correlated with a favorable survival in smokers and those with squamous cell carcinoma, respectively. Finally, the four proteins (CDK4, HSP90, p-CREB and CREB) were used to calculate the risk score of each individual patient with NSCLC to predict survival. Conclusion: In summary, our data demonstrated a broad disturbance of functionally important regulatory proteins in NSCLC and some of these can be selected as clinically useful biomarkers for diagnosis, classification and prognosis. PMID:24959380

  16. Ninjurin1 suppresses metastatic property of lung cancer cells through inhibition of interleukin 6 signaling pathway.

    PubMed

    Jang, Yeong-Su; Kang, Ju-Hee; Woo, Jong Kyu; Kim, Hwan Mook; Hwang, Jong-Ik; Lee, Sang-Jin; Lee, Ho-Young; Oh, Seung Hyun

    2016-07-15

    Nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a cell surface molecule that can mediate homophilic adhesion and promote neurite outgrowth from cultured dorsal root ganglion (DRG) neurons. Interestingly, Ninj1 overexpressed in human cancer; however, its role in metastasis is not clear. This study showed that inhibition of Ninj1 promotes lung cancer metastasis through interleukin 6 (IL-6)/STAT3 signaling. Ninj1 levels were relatively low in highly motile lung cancer cells. While inhibition of Ninj1 enhanced cell migration in lung cancer cells, overexpression of Ninj1 significantly suppressed it. We found that inhibition of Ninj1 significantly increased expression and secretion of IL-6 in A549 cells. We also found that inhibition of IL-6 decreased intercellular adhesion molecule 1 (ICAM-1) expression. In addition, inhibition of Ninj1 significantly increased cell motility and invasiveness of lung cancer cells. In an in vivo model, we found that Ninj1 suppression did not affect tumor growth but induced significant increase in incidence of lung metastasis, and sizes and number of tumor nodules. Taken together, our data clearly demonstrate that Ninj1 suppresses migration, invasion and metastasis of lung cancer via inhibition of the IL-6 signaling pathway in vitro and in vivo. PMID:26815582

  17. mir-1-mediated paracrine effect of cancer-associated fibroblasts on lung cancer cell proliferation and chemoresistance.

    PubMed

    Li, Jianmin; Guan, Jing; Long, Xiaoping; Wang, Yang; Xiang, Xudong

    2016-06-01

    Lung cancer is the leading cause of cancer-related mortality in humans worldwide. Moreover, the overall 5-year survival rate is only 15%. Pathologically almost 80% of all lung cancer cases are non-small cell lung cancer (NSCLC). Cancer-associated fibroblasts (CAFs) have been found to exist in a large number of NSCLCs. CAFs have been proven to promote tumor progression, metastasis and resistance to therapy through paracrine effects in most solid tumors. In the present study, firstly we isolated CAFs from patient tissues and demonstrated that they promoted cell proliferation and chemoresistance to cisplatin in the lung cancer cell lines A549 and 95D in a paracrine manner. Secondly, using ELISA and quantative PCR, we found that a higher amount of stromal cell-derived factor 1 (SDF-1) existed in the CAFs rather than that observed in the normal fibroblasts (NFs). Thirdly, we detected that SDF-1 facilitated lung cancer cell proliferation and drug resistance via the CXCR4-mediated signaling pathway which involved NF-κB and Bcl-xL. Moreover, we also confirmed that the expression level of SDF-1 in the CAFs was negatively regulated by microRNA mir-1 through microRNA overexpression and quantitative PCR. Overall, our data provide one explanation for the effects of CAFs on lung cancer cells. Meanwhile, our results also suggest CAFs as a potential therapeutic target in tumor treatment. PMID:27035564

  18. Inhibitory Activity of (+)-Usnic Acid against Non-Small Cell Lung Cancer Cell Motility

    PubMed Central

    Yang, Yi; Nguyen, Thanh Thi; Jeong, Min-Hye; Crişan, Florin; Yu, Young Hyun; Ha, Hyung-Ho; Choi, Kyung Hee; Jeong, Hye Gwang; Jeong, Tae Cheon; Lee, Kwang Youl; Kim, Kyung Keun; Hur, Jae-Seoun; Kim, Hangun

    2016-01-01

    Lichens are symbiotic organisms that produce various unique chemicals that can be used for pharmaceutical purposes. With the aim of screening new anti-cancer agents that inhibit cancer cell motility, we tested the inhibitory activity of seven lichen species collected from the Romanian Carpathian Mountains against migration and invasion of human lung cancer cells and further investigated the molecular mechanisms underlying their anti-metastatic activity. Among them, Alectoria samentosa, Flavocetraria nivalis, Alectoria ochroleuca, and Usnea florida showed significant inhibitory activity against motility of human lung cancer cells. HPLC results showed that usnic acid is the main compound in these lichens, and (+)-usnic acid showed similar inhibitory activity that crude extract have. Mechanistically, β-catenin-mediated TOPFLASH activity and KITENIN-mediated AP-1 activity were decreased by (+)-usnic acid treatment in a dose-dependent manner. The quantitative real-time PCR data showed that (+)-usnic acid decreased the mRNA level of CD44, Cyclin D1 and c-myc, which are the downstream target genes of both β-catenin/LEF and c-jun/AP-1. Also, Rac1 and RhoA activities were decreased by treatment with (+)-usnic acid. Interestingly, higher inhibitory activity for cell invasion was observed when cells were treated with (+)-usnic acid and cetuximab. These results implied that (+)-usnic acid might have potential activity in inhibition of cancer cell metastasis, and (+)-usnic acid could be used for anti-cancer therapy with a distinct mechanisms of action. PMID:26751081

  19. Inhibitory Activity of (+)-Usnic Acid against Non-Small Cell Lung Cancer Cell Motility.

    PubMed

    Yang, Yi; Nguyen, Thanh Thi; Jeong, Min-Hye; Crişan, Florin; Yu, Young Hyun; Ha, Hyung-Ho; Choi, Kyung Hee; Jeong, Hye Gwang; Jeong, Tae Cheon; Lee, Kwang Youl; Kim, Kyung Keun; Hur, Jae-Seoun; Kim, Hangun

    2016-01-01

    Lichens are symbiotic organisms that produce various unique chemicals that can be used for pharmaceutical purposes. With the aim of screening new anti-cancer agents that inhibit cancer cell motility, we tested the inhibitory activity of seven lichen species collected from the Romanian Carpathian Mountains against migration and invasion of human lung cancer cells and further investigated the molecular mechanisms underlying their anti-metastatic activity. Among them, Alectoria samentosa, Flavocetraria nivalis, Alectoria ochroleuca, and Usnea florida showed significant inhibitory activity against motility of human lung cancer cells. HPLC results showed that usnic acid is the main compound in these lichens, and (+)-usnic acid showed similar inhibitory activity that crude extract have. Mechanistically, β-catenin-mediated TOPFLASH activity and KITENIN-mediated AP-1 activity were decreased by (+)-usnic acid treatment in a dose-dependent manner. The quantitative real-time PCR data showed that (+)-usnic acid decreased the mRNA level of CD44, Cyclin D1 and c-myc, which are the downstream target genes of both β-catenin/LEF and c-jun/AP-1. Also, Rac1 and RhoA activities were decreased by treatment with (+)-usnic acid. Interestingly, higher inhibitory activity for cell invasion was observed when cells were treated with (+)-usnic acid and cetuximab. These results implied that (+)-usnic acid might have potential activity in inhibition of cancer cell metastasis, and (+)-usnic acid could be used for anti-cancer therapy with a distinct mechanisms of action. PMID:26751081

  20. Identification of potential erythrocyte phospholipid fatty acid biomarkers of advanced lung adenocarcinoma, squamous cell lung carcinoma, and small cell lung cancer.

    PubMed

    Sánchez-Rodríguez, Patricia; Rodríguez, Marina C; Sánchez-Yagüe, Jesús

    2015-07-01

    New biomarkers for lung cancer would be valuable. Our aim was to analyze the fatty acid profiles of the main phospholipid species in erythrocytes from patients with advanced squamous cell lung carcinoma (SCC), lung adenocarcinoma (ADC), and small cell lung cancer (SCLC) and benign lung diseases (chronic obstructive pulmonary disease (COPD) and asthma) to determine the fatty acids that could be use as lung cancer markers. Twenty-eight, 18, 14, 16, and 15 patients with, respectively, SCC, ADC, SCLC, asthma, and COPD and 50 healthy subjects were enrolled in the study. Fatty acid profiles were investigated using gas chromatography/mass spectrometry followed by receiver operating characteristic (ROC) curve analysis. The fatty acid profiles changed significantly in the different pathologies analyzed. Based on the diagnostic yields and operating characteristics, the most significant fatty acids that might be used as biomarkers were as follows: ADC--arachidonic acid (20:4n6) in phosphatidylcholine and oleic acid (18:1n9) in phosphatidylethanolamine (PE); SCC--eicosapentaenoic acid (20:5n3) in PE and palmitic acid (16:0) in phosphatidylserine + phosphatidylinositol (PS+PI); SCLC--eicosadienoic acid (20:2n6) in PS+PI and lignoceric acid (24:0) in sphingomyelin. In conclusion, fatty acids from erythrocyte phospholipid species might serve as biomarkers in the diagnosis, and probably in other aspects related to clinical disease management, of ADC, SCC, and SCLC. PMID:25702090

  1. Wnt signaling pathway in non-small cell lung cancer.

    PubMed

    Stewart, David J

    2014-01-01

    Wnt/β-catenin alterations are prominent in human malignancies. In non-small cell lung cancer (NSCLC), β-catenin and APC mutations are uncommon, but Wnt signaling is important in NSCLC cell lines, and Wnt inhibition reduces proliferation. Overexpression of Wnt-1, -2, -3, and -5a and of Wnt-pathway components Frizzled-8, Dishevelled, Porcupine, and TCF-4 is common in resected NSCLC and is associated with poor prognosis. Conversely, noncanonical Wnt-7a suppresses NSCLC development and is often downregulated. Although β-catenin is often expressed in NSCLCs, it was paradoxically associated with improved prognosis in some series, possibly because of E-cadherin interactions. Downregulation of Wnt inhibitors (eg, by hypermethylation) is common in NSCLC tumor cell lines and resected samples; may be associated with high stage, dedifferentiation, and poor prognosis; and has been reported for AXIN, sFRPs 1-5, WIF-1, Dkk-1, Dkk-3, HDPR1, RUNX3, APC, CDX2, DACT2, TMEM88, Chibby, NKD1, EMX2, ING4, and miR-487b. AXIN is also destabilized by tankyrases, and GSK3β may be inactivated through phosphorylation by EGFR. Preclinically, restoration of Wnt inhibitor function is associated with reduced Wnt signaling, decreased cell proliferation, and increased apoptosis. Wnt signaling may also augment resistance to cisplatin, docetaxel, and radiotherapy, and Wnt inhibitors may restore sensitivity. Overall, available data indicate that Wnt signaling substantially impacts NSCLC tumorigenesis, prognosis, and resistance to therapy, with loss of Wnt signaling inhibitors by promoter hypermethylation or other mechanisms appearing to be particularly important. Wnt pathway antagonists warrant exploration clinically in NSCLC. Agents blocking selected specific β-catenin interactions and approaches to increase expression of downregulated Wnt inhibitors may be of particular interest. PMID:24309006

  2. miR-411 contributes the cell proliferation of lung cancer by targeting FOXO1.

    PubMed

    Zhao, Zhiju; Qin, Limei; Li, Shu

    2016-04-01

    Lung cancer is the leading cause of cancer deaths worldwide; the study of microRNAs gives new hope for lung cancer treatment. miR-411 has been demonstrated to be an independent prognostic factor for lung adenocarcinoma, but the role and regulatory mechanism are largely unknown. In the present study, we found miR-411 was overexpressed in the lung cancer cells; overexpression of miR-411 promoted anchorage-dependent and anchorage-independent growths of lung cancer, while miR-411 knockdown reduced this effect. Further study showed forkhead box O1 (FOXO1) was a target of miR-411. Overexpression of miR-411 suppressed the expression of FOXO1; the effect of suppression was abrogated when the mutation occurred in the 3'UTR of FOXO1. Knockdown of FOXO1 in cells which miR-411 was inhibited recapitulated the phenotype of miR-411 overexpression. Taken together, our study revealed miR-411 promoted cell proliferation of lung cancer by targeting tumor suppressor gene FOXO1 and miR-411 might be a potential target for lung cancer therapy. PMID:26572153

  3. Inhibition of CK2α down-regulates Notch1 signalling in lung cancer cells

    PubMed Central

    Zhang, Shulin; Long, Hao; Yang, Yi-Lin; Wang, Yucheng; Hsieh, David; Li, Weiming; Au, Alfred; Stoppler, Hubert J; Xu, Zhidong; Jablons, David M; You, Liang

    2013-01-01

    Protein kinase CK2 is frequently elevated in a variety of human cancers. The Notch1 signalling pathway has been implicated in stem cell maintenance and its aberrant activation has been shown in several types of cancer including lung cancer. Here, we show, for the first time, that CK2α is a positive regulator of Notch1 signalling in lung cancer cell lines A549 and H1299. We found that Notch1 protein level was reduced after CK2α silencing. Down-regulation of Notch1 transcriptional activity was demonstrated after the silencing of CK2α in lung cancer cells. Furthermore, small-molecule CK2α inhibitor CX-4945 led to a dose-dependent inhibition of Notch1 transcriptional activity. Conversely, forced overexpression of CK2α resulted in an increase in Notch1 transcriptional activity. Finally, the inhibition of CK2α led to a reduced proportion of stem-like CD44 + /CD24− cell population. Thus, we report that the inhibition of CK2α down-regulates Notch1 signalling and subsequently reduces a cancer stem-like cell population in human lung cancer cells. Our data suggest that CK2α inhibitors may be beneficial to the lung cancer patients with activated Notch1 signalling. PMID:23651443

  4. The Distribution of Human Stem Cell-like Memory T Cell in Lung Cancer.

    PubMed

    Hong, Hai; Gu, Yong; Sheng, Si Yuan; Lu, Chuan Gang; Zou, Jian Yong; Wu, Chang You

    2016-01-01

    Human stem cell-like memory T (Tscm) cells are long-lived, self-renewing memory lymphocytes that can differentiate into effector cells and mediate strong antitumour response in murine model. The distribution and function of Tscm cells in human lung cancer remain unknown. In this study, we investigated the properties of human Tscm cells in the blood and lymph node of non-small cell lung cancer (NSCLC) patients. There were more CD4 Tscm cells in blood from NSCLC patients than from healthy donors, fewer CD4 and CD8 TSCM cells in blood than in lymph node from NSCLC patients. To further analyze their properties, we stimulated peripheral blood mononuclear cells from NSCLC patients by mitogens to examine cytokine production. Our data suggest that both CD4 and CD8 Tscm cells in blood produced interferon-γ significantly increased in NSCLC patients compare with healthy subjects. In addition, fewer Tscm cells produced interferon-γ in lymph node than in blood from NSCLC patients. Our results strongly suggest that the distribution and function of CD4 Tscm cells in NSCLC patients is upregulated. Understanding of the properties of stem-like memory T cells will supply a good rationale for designing the new adoptive immunotherapy in cancer. PMID:27244531

  5. [Serotonin syndrome in a patient with small cell lung cancer].

    PubMed

    Takahashi, Chieko; Goto, Emi; Taira, Sachiko; Kataoka, Noriaki; Nishihara, Masami; Katsumata, Takahiro; Goto, Isao; Takiuchi, Hiroya

    2013-08-01

    The patient was a 67-year-old male who had been treated for several years with 150 mg fluvoxamine maleate due to depression. He visited our hospital with primary symptoms of swelling of the right upper extremity and dyspnea in August, XXXX. As a result of examinations, he was diagnosed with stage IIIB extended small cell lung cancer(T4N3M0). One course of carboplatin/etoposide(CBDCA/VP-16)therapy was started on October 1. Since the tumor size was reduced, thoracic effusion disappeared, and superior vena cava syndrome was alleviated, the therapy was changed to cisplatin/irinotecan (CDDP/CPT-11)on October 23, and the 3rd course was initiated on November 22. Anxiety and tremor appeared on the 4th day of the 3rd course and because they were exacerbated, and myoclonus appeared, a diagnosis of serotonin syndrome was made on the 38th day, and the administration of fluvoxamine maleate was discontinued. The symptoms were alleviated after the discontinuation, and the 4th course could be implemented. In this patient, serotonin syndrome was considered to have been induced by serotonin secretion promoted by the CDDP administration, and by serotonin in the brain increasing abnormally due to the SSRI. PMID:23986051

  6. Small cell lung cancer with metastasis to the thyroid in a patient with toxic multinodular goiter.

    PubMed

    Ozgu, Eylem Sercan; Gen, Ramazan; Ilvan, Ahmet; Ozge, Cengiz; Polat, Ayşe; Vayisoglu, Yusuf

    2012-11-01

    Thyroid metastasis of lung cancer is rarely observed in clinical practice. The primary cancers which metastasize to the thyroid gland are mostly renal cell carcinoma, lung cancer, and breast cancer. Transient destructive thyrotoxicosis is caused by massive metastasis of extrathyroid tumors. We herein present a case report of a patient with small cell carcinoma of lung with metastasis to the thyroid and thyrotoxicosis due to toxic multinodular goiter. A 66-year-old man complained of swelling around the right side of the neck, dyspnea, progressive weight loss, and palpitation starting since 3 months before his admission. The patient was diagnosed with small cell carcinoma of lung with metastasis to the thyroid and thyrotoxicosis due to toxic multinodular goiter. The case report presented here illustrates the challenge of making a definitive and adequate diagnosis, particularly if the patient presents with 2 potential causes of thyrotoxicosis. Thyroid scintigraphy is an important tool for differential diagnosis of thyrotoxicosis. PMID:23172496

  7. Chemoprevention of lung cancer.

    PubMed

    Keith, Robert L

    2009-04-15

    Lung cancer is the leading cause of cancer death in the United States, and the majority of diagnoses are made in former smokers. While avoidance of tobacco abuse and smoking cessation clearly will have the greatest impact on lung cancer development, effective chemoprevention could prove to be more effective than treatment of established disease. Chemoprevention is the use of dietary or pharmaceutical agents to reverse or inhibit the carcinogenic process and has been successfully applied to common malignancies other than lung. Despite previous studies in lung cancer chemoprevention failing to identify effective agents, our ability to determine higher risk populations and the understanding of lung tumor and pre-malignant biology continues to advance. Additional biomarkers of risk continue to be investigated and validated. The World Health Organization/International Association for the Study of Lung Cancer classification for lung cancer now recognizes distinct histologic lesions that can be reproducibly graded as precursors of non-small cell lung cancer. For example, carcinogenesis in the bronchial epithelium starts with normal epithelium and progresses through hyperplasia, metaplasia, dysplasia, and carcinoma in situ to invasive squamous cell cancer. Similar precursor lesions exist for adenocarcinoma, and these pre-malignant lesions are targeted by chemopreventive agents in current and future trials. At this time, chemopreventive agents can only be recommended as part of well-designed clinical trials, and multiple trials are currently in progress and additional trials are in the planning stages. This review will discuss the principles of chemoprevention, summarize the completed trials, and discuss ongoing and potential future trials with a focus on targeted pathways. PMID:19349487

  8. The role of ifosfamide in small cell lung cancer.

    PubMed

    Loehrer, P J

    1996-06-01

    The emergence of chemotherapy has dramatically improved both quality of life and survival in patients with small cell lung cancer (SCLC). Nonetheless, achieving long-term survival in SCLC patients has been a problem. Early studies of combination chemotherapy with cyclophosphamide/doxorubicin/vincristine (CAV) and cyclophosphamide/methotrexate/lomustine/vincristine (CMCV) reported impressive response rates in patients with SCLC. Ifosfamide, an analogue of cyclophosphamide, has demonstrated single-agent activity against SCLC, achieving overall response rates ranging from 5.6% to 76.5%. Because of this, and because of the agent's proven synergism in combination chemotherapy for recurrent testicular cancer and its relative non-myelosuppressive qualities (compared with cyclophosphamide), the incorporation of ifosfamide into combination chemotherapy for SCLC was rational. The Hoosier Oncology Group reported high response rates with VIP (ifosfamide combined with etoposide/cisplatin) in SCLC patients and proved the superiority of VIP over etoposide/cisplatin in patients with extensive disease. Presently, this group is evaluating the role of chronic oral etoposide as maintenance chemotherapy for patients with extensive SCLC that responds to initial VIP treatment. Salvage treatment with daily oral etoposide has also produced encouraging results, leading the Hoosier Oncology Group to incorporate oral etoposide as part of the VIP regimen (VoIP). It is currently unclear whether combination chemotherapy containing daily oral etoposide will have a major impact on survival. Further trials of combination chemotherapy with newer active agents like paclitaxel and topotecan, as well as with proven single agents like ifosfamide, are clearly warranted to improve the outcome of patients with SCLC. PMID:8711501

  9. Synthesis and Characterization of Inhalable Flavonoid Nanoparticle for Lung Cancer Cell Targeting.

    PubMed

    Lee, Wing-Hin; Loo, Ching-Yee; Ong, Hui-Xin; Traini, Daniela; Young, Paul M; Rohanizadeh, Ramin

    2016-02-01

    Current cancer treatments are not adequate to cure cancer disease, as most chemotherapeutic drugs do not differentiate between cancerous and non-cancerous cells; which lead to systemic toxicity and adverse effects. We have developed a promising approach to deliver a potential anti-cancer compound (curcumin) for lung cancer treatment through pulmonary delivery. Three different sizes of curcumin micellar nanoparticles (Cur-NPs) were fabricated and their cytotoxicity effects (proliferation, apoptosis, cell cycle progression) were evaluated against non-small-cell lung cancer, human lung carcinoma (A549) and human lung adenocarcinoma (Calu-3). The in vitro cytotoxicity assay showed that Cur-NPs were more effective to kill lung cancer cells compared to DMSO-solubilised raw curcumin. The potency of the anti-cancer killing activities was size-dependent. Both raw curcumin and Cur-NPs were not toxic to healthy lung cells (BEAS-2B). Smaller Cur-NPs accumulated within nucleus, membrane and cytoplasm. Cur-NPs also induced apoptosis and caused G2/M arrest in both A549 and Calu-3 cell lines. Compared to raw curcumin, Cur-NPs were more effective in suppressing the expression of the inflammatory marker, Interleukin-8 (IL8). The aerosol performance of Cur-NPs was characterized using the next generation impactor (NGI). All Cur-NPs showed promising aerosolization property with mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) ranging between 4.8-5.2 and 2.0-2.1, respectively. This study suggests that inhaled curcumin nanoparticles could potentially be used for lung cancer treatment with minimal side effects. PMID:27305771

  10. HOXA9 inhibits migration of lung cancer cells and its hypermethylation is associated with recurrence in non-small cell lung cancer.

    PubMed

    Hwang, Jung-Ah; Lee, Bo Bin; Kim, Yujin; Hong, Seung-Hyun; Kim, Young-Ho; Han, Joungho; Shim, Young Mog; Yoon, Chae-Yeong; Lee, Yeon-Su; Kim, Duk-Hwan

    2015-06-01

    This study was aimed at understanding the clinicopathological significance of HOXA9 hypermethylation in non-small cell lung cancer (NSCLC). HOXA9 hypermethylation was characterized in six lung cancer cell lines, and its clinicopathological significance was analyzed using methylation-specific PCR in 271 formalin-fixed paraffin-embedded tissues and 27 fresh-frozen tumor and matched normal tissues from 298 NSCLC patients, and Ki-67 expression was analyzed using immunohistochemistry. The promoter region of HOXA9 was highly methylated in six lung cancer cell lines, but not in normal bronchial epithelial cells. The loss of expression was restored by treatment of the cells with a demethylating agent, 5-aza-2'-deoxycytidine (5-Aza-dC). Transient transfection of HOXA9 into H23 lung cancer cells resulted in the inhibition of cell migration but not proliferation. Conversely, sequence-specific siRNA-mediated knockdown of HOXA9 enhanced cell migration. The mRNA levels of HOXA9 in 27 fresh-frozen tumor tissues were significantly lower than in matched normal tissues (P<0.0001; Wilcoxon signed-rank test). HOXA9 hypermethylation was found in 191 (70%) of 271 primary NSCLCs. HOXA9 hypermethylation was not associated with tumor size (P=0.12) and Ki-67 proliferation index (P=0.15). However, patients with HOXA9 hypermethylation had poor recurrence-free survival (hazard ratio=3.98, 95% confidence interval = 1.07-17.09, P=0.01) in never-smokers, after adjusting for age, sex, tumor size, adjuvant therapy, pathologic stage, and histology. In conclusion, the present study suggests that HOXA9 inhibits migration of lung cancer cells and its hypermethylation is an independent prognostic factor for recurrence-free survival in never-smokers with NSCLC. PMID:24817037

  11. TASK-1 Regulates Apoptosis and Proliferation in a Subset of Non-Small Cell Lung Cancers.

    PubMed

    Leithner, Katharina; Hirschmugl, Birgit; Li, Yingji; Tang, Bi; Papp, Rita; Nagaraj, Chandran; Stacher, Elvira; Stiegler, Philipp; Lindenmann, Jörg; Olschewski, Andrea; Olschewski, Horst; Hrzenjak, Andelko

    2016-01-01

    Lung cancer is the leading cause of cancer deaths worldwide; survival times are poor despite therapy. The role of the two-pore domain K+ (K2P) channel TASK-1 (KCNK3) in lung cancer is at present unknown. We found that TASK-1 is expressed in non-small cell lung cancer (NSCLC) cell lines at variable levels. In a highly TASK-1 expressing NSCLC cell line, A549, a characteristic pH- and hypoxia-sensitive non-inactivating K+ current was measured, indicating the presence of functional TASK-1 channels. Inhibition of TASK-1 led to significant depolarization in these cells. Knockdown of TASK-1 by siRNA significantly enhanced apoptosis and reduced proliferation in A549 cells, but not in weakly TASK-1 expressing NCI-H358 cells. Na+-coupled nutrient transport across the cell membrane is functionally coupled to the efflux of K+ via K+ channels, thus TASK-1 may potentially influence Na+-coupled nutrient transport. In contrast to TASK-1, which was not differentially expressed in lung cancer vs. normal lung tissue, we found the Na+-coupled nutrient transporters, SLC5A3, SLC5A6, and SLC38A1, transporters for myo-inositol, biotin and glutamine, respectively, to be significantly overexpressed in lung adenocarcinomas. In summary, we show for the first time that the TASK-1 channel regulates apoptosis and proliferation in a subset of NSCLC. PMID:27294516

  12. TASK-1 Regulates Apoptosis and Proliferation in a Subset of Non-Small Cell Lung Cancers

    PubMed Central

    Leithner, Katharina; Hirschmugl, Birgit; Li, Yingji; Tang, Bi; Papp, Rita; Nagaraj, Chandran; Stacher, Elvira; Stiegler, Philipp; Lindenmann, Jörg; Olschewski, Andrea; Olschewski, Horst; Hrzenjak, Andelko

    2016-01-01

    Lung cancer is the leading cause of cancer deaths worldwide; survival times are poor despite therapy. The role of the two-pore domain K+ (K2P) channel TASK-1 (KCNK3) in lung cancer is at present unknown. We found that TASK-1 is expressed in non-small cell lung cancer (NSCLC) cell lines at variable levels. In a highly TASK-1 expressing NSCLC cell line, A549, a characteristic pH- and hypoxia-sensitive non-inactivating K+ current was measured, indicating the presence of functional TASK-1 channels. Inhibition of TASK-1 led to significant depolarization in these cells. Knockdown of TASK-1 by siRNA significantly enhanced apoptosis and reduced proliferation in A549 cells, but not in weakly TASK-1 expressing NCI-H358 cells. Na+-coupled nutrient transport across the cell membrane is functionally coupled to the efflux of K+ via K+ channels, thus TASK-1 may potentially influence Na+-coupled nutrient transport. In contrast to TASK-1, which was not differentially expressed in lung cancer vs. normal lung tissue, we found the Na+-coupled nutrient transporters, SLC5A3, SLC5A6, and SLC38A1, transporters for myo-inositol, biotin and glutamine, respectively, to be significantly overexpressed in lung adenocarcinomas. In summary, we show for the first time that the TASK-1 channel regulates apoptosis and proliferation in a subset of NSCLC. PMID:27294516

  13. Heat shock protein 27 promotes cell proliferation through activator protein-1 in lung cancer

    PubMed Central

    ZHANG, SAI; HU, YANGMIN; HUANG, YUWEN; XU, HUIMIN; WU, GONGXIONG; DAI, HAIBIN

    2015-01-01

    Heat shock protein 27 (HSP27) is an important regulator involved in the development of lung cancer. However, limited evidence exists concerning the underlying molecular mechanisms of its action. The results of the present study revealed that HSP27 was highly expressed in the lung cancer tissues of mice. In an in vitro model, the overexpression of HSP27 promoted cell proliferation, while HSP27 knockdown inhibited cell proliferation. HSP27 promoted cell proliferation in vitro by directly upregulating the expression of HSP27 target genes, which required the activation of the activator protein-1 (AP-1) signaling pathway. This was evaluated by the phosphorylation status of an important pathway component, c-Jun in lung cancer tissue and cells. These results suggested that HSP27 has a promotional role in lung cancer, and therefore indicated a novel mechanism involving lung cancer cell proliferation, which may underlie poor responses to therapy. Therefore, HSP27 may be a suitable therapeutic target for the treatment of lung cancer. PMID:26137108

  14. Effect of synchronous solitary bone metastasectomy and lung cancer resection on non-small cell lung cancer patients

    PubMed Central

    ZHAO, TIANCHENG; GAO, ZONGLI; WU, WEIMING; HE, WEIWEI; YANG, YI

    2016-01-01

    Lung cancer is the most frequent cause of cancer-associated mortality among men and women globally. The skeleton is one of the most common metastatic sites. The majority of patients exhibiting bone metastases are treated using systemic therapy or symptom-based palliative approaches without surgery. The present study attempted to improve the therapeutic effects of synchronous surgeries in resectable non-small cell lung cancer patients exhibiting solitary bone metastasis. A total of 5 patients underwent synchronous lung cancer resections and solitary bone metastasectomies between October 2009 and November 2011 in the Department of Cardiothoracic Surgery, Shanghai Sixth People's Hospital (Shanghai, China). All patients had received fluorodeoxyglucose positron emission tomography-computed tomography or bone scintigraphy to demonstrate the presence of solitary bone metastasis and to exclude the presence of metastases at alternative sites. The patients received standard lung cancer and mediastinal lymph node resections. In addition, bone lesions were assessed by orthopedists and operated on synchronously with standard procedures. Following surgery, all patients were administered standard chemotherapeutic regimens. Perioperative indicators, including time for thoracic drainage, length of hospital stay, incidence of post-operative complications and progression-free survival (PFS) time, were observed. The average time for post-operative drainage was 4.6±1.1 days, and the average length of post-operative hospitalization was 8.8±2.2 days. All procedures were performed safely with no serious complications. The PFS of the patients was 13.2±7.7 months. While 2 patients presenting with spinal metastases succumbed at ~1 year post-surgery, the remaining 3 patients presenting with limb bone metastases survived for >16 months post-surgery, and were alive at the last follow-up. In conclusion, the present study indicated that a synchronous metastasectomy and lung tumor resection is

  15. Targeting Protease-Activated Receptor-1 with Cell-Penetrating Pepducins in Lung Cancer

    PubMed Central

    Cisowski, Jaroslaw; O'Callaghan, Katie; Kuliopulos, Athan; Yang, John; Nguyen, Nga; Deng, Qing; Yang, Eric; Fogel, Michael; Tressel, Sarah; Foley, Caitlin; Agarwal, Anika; Hunt, Stephen W.; McMurry, Tom; Brinckerhoff, Larry; Covic, Lidija

    2011-01-01

    Protease-activated receptors (PARs) are G-protein–coupled receptors that are activated by proteolytic cleavage and generation of a tethered ligand. High PAR1 expression has been documented in a variety of invasive cancers of epithelial origin. In the present study, we investigated the contribution of the four PAR family members to motility of lung carcinomas and primary tumor samples from patients. We found that of the four PARs, only PAR1 expression was highly increased in the lung cancer cell lines. Primary lung cancer cells isolated from patient lung tumors migrated at a 10- to 40-fold higher rate than epithelial cells isolated from nonmalignant lung tissue. Cell-penetrating pepducin inhibitors were generated against the first (i1) and third (i3) intracellular loops of PAR1 and tested for their ability to inhibit PAR1-driven migration and extracellular regulated kinase (ERK)1/2 activity. The PAR1 pepducins showed significant inhibition of cell migration in both primary and established cell lines similar to silencing of PAR1 expression with short hairpin RNA (shRNA). Unlike i1 pepducins, the i3 loop pepducins were effective inhibitors of PAR1-mediated ERK activation and tumor growth. Comparable in efficacy with Bevacizumab, monotherapy with the PAR1 i3 loop pepducin P1pal-7 provided significant 75% inhibition of lung tumor growth in nude mice. We identify the PAR1–ERK1/2 pathway as a feasible target for therapy in lung cancer. PMID:21703428

  16. [Advances in Bevacizumab Therapy for Non-small Cell Lung Cancer 
with Brain Metastases].

    PubMed

    Qu, Liyan; Geng, Rui; Song, Xia

    2016-08-20

    Brain metastases are frequently encountered in patients with non-small cell lung cancer (NSCLC) and are a significant cause of morbidity and mortality. Antiangiogenesis therapy plays a major role in the management of brain metastases in lung cancer. Bevacizumab have become the novel method for the treatment of lung cancer with brain metastases beyond the whole brain radiation therapy, stereotactic radiosurgery and chemotherapy. Recently, more and more studies and trials laid emphasis on the bevacizumab for NSCLC with brain metastases treatment. The key point is the efficacy and safety. In this review, bevacizumab therapy of NSCLC with brain metastases were summarized. PMID:27561800

  17. Erlotinib in Treating Patients With Advanced Non-Small Cell Lung Cancer, Ovarian Cancer, or Squamous Cell Carcinoma of the Head and Neck

    ClinicalTrials.gov

    2013-01-08

    Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage IIIA Non-small Cell Lung Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIC Ovarian Epithelial Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx

  18. Gli1 Mediates Lung Cancer Cell Proliferation and Sonic Hedgehog-Dependent Mesenchymal Cell Activation

    PubMed Central

    Bermudez, Olga; Hennen, Elisabeth; Koch, Ina; Lindner, Michael; Eickelberg, Oliver

    2013-01-01

    Non-Small-Cell-Lung-Cancer (NSCLC) represents approximately 85% of all lung cancers and remains poorly understood. While signaling pathways operative during organ development, including Sonic Hedgehog (Shh) and associated Gli transcription factors (Gli1-3), have recently been found to be reactivated in NSCLC, their functional role remains unclear. Here, we hypothesized that Shh/Gli1-3 could mediate NSCLC autonomous proliferation and epithelial/stromal signaling in the tumoral tissue. In this context, we have investigated the activity of Shh/Gli1-3 signaling in NSCLC in both, cancer and stromal cells. We report here that inhibition of Shh signaling induces a significant decrease in the proliferation of NSCLC cells. This effect is mediated by Gli1 and Gli2, but not Gli3, through regulation of cyclin D1 and cyclin D2 expression. While exogenous Shh was unable to induce signaling in either A549 lung adenocarcinoma or H520 lung squamous carcinoma cells, both cells were found to secrete Shh ligand, which induced fibroblast proliferation, survival, migration, invasion, and collagen synthesis. Furthermore, Shh secreted by NSCLC mediates the production of proangiogenic and metastatic factors in lung fibroblasts. Our results thus provide evidence that Shh plays an important role in mediating epithelial/mesenchymal crosstalk in NSCLC. While autonomous Gli activity controls NSCLC proliferation, increased Shh expression by NSCLC is associated with fibroblast activation in tumor-associated stroma. Our study highlights the relevance of studying stromal-associated cells in the context of NSCLC regarding new prognosis and therapeutic options. PMID:23667589

  19. Gli1 mediates lung cancer cell proliferation and Sonic Hedgehog-dependent mesenchymal cell activation.

    PubMed

    Bermudez, Olga; Hennen, Elisabeth; Koch, Ina; Lindner, Michael; Eickelberg, Oliver

    2013-01-01

    Non-Small-Cell-Lung-Cancer (NSCLC) represents approximately 85% of all lung cancers and remains poorly understood. While signaling pathways operative during organ development, including Sonic Hedgehog (Shh) and associated Gli transcription factors (Gli1-3), have recently been found to be reactivated in NSCLC, their functional role remains unclear. Here, we hypothesized that Shh/Gli1-3 could mediate NSCLC autonomous proliferation and epithelial/stromal signaling in the tumoral tissue. In this context, we have investigated the activity of Shh/Gli1-3 signaling in NSCLC in both, cancer and stromal cells. We report here that inhibition of Shh signaling induces a significant decrease in the proliferation of NSCLC cells. This effect is mediated by Gli1 and Gli2, but not Gli3, through regulation of cyclin D1 and cyclin D2 expression. While exogenous Shh was unable to induce signaling in either A549 lung adenocarcinoma or H520 lung squamous carcinoma cells, both cells were found to secrete Shh ligand, which induced fibroblast proliferation, survival, migration, invasion, and collagen synthesis. Furthermore, Shh secreted by NSCLC mediates the production of proangiogenic and metastatic factors in lung fibroblasts. Our results thus provide evidence that Shh plays an important role in mediating epithelial/mesenchymal crosstalk in NSCLC. While autonomous Gli activity controls NSCLC proliferation, increased Shh expression by NSCLC is associated with fibroblast activation in tumor-associated stroma. Our study highlights the relevance of studying stromal-associated cells in the context of NSCLC regarding new prognosis and therapeutic options. PMID:23667589

  20. High-dose chemotherapy in small-cell lung cancer.

    PubMed

    Pasini, F; Durante, E; De Manzoni, D; Rosti, G; Pelosi, G

    2002-01-01

    Small cell lung cancer (SCLC) is highly sensitive both to radiotherapy and chemotherapy. Given its high chemo sensitivity, even two decades ago, SCLC was one of the first malignancies deemed suitable for maximising the dose and dose intensity with the support of autologous bone marrow (ABMT). On the whole, results were disappointing and the procedure was practically abandoned. Nowadays some interest is again emerging due to improvements in supportive care, such as the availability of hematopoietic growth factors and the peripheral blood progenitor cells (PBPC). Data of 505 patients included in 26 studies were reviewed. About two thirds of these patients had LD (limited disease). Late intensification protocols were used in 311 patients who, however, represented only the 30% of the population initially given conventional chemotherapy. Of the patients not achieving complete remission (CR) after induction, high-dose induced a CR in 39% of the cases. The use of early intensification was reported in 8 studies including 194 patients. The CR rate was 51.5%. Overall, the probability of achieving the CR was 2-3 times higher in LD than in ED (extensive disease). Relapses occurred at the site of the primary in more than half of the cases, showing that the course of the disease was not modified by the use of high-dose chemotherapy. Toxic deaths occurred in 7% of the treated patients, without difference in the two treatment methods. Though the schedules were too variable to draw firm conclusions, the ICE (ifosfamide, carboplatin, etoposide) and the CBP (cyclophosphamide, cisplatin, carmustine) regimens apparently provided better results, with a 2-year survival rate of 30-50% in the LD subset. An european multicenter randomized trial is ongoing. At the present time high-dose chemotherapy is still to be considered experimental treatment, since major problems such as the selection of the patients, doses and timing of chemotherapy and radiotherapy remain unsolved. PMID:12552940

  1. miR-937 contributes to the lung cancer cell proliferation by targeting INPP4B.

    PubMed

    Zhang, Li; Zeng, Daxiong; Chen, Ying; Li, Ning; Lv, Yantian; Li, Yong; Xu, Xiao; Xu, Guopeng

    2016-06-15

    Lung cancer is the leading cause of cancer death worldwide, microRNAs play critical role in the initiation and development of lung cancer. Here, we used MTT assay, colony formation assay, soft agar growth assay and BrdU incorporation assay to investigate miR-937's role in lung cancer. We found that miR-937 was upregulated in lung cancer tissues and cells. Overexpression of miR-937 in A549 promoted anchorage -dependent and -independent growth, whereas knockdown of miR-937 reduced this effect. Meanwhile, we also found miR-937 overexpression increased CCND1 and c-Myc levels in both mRNA and protein levels, knockdown of miR-937 reduced this effect, confirming miR-937 promoted cell proliferation. Mechanism analyses found polyphosphate 4-phosphatase type II (INPP4B) was the target of miR-937, miR-937 directly bound to the 3'UTR of INPP4B, knockdown of INPP4B in A549 with miR-937 inhibitor promoted anchorage -dependent and -independent growth, suggesting miR-937 contributed to cell proliferation of lung cancer by inhibiting INPP4B, it might be a valuable target for lung cancer therapy. PMID:27179609

  2. The proteasomal and apoptotic phenotype determine bortezomib sensitivity of non-small cell lung cancer cells

    PubMed Central

    Voortman, Jens; Chęcińska, Agnieszka; Giaccone, Giuseppe

    2007-01-01

    Bortezomib is a novel anti-cancer agent which has shown promising activity in non-small lung cancer (NSCLC) patients. However, only a subset of patients respond to this treatment. We show that NSCLC cell lines are differentially sensitive to bortezomib, IC50 values ranging from 5 to 83 nM. The apoptosis-inducing potential of bortezomib in NSCLC cells was found to be dependent not only on the apoptotic phenotype but also on the proteasomal phenotype of individual cell lines. Upon effective proteasome inhibition, H460 cells were more susceptible to apoptosis induction by bortezomib than SW1573 cells, indicating a different apoptotic phenotype. However, exposure to a low dose of bortezomib did only result in SW1573 cells, and not in H460 cells, in inhibition of proteasome activity and subsequent apoptosis. This suggests a different proteasomal phenotype as well. Additionally, overexpression of anti-apoptotic protein Bcl-2 in H460 cells did not affect the proteasomal phenotype of H460 cells but did result in decreased bortezomib-induced apoptosis. In conclusion, successful proteasome-inhibitor based treatment strategies in NSCLC face the challenge of having to overcome apoptosis resistance as well as proteasomal resistance of individual lung cancer cells. Further studies in NSCLC are warranted to elucidate underlying mechanisms. PMID:18021420

  3. Hyperoside induces both autophagy and apoptosis in non-small cell lung cancer cells in vitro

    PubMed Central

    Fu, Ting; Wang, Ling; Jin, Xiang-nan; Sui, Hai-juan; Liu, Zhou; Jin, Ying

    2016-01-01

    Aim: Hyperoside (quercetin-3-O-β-D-galactopyranoside) is a flavonol glycoside found in plants of the genera Hypericum and Crataegus, which exhibits anticancer, anti-oxidant, and anti-inflammatory activities. In this study we investigated whether autophagy was involved in the anticancer mechanisms of hyperoside in human non-small cell lung cancer cells in vitro. Methods: Human non-small cell lung cancer cell line A549 was tested, and human bronchial epithelial cell line BEAS-2B was used for comparison. The expression of LC3-II, apoptotic and signaling proteins was measured using Western blotting. Autophagosomes were observed with MDC staining, LC3 immunocytochemistry, and GFP-LC3 fusion protein techniques. Cell viability was assessed using MTT assay. Results: Hyperoside (0.5, 1, 2 mmol/L) dose-dependently increased the expression of LC3-II and autophagosome numbers in A549 cells, but had no such effects in BEAS-2B cells. Moreover, hyperoside dose-dependently inhibited the phosphorylation of Akt, mTOR, p70S6K and 4E-BP1, but increased the phosphorylation of ERK1/2 in A549 cells. Insulin (200 nmol/L) markedly enhanced the phosphorylation of Akt and decreased LC3-II expression in A549 cells, which were reversed by pretreatment with hyperoside, whereas the MEK1/2 inhibitor U0126 (20 μmol/L) did not blocked hyperoside-induced LC3-II expression. Finally, hyperoside dose-dependently suppressed the cell viability and induced apoptosis in A549 cells, which were significantly attenuated by pretreatment with the autophagy inhibitor 3-methyladenine (2.5 mmol/L). Conclusion: Hyperoside induces both autophagy and apoptosis in human non-small cell lung cancer cells in vitro. The autophagy is induced through inhibiting the Akt/mTOR/p70S6K signal pathways, which contributes to anticancer actions of hyperoside. PMID:26948085

  4. Cytotoxic Effect of a Novel Synthesized Carbazole Compound on A549 Lung Cancer Cell Line

    PubMed Central

    Molatlhegi, Refilwe P.; Phulukdaree, Alisa; Anand, Krishnan; Gengan, Robert M.; Tiloke, Charlette; Chuturgoon, Anil A.

    2015-01-01

    Increased death rates due to lung cancer have necessitated the search for potential novel anticancer compounds such as carbazole derivatives. Carbazoles are aromatic heterocyclic compounds with anticancer, antibacterial and anti-inflammatory activity. The study investigated the ability of the novel carbazole compound (Z)-4-[9-ethyl-9aH-carbazol-3-yl) amino] pent-3-en-2-one (ECAP) to induce cytotoxicity of lung cancer cells and its mechanism of action. ECAP was synthesized as a yellow powder with melting point of 240-247 °C. The 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), lipid peroxidation and comet assays were used to assess the cytotoxic effect of the compound on A549 lung cancer cells. Protein expression was determined using western blots, apoptosis was measured by luminometry (caspase-3/7, -8 and -9) assay and flow cytometry was used to measure phosphatidylserine (PS) externalisation. ECAP induced a p53 mediated apoptosis of lung cancer cells due to a significant reduction in the expression of antioxidant defence proteins (Nrf2 and SOD), Hsp70 (p < 0.02) and Bcl-2 (p < 0.0006), thereby up-regulating reactive oxygen species (ROS) production. This resulted in DNA damage (p < 0.0001), up-regulation of Bax expression and caspase activity and induction of apoptosis in lung cancer cells. The results show the anticancer potential of ECAP on lung cancer. PMID:26134408

  5. Gefitinib in the treatment of nonsmall cell lung cancer with activating epidermal growth factor receptor mutation

    PubMed Central

    Nurwidya, Fariz; Takahashi, Fumiyuki; Takahashi, Kazuhisa

    2016-01-01

    Lung cancer is still the main cause of cancer-related deaths worldwide, with most patients present with advanced disease and poor long-term prognosis. The aim of lung cancer treatment is to slow down the progression of the disease, to relieve the patients from the lung cancer symptoms and whenever possible, to increase the overall survival. The discovery of small molecule targeting tyrosine kinase of epidermal growth factor receptor opens a new way in the management of advanced nonsmall cell lung cancer (NSCLC). This review will discuss several Phase II and III trials evaluated the clinical efficacy of gefitinib as monotherapy in pretreated patients with advanced NSCLC, as well as both monotherapy and combined with chemotherapy in chemotherapy-naive patients. PMID:27433059

  6. Rap2b promotes proliferation, migration, and invasion of lung cancer cells.

    PubMed

    Peng, Yi-Gen; Zhang, Zheng-Qun; Chen, Yan-Bin; Huang, Jian-An

    2016-10-01

    Rap2b, a member of the guanosine triphosphate-binding proteins, is widely up-regulated in many types of tumors. However, the functional role of Rap2b in tumorigenesis of lung cancer remains to be fully elucidated. In this study, we investigated the effect of Rap2b on the lung cancer malignant phenotype, such as cell proliferation and metastasis. We found that Rap2b could promote the abilities of lung cancer cell wound healing, migration, and invasion via increasing matrix metalloproteinase-2 enzyme activity. Furthermore, Rap2b overexpression could increase the phosphorylation level of extracellular signal-regulated protein kinases 1/2. In conclusion, our results suggested that Rap2b may be a potential therapeutic target for lung cancer. PMID:26671640

  7. Screening for lung cancer.

    PubMed Central

    Carter, D.

    1981-01-01

    The survival from bronchogenic carcinoma is highly dependent upon stage at the time of treatment. This is particularly true for squamous cell carcinoma, adenocarcinoma, and large cell carcinoma, but holds true for small cell carcinoma as well. The problem presented to the medical profession has been to find a practical means of detecting lung cancer while it is still at an early stage. Three studies in progress have indicated that a larger proportion of the patients may be found to have early stage lung cancer when screened with a combination of chest X-rays and sputum cytology. However, the detection of these early stage cases has not yet been translated into an improvement in the overall mortality rate from lung cancer. PMID:6278787

  8. Airway basal cells of healthy smokers express an embryonic stem cell signature relevant to lung cancer.

    PubMed

    Shaykhiev, Renat; Wang, Rui; Zwick, Rachel K; Hackett, Neil R; Leung, Roland; Moore, Malcolm A S; Sima, Camelia S; Chao, Ion Wa; Downey, Robert J; Strulovici-Barel, Yael; Salit, Jacqueline; Crystal, Ronald G

    2013-09-01

    Activation of the human embryonic stem cell (hESC) signature genes has been observed in various epithelial cancers. In this study, we found that the hESC signature is selectively induced in the airway basal stem/progenitor cell population of healthy smokers (BC-S), with a pattern similar to that activated in all major types of human lung cancer. We further identified a subset of 6 BC-S hESC genes, whose coherent overexpression in lung adenocarcinoma (AdCa) was associated with reduced lung function, poorer differentiation grade, more advanced tumor stage, remarkably shorter survival, and higher frequency of TP53 mutations. BC-S shared with hESC and a considerable subset of lung carcinomas a common TP53 inactivation molecular pattern which strongly correlated with the BC-S hESC gene expression. These data provide transcriptome-based evidence that smoking-induced reprogramming of airway BC toward the hESC-like phenotype might represent a common early molecular event in the development of aggressive lung carcinomas in humans. PMID:23857717

  9. Osteoactivin (GPNMB) ectodomain protein promotes growth and invasive behavior of human lung cancer cells

    PubMed Central

    Oyewumi, Moses O.; Manickavasagam, Dharani; Novak, Kimberly; Wehrung, Daniel; Paulic, Nikola; Moussa, Fouad M.; Sondag, Gregory R.; Safadi, Fayez F.

    2016-01-01

    The potential application of GPNMB/OA as a therapeutic target for lung cancer will require a greater understanding of the impact of GPNMB/OA ectodomain (ECD) protein shedding into tumor tissues. Thus, in this work we characterized GPNMB/OA expression and extent of shedding of its ECD protein while evaluating the impact on lung cancer progression using three non-small cell lung cancer (NSCLC) cell lines: A549, SK-MES-1 and calu-6. We observed a direct correlation (R2 = 0.89) between GPNMB/OA expression on NSCLC cells and the extent of GPNMB/OA ECD protein shedding. Meanwhile, siRNA-mediated knockdown of GPNMB/OA in cancer cells significantly reduced GPNMB/OA ECD protein shedding, migration, invasion and adhesion to extracellular matrix materials. Also, exogenous treatment of cancer cells (expressing low GPNMB/OA) with recombinant GPNMB/OA protein (rOA) significantly facilitated cell invasion and migration, but the effects of rOA was negated by inclusion of a selective RGD peptide. Further studies in athymic (nu/nu) mice-bearing calu-6 showed that intratumoral supplementation with rOA effectively facilitated in vivo tumor growth as characterized by a high number of proliferating cells (Ki67 staining) coupled with a low number of apoptotic cells. Taken together, our results accentuate the relevance of GPNMB/OA ECD protein shedding to progression of lung cancer. Thus, strategies that suppress GPNMB/OA expression on lung cancer cells as well as negate shedding of GPNMB/OA ECD protein are worthy of consideration in lung cancer therapeutics. PMID:26883195

  10. Epidermal growth factor receptor in non-small cell lung cancer

    PubMed Central

    2015-01-01

    Following the identification of a group of patients in the initial tyrosine kinase inhibitor (TKI) trials for lung cancer, there has been detailed focus on which patients may benefit from inhibitor therapy. This article reviews the background, genetics and prevalence of epidermal growth factor mutations in non-small cell lung cancer (NSCLC). Additionally, the prevalence in unselected patients is compared against various other reviews. PMID:25870793

  11. Anti-tumoral effect of desmethylclomipramine in lung cancer stem cells.

    PubMed

    Bongiorno-Borbone, Lucilla; Giacobbe, Arianna; Compagnone, Mirco; Eramo, Adriana; De Maria, Ruggero; Peschiaroli, Angelo; Melino, Gerry

    2015-07-10

    Lung cancer is the most feared of all cancers because of its heterogeneity and resistance to available treatments. Cancer stem cells (CSCs) are the cell population responsible for lung cancer chemoresistance and are a very good model for testing new targeted therapies. Clomipramine is an FDA-approved antidepressant drug, able to inhibit in vitro the E3 ubiquitin ligase Itch and potentiate the pro-apoptotic effects of DNA damaging induced agents in several cancer cell lines. Here, we investigated the potential therapeutic effect of desmethylclomipramine (DCMI), the active metabolite of Clomipramine, on the CSCs homeostasis. We show that DCMI inhibits lung CSCs growth, decreases their stemness potential and increases the cytotoxic effect of conventional chemotherapeutic drugs. Being DCMI an inhibitor of the E3 ubiquitin ligase Itch, we also verified the effect of Itch deregulation on CSCs survival. We found that the siRNA-mediated depletion of Itch induces similar anti-proliferative effects on lung CSCs, suggesting that DCMI might exert its effect, at least in part, by inhibiting Itch. Notably, Itch expression is a negative prognostic factor in two primary lung tumors datasets, supporting the potential clinical relevance of Itch inhibition to circumvent drug resistance in the treatment of lung cancer. PMID:26219257

  12. Nicotine prevents the apoptosis induced by menadione in human lung cancer cells

    SciTech Connect

    Zhang Tao; Lu Heng; Shang Xuan; Tian Yihao; Zheng Congyi; Wang Shiwen; Cheng Hanhua . E-mail: hhcheng@whu.edu.cn; Zhou Rongjia . E-mail: rjzhou@whu.edu.cn

    2006-04-14

    Approximately 50% of long-term cigarette smokers die prematurely from the adverse effects of smoking, including on lung cancer and other illnesses. Nicotine is a main component in tobacco and has been implicated as a potential factor in the pathogenesis of human lung cancer. However, the mechanism of nicotine action in the development of lung cancer remains largely unknown. In the present study, we designed a nicotine-apoptosis system, by pre-treatment of nicotine making lung cancer cell A549 to be in a physiological nicotine environment, and observed that nicotine promoted cell proliferation and prevented the menadione-induced apoptosis, and exerts its role of anti-apoptosis by shift of apoptotic stage induced by menadione from late apoptotic stage to early apoptotic stage, in which NF-{kappa}B was up-regulated. Interference analysis of NF-{kappa}B in A549 cells showed that knock down of NF-{kappa}B resulted in apoptosis promotion and counteracted the protective effect of nicotine. The findings suggest that nicotine has potential effect in lung cancer genesis, especially in patients with undetectable early tumor development and development of specific NF-{kappa}B inhibitors would represent a potentially exciting new pharmacotherapy for tobacco-related lung cancer.

  13. Anti-tumoral effect of desmethylclomipramine in lung cancer stem cells

    PubMed Central

    Bongiorno-Borbone, Lucilla; Giacobbe, Arianna; Compagnone, Mirco; Eramo, Adriana; De Maria, Ruggero; Peschiaroli, Angelo; Melino, Gerry

    2015-01-01

    Lung cancer is the most feared of all cancers because of its heterogeneity and resistance to available treatments. Cancer stem cells (CSCs) are the cell population responsible for lung cancer chemoresistance and are a very good model for testing new targeted therapies. Clomipramine is an FDA-approved antidepressant drug, able to inhibit in vitro the E3 ubiquitin ligase Itch and potentiate the pro-apoptotic effects of DNA damaging induced agents in several cancer cell lines. Here, we investigated the potential therapeutic effect of desmethylclomipramine (DCMI), the active metabolite of Clomipramine, on the CSCs homeostasis. We show that DCMI inhibits lung CSCs growth, decreases their stemness potential and increases the cytotoxic effect of conventional chemotherapeutic drugs. Being DCMI an inhibitor of the E3 ubiquitin ligase Itch, we also verified the effect of Itch deregulation on CSCs survival. We found that the siRNA-mediated depletion of Itch induces similar anti-proliferative effects on lung CSCs, suggesting that DCMI might exert its effect, at least in part, by inhibiting Itch. Notably, Itch expression is a negative prognostic factor in two primary lung tumors datasets, supporting the potential clinical relevance of Itch inhibition to circumvent drug resistance in the treatment of lung cancer. PMID:26219257

  14. Spotlight on gefitinib in non-small-cell lung cancer.

    PubMed

    Frampton, James E; Easthope, Stephanie E

    2005-01-01

    Gefitinib (Iressa), the first commercially available epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitor, is indicated in the management of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). However, approved uses differ between countries; in most markets, gefitinib is approved for third-line use only (e.g. the US, Canada and Switzerland), although in some it is approved for both second- and third-line use (e.g. Japan and Australia) and, additionally, in patients considered unsuitable for chemotherapy (e.g. Indonesia and the Philippines). Few third-line treatment options exist for patients with inoperable advanced NSCLC who have failed both docetaxel and platinum-based chemotherapy regimens. Gefitinib represents a significant advance in the treatment of this population; a once-daily oral dosage of 250 mg/day was well tolerated, produced objective tumour responses and disease stabilization, and improved disease-related symptoms and quality of life. It also produced overall survival outcomes that compared favorably with historical outcomes in a similar group of patients treated with three or four different chemotherapy regimens. These findings have been supported by observations from a global compassionate-use program. Ongoing or planned clinical trials are designed to confirm and/or further define the role of the drug in the above and other clinical settings. Preliminary data demonstrate the presence of activating mutations in EGFR-TK among patients whose disease was highly responsive to treatment with gefitinib, although such mutations have not been correlated to all patients who benefit from the drug. Further studies are needed to fully elucidate the clinical implications of EGFR mutations and to identify patients likely to benefit from EGFR-targeted therapy. PMID:15813676

  15. Overexpression of TRPV3 Correlates with Tumor Progression in Non-Small Cell Lung Cancer.

    PubMed

    Li, Xiaolei; Zhang, Qianhui; Fan, Kai; Li, Baiyan; Li, Huifeng; Qi, Hanping; Guo, Jing; Cao, Yonggang; Sun, Hongli

    2016-01-01

    (1) BACKGROUND: Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP channels family of Ca(2+)-permeant channels. The proteins of some TRP channels are highly expressed in cancer cells. This study aimed to assess the clinical significance and biological functions of TRPV3 in non-small cell lung cancer (NSCLC); (2) METHODS: Immunohistochemistry was used to detect the expression of TRPV3 in NSCLC tissues and adjacent noncancerous lung tissues. Western blot was used to detect the protein expressions of TRPV3, CaMKII, p-CaMKII, CyclinA, CyclinD, CyclinE1, CDK2, CDK4, and P27. Small interfering RNA was used to deplete TRPV3 expression. A laser scanning confocal microscope was used to measure intracellular calcium concentration ([Ca(2+)]i). Flow cytometry was used to analyze cell cycle; (3) RESULTS: TRPV3 was overexpressed in 65 of 96 (67.7%) human lung cancer cases and correlated with differentiation (p = 0.001) and TNM stage (p = 0.004). Importantly, TRPV3 expression was associated with short overall survival. In addition, blocking or knockdown of TRPV3 could inhibit lung cancer cell proliferation. Moreover, TRPV3 inhibition could decrease [Ca(2+)]i of lung cancer cells and arrest cell cycle at the G1/S boundary. Further results revealed that TRPV3 inhibition decreased expressions of p-CaMKII, CyclinA, CyclinD1, CyclinE, and increased P27 level; (4) CONCLUSIONS: Our findings demonstrate that TRPV3 was overexpressed in NSCLC and correlated with lung cancer progression. TRPV3 activation could promote proliferation of lung cancer cells. TRPV3 might serve as a potential companion drug target in NSCLC. PMID:27023518

  16. Overexpression of TRPV3 Correlates with Tumor Progression in Non-Small Cell Lung Cancer

    PubMed Central

    Li, Xiaolei; Zhang, Qianhui; Fan, Kai; Li, Baiyan; Li, Huifeng; Qi, Hanping; Guo, Jing; Cao, Yonggang; Sun, Hongli

    2016-01-01

    (1) Background: Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP channels family of Ca2+-permeant channels. The proteins of some TRP channels are highly expressed in cancer cells. This study aimed to assess the clinical significance and biological functions of TRPV3 in non-small cell lung cancer (NSCLC); (2) Methods: Immunohistochemistry was used to detect the expression of TRPV3 in NSCLC tissues and adjacent noncancerous lung tissues. Western blot was used to detect the protein expressions of TRPV3, CaMKII, p-CaMKII, CyclinA, CyclinD, CyclinE1, CDK2, CDK4, and P27. Small interfering RNA was used to deplete TRPV3 expression. A laser scanning confocal microscope was used to measure intracellular calcium concentration ([Ca2+]i). Flow cytometry was used to analyze cell cycle; (3) Results: TRPV3 was overexpressed in 65 of 96 (67.7%) human lung cancer cases and correlated with differentiation (p = 0.001) and TNM stage (p = 0.004). Importantly, TRPV3 expression was associated with short overall survival. In addition, blocking or knockdown of TRPV3 could inhibit lung cancer cell proliferation. Moreover, TRPV3 inhibition could decrease [Ca2+]i of lung cancer cells and arrest cell cycle at the G1/S boundary. Further results revealed that TRPV3 inhibition decreased expressions of p-CaMKII, CyclinA, CyclinD1, CyclinE, and increased P27 level; (4) Conclusions: Our findings demonstrate that TRPV3 was overexpressed in NSCLC and correlated with lung cancer progression. TRPV3 activation could promote proliferation of lung cancer cells. TRPV3 might serve as a potential companion drug target in NSCLC. PMID:27023518

  17. Moscatilin inhibits lung cancer cell motility and invasion via suppression of endogenous reactive oxygen species.

    PubMed

    Kowitdamrong, Akkarawut; Chanvorachote, Pithi; Sritularak, Boonchoo; Pongrakhananon, Varisa

    2013-01-01

    Lung cancer is the leading cause of death among cancer patients worldwide, and most of them have died from metastasis. Migration and invasion are prerequisite processes associated with high metastasis potential in cancers. Moscatilin, a bibenzyl derivative isolated from the Thai orchid Dendrobium pulchellum, has been shown to have anticancer effect against numerous cancer cell lines. However, little is known regarding the effect of moscatilin on cancer cell migration and invasion. The present study demonstrates that nontoxic concentrations of moscatilin were able to inhibit human nonsmall cell lung cancer H23 cell migration and invasion. The inhibitory effect of moscatilin was associated with an attenuation of endogenous reactive oxygen species (ROS), in which hydroxyl radical (OH(∙)) was identified as a dominant species in the suppression of filopodia formation. Western blot analysis also revealed that moscatilin downregulated activated focal adhesion kinase (phosphorylated FAK, Tyr 397) and activated ATP-dependent tyrosine kinase (phosphorylated Akt, Ser 473), whereas their parental counterparts were not detectable changed. In conclusion, our results indicate the novel molecular basis of moscalitin-inhibiting lung cancer cell motility and invasion and demonstrate a promising antimetastatic potential of such an agent for lung cancer therapy. PMID:23738332

  18. Moscatilin Inhibits Lung Cancer Cell Motility and Invasion via Suppression of Endogenous Reactive Oxygen Species

    PubMed Central

    Kowitdamrong, Akkarawut; Chanvorachote, Pithi; Sritularak, Boonchoo

    2013-01-01

    Lung cancer is the leading cause of death among cancer patients worldwide, and most of them have died from metastasis. Migration and invasion are prerequisite processes associated with high metastasis potential in cancers. Moscatilin, a bibenzyl derivative isolated from the Thai orchid Dendrobium pulchellum, has been shown to have anticancer effect against numerous cancer cell lines. However, little is known regarding the effect of moscatilin on cancer cell migration and invasion. The present study demonstrates that nontoxic concentrations of moscatilin were able to inhibit human nonsmall cell lung cancer H23 cell migration and invasion. The inhibitory effect of moscatilin was associated with an attenuation of endogenous reactive oxygen species (ROS), in which hydroxyl radical (OH∙) was identified as a dominant species in the suppression of filopodia formation. Western blot analysis also revealed that moscatilin downregulated activated focal adhesion kinase (phosphorylated FAK, Tyr 397) and activated ATP-dependent tyrosine kinase (phosphorylated Akt, Ser 473), whereas their parental counterparts were not detectable changed. In conclusion, our results indicate the novel molecular basis of moscalitin-inhibiting lung cancer cell motility and invasion and demonstrate a promising antimetastatic potential of such an agent for lung cancer therapy. PMID:23738332

  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. Crocin inhibits cell proliferation and enhances cisplatin and pemetrexed chemosensitivity in lung cancer cells

    PubMed Central

    Chen, Shuangshuang; Zhao, Shuang; Wang, Xinxing; Zhang, Luo; Jiang, Enze; Gu, Yuan; Shangguan, Anna Junjie; Zhao, Hong

    2015-01-01

    Background Crocin is the major constituent of saffron, a naturally derived Chinese medicine obtained from the dried stigma of the Crocus sativus flower. It has a variety of pharmacological effects, including anti-oxidative, immunity enhancement, and anti-tumorigenic properties; however, the molecular mechanisms underlying these effects remain unknown. Methods To investigate the effects of crocin on proliferation and apoptosis of lung adenocarcinoma cells, lung adenocarcinoma cell lines, A549 and SPC-A1, were treated with crocin at different dosages. Cell morphological changes were observed by light microscopy. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to detect the inhibitory effect of crocin on cell proliferation and sensitivity to chemotherapeutic drugs. Flow cytometry was used to characterize cell apoptosis and cell cycle profiles. Reverse transcription-polymerase chain reaction was used to detect mRNA levels of apoptosis-related genes. Results Crocin inhibited cell proliferation and induced apoptosis in A549 and SPC-A1 cells in a concentration-dependent manner, accompanied with an increase of G0/G1 arrest. Crocin significantly increased the mRNA levels of both p53 and B-cell lymphoma 2-associated X protein (Bax), while decreasing B-cell lymphoma 2 (Bcl-2) mRNA expressions. In addition, crocin combined with either cisplatin or pemetrexed showed additive effects on cell proliferation in two lung cancer cell lines. Conclusions Crocin significantly suppressed the proliferation of human lung adenocarcinoma cells and enhanced the chemo sensitivity of these cells to both cisplatin and pemetrexed. The actions of molecular mechanism could be through the induction of cell cycle arrest and apoptosis by p53 and Bax up-regulation but Bcl-2 down-regulation. PMID:26798587

  1. Targeting lung cancer stem-like cells with TRAIL gene armed oncolytic adenovirus

    PubMed Central

    Yang, Yu; Xu, Haineng; Huang, Weidan; Ding, Miao; Xiao, Jing; Yang, Dongmei; Li, Huaguang; Liu, Xin-Yuan; Chu, Liang

    2015-01-01

    Lung cancer stem cell (LCSC) is critical in cancer initiation, progression, drug resistance and relapse. Disadvantages showed in conventional lung cancer therapy probably because of its existence. In this study, lung cancer cell line A549 cells propagated as spheroid bodies (named as A549 sphere cells) in growth factors-defined serum-free medium. A549 sphere cells displayed CSC properties, including chemo-resistance, increased proportion of G0/G1 cells, slower proliferation rate, ability of differentiation and enhanced tumour formation ability in vivo. Oncolytic adenovirus ZD55 carrying EGFP gene, ZD55-EGFP, infected A549 sphere cells and inhibited cell growth. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) armed oncolytic adenovirus, ZD55-TRAIL, exhibited enhanced cytotoxicity and induced A549 sphere cells apoptosis through mitochondrial pathway. Moreover, small molecules embelin, LY294002 and resveratrol improved the cytotoxicity of ZD55-TRAIL. In the A549 sphere cells xenograft models, ZD55-TRAIL significantly inhibited tumour growth and improved survival status of mice. These results suggested that gene armed oncolytic adenovirus is a potential approach for lung cancer therapy through targeting LCSCs. PMID:25683371

  2. Cytotoxic effects of natural and semisynthetic cucurbitacins on lung cancer cell line A549.

    PubMed

    Silva, Izabella Thaís; Geller, Fabiana Cristina; Persich, Lara; Dudek, Sabine Eva; Lang, Karen Luise; Caro, Miguel Soriano Balparda; Durán, Fernando Javier; Schenkel, Eloir Paulo; Ludwig, Stephan; Simões, Cláudia Maria Oliveira

    2016-04-01

    Cucurbitacins and their derivatives are triterpenoids that are found in various plant families, and are known for their pharmacological and biological activities, including anti-cancer effects. Lung cancer represents a major public health problem, with non-small-cell lung cancer (NSCLC) being the most frequent and aggressive type of lung cancer. The objective of this work was to evaluate four cucurbitacins (CUCs) for their cytotoxic activity, effects on apoptosis induction, cell cycle progression, anti-migratory, and anti-invasive effects on the human NSCLC cell line (A549 cells). Our findings showed that these CUCs could suppress human NSCLC cell growth in vitro through their effects on the PI3Kinase and MAPK pathways, which lead to programmed cell death induction, as well as inhibition of cell migration and cell invasion. Additionally, these effects culminate in apoptosis induction and G2/M cell cycle arrest by modulating cyclin B1 expression, and in the mitigation of strategic steps of lung cancer metastasis, including migration and invasion of A549 cells. These results suggest that two natural (DDCB and CB) and two novel semisynthetic derivatives of cucurbitacin B (ACB and DBCB) could be considered as promising compounds with antitumor potential. PMID:26780083

  3. Maackia amurensis agglutinin enhances paclitaxel induced cytotoxicity in cultured non-small cell lung cancer cells.

    PubMed

    Chhetra Lalli, Rakhee; Kaur, Kiranjeet; Dadsena, Shashank; Chakraborti, Anuradha; Srinivasan, Radhika; Ghosh, Sujata

    2015-08-01

    Maackia amurensis agglutinin (MAA) is gaining recognition as the potential diagnostic agent for cancer. Previous studies from our laboratory have demonstrated that this lectin could interact specifically with the cells and biopsy samples of non-small cell lung cancer (NSCLC) origin but not with normal lung fibroblast cells. Moreover, this lectin was also found to induce apoptosis in NSCLC cells. Further, the biological activity of this lectin was shown to survive gastrointestinal proteolysis and inhibit malignant cell growth and tumorigenesis in mice model of melanoma thereby indicating the therapeutic potential of this lectin. Paclitaxel is one of the widely used traditional chemotherapeutic drugs for treatment of NSCLC but it exerts side-effects on normal healthy cells too. Studies have revealed that lectins have potential to act as an adjuvant chemotherapeutic agent in cancer of different origin. Thus, in the present study, an attempt was made to assess the chemo-adjuvant role of MAA in three types of NSCLC cell lines [adenocarcinoma cell line (A549), squamous cell carcinoma cell line (NCI-H520) and large cell carcinoma cell line (NCI-H460)]. We have observed that the non-cytotoxic concentration of this lectin was able to enhance the cytotoxic activity of Paclitaxel even at low dose by inducing apoptosis through intrinsic/mitochondrial pathway in all the three types of NSCLC cell lines, although the involvement of extrinsic pathway of apoptosis in case of NCI-H460 cell line could not be ruled out. Further, this lectin was also found to augment the chemo-preventive activity of this drug by arresting cells in G2-M phase of the cell cycle. Collectively, our results have suggested that Maackia amurensis agglutinin may have the potential to be used as adjuvant chemotherapeutic agent in case of NSCLC. PMID:25978938

  4. Effects of theanine on growth of human lung cancer and leukemia cells as well as migration and invasion of human lung cancer cells.

    PubMed

    Liu, Qian; Duan, Huiying; Luan, Jinling; Yagasaki, Kazumi; Zhang, Guoying

    2009-04-01

    The aim of this study is to investigate the effects of theanine, a tea characteristic amino acid, on human lung cancer and leukemia cells. In the present study, we have demonstrated that theanine suppressed the in vitro and ex vivo growth of human non-small cell lung cancer A549 and leukemia K562 cell lines in dose- and time-dependant manners. In addition, theanine displayed the inhibitory effect on the migration of A549 cells. More importantly, theanine enhanced the anticancer activity of anticancer agents such as trichostatin A (the histone deacetylase inhibitor), berbamine and norcantharidin (the anticancer drugs in China) by strongly reducing the viability and/or migration rate in A549 cells. In addition, theanine significantly suppressed A549 cell invasion. Suppression of A549 cell migration may be one of the important mechanisms of action of theanine against the A549 cell invasion. Our present results suggest that theanine may have the wide therapeutic and/or adjuvant therapeutic application in the treatment of human lung cancer and leukemia. PMID:19760127

  5. New and emerging targeted treatments in advanced non-small-cell lung cancer.

    PubMed

    Hirsch, Fred R; Suda, Kenichi; Wiens, Jacinta; Bunn, Paul A

    2016-09-01

    Targeted therapies are substantially changing the management of lung cancers. These treatments include drugs that target driver mutations, those that target presumed important molecules in cancer cell proliferation and survival, and those that inhibit immune checkpoint molecules. This area of research progresses day by day, with novel target discoveries, novel drug development, and use of novel combination treatments. Researchers and clinicians have also extensively investigated the predictive biomarkers and the molecular mechanisms underlying inherent or acquired resistance to these targeted therapies. We review recent progress in the development of targeted treatments for patients with advanced non-small-cell lung cancer, especially focusing on data from published clinical trials. PMID:27598681

  6. Epigenetics in non-small cell lung cancer: from basics to therapeutics

    PubMed Central

    Ansari, Junaid; El-Osta, Hazem

    2016-01-01

    Lung cancer remains the number one cause of cancer-related deaths worldwide with 221,200 estimated new cases and 158,040 estimated deaths in 2015. Approximately 80% of cases are non-small cell lung cancer (NSCLC). The diagnosis is usually made at an advanced stage where the prognosis is poor and therapeutic options are limited. The evolution of lung cancer is a multistep process involving genetic, epigenetic, and environmental factor interactions that result in the dysregulation of key oncogenes and tumor suppressor genes, culminating in activation of cancer-related signaling pathways. The past decade has witnessed the discovery of multiple molecular aberrations that drive lung cancer growth, among which are epidermal growth factor receptor (EGFR) mutations and translocations involving the anaplastic lymphoma kinase (ALK) gene. This has translated into therapeutic agent developments that target these molecular alterations. The absence of targetable mutations in 50% of NSCLC cases and targeted therapy resistance development underscores the importance for developing alternative therapeutic strategies for treating lung cancer. Among these strategies, pharmacologic modulation of the epigenome has been used to treat lung cancer. Epigenetics approaches may circumvent the problem of tumor heterogeneity by affecting the expression of multiple tumor suppression genes (TSGs), halting tumor growth and survival. Moreover, it may be effective for tumors that are not driven by currently recognized druggable mutations. This review summarizes the molecular pathology of lung cancer epigenetic aberrations and discusses current efforts to target the epigenome with different pharmacological approaches. Our main focus will be on hypomethylating agents, histone deacetylase (HDAC) inhibitors, microRNA modulations, and the role of novel epigenetic biomarkers. Last, we will address the challenges that face this old-new strategy in treating lung cancer. PMID:27186511

  7. Epigenetics in non-small cell lung cancer: from basics to therapeutics.

    PubMed

    Ansari, Junaid; Shackelford, Rodney E; El-Osta, Hazem

    2016-04-01

    Lung cancer remains the number one cause of cancer-related deaths worldwide with 221,200 estimated new cases and 158,040 estimated deaths in 2015. Approximately 80% of cases are non-small cell lung cancer (NSCLC). The diagnosis is usually made at an advanced stage where the prognosis is poor and therapeutic options are limited. The evolution of lung cancer is a multistep process involving genetic, epigenetic, and environmental factor interactions that result in the dysregulation of key oncogenes and tumor suppressor genes, culminating in activation of cancer-related signaling pathways. The past decade has witnessed the discovery of multiple molecular aberrations that drive lung cancer growth, among which are epidermal growth factor receptor (EGFR) mutations and translocations involving the anaplastic lymphoma kinase (ALK) gene. This has translated into therapeutic agent developments that target these molecular alterations. The absence of targetable mutations in 50% of NSCLC cases and targeted therapy resistance development underscores the importance for developing alternative therapeutic strategies for treating lung cancer. Among these strategies, pharmacologic modulation of the epigenome has been used to treat lung cancer. Epigenetics approaches may circumvent the problem of tumor heterogeneity by affecting the expression of multiple tumor suppression genes (TSGs), halting tumor growth and survival. Moreover, it may be effective for tumors that are not driven by currently recognized druggable mutations. This review summarizes the molecular pathology of lung cancer epigenetic aberrations and discusses current efforts to target the epigenome with different pharmacological approaches. Our main focus will be on hypomethylating agents, histone deacetylase (HDAC) inhibitors, microRNA modulations, and the role of novel epigenetic biomarkers. Last, we will address the challenges that face this old-new strategy in treating lung cancer. PMID:27186511

  8. Safety of topotecan in the treatment of recurrent small-cell lung cancer and ovarian cancer.

    PubMed

    Garst, Jennifer

    2007-01-01

    The topoisomerase I inhibitor, topotecan, is approved for the treatment of recurrent small-cell lung cancer (SCLC) and ovarian cancer (OC). Patients with recurrent SCLC and OC typically experience multiple relapses and receive multiple rounds of chemotherapy. In these settings, disease stabilisation is considered a treatment benefit, and quality-of-life effects and cumulative toxicities of treatments should be considered. Many patients with recurrent cancer may be predisposed to treatment-related adverse events because of advanced age, renal impairment or extensive prior therapy. The standard regimen of topotecan, 1.5 mg/m(2) on days 1-5 of a 21-day cycle, has generally mild nonhaematological toxicity and a well-defined haematological toxicity profile characterised by reversible and noncumulative neutropenia. Alternative regimens may lower the incidence of haematological toxicities and maintain antitumour efficacy. Topotecan may provide physicians with a versatile therapeutic option for the treatment of patients with relapsed SCLC or OC. PMID:17181452

  9. Advances in the diagnosis and treatment of non-small cell lung cancer.

    PubMed

    Pillai, Rathi N; Ramalingam, Suresh S

    2014-03-01

    The diagnostic and therapeutic landscape of non-small cell lung cancer (NSCLC) has changed dramatically in the past 50 years since the Surgeon General's report on smoking and lung cancer. Early detection is now a reality for lung cancer. The use of low-dose computed tomography scans for early detection decreases mortality and is beginning to be used in routine clinical practice. Technological advances such as positron emission tomography and endobronchial ultrasound have improved the accuracy of NSCLC staging. The cure rate for early-stage NSCLC has improved as a result of multimodality treatment approaches. The role of systemic therapy has also expanded to earlier stages of the disease. In recent years, the initial steps toward personalized medicine by utilization of targeted treatments based on tumor genotype have been undertaken. Emerging technological advances and greater insights into tumor biology are poised to greatly reduce the burden of lung cancer in the years to come. PMID:24516099

  10. Lung cancer chemoprevention.

    PubMed

    Keith, Robert L

    2012-05-01

    Lung cancer is the leading cause of cancer death in the United States, and the majority of diagnoses are made in former smokers. Although avoidance of tobacco abuse and smoking cessation clearly will have the greatest impact on lung cancer development, effective chemoprevention could prove to be more effective than treatment of established, advanced-stage disease. Chemoprevention is the use of dietary or pharmaceutical agents to reverse or block the carcinogenic process and has been successfully applied to common malignancies other than lung (including recent reports on the prevention of breast cancer in high-risk individuals). Despite previous studies in lung cancer chemoprevention failing to identify effective agents, our ability to define the highest-risk populations and the understanding of lung tumor and premalignant biology continue to make advances. Squamous cell carcinogenesis in the bronchial epithelium starts with normal epithelium and progresses through hyperplasia, metaplasia, dysplasia, and carcinoma in situ to invasive cancer. Precursor lesions also have been identified for adenocarcinoma, and these premalignant lesions are targeted by chemopreventive agents in current and future trials. Chemopreventive agents can currently only be recommended as part of well-designed clinical trials, and multiple trials have recently been completed or are enrolling subjects. PMID:22550242

  11. Overexpression of Cathepsin L is associated with gefitinib resistance in non-small cell lung cancer.

    PubMed

    Cui, F; Wang, W; Wu, D; He, X; Wu, J; Wang, M

    2016-07-01

    Lung cancer, the most common malignancy, is still the leading cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) accounts for 80 % of all lung cancers. Recent studies showed Cathepsin L (CTSL) is overexpressed in various cancerous tissues; however, the association between CTSL expression and EGFR-TKI resistance remains unknown. In this study, we investigated the expression of CTSL in lung cancer specimens and matched normal tissues by quantitative real-time PCR and IHC. The functional role of CTSL in resistant PC-9/GR cell line was investigated by proliferation and apoptosis analysis compared with control PC-9 cells. Our results found that the level of CTSL expression was higher in NSCLC tissues compared with matched normal adjacent tissue samples, and CTSL was more highly expressed in PC-9/GR cells compared to PC-9 cells. Knocking-down of CTSL in PC-9/GR cells could decrease cell proliferation and potentiate apoptosis induced by gefitinib, suggesting CTSL may contribute to gefitinib resistance in NSCLC. CTSL might be explored as a candidate of therapeutic target for modulating EGFR-TKI sensitivity in NSCLC. PMID:26474873

  12. Human lung cancer-derived microparticles enhanced angiogenesis and growth of hepatoma cells in rodent lung parenchyma

    PubMed Central

    Ko, Sheung-Fat; Hsu, Shu-Yuan; Chen, Chih-Hung; Sung, Pei-Hsun; Zhen, Meng-Shen TongYen-Yi; Chen, Yi-Ling; Huang, Tien-Hung; Chen, Sheng-Yi; Kao, Gour-Shenq; Chen, Hong-Hwa; Chang, Chia-Lo; Sun, Cheuk-Kwan; Chang, Hsueh-Wen; Yip, Hon-Kan

    2016-01-01

    This study tested the hypothesis that human lung cancer-derived microparticles (LcD-MPs) played an important role in tumor angiogenesis and growth. Fischer 344 rats (F344, n=18) were equally categorized into group 1 [Sham Control (3.0 mL normal saline intravenous injection (IV))], group 2 [hepatoma cell line (2.0 x 106 cells, IV)], and group 3 [hepatoma cell line + LcD-MPs (3.0 x 106, IV)]. Animals were euthanized by day 28 after hepatoma cells transfusion. Our result showed that the gross pathology confirmed growth of hepatoma cell line in lung parenchyma. The size and weight of the lungs were significantly increased in group 2 and further elevated in group 3 than in group 1 (all p<0.001). Histopathological analysis demonstrated that the lung crowded score and number of small vessel exhibited an identical pattern, whereas the number of alveolar sacs showed an opposite pattern compared to that of total lung weight among the three groups (all p<0.0001). The cellular expressions of CD34+, CXCR4+, c-Kit+, CK19+, VEGF+ and vimentin+ cells in lung parenchyma exhibited an identical pattern compared to those of total lung weight among all groups (all p<0.001). The protein expressions of apoptotic (Bax, cleaved caspase-3 and c-PARP), fibrotic (Smad3, TGF-β), and tumor suppression (PTEN) biomarkers showed an identical pattern, whereas that of anti-apoptotic (Bcl-2) and anti-fibrotic (Smad1/5, BMP-2) biomarkers were displayed an opposite pattern compared to that of total lung weight among all groups (all p<0.001). The MPs could enhance angiogenesis and accelerated hepatoma cell growth in rodent lung parenchyma. PMID:27186261

  13. Human lung cancer-derived microparticles enhanced angiogenesis and growth of hepatoma cells in rodent lung parenchyma.

    PubMed

    Ko, Sheung-Fat; Hsu, Shu-Yuan; Chen, Chih-Hung; Sung, Pei-Hsun; Zhen, Meng-Shen TongYen-Yi; Chen, Yi-Ling; Huang, Tien-Hung; Chen, Sheng-Yi; Kao, Gour-Shenq; Chen, Hong-Hwa; Chang, Chia-Lo; Sun, Cheuk-Kwan; Chang, Hsueh-Wen; Yip, Hon-Kan

    2016-01-01

    This study tested the hypothesis that human lung cancer-derived microparticles (LcD-MPs) played an important role in tumor angiogenesis and growth. Fischer 344 rats (F344, n=18) were equally categorized into group 1 [Sham Control (3.0 mL normal saline intravenous injection (IV))], group 2 [hepatoma cell line (2.0 x 10(6) cells, IV)], and group 3 [hepatoma cell line + LcD-MPs (3.0 x 10(6), IV)]. Animals were euthanized by day 28 after hepatoma cells transfusion. Our result showed that the gross pathology confirmed growth of hepatoma cell line in lung parenchyma. The size and weight of the lungs were significantly increased in group 2 and further elevated in group 3 than in group 1 (all p<0.001). Histopathological analysis demonstrated that the lung crowded score and number of small vessel exhibited an identical pattern, whereas the number of alveolar sacs showed an opposite pattern compared to that of total lung weight among the three groups (all p<0.0001). The cellular expressions of CD34(+), CXCR4(+), c-Kit(+), CK19(+), VEGF(+) and vimentin+ cells in lung parenchyma exhibited an identical pattern compared to those of total lung weight among all groups (all p<0.001). The protein expressions of apoptotic (Bax, cleaved caspase-3 and c-PARP), fibrotic (Smad3, TGF-β), and tumor suppression (PTEN) biomarkers showed an identical pattern, whereas that of anti-apoptotic (Bcl-2) and anti-fibrotic (Smad1/5, BMP-2) biomarkers were displayed an opposite pattern compared to that of total lung weight among all groups (all p<0.001). The MPs could enhance angiogenesis and accelerated hepatoma cell growth in rodent lung parenchyma. PMID:27186261

  14. A novel miRNA-mediated STOP sign in lung cancer: miR-340 inhibits the proliferation of lung cancer cells through p27KIP1

    PubMed Central

    Fernandez, Serena; Risolino, Maurizio; Verde, Pasquale

    2015-01-01

    Oncosuppressor miRNAs inhibit cancer cell proliferation by targeting key components of the cell cycle machinery. In our recent report we showed that miR-340 is a novel tumor suppressor in non-small cell lung cancer. miR-340 inhibits neoplastic cell proliferation and induces p27KIP1 by targeting multiple translational and post-translational regulators of this cyclin-dependent kinase inhibitor. PMID:27308439

  15. Molecular and Cellular Effects of Hydrogen Peroxide on Human Lung Cancer Cells: Potential Therapeutic Implications

    PubMed Central

    2016-01-01

    Lung cancer has a very high mortality-to-incidence ratio, representing one of the main causes of cancer mortality worldwide. Therefore, new treatment strategies are urgently needed. Several diseases including lung cancer have been associated with the action of reactive oxygen species (ROS) from which hydrogen peroxide (H2O2) is one of the most studied. Despite the fact that H2O2 may have opposite effects on cell proliferation depending on the concentration and cell type, it triggers several antiproliferative responses. H2O2 produces both nuclear and mitochondrial DNA lesions, increases the expression of cell adhesion molecules, and increases p53 activity and other transcription factors orchestrating cancer cell death. In addition, H2O2 facilitates the endocytosis of oligonucleotides, affects membrane proteins, induces calcium release, and decreases cancer cell migration and invasion. Furthermore, the MAPK pathway and the expression of genes related to inflammation including interleukins, TNF-α, and NF-κB are also affected by H2O2. Herein, we will summarize the main effects of hydrogen peroxide on human lung cancer leading to suggesting it as a potential therapeutic tool to fight this disease. Because of the multimechanistic nature of this molecule, novel therapeutic approaches for lung cancer based on the use of H2O2 may help to decrease the mortality from this malignancy. PMID:27375834

  16. Molecular and Cellular Effects of Hydrogen Peroxide on Human Lung Cancer Cells: Potential Therapeutic Implications.

    PubMed

    Vilema-Enríquez, Gabriela; Arroyo, Aurora; Grijalva, Marcelo; Amador-Zafra, Ricardo Israel; Camacho, Javier

    2016-01-01

    Lung cancer has a very high mortality-to-incidence ratio, representing one of the main causes of cancer mortality worldwide. Therefore, new treatment strategies are urgently needed. Several diseases including lung cancer have been associated with the action of reactive oxygen species (ROS) from which hydrogen peroxide (H2O2) is one of the most studied. Despite the fact that H2O2 may have opposite effects on cell proliferation depending on the concentration and cell type, it triggers several antiproliferative responses. H2O2 produces both nuclear and mitochondrial DNA lesions, increases the expression of cell adhesion molecules, and increases p53 activity and other transcription factors orchestrating cancer cell death. In addition, H2O2 facilitates the endocytosis of oligonucleotides, affects membrane proteins, induces calcium release, and decreases cancer cell migration and invasion. Furthermore, the MAPK pathway and the expression of genes related to inflammation including interleukins, TNF-α, and NF-κB are also affected by H2O2. Herein, we will summarize the main effects of hydrogen peroxide on human lung cancer leading to suggesting it as a potential therapeutic tool to fight this disease. Because of the multimechanistic nature of this molecule, novel therapeutic approaches for lung cancer based on the use of H2O2 may help to decrease the mortality from this malignancy. PMID:27375834

  17. ARVCF expression is significantly correlated with the malignant phenotype of non-small cell lung cancer.

    PubMed

    Zhang, Di; Tang, Na; Liu, Yang; Wang, En-Hua

    2015-06-01

    Armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF) is a member of the p120 catenin (p120ctn) family; it contains nine central Armadillo repeats and binds to the juxtamembrane domain of E-cadherin. We used immunohistochemistry to measure ARVCF expression in 121 patients with NSCLC and western blotting to examine differences in ARVCF expression between lung cancer and adjacent normal lung tissues. We interfered with ARVCF expression in two lung cancer cell lines and measured its effects on invasion and proliferation. ARVCF expression correlated with the malignant phenotype and poor prognosis. We also observed ARVCF-dependent changes in small GTPase (mainly RhoA) activity in lung cancer cells. We confirmed that ARVCF plays an important role in the malignant phenotype. PMID:25683624

  18. Knockdown of Aurora-B inhibits the growth of non-small cell lung cancer A549 cells

    PubMed Central

    YU, JING JING; ZHOU, LONG DIAN; ZHAO, TIAN TIAN; BAI, WEI; ZHOU, JING; ZHANG, WEI

    2015-01-01

    Elevated expression of Aurora-B affects cell apoptosis and proliferation in a variety of solid tumors. However, the role of Aurora-B has been poorly evaluated in non-small cell lung cancer (NSCLC). In the present study, it was found that Aurora-B was overexpressed in tissue specimens obtained from 174 patients with lung cancer. It was also demonstrated that knockdown of Aurora-B induces apoptosis and inhibits the growth of lung cancer A549 cells in vitro and in vivo. Furthermore, it was found that silencing Aurora-B decreased the activity of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Therefore, it was concluded that knockdown of Aurora-B induces apoptosis and inhibits growth in NSCLC A549 cells, in addition to inhibiting the activity of the PI3K/AKT signaling pathway. Targeting Aurora-B may provide a novel target for lung cancer therapy. PMID:26622725

  19. Targeting the KRAS variant for treatment of non-small cell lung cancer: potential therapeutic applications.

    PubMed

    Ricciuti, Biagio; Leonardi, Giulia Costanza; Metro, Giulio; Grignani, Francesco; Paglialunga, Luca; Bellezza, Guido; Baglivo, Sara; Mencaroni, Clelia; Baldi, Alice; Zicari, Daniela; Crinò, Lucio

    2016-01-01

    Lung cancer is the leading cause of cancer deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 80% of all lung cancers. Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the deadliest cancer-related proteins and plays a pivotal role in the most aggressive and lethal human cancers, including lung adenocarcinoma where it represents one of the most frequently mutated oncogene. Although therapeutic progresses have made an impact over the last decade, median survival for patients with advanced lung cancer remains disappointing, with a 5-year worldwide survival rate of <15%. For more than 20 years it has been recognized that constitutively active signaling downstream of KRAS is a fundamental driver of lung tumorigenesis. However, years of pursuit have failed to yield a drug that can safely curb KRAS activity; up to now no approved therapies exist for KRAS-mutant NSCLC. The aim of this review is to discuss the current knowledge of KRAS-mutated NSCLC, touching upon KRAS clinical relevance as a prognostic and predictive biomarker, with an emphasis on novel therapeutic approaches for the treatment of KRAS-variant NSCLC. PMID:26714748

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

    SciTech Connect

    Person, Rachel J.; Olive Ngalame, Ntube N.; Makia, Ngome L.; Bell, Matthew W.; Waalkes, Michael P.; Tokar, Erik J.

    2015-07-01

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

  1. KRAS Mutation in Small Cell Lung Carcinoma and Extrapulmonary Small Cell Cancer

    PubMed Central

    Kodaz, Hilmi; Taştekin, Ebru; Erdoğan, Bülent; Hacıbekiroğlu, İlhan; Tozkır, Hilmi; Gürkan, Hakan; Türkmen, Esma; Demirkan, Bora; Uzunoğlu, Sernaz; Çiçin, İrfan

    2016-01-01

    Background: Lung cancer is one of the most lethal cancers. It is mainly classified into 2 groups: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Extrapulmonary small cell carcinomas (EPSCC) are very rare. The Ras oncogene controls most of the cellular functions in the cell. Overall, 21.6% of human cancers contain a Kirsten Ras (KRAS) mutation. SCLC and EPSCC have several similar features but their clinical course is different. Aims: We investigated the KRAS mutation status in SCLC and EPSCC. Study design: Mutation research. Methods: Thirty-seven SCLC and 15 EPSCC patients were included in the study. The pathological diagnoses were confirmed by a second pathologist. KRAS analysis was performed in our medical genetic department. DNA isolation was performed with primary tumor tissue using the QIAamp DNA FFPE Tissue kit (Qiagen; Hilden, Germany) in all patients. The therascreen KRAS Pyro Kit 24 V1 (Qiagen; Hilden, Germany) was used for KRAS analyses. Results: Thirty-four (91.9%) of the SCLC patients were male, while 11 (73.3%) of the EPSCC l patients were female. SCLC was more common in males, and EPSCC in females (p=0.001). A KRAS mutation was found in 6 (16.2%) if SCLC patients. The most common mutation was Q61R (CAA>CGA). Among the 15 EPSCC patients, 2 had a KRAS mutation (13.3%). When KRAS mutant and wild type patients were compared in the SCLC group, no difference was found for overall survival (p=0.6). Conclusion: In previous studies, the incidence of KRAS mutation in SCLC was 1–3%; however, it was 16.2% in our study. Therefore, there may be ethnic and geographical differences in the KRAS mutations of SCLC. As a result, KRAS mutation should not be excluded in SCLC.

  2. The Effect of Adenovirus-Mediated Gene Expression of FHIT in Small Cell Lung Cancer Cells

    PubMed Central

    Zandi, Roza; Xu, Kai; Poulsen, Hans S.; Roth, Jack A.; Ji, Lin

    2012-01-01

    The candidate tumor suppressor fragile histidine traid (FHIT) is frequently inactivated in small cell lung cancer (SCLC). Mutations in the p53 gene also occur in the majority of SCLC leading to the accumulation of the mutant protein. Here we evaluated the effect of FHIT gene therapy alone or in combination with the mutant p53-reactivating molecule, PRIMA-1Met/APR-246, in SCLC. Overexpression of FHIT by recombinant adenoviral vector (Ad-FHIT)-mediated gene transfer in SCLC cells inhibited their growth by inducing apoptosis and when combined with PRIMA-1Met/APR-246, a synergistic cell growth inhibition was achieved. PMID:22085272

  3. Promising Targets and Current Clinical Trials in Metastatic Squamous Cell Lung Cancer

    PubMed Central

    Vincent, Mark D.

    2014-01-01

    Squamous cancer of the lung (SQCC), although no longer the premier variant of non-small cell lung cancer, continues to impose a heavy world-wide burden. Advanced SQCC has enjoyed little of the recent progress benefiting patients with adenocarcinoma of the lung, but that has now begun to change. This article reviews the underlying molecular pathology of SQCC, as well as potential new targets and the corresponding novel targeted agents; included are some of which may soon be approvable in this notoriously hard-to-treat indication. PMID:25538887

  4. Epidemiology of Lung Cancer

    PubMed Central

    Ridge, Carole A.; McErlean, Aoife M.; Ginsberg, Michelle S.

    2013-01-01

    Incidence and mortality attributed to lung cancer has risen steadily since the 1930s. Efforts to improve outcomes have not only led to a greater understanding of the etiology of lung cancer, but also the histologic and molecular characteristics of individual lung tumors. This article describes this evolution by discussing the extent of the current lung cancer epidemic including contemporary incidence and mortality trends, the risk factors for development of lung cancer, and details of promising molecular targets for treatment. PMID:24436524

  5. Short course prophylactic cranial irradiation for small cell lung cancer

    SciTech Connect

    Feld, R.; Clamon, G.H.; Blum, R.; Moran, E.; Weiner, R.; Kramer, B.; Evans, W.K.; Herman, J.G.; Hoffman, F.; Burmeister, L.

    1985-10-01

    Ninety-one patients with small cell carcinoma of the lung were given a shortened, intensive course of prophylactic cranial irradiation consisting of 2,000 rad in five fractions. The CNS relapse rate was 21%, but in only one of 91 patients was the brain the first and only site of relapse. Acute toxicities consisting of headache (16%) and nausea and vomiting (15%) were observed. Results are compared with previous results from other studies of cranial irradiation.

  6. Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer

    SciTech Connect

    Jang, Sang-Min; An, Joo-Hee; Kim, Chul-Hong; Kim, Jung-Woong Choi, Kyung-Hee

    2015-08-07

    Lung cancer is the leading cause of cancer-mediated death. Although various therapeutic approaches are used for lung cancer treatment, these mainly target the tumor suppressor p53 transcription factor, which is involved in apoptosis and cell cycle arrest. However, p53-targeted therapies have limited application in lung cancer, since p53 is found to be mutated in more than half of lung cancers. In this study, we propose tumor suppressor FOXA2 as an alternative target protein for therapies against lung cancer and reveal a possible FOXA2-centered transcriptional regulation network by identifying new target genes and binding partners of FOXA2 by using various screening techniques. The genes encoding Glu/Asp-rich carboxy-terminal domain 2 (CITED2), nuclear receptor subfamily 0, group B, member 2 (NR0B2), cell adhesion molecule 1 (CADM1) and BCL2-associated X protein (BAX) were identified as putative target genes of FOXA2. Additionally, the proteins including highly similar to heat shock protein HSP 90-beta (HSP90A), heat shock 70 kDa protein 1A variant (HSPA1A), histone deacetylase 1 (HDAC1) and HDAC3 were identified as novel interacting partners of FOXA2. Moreover, we showed that FOXA2-dependent promoter activation of BAX and p21 genes is significantly reduced via physical interactions between the identified binding partners and FOXA2. These results provide opportunities to understand the FOXA2-centered transcriptional regulation network and novel therapeutic targets to modulate this network in p53-deficient lung cancer. - Highlights: • Identification of new target genes of FOXA2. • Identifications of novel interaction proteins of FOXA2. • Construction of FOXA2-centered transcriptional regulatory network in non-small cell lung cancer.

  7. Multiplex detection of lung cancer cells at the single-molecule level.

    PubMed

    Hu, Juan; Zhang, Chun-yang

    2014-11-14

    We develop a simple and sensitive method for multiplex detection of lung cancer cells at the single-molecule level, with a detection limit of 15 cells per mL for A549 cells and 4 cells per mL for H23 cells, without the involvement of any sequence-based amplification. This method holds great potential for further application in early clinical diagnosis, especially for the detection of rare tumor cells. PMID:25245541

  8. EZH2 promotes progression of small cell lung cancer by suppressing the TGF-β-Smad-ASCL1 pathway

    PubMed Central

    Murai, Fumihiko; Koinuma, Daizo; Shinozaki-Ushiku, Aya; Fukayama, Masashi; Miyaozono, Kohei; Ehata, Shogo

    2015-01-01

    Transforming growth factor-β (TGF-β) induces apoptosis in many types of cancer cells and acts as a tumor suppressor. We performed a functional analysis of TGF-β signaling to identify a molecular mechanism that regulated survival in small cell lung cancer cells. Here, we found low expression of TGF-β type II receptor (TβRII) in most small cell lung cancer cells and tissues compared to normal lung epithelial cells and normal lung tissues, respectively. When wild-type TβRII was overexpressed in small cell lung cancer cells, TGF-β suppressed cell growth in vitro and tumor formation in vivo through induction of apoptosis. Components of polycomb repressive complex 2, including enhancer of zeste 2 (EZH2), were highly expressed in small cell lung cancer cells; this led to epigenetic silencing of TβRII expression and suppression of TGF-β-mediated apoptosis. Achaete-scute family bHLH transcription factor 1 (ASCL1; also known as ASH1), a Smad-dependent target of TGF-β, was found to induce survival in small cell lung cancer cells. Thus, EZH2 promoted small cell lung cancer progression by suppressing the TGF-β-Smad-ASCL1 pathway.

  9. Celecoxib increases lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1

    PubMed Central

    Frank, Marcus; Linnebacher, Michael; Hinz, Burkhard

    2015-01-01

    The antitumorigenic mechanism of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib is still a matter of debate. Using lung cancer cell lines (A549, H460) and metastatic cells derived from a lung cancer patient, the present study investigates the impact of celecoxib on the expression of intercellular adhesion molecule 1 (ICAM-1) and cancer cell lysis by lymphokine-activated killer (LAK) cells. Celecoxib, but not other structurally related selective COX-2 inhibitors (i.e., etoricoxib, rofecoxib, valdecoxib), was found to cause a substantial upregulation of ICAM-1 protein levels. Likewise, ICAM-1 mRNA expression was increased by celecoxib. Celecoxib enhanced the susceptibility of cancer cells to be lysed by LAK cells with the respective effect being reversed by a neutralizing ICAM-1 antibody. In addition, enhanced killing of celecoxib-treated cancer cells was reversed by preincubation of LAK cells with an antibody to lymphocyte function associated antigen 1 (LFA-1), suggesting intercellular ICAM-1/LFA-1 crosslink as crucial event within this process. Finally, celecoxib elicited no significant increase of LAK cell-mediated lysis of non-tumor bronchial epithelial cells, BEAS-2B, associated with a far less ICAM-1 induction as compared to cancer cells. Altogether, our data demonstrate celecoxib-induced upregulation of ICAM-1 on lung cancer cells to be responsible for intercellular ICAM-1/LFA-1 crosslink that confers increased cancer cell lysis by LAK cells. These findings provide proof for a novel antitumorigenic mechanism of celecoxib. PMID:26513172

  10. Role of positron emission tomography-computed tomography in non-small cell lung cancer.

    PubMed

    Garg, Pankaj Kumar; Singh, Saurabh Kumar; Prakash, Gaurav; Jakhetiya, Ashish; Pandey, Durgatosh

    2016-03-26

    Lung cancer is the leading cause of cancer-related mortality worldwide. Non-small cell carcinoma and small cell carcinoma are the main histological subtypes and constitutes around 85% and 15% of all lung cancer respectively. Multimodality treatment plays a key role in the successful management of lung cancer depending upon the histological subtype, stage of disease, and performance status. Imaging modalities play an important role in the diagnosis and accurate staging of the disease, in assessing the response to neoadjuvant therapy, and in the follow-up of the patients. Last decade has witnessed voluminous upsurge in the use of positron emission tomography-computed tomography (PET-CT); role of PET-CT has widened exponentially in the management of lung cancer. The present article reviews the role of 18-fluoro-deoxyglucose PET-CT in the management of non small cell lung cancer with emphasis on staging of the disease and the assessment of response to neoadjuvant therapy based on available literature. PMID:27018223

  11. Role of positron emission tomography-computed tomography in non-small cell lung cancer

    PubMed Central

    Garg, Pankaj Kumar; Singh, Saurabh Kumar; Prakash, Gaurav; Jakhetiya, Ashish; Pandey, Durgatosh

    2016-01-01

    Lung cancer is the leading cause of cancer-related mortality worldwide. Non-small cell carcinoma and small cell carcinoma are the main histological subtypes and constitutes around 85% and 15% of all lung cancer respectively. Multimodality treatment plays a key role in the successful management of lung cancer depending upon the histological subtype, stage of disease, and performance status. Imaging modalities play an important role in the diagnosis and accurate staging of the disease, in assessing the response to neoadjuvant therapy, and in the follow-up of the patients. Last decade has witnessed voluminous upsurge in the use of positron emission tomography-computed tomography (PET-CT); role of PET-CT has widened exponentially in the management of lung cancer. The present article reviews the role of 18-fluoro-deoxyglucose PET-CT in the management of non small cell lung cancer with emphasis on staging of the disease and the assessment of response to neoadjuvant therapy based on available literature. PMID:27018223

  12. Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells.

    PubMed

    Olkhanud, Purevdorj B; Baatar, Dolgor; Bodogai, Monica; Hakim, Fran; Gress, Ronald; Anderson, Robin L; Deng, Jie; Xu, Mai; Briest, Susanne; Biragyn, Arya

    2009-07-15

    Cancer metastasis is a leading cause of cancer morbidity and mortality. More needs to be learned about mechanisms that control this process. In particular, the role of chemokine receptors in metastasis remains controversial. Here, using a highly metastatic breast cancer (4T1) model, we show that lung metastasis is a feature of only a proportion of the tumor cells that express CCR4. Moreover, the primary tumor growing in mammary pads activates remotely the expression of TARC/CCL17 and MDC/CCL22 in the lungs. These chemokines acting through CCR4 attract both tumor and immune cells. However, CCR4-mediated chemotaxis was not sufficient to produce metastasis, as tumor cells in the lung were efficiently eliminated by natural killer (NK) cells. Lung metastasis required CCR4(+) regulatory T cells (Treg), which directly killed NK cells using beta-galactoside-binding protein. Thus, strategies that abrogate any part of this process should improve the outcome through activation of effector cells and prevention of tumor cell migration. We confirm this prediction by killing CCR4(+) cells through delivery of TARC-fused toxins or depleting Tregs and preventing lung metastasis. PMID:19567680

  13. Targets and Mechanisms of Photodynamic Therapy in Lung Cancer Cells: A Brief Overview

    PubMed Central

    Chiaviello, Angela; Postiglione, Ilaria; Palumbo, Giuseppe

    2011-01-01

    Lung cancer remains one of the most common cancer-related causes of death. This type of cancer typically develops over a period of many years, and if detected at an early enough stage can be eliminated by a variety of treatments including photodynamic therapy (PDT). A critical discussion on the clinical applications of PDT in lung cancer is well outside the scope of the present report, which, in turn focuses on mechanistic and other aspects of the photodynamic action at a molecular and cellular level. The knowledge of these issues at pre-clinical levels is necessary to develop, check and adopt appropriate clinical protocols in the future. This report, besides providing general information, includes a brief overview of present experimental PDT and provides some non-exhaustive information on current strategies aimed at further improving the efficacy, especially in regard to lung cancer cells. PMID:24212652

  14. Non small-cell lung cancer with metastasis to thigh muscle and mandible: two case reports

    PubMed Central

    2013-01-01

    Introduction Lung cancer is the leading cause of cancer-related death in Europe and the US. Isolated metastases to skeletal muscle and the mandible are very uncommon. Case presentation This report presents two cases. Case 1 concerns a 45-year-old Caucasian woman affected by muscle metastasis of the right thigh from non-small-cell lung cancer. Case 2 concerns a 61-year-old Caucasian man affected by mandible metastasis from non-small-cell lung cancer. Both metastases were detected by diagnostic imaging studies. Both patients were treated with radiation therapy with palliative and antalgic intent. Conclusion Radiation therapy was effective and well tolerated in both cases. Both our patients are alive, with follow-up of 18 months and five months, respectively. PMID:23566415

  15. Cell-free DNA levels in plasma of patients with non-small-cell lung cancer and inflammatory lung disease

    PubMed Central

    Szpechcinski, A; Chorostowska-Wynimko, J; Struniawski, R; Kupis, W; Rudzinski, P; Langfort, R; Puscinska, E; Bielen, P; Sliwinski, P; Orlowski, T

    2015-01-01

    Background: The analysis of plasma cell-free DNA (cfDNA) is expected to provide useful biomarkers for early diagnosis of non-small-cell lung cancer (NSCLC). However, it remains unclear whether the intense release of cfDNA into the bloodstream of NSCLC patients results from malignancy or chronic inflammatory response. Consequently, the current diagnostic utility of plasma cfDNA quantification has not been thoroughly validated in subjects with chronic respiratory inflammation. Here we assess the effect of chronic respiratory inflammation on plasma cfDNA levels and evaluate the potential clinical value of this phenomenon as an early lung cancer diagnostic tool. Methods: We measured plasma cfDNA concentrations in 50 resectable NSCLC patients, 101 patients with chronic respiratory inflammation (chronic obstructive pulmonary disease, sarcoidosis, or asthma) and 40 healthy volunteers using real-time PCR. Results: We found significantly higher plasma cfDNA levels in NSCLC patients than in subjects with chronic respiratory inflammation and healthy individuals (P<0.0001). There were no significant differences in plasma cfDNA levels between patients with chronic respiratory inflammation and healthy volunteers. The cutoff point of >2.8 ng ml−1 provided 90% sensitivity and 80.5% specificity in discriminating NSCLC from healthy individuals (area under the curve (AUC)=0.90). The receiver-operating characteristics curve distinguishing NSCLC patients from subjects with chronic respiratory inflammation indicated 56% sensitivity and 91% specificity at the >5.25-ng ml−1 cutoff (AUC=0.76). Conclusions: We demonstrated that elevated plasma cfDNA levels in NSCLC resulted primarily from tumour development rather than inflammatory response, raising the potential clinical implications for lung cancer screening and early diagnosis. Further research is necessary to better characterise and identify factors and processes regulating cfDNA levels in the blood under normal and

  16. Sinomenine inhibits A549 human lung cancer cell invasion by mediating the STAT3 signaling pathway

    PubMed Central

    Jiang, Shulong; Gao, Yebo; Hou, Wei; Liu, Rui; Qi, Xin; Xu, Xia; Li, Jie; Bao, Yanju; Zheng, Honggang; Hua, Baojin

    2016-01-01

    Increasing evidence suggests that the failure of lung cancer treatment may occur as a result of tumor invasion and metastasis. Signal transducer and activator of transcription 3 (STAT3), an epithelial-mesenchymal transition-inducing transcription factor, is a key signaling molecule involved in the proliferation, apoptosis, invasion and metastasis of tumor cells. Sinomenine is an alkaloid compound with an antineoplastic potential against a variety of cancer cells. The aim of the present study was to assess the antitumor mechanisms of sinomenine in the A549 human lung cancer cell line. The results demonstrated that sinomenine manifested dose-dependent cytotoxicity and induced apoptosis in A549 cells. The protein expression of Janus kinase 2, STAT3, phosphorylated-STAT3, Snail, N-cadherin and vimentin decreased in sinomenine-treated cells, while E-cadherin protein expression increased. The regulation of STAT3, N-cadherin and E-cadherin by sinomenine was further confirmed by reverse transcription-quantitative polymerase chain reaction and immunofluorescent staining. It was demonstrated that sinomenine exerts inhibitory effects on A549 human lung cancer cell invasion, possibly through the inhibition of STAT3 signaling. These results provide a novel insight into the role of sinomenine in the treatment of non-small cell lung cancer. PMID:27446441

  17. Manipulations in HIWI level exerts influence on the proliferation of human non-small cell lung cancer cells

    PubMed Central

    WANG, YUGUANG; LIU, JIA; WU, GUANGYAO; YANG, FANG

    2016-01-01

    Lung cancer is the leading cause of cancer-associated mortality worldwide, although molecular imaging techniques, including fludeoxyglucose positron emission tomography, have markedly improved the diagnosis of lung cancer. HIWI is a member of the human piwi family, members of which are known for their roles in RNA silencing. HIWI has been shown to serve a crucial function in stem cell self-renewal, and previous studies have reported HIWI overexpression in lung cancers. Furthermore, HIWI has been proposed to regulate the maintenance of cancer stem cell populations in lung cancers. The present study investigated the mRNA and protein expression levels of HIWI in non-small cell lung cancer (NSCLC) specimens harvested from 57 patients, using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Subsequently, the HIWI expression level was manipulated using gain-of-function and loss-of-function strategies, and the role of HIWI in the proliferation of human A549 NSCLC cells was investigated using Cell Counting Kit-8 and colony formation assays. The mRNA and protein expression levels of HIWI were significantly upregulated in the intratumor NSCLC specimens, as compared with the peritumor specimens. Furthermore, the mRNA and protein expression levels of HIWI in A549 cells were successfully manipulated using the two strategies. Overexpression and knockout of HIWI were associated with the promotion and inhibition of A549 cell proliferation, respectively. The results of the present study suggested that HIWI is overexpressed in NSCLC tissues and demonstrated that upregulation of HIWI may promote the growth of lung cancer cells; thus suggesting that HIWI may have an oncogenic role in lung cancer. PMID:27168836

  18. Erlotinib Hydrochloride and Cetuximab in Treating Patients With Advanced Gastrointestinal Cancer, Head and Neck Cancer, Non-Small Cell Lung Cancer, or Colorectal Cancer

    ClinicalTrials.gov

    2015-09-28

    Adenocarcinoma of the Colon; Adenocarcinoma of the Rectum; Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Gastrointestinal Stromal Tumor; Metastatic Gastrointestinal Carcinoid Tumor; Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adult Primary Liver Cancer; Recurrent Anal Cancer; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Colon Cancer; Recurrent Esophageal Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Intestine Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Small Intestine Adenocarcinoma; Small Intestine Leiomyosarcoma; Small Intestine Lymphoma; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Anal Cancer; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Colon Cancer; Stage IV Esophageal Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Gastric Cancer

  19. CD24+/CD38- as new prognostic marker for non-small cell lung cancer

    PubMed Central

    2013-01-01

    Background Lung cancer is the leading cause of death among cancers in the world. The annual death toll due to this disease exceeds the combined deaths caused by colon, breast, prostate, and pancreatic cancers. As a result, there has been a tremendous effort to identify new biomarkers for early detection and diagnosis of lung cancer. Methods In this study we report the results of screening a panel of eight non-small cell lung cancer (NSCLC) cell lines originating from different subtypes of lung cancer in an attempt to identify potential biomarkers unique to this disease. We used real-time polymerase chain reaction and flow cytometry techniques to analyze the expression of ALDHA1, EpCAM, CD133, CD24, and CD38 in this panel. Results We demonstrate for the first time that the majority of NSCLC cells do not express levels of CD38 that would qualify it as a new biomarker for the disease. In contrast, we found that CD24 is over-expressed in 6 out of 8 of the cell lines. The combined CD24+/CD38-/low phenotype was detected in 50% of the cell lines that are also positive for CD133 and EpCAM. Conclusions We report that CD24+/CD38-/low signature could potentially be used as a new biomarker for the early detection of NSCLC. PMID:24094028

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

    SciTech Connect

    Hemstroem, Therese H.; Joseph, Bertrand; Schulte, Gunnar; Lewensohn, Rolf; Zhivotovsky, Boris . E-mail: Boris.Zhivotovsky@imm.ki.se

    2005-04-15

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

  1. Lung Cancer – Vaccines

    PubMed Central

    Kelly, Ronan J.; Giaccone, Giuseppe

    2011-01-01

    In lung cancer, early attempts to modulate the immune system via vaccine based therapeutics have to date, been unsuccessful. An improved understanding of tumor immunology has facilitated the production of more sophisticated lung cancer vaccines. It is anticipated, that it will likely require multiple epitopes of a diverse set of genes restricted to multiple haplotypes to generate a truly effective vaccine that is able to overcome the various immunologic escape mechanisms that tumors employ. Other issues to overcome include optimal patient selection, which adjuvant agent to use and how to adequately monitor for an immunological response. This review discusses the most promising vaccination strategies for non small cell lung cancer including the allogeneic tumor cell vaccine belagenpumatucel-L, which is a mixture of 4 allogeneic non small cell lung cancer cell lines genetically modified to secrete an antisense oligonucleotide to TGF-β2 and three other target protein-specific vaccines designed to induce responses against melanoma-associated antigen A3 (MAGE-A3), mucin 1 (MUC1) and epidermal growth factor (EGF). PMID:21952280

  2. 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 PMID:25398122

  3. Epidemiology of Lung Cancer.

    PubMed

    Mao, Yousheng; Yang, Ding; He, Jie; Krasna, Mark J

    2016-07-01

    Lung cancer has been transformed from a rare disease into a global problem and public health issue. The etiologic factors of lung cancer become more complex along with industrialization, urbanization, and environmental pollution around the world. Currently, the control of lung cancer has attracted worldwide attention. Studies on the epidemiologic characteristics of lung cancer and its relative risk factors have played an important role in the tertiary prevention of lung cancer and in exploring new ways of diagnosis and treatment. This article reviews the current evolution of the epidemiology of lung cancer. PMID:27261907

  4. [Smoking and lung cancer].

    PubMed

    Postmus, P E

    1999-11-01

    Since fifty years it is clear now that smoking of tobacco products is responsible for the lung cancer epidemic that is currently in progress worldwide. Although in the Western world a small decrease of lung cancer in males is found, the number of female patients is steadily increasing. Changes in tobacco production have resulted in exposition of smokers to other carcinogens. This is probably the cause of the change in the histological pattern with an increase of adenocarcinoma and stabilisation of squamous cell lung cancer. Despite the bad prognosis there is some hope that with improvement of early detection methods more patients can be cured. However, for a real change it is necessary to discourage smoking by all means. PMID:11930407

  5. [Single-cell detection of EGFR gene mutation in circulating tumor cells in lung cancer].

    PubMed

    Shuai, Sun; Yuliang, Deng

    2015-12-01

    Circulating tumor cells (CTCs) are cells that shed from a primary tumor and enter the peripheral blood circulation. The CTCs are closely associated with tumor development and metastasis because of its high heterogeneity. However, there are still no effective methods to detect single-cell heterogeneity of the CTCs. To this end, we developed a method to detect gene mutation in CTCs at the single-cell level and applied it to the detection of EGFR gene mutation in single lung cancer CTC. Specifically, the rare CTCs were captured from blood using an integrated microfluidic system, and then were released into a microchip with thousands of nanoliter wells to isolate single CTC. The single CTC was then transferred into a PCR tube under the microscope for single-cell genome amplification and detection of EGFR gene mutation. We firstly modified chip and capillary and optimized PCR conditions (annealing temperature, number of cycles) using non-small-cell lung cancer (NSCLC) cell lines A549, NCI-H1650 and NCI-H1975 as samples, which showed maximal amplification after 30 cycles with an annealing temperature at 59℃. We then successfully detected blood samples from NSCLC patients using this method. 5 CTCs were obtained from 2 mL patient's blood and the sequencing of EGFR exons 18, 19, 20 and 21 showed no mutations. Our results demonstrated that this method is sensitive enough to detect gene mutation in single CTC and has guiding significance in clinic research. PMID:26704950

  6. Potential targets for lung squamous cell carcinoma

    Cancer.gov

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

  7. Pemetrexed for advanced non-small cell lung cancer patients with interstitial lung disease

    PubMed Central

    2014-01-01

    Background Non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) need to be approached carefully given the high incidence of pulmonary toxicity. Pemetrexed (PEM) is the key drug for the treatment of NSCLC. However, its safety, especially with respect to the exacerbation of ILD, and efficacy in NSCLC patients with ILD have yet to be established. Method We investigated the safety and efficacy of PEM monotherapy in NSCLC patients with or without idiopathic interstitial pneumonia (IIPs). The medical charts of these patients were retrospectively reviewed. Results Twenty-five patients diagnosed as having IIPs (IIPs group) and 88 patients without ILD (non-ILD group) were treated with PEM monotherapy at Juntendo University Hospital between 2009 and 2013. In the IIPs group, 12 patients were found to have usual interstitial pneumonitis (UIP) on chest computed tomography (CT) (UIP group) and the other 13 patients showed a non-UIP pattern on chest CT (non-UIP IIPs group). Three patients in the IIPs group (2 in the UIP group and 1 in the non-UIP IIPs group) and 1 in the non-ILD group developed pulmonary toxicity during treatment (3.5% overall, 12.0% in the IIPs group versus 1.1% in the non-ILD group). Moreover, all 3 patients in the IIPs group died of pulmonary toxicity. Overall survival tended to be longer in the non-ILD group than in the IIPs group (p = 0.08). Multivariate analyses demonstrated that IIPs was the only significant independent risk factor for PEM-related pulmonary toxicity. Conclusion We found that the incidence of PEM-related pulmonary toxicity was significantly higher amongst NSCLC patients with IIPs than among those without IIPs. Particular care must be taken when administering PEM to treat NSCLC patients with IIPs. PMID:25012241

  8. Actual status of therapeutic vaccination in non-small cell lung cancer

    PubMed Central

    Ramlau, Katarzyna; Goździk-Spychalska, Joanna; Spychalski, Łukasz; Bryl, Maciej; Gołda-Gocka, Iwona; Kopczyńska, Anna; Barinow-Wojewódzki, Aleksander; Ramlau, Rodryg

    2014-01-01

    Lung cancer is the leading cause of cancer-related death worldwide. Although treatment methods such as surgery, radiotherapy and/or chemotherapy have improved, prognosis remains unsatisfactory, and developing new therapeutic strategies is still an urgent matter. Immunotherapy is a novel therapeutic approach wherein activated immune cells can specifically kill tumour cells. Several lung cancer vaccines have demonstrated prolonged survival time in phase II and III trials, and several clinical trials are under investigation. However, many clinical trials involving cancer vaccination with defined tumour antigens have shown this method to work only in a small number of patients. Cancer immunotherapy is not completely effective in eradicating tumour cells because they evade host immune control. PMID:24966788

  9. Dihydroartemisinin inhibits cell proliferation via AKT/GSK3β/cyclinD1 pathway and induces apoptosis in A549 lung cancer cells

    PubMed Central

    Liao, Kui; Li, Juan; Wang, Zhiling

    2014-01-01

    Lung cancer is the most common cause of cancer-related death in the world. The main types of lung cancer are small cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC); non small cell lung carcinoma (NSCLC) includes squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, Non small cell lung carcinoma accounts for about 80% of the total lung cancer cases. Dihydroartemisinin (DHA) inhibits cell proliferation and induces apoptosis in several cancer cell lines. The effects of DHA on cell growth and proliferation in lung cancer cells remain to be elucidated. Here, we demonstrate that DHA inhibited cell proliferation in the A549 lung cancer cell line through suppression of the AKT/Gsk-3β/cyclin D1 signaling pathway. DHA significantly inhibited cell proliferation of A549 cells in a concentration and time dependent manner as determined by MTS assay. Flow cytometry analysis demonstrated that DHA treatment of A549 cells resulted in cell cycle arrest at the G1 phase, which correlated with apparent downregulation of both mRNA and protein levels of both PCNA and cyclin D1. These results suggest that DHA is a potential natural product for the treatment of lung cancer. PMID:25674233

  10. Calretinin mediates apoptosis in small cell lung cancer cells expressing tetraspanin CD9☆

    PubMed Central

    He, Ping; Kuhara, Hanako; Tachibana, Isao; Jin, Yingji; Takeda, Yoshito; Tetsumoto, Satoshi; Minami, Toshiyuki; Kohmo, Satoshi; Hirata, Haruhiko; Takahashi, Ryo; Inoue, Koji; Nagatomo, Izumi; Kida, Hiroshi; Kijima, Takashi; Naka, Tetsuji; Morii, Eiichi; Kawase, Ichiro; Kumanogoh, Atsushi

    2013-01-01

    A majority of small cell lung cancer (SCLC) cells lack a metastasis suppressor, tetraspanin CD9, and CD9 expression promotes their apoptosis. By a proteomics-based approach, we compared an SCLC cell line with its CD9 transfectant and found that a calcium-binding neuronal protein, calretinin, is upregulated in CD9-positive SCLC cells. Ectopic or anticancer drug-induced CD9 expression upregulated calretinin, whereas CD9 knockdown down-regulated calretinin in SCLC cells. When calretinin was knocked down, CD9-positive SCLC cells revealed increased Akt phosphorylation and decreased apoptosis. These results suggest that CD9 positively regulates the expression of calretinin that mediates proapoptotic effect in SCLC cells. PMID:23772398

  11. Bevacizumab‐induced chronic interstitial pneumonia during maintenance therapy in non‐small cell lung cancer

    PubMed Central

    Sekimoto, Yasuhito; Shukuya, Takehiko; Koyama, Ryo; Nagaoka, Tetsutaro; Takahashi, Kazuhisa

    2016-01-01

    Abstract Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor receptor and a key drug for advanced non‐small cell lung cancer. There are few reports describing bevacizumab‐induced chronic interstitial pneumonia. A 62‐year‐old man with advanced non‐small cell lung cancer was admitted to our hospital with dyspnea. He previously received four courses of carboplatin plus paclitaxel with bevacizumab combination therapy and thereafter received four courses of maintenance bevacizumab monotherapy. A chest‐computed tomography scan on admission revealed diffuse ground glass opacity. He had not received any other drugs and did not have pneumonia. Thus, he was diagnosed with bevacizumab‐induced chronic interstitial pneumonia and was treated with a high dose of corticosteroids. After steroid treatment, his dyspnea and radiological findings improved. This case report is the first description of bevacizumab‐induced chronic interstitial pneumonia during maintenance therapy in a patient with non‐small cell lung cancer. PMID:27081491

  12. [Targeted Therapy and Immunotherapy for Non-small Cell Lung Cancer 
with Brain Metastasis].

    PubMed

    Song, Qi; Jiao, Shunchang; Li, Fang

    2016-08-20

    Brain metastasis, a common complication of non-small cell lung cancer (NSCLC) with an incidence rate of 30%-50%, significantly affects the patients' quality of life. The prognosis of patients of NSCLC with brain metastasis is extremely poor, the average median survival is only 1 m-2 m without treatment. The targeted therapy based on lung cancer driven gene is a new treatment. Besides, the immunotherapy which can enhance the effect of anti-cancer by simulating the immune system is a new approach. The combination of targeted therapy and immunotherapy can greatly benefit patients in clinical work. PMID:27561803

  13. [Stereotactic radiotherapy is established treatment in localized non-small cell lung cancer].

    PubMed

    Sailas, Liisa; Virsunen, Heli

    2016-01-01

    Surgery has been the standard treatment in localized non-small cell lung cancer. Some of the early stage lung cancer patients are not suitable for surgery owing to associated diseases or refusing surgery. Ninety percent of untreated patients die within five years. Stereotactic ablative radiotherapy is a technique in which highly focused radiation treatment is given at a couple of high single doses to the tumor region. The treatment results in an average of 90% local control of the cancer, and the adverse effects are minor. Treatment outcome is equivalent to those of surgical therapy and is better than obtained with conventional external radiation therapy. PMID:27132296

  14. MOLECULARLY TARGETED THERAPIES IN NON-SMALL CELL LUNG CANCER ANNUAL UPDATE 2014

    PubMed Central

    Morgensztern, Daniel; Campo, Meghan J.; Dahlberg, Suzanne E.; Doebele, Robert C.; Garon, Edward; Gerber, David E.; Goldberg, Sarah B.; Hammerman, Peter S.; Heist, Rebecca; Hensing, Thomas; Horn, Leora; Ramalingam, Suresh S.; Rudin, Charles M.; Salgia, Ravi; Sequist, Lecia; Shaw, Alice T.; Simon, George R.; Somaiah, Neeta; Spigel, David R.; Wrangle, John; Johnson, David; Herbst, Roy S.; Bunn, Paul; Govindan, Ramaswamy

    2015-01-01

    There have been significant advances in the understanding of the biology and treatment of non-small cell lung cancer (NSCLC) over the past few years. A number of molecularly targeted agents are in the clinic or in development for patients with advanced NSCLC (Table 1). We are beginning to understand the mechanisms of acquired resistance following exposure to tyrosine kinase inhibitors in patients with oncogene addicted NSCLC. The advent of next generation sequencing has enabled to study comprehensively genomic alterations in lung cancer. Finally, early results from immune checkpoint inhibitors are very encouraging. This review summarizes recent advances in the area of cancer genomics, targeted therapies and immunotherapy. PMID:25535693

  15. 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

  16. Gigantol, a bibenzyl from Dendrobium draconis, inhibits the migratory behavior of non-small cell lung cancer cells.

    PubMed

    Charoenrungruang, Sopanya; Chanvorachote, Pithi; Sritularak, Boonchoo; Pongrakhananon, Varisa

    2014-06-27

    Lung cancer is one of the most common causes of cancer death due to its high metastasis potential. The process of cancer migration is an early step that is required for successful metastasis. The discovery and development of natural compounds for cancer therapy have garnered increasing attention in recent years. Gigantol (1) is a bibenzyl compound derived from the Thai orchid, Dendrobium draconis. It exhibits significant cytotoxic activity against several cancer cell lines; however, until recently, the role of 1 on tumor metastasis has not been characterized. This study demonstrates that 1 suppresses the migratory behavior of non-small cell lung cancer H460 cells. Western blot analysis reveals that 1 down-regulates caveolin-1 (Cav-1), activates ATP-dependent tyrosine kinase (phosphorylated Akt at Ser 473), and cell division cycle 42 (Cdc42), thereby suppressing filopodia formation. The inhibitory effect of 1 on cell movement is also exhibited in another lung cancer cell line, H292, but not in normal human keratinocytes (HaCat). The inhibitory activity of 1 on lung cancer migration suggests that this compound may be suitable for further development for the treatment of cancer metastasis. PMID:24844664

  17. A pyrazolopyran derivative preferentially inhibits the activity of human cytosolic serine hydroxymethyltransferase and induces cell death in lung cancer cells.

    PubMed

    Marani, Marina; Paone, Alessio; Fiascarelli, Alessio; Macone, Alberto; Gargano, Maurizio; Rinaldo, Serena; Giardina, Giorgio; Pontecorvi, Valentino; Koes, David; McDermott, Lee; Yang, Tianyi; Paiardini, Alessandro; Contestabile, Roberto; Cutruzzolà, Francesca

    2016-01-26

    Serine hydroxymethyltransferase (SHMT) is a central enzyme in the metabolic reprogramming of cancer cells, providing activated one-carbon units in the serine-glycine one-carbon metabolism. Previous studies demonstrated that the cytoplasmic isoform of SHMT (SHMT1) plays a relevant role in lung cancer. SHMT1 is overexpressed in lung cancer patients and NSCLC cell lines. Moreover, SHMT1 is required to maintain DNA integrity. Depletion in lung cancer cell lines causes cell cycle arrest and uracil accumulation and ultimately leads to apoptosis. We found that a pyrazolopyran compound, namely 2.12, preferentially inhibits SHMT1 compared to the mitochondrial counterpart SHMT2. Computational and crystallographic approaches suggest binding at the active site of SHMT1 and a competitive inhibition mechanism. A radio isotopic activity assay shows that inhibition of SHMT by 2.12 also occurs in living cells. Moreover, administration of 2.12 in A549 and H1299 lung cancer cell lines causes apoptosis at LD50 34 μM and rescue experiments underlined selectivity towards SHMT1. These data not only further highlight the relevance of the cytoplasmic isoform SHMT1 in lung cancer but, more importantly, demonstrate that, at least in vitro, it is possible to find selective inhibitors against one specific isoform of SHMT, a key target in metabolic reprogramming of many cancer types. PMID:26717037

  18. A pyrazolopyran derivative preferentially inhibits the activity of human cytosolic serine hydroxymethyltransferase and induces cell death in lung cancer cells

    PubMed Central

    Fiascarelli, Alessio; Macone, Alberto; Gargano, Maurizio; Rinaldo, Serena; Giardina, Giorgio; Pontecorvi, Valentino; Koes, David; McDermott, Lee; Yang, Tianyi; Paiardini, Alessandro; Contestabile, Roberto; Cutruzzolà, Francesca

    2016-01-01

    Serine hydroxymethyltransferase (SHMT) is a central enzyme in the metabolic reprogramming of cancer cells, providing activated one-carbon units in the serine-glycine one-carbon metabolism. Previous studies demonstrated that the cytoplasmic isoform of SHMT (SHMT1) plays a relevant role in lung cancer. SHMT1 is overexpressed in lung cancer patients and NSCLC cell lines. Moreover, SHMT1 is required to maintain DNA integrity. Depletion in lung cancer cell lines causes cell cycle arrest and uracil accumulation and ultimately leads to apoptosis. We found that a pyrazolopyran compound, namely 2.12, preferentially inhibits SHMT1 compared to the mitochondrial counterpart SHMT2. Computational and crystallographic approaches suggest binding at the active site of SHMT1 and a competitive inhibition mechanism. A radio isotopic activity assay shows that inhibition of SHMT by 2.12 also occurs in living cells. Moreover, administration of 2.12 in A549 and H1299 lung cancer cell lines causes apoptosis at LD50 34 μM and rescue experiments underlined selectivity towards SHMT1. These data not only further highlight the relevance of the cytoplasmic isoform SHMT1 in lung cancer but, more importantly, demonstrate that, at least in vitro, it is possible to find selective inhibitors against one specific isoform of SHMT, a key target in metabolic reprogramming of many cancer types. PMID:26717037

  19. Lentivirus-mediated gene silencing of NOB1 suppresses non-small cell lung cancer cell proliferation.

    PubMed

    Huang, Weiyi; Zhong, Weiqing; Xu, Jun; Su, Benhua; Huang, Guanghui; Du, Jiajun; Liu, Qi

    2015-09-01

    NIN/RPN12 binding protein 1 (NOB1p) encoded by NOB1 has been found to be an essential factor in 26S proteasome biogenesis which participates in protein degradation. However, the functions of NOB1 in non-small cell lung cancer cells are largely unknown. In the present study, lentivirus-mediated NOB1 shRNA transfection in two non-small cell lung cancer cell lines (A549 and H1299) was accomplished, as determined by fluorescence imaging. Downregulation of NOB1 expression was confirmed by real-time PCR and western blotting. NOB1 silencing resulted in a significant decline in the proliferation and colony formation capability of non-small cell lung cancer cells. Moreover, flow cytometry showed that A549 cells were arrested in the G0/G1 phase of the cell cycle after NOB1 suppression. Furthermore, depletion of NOB1 resulted in a significant decrease in CDK4 and cyclin D1 expression. These results suggest that NOB1 may act as an important regulator in non-small cell lung cancer growth and could be a therapeutic target of non‑small cell lung cancer. PMID:26178254

  20. Nicotine-induced resistance of non-small cell lung cancer to treatment--possible mechanisms.

    PubMed

    Czyżykowski, Rafał; Połowinczak-Przybyłek, Joanna; Potemski, Piotr

    2016-01-01

    Cigarette smoking is the leading risk factor of lung cancer. Data from several clinical studies suggest that continuation of smoking during therapy of tobacco-related cancers is associated with lower response rates to chemotherapy and/or radiotherapy, and even with decreased survival. Although nicotine--an addictive component of tobacco--is not a carcinogen, it may influence cancer development and progression or effectiveness of anti-cancer therapy. Several in vitro and in vivo trials have evaluated the influence of nicotine on lung cancer cells. The best known mechanisms by which nicotine impacts cancer biology involve suppression of apoptosis induced by certain drugs or radiation, promotion of proliferation, angiogenesis, invasion and migration of cancer cells. This effect is mainly mediated by membranous nicotinic acetylcholine receptors whose stimulation leads to sustained activation of such intracellular pathways as PI3K/Akt/mTOR, RAS/RAF/MEK/ERK and JAK/STAT, induction of NF-κB activity, enhanced transcription of mitogenic promoters, inhibition of the mitochondrial death pathway or stimulation of pro-angiogenic factors. We herein summarize the mechanisms underlying nicotine's influence on biology of lung cancer cells and the effectiveness of anti-cancer therapy. PMID:26943316

  1. Analysis of non-thermal plasma-induced cell injury in human lung cancer cell lines

    NASA Astrophysics Data System (ADS)

    Kurita, Hirofumi; Sano, Kaori; Wada, Motoi; Mizuno, Kazue; Ono, Ryo; Yasuda, Hachiro; Takashima, Kazunori; Mizuno, Akira

    2015-09-01

    Recent progress of biomedical application of atmospheric pressure plasma shows that the biological effects are mainly due to reactive oxygen and nitrogen species (RONS) in liquid produced by the plasma exposure. To elucidate the cellular responses induced by exposure to the plasma, we focused on identification and quantification of reactive chemical species in plasma-exposed cell culture medium, and cell injury in mammalian cells after treatment of the plasma-exposed medium. In this study, we examined human lung cancer cell lines. The contribution of H2O2 to the cellular responses was considered. Here, an atmospheric pressure plasma jet (APPJ) sustained by a pulsed power supply in argon was used. After APPJ exposure to cell culture medium, RONS detection in liquid was conducted. It showed that OH radical, ONOO-, NO2-, NO3-, and H2O2 were produced in the plasma-exposed medium. Cellular responses of human lung cancer cell lines to the plasma-exposed medium in a concentration-dependence manner were also studied. It showed that the plasma-exposed medium and the H2O2 treatment gave similar reduction in viability and induction of apoptosis. This work was partly supported by MEXT KAKENHI Grant Number 24108005 and JSPS KAKENHI Grant Number 26390096.

  2. Adaptive Responses to Dasatinib-Treated Lung Squamous Cell Cancer Cells Harboring DDR2 Mutations

    PubMed Central

    Watters, January M.; Fang, Bin; Kinose, Fumi; Song, Lanxi; Koomen, John M.; Teer, Jamie K.; Fisher, Kate; Chen, Yian Ann; Rix, Uwe; Haura, Eric B.

    2014-01-01

    DDR2 mutations occur in ~4% of lung squamous cell cancer (SCC) where the tyrosine kinase inhibitor dasatinib has emerged as a new therapeutic option. We found that ERK and AKT phosphorylation was weakly inhibited by dasatinib in DDR2-mutant lung SCC cells, suggesting that dasatinib inhibits survival signals distinct from other oncogenic RTKs and/or compensatory signals exist that dampen dasatinib activity. To gain better insight into dasatinib’s action in these cells, we assessed altered global tyrosine phosphorylation (pY) after dasatinib exposure, employing a mass spectrometry (MS)-based quantitative phosphoproteomics approach. Overlaying protein-protein interaction relationships upon this dasatinib-regulated pY network revealed decreased phosphorylation of Src family kinases and their targets. Conversely, dasatinib enhanced tyrosine phosphorylation in a panel of receptor tyrosine kinases (RTK) and their signaling adaptor complexes, including EGFR, MET/GAB1, and IGF-1R/IRS2, implicating a RTK-driven adaptive response associated with dasatinib. To address the significance of this observation, these results were further integrated with results from a small molecule chemical library screen. We found that dasatinib combined with MET and IGF-1R inhibitors had a synergistic effect and ligand stimulation of EGFR and MET rescued DDR2-mutant lung SCC cells from dasatinib-induced loss of cell viability. Importantly, we observed high levels of tyrosine-phosphorylated EGFR and MET in a panel of human lung SCC tissues harboring DDR2 mutations. Our results highlight potential RTK-driven adaptive resistant mechanisms upon DDR2 targeting, and they suggest new, rationale co-targeting strategies for DDR2-mutant lung SCC. PMID:25348954

  3. Migration Suppression of Small Cell Lung Cancer by Polysaccharides from Nostoc commune Vaucher.

    PubMed

    Guo, Min; Ding, Guo-Bin; Yang, Peng; Zhang, Lichao; Wu, Haili; Li, Hanqing; Li, Zhuoyu

    2016-08-17

    Nostoc commune Vauch., classified into cyanobacteria, has been always well appreciated as a healthy food and medicine worldwide owing to its rich nutrition and potent bioactivities. Nevertheless, the inhibitory effect of polysaccharides from N. commune Vauch. (NVPS) against cancer cell progression and metastasis is still being unraveled. The results in this study showed that NVPS remarkably suppressed cell migration through blocking the epithelial-mesenchymal transition program in NCI-H446 and NCI-H1688 human small cell lung cancer cells. The inhibitory effects were attributed to the suppression of integrin β1/FAK signaling through regulating cell-matrix adhesion. Furthermore, NVPS treatment could increase E-cadherin expression, but down-regulate N-cadherin, Vimentin, and MMP-9 expression, which resulted in the blockage of STAT3 nuclear translocation and JAK1 signaling. These findings suggest that NVPS may be a good candidate for development as a possible antitumor agent against small cell lung cancer. PMID:27465400

  4. Dendrofalconerol A sensitizes anoikis and inhibits migration in lung cancer cells.

    PubMed

    Pengpaeng, Premkamol; Sritularak, Boonchoo; Chanvorachote, Pithi

    2015-04-01

    Resistance to anoikis, enhanced cell motility, and growth in anchorage-independent conditions are hallmarks of highly metastatic cancer cells. The present study demonstrates the anoikis-sensitizing and anti-migration activities of dendrofalconerol A (DF-A), a pure bis(bibenzyl) isolated from the stem of Dendrobium falconeri (Orchidaceae), and its underlying mechanisms in human lung cancer H460 cells. DF-A at non-toxic concentrations significantly increased the anoikis response of the cancer cells, but caused no toxic effect on normal keratinocytes. In addition, DF-A significantly inhibited the growth of lung cancer cells in anchorage-independent conditions. Western blot analysis revealed that the anoikis-sensitizing effect of such a compound involves its ability to suppress survival signals as well as anti-apoptotic proteins, namely, activated protein kinase B (Akt) and Bcl-2. Furthermore, DF-A decreased caveolin-1 (Cav-1), a protein responsible for aggressiveness, while having no effect on Bax, Mcl-1, and activated Erk (p42/44) proteins. In the case of cell motility, DF-A exhibited strong anti-migration activity with the mechanism involving suppression of pFAK and Rho-GTP, but had no effect on Rac-GTP in lung cancer cells. Taken together, DF-A possesses anoikis-sensitizing activity along with anti-migration effects, and may be developed as a novel active compound for cancer treatment. PMID:25391454

  5. A Highly Efficient Gene Expression Programming (GEP) Model for Auxiliary Diagnosis of Small Cell Lung Cancer

    PubMed Central

    Si, Hongzong; Liu, Shihai; Li, Xianchao; Gao, Caihong; Cui, Lianhua; Li, Chuan; Yang, Xue; Yao, Xiaojun

    2015-01-01

    Background Lung cancer is an important and common cancer that constitutes a major public health problem, but early detection of small cell lung cancer can significantly improve the survival rate of cancer patients. A number of serum biomarkers have been used in the diagnosis of lung cancers; however, they exhibit low sensitivity and specificity. Methods We used biochemical methods to measure blood levels of lactate dehydrogenase (LDH), C-reactive protein (CRP), Na+, Cl-, carcino-embryonic antigen (CEA), and neuron specific enolase (NSE) in 145 small cell lung cancer (SCLC) patients and 155 non-small cell lung cancer and 155 normal controls. A gene expression programming (GEP) model and Receiver Operating Characteristic (ROC) curves incorporating these biomarkers was developed for the auxiliary diagnosis of SCLC. Results After appropriate modification of the parameters, the GEP model was initially set up based on a training set of 115 SCLC patients and 125 normal controls for GEP model generation. Then the GEP was applied to the remaining 60 subjects (the test set) for model validation. GEP successfully discriminated 281 out of 300 cases, showing a correct classification rate for lung cancer patients of 93.75% (225/240) and 93.33% (56/60) for the training and test sets, respectively. Another GEP model incorporating four biomarkers, including CEA, NSE, LDH, and CRP, exhibited slightly lower detection sensitivity than the GEP model, including six biomarkers. We repeat the models on artificial neural network (ANN), and our results showed that the accuracy of GEP models were higher than that in ANN. GEP model incorporating six serum biomarkers performed by NSCLC patients and normal controls showed low accuracy than SCLC patients and was enough to prove that the GEP model is suitable for the SCLC patients. Conclusion We have developed a GEP model with high sensitivity and specificity for the auxiliary diagnosis of SCLC. This GEP model has the potential for the wide use

  6. Unbiased Selection of Peptide-Peptoid Hybrids Specific for Lung Cancer Compared to Normal Lung Epithelial Cells.

    PubMed

    Matharage, Jaya M; Minna, John D; Brekken, Rolf A; Udugamasooriya, D Gomika

    2015-12-18

    To develop widely applicable diagnostic and potentially therapeutic approaches overcoming protein heterogeneity in human cancer, we have developed a technology to unbiasedly select high specificity compound(s) that bind any biomolecule (e.g., proteins, lipids, carbohydrates) presented on the cancer cell surface but not on normal cells. We utilized a peptidomimetic based on-bead two-color (OBTC) combinatorial cell screen that can detect differences between two cell surfaces at high accuracy by looking for beads (where each bead in the library had one peptide-peptoid hybrid on the surface) that only bound cancer but not normal cells. We screened a library of 393 216 compounds targeting HCC4017 lung adenocarcinoma cells (labeled in red) in the presence of HBEC30KT normal bronchial epithelial cells (labeled in green) derived from the same tissue of the same patient. This screen identified a peptide-peptoid hybrid called PPS1 which displayed high specific binding for HCC4017 cancer cells over HBEC30KT cells. Specificity was validated through on-bead, ELISA-like and magnetic bead pulldown studies, while a scrambled version of PPS1 did not show any binding. Of interest, the simple dimeric version (PPS1D1) displayed cytotoxic activity on HCC4017 cells, but not on normal HBEC30KT cells. PPS1D1 also strongly accumulated in HCC4017 lung cancer xenografts in mice over control constructs. We conclude that such combinatorial screens using tumor and normal cells from the same patient have significant potential to develop new reagents for cancer biology, diagnosis, and potentially therapy. PMID:26509598

  7. Radiofrequency ablation in primary non-small cell lung cancer: What a radiologist needs to know

    PubMed Central

    Bhatia, Shivank; Pereira, Keith; Mohan, Prasoon; Narayanan, Govindarajan; Wangpaichitr, Medhi; Savaraj, Niramol

    2016-01-01

    Lung cancer continues to be one of the leading causes of death worldwide. In advanced cases of lung cancer, a multimodality approach is often applied, however with poor local control rates. In early non-small cell lung cancer (NSCLC), surgery is the standard of care. Only 15-30% of patients are eligible for surgical resection. Improvements in imaging and treatment delivery systems have provided new tools to better target these tumors. Stereotactic body radiation therapy (SBRT) has evolved as the next best option. The role of radiofrequency ablation (RFA) is also growing. Currently, it is a third-line option in stage 1 NSCLC, when SBRT cannot be performed. More recent studies have demonstrated usefulness in recurrent tumors and some authors have also suggested combination of RFA with other modalities in larger tumors. Following the National Lung Screening Trial (NLST), screening by low-dose computed tomography (CT) has demonstrated high rates of early-stage lung cancer detection in high-risk populations. Hence, even considering the current role of RFA as a third-line option, in view of increasing numbers of occurrences detected, the number of potential RFA candidates may see a steep uptrend. In view of all this, it is imperative that interventional radiologists be familiar with the techniques of lung ablation. The aim of this article is to discuss the procedural technique of RFA in the lung and review the current evidence regarding RFA for NSCLC. PMID:27081229

  8. Autophagy inhibition enhances isorhamnetin‑induced mitochondria‑dependent apoptosis in non‑small cell lung cancer cells.

    PubMed

    Ruan, Yushu; Hu, Ke; Chen, Hongbo

    2015-10-01

    Isorhamnetin (ISO) is a flavonoid from plants of the Polygonaceae family and is also an immediate metabolite of quercetin in mammals. To date, the anti‑tumor effects of ISO and the underlying mechanisms have not been elucidated in lung cancer cells. The present study investigated the inhibitory effects of ISO on the growth of human lung cancer A549 cells. Treatment of the lung cancer cells with ISO significantly suppressed cell proliferation and colony formation. ISO treatment also resulted in a significant increase in apoptotic cell death of A549 cells in a time- and dose-dependent manner. Further investigation showed that the apoptosis proceeded via the mitochondria‑dependent pathway as indicated by alteration of the mitochondrial membrane potential, the release of cytochrome C and caspase activation. Of note, treatment with ISO also induced the formation of autophagosomes and light chain 3‑II protein in A549 cells. Furthermore, co‑treatment with autophagy inhibitors 3‑methyladenine and hydroxychloroquine significantly inhibited the ISO‑induced autophagy and enhanced the ISO‑induced apoptotic cell death in vitro as well as in vivo. Thus, the results of the present study suggested that ISO is a potential anti‑lung cancer agent. In addition, the results indicated that the inhibition of autophagy may be a useful strategy for enhancing the chemotherapeutic effect of ISO on lung cancer cells. PMID:26238746

  9. CIP2A regulates cancer metabolism and CREB phosphorylation in non-small cell lung cancer.

    PubMed

    Peng, Bo; Lei, Ningjing; Chai, Yurong; Chan, Edward K L; Zhang, Jian-Ying

    2015-01-01

    The cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently characterized endogenous inhibitor of the phosphatase activity of protein phosphatase 2A (PP2A), which extends the half-life of oncogenic protein c-myc and promotes in vivo tumor growth. The function of CIP2A in cancer progression is still poorly understood. To uncover the underlying mechanism of CIP2A-mediated cell proliferation, we implemented a two-dimensional electrophoresis (2DE)-based proteomic approach to examine lung cancer cell H1299 with and without CIP2A. We found 47 proteins differentially expressed where 19 proteins were upregulated and 28 proteins were downregulated. These were categorized into functional groups such as metabolism (25%), transcriptional and translational control (23%), and the signaling pathway and protein degradation (20%). On one hand, we validate our proteomic work by measuring the metabolic change. The knockdown of CIP2A decreased the expression of LDH-A as well as the enzymatic activity, accompanying with a decreased lactate production, an increased NADH/NAD+ ratio and ROS production. On the other hand, we found that CIP2A may regulate CREB activity through bioinformatics analysis. Our following experiments showed that, CIP2A positively regulated the phosphorylation of CREB in response to the serum treatment. Therefore, our proteomic study suggested that CIP2A mediates cancer progression through the metabolic pathway and intracellular signaling cascade. PMID:25325377

  10. Left behind? Drug discovery in extensive-stage small-cell lung cancer.

    PubMed

    Riess, Jonathan W; Lara, Primo N

    2014-03-01

    Systemic therapy and subsequent survival for patients with extensive-stage small-cell lung cancer (SCLC) are poor and have remained unchanged in the past quarter century. To improve outcomes in these patients, a new drug development paradigm must be adopted that moves away from empiricism and instead focuses on tumor biology and heterogeneity as a means to increase target and drug class diversity. By incorporating tools that have led to new diagnostic and treatment options in non-small-cell lung cancer, there could be hope yet for the future of SCLC therapeutics. PMID:24529447

  11. Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer

    PubMed Central

    Aftab, Blake T.; Dobromilskaya, Irina; Liu, Jun O.; Rudin, Charles M.

    2011-01-01

    The anti-angiogenic agent bevacizumab has been approved for the treatment of non-small cell lung cancer, although the survival benefit associated with this agent is marginal, and toxicities and cost are substantial. A recent screen for selective inhibitors of endothelial cell proliferation identified the oral anti-fungal drug itraconazole as a novel agent with potential anti-angiogenic activity. Here we define and characterize the anti-angiogenic and anti-cancer activities of itraconazole in relevant preclinical models of angiogenesis and lung cancer. Itraconazole consistently demonstrated potent, specific, and dose-dependent inhibition of endothelial cell proliferation, migration, and tube formation in response to both vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (bFGF)-mediated angiogenic stimulation. In vivo, using primary xenograft models of human non-small cell lung cancer, oral itraconazole showed single agent growth-inhibitory activity associated with induction of tumor HIF1α expression and marked inhibition of tumor vascularity. Itraconazole significantly enhanced the anti-tumor efficacy of the chemotherapeutic agent cisplatin in the same model systems. Taken together, these data suggest that itraconazole has potent and selective inhibitory activity against multiple key aspects of tumor-associated angiogenesis in vitro and in vivo, and strongly support clinical translation of its use. Based on these observations we have initiated a randomized phase II study comparing the efficacy of standard cytotoxic therapy with or without daily oral itraconazole in patients with recurrent metastatic non-small cell lung cancer. PMID:21896639

  12. MiRNA-1469 promotes lung cancer cells apoptosis through targeting STAT5a

    PubMed Central

    Xu, Chengshan; Zhang, Ling; Li, Hengheng; Liu, Zhihua; Duan, Lianning; Lu, Chengrong

    2015-01-01

    MicroRNAs play key roles in cell growth, differentiation, and apoptosis. In this study, we described the regulation and function of miR-1469 in apoptosis of lung cancer cells (A549 and NCI-H1650). Expression analysis verified that miR-1469 expression significantly increased in apoptotic cells. Overexpression of miR-1469 in lung cancer cells increased cell apoptosis induced by etoposide. Additionally, we identified that Stat5a is a downstream target of miR-1469, which can bind directly to the 3’-untranslated region of the Stat5a, subsequently reducing both the mRNA and protein levels of Stat5a. Finally, co-expression of miR-1469 and Stat5a in A549 and NCI-H1650 cells partially abrogated the effect of miR-1469 on cell apoptosis. Our results show that miR-1469 functions as an apoptosis enhancer to regulate lung cancer apoptosis through targeting Stat5a and may become a critical therapeutic target in lung cancer. PMID:26045996

  13. MiRNA-1469 promotes lung cancer cells apoptosis through targeting STAT5a.

    PubMed

    Xu, Chengshan; Zhang, Ling; Li, Hengheng; Liu, Zhihua; Duan, Lianning; Lu, Chengrong

    2015-01-01

    MicroRNAs play key roles in cell growth, differentiation, and apoptosis. In this study, we described the regulation and function of miR-1469 in apoptosis of lung cancer cells (A549 and NCI-H1650). Expression analysis verified that miR-1469 expression significantly increased in apoptotic cells. Overexpression of miR-1469 in lung cancer cells increased cell apoptosis induced by etoposide. Additionally, we identified that Stat5a is a downstream target of miR-1469, which can bind directly to the 3'-untranslated region of the Stat5a, subsequently reducing both the mRNA and protein levels of Stat5a. Finally, co-expression of miR-1469 and Stat5a in A549 and NCI-H1650 cells partially abrogated the effect of miR-1469 on cell apoptosis. Our results show that miR-1469 functions as an apoptosis enhancer to regulate lung cancer apoptosis through targeting Stat5a and may become a critical therapeutic target in lung cancer. PMID:26045996

  14. Isolating and Testing Circulating Tumor DNA and Soluble Immune Markers During the Course of Treatment for Lung Cancer

    ClinicalTrials.gov

    2016-07-11

    Lung Cancer; Lung Neoplasms; Cancer of Lung; Cancer of the Lung; Neoplasms, Lung; Neoplasms, Pulmonary; Pulmonary Cancer; Pulmonary Neoplasms; Carcinoma, Non-small-cell Lung; Adenocarcinoma; Squamous Cell Carcinoma

  15. Receptor tyrosine kinase expression of circulating tumor cells in small cell lung cancer

    PubMed Central

    Hamilton, Gerhard; Rath, Barbara; Klameth, Lukas; Hochmair, Maximilian

    2015-01-01

    Small cell lung cancer (SCLC) has a poor prognosis and is found disseminated at first presentation in the majority of cases. The cell biological mechanisms underlying metastasis and drug resistance are not clear. SCLC is characterized by high numbers of circulating tumor cells (CTCs) and we were able to expand several CTC lines ex vivo and to relate chitinase-3-like-1/YKL-40 (CHI3L1) as marker. Availability of expanded SCLC CTC cells allowed for a screening of receptor tyrosine kinases (RTKs) expressed. The metastatic CHI3L1-negative SCLC cell line SCLC26A, established from a pleural effusion was used for comparison. The CTC cell line BHGc10 was found to exhibit increased expression of RYK, AXL, Tie-1, Dtk, ROR1/2, several ephrins (Eph) and FGF/EGF receptors compared to SCLC26A. All of these RTKs have been associated with cell motility, invasion and poor prognosis in diverse cancer entities without knowledge of their association with CTCs. The identification of RYK, AXL and ROR1/2 as pseudokinases, lacking activity, seems to be related to the observed failure of RTK inhibitors in SCLC. These kinases are involved in the noncanonical WNT pathway and their expression in SCLC CTCs represents a cancer stem cell-like phenotype. PMID:26328272

  16. Raman microscopy in the diagnosis and prognosis of surgically resected nonsmall cell lung cancer

    NASA Astrophysics Data System (ADS)

    Magee, Nicholas David; Beattie, James Renwick; Carland, Chris; Davis, Richard; McManus, Kieran; Bradbury, Ian; Fennell, Dean Andrew; Hamilton, Peter William; Ennis, Madeleine; McGarvey, John Joseph; Elborn, Joseph Stuart

    2010-03-01

    The main curative therapy for patients with nonsmall cell lung cancer is surgery. Despite this, the survival rate is only 50%, therefore it is important to more efficiently diagnose and predict prognosis for lung cancer patients. Raman spectroscopy is useful in the diagnosis of malignant and premalignant lesions. The aim of this study is to investigate the ability of Raman microscopy to diagnose lung cancer from surgically resected tissue sections, and predict the prognosis of these patients. Tumor tissue sections from curative resections are mapped by Raman microscopy and the spectra analzsed using multivariate techniques. Spectra from the tumor samples are also compared with their outcome data to define their prognostic significance. Using principal component analysis and random forest classification, Raman microscopy differentiates malignant from normal lung tissue. Principal component analysis of 34 tumor spectra predicts early postoperative cancer recurrence with a sensitivity of 73% and specificity of 74%. Spectral analysis reveals elevated porphyrin levels in the normal samples and more DNA in the tumor samples. Raman microscopy can be a useful technique for the diagnosis and prognosis of lung cancer patients receiving surgery, and for elucidating the biochemical properties of lung tumors.

  17. The histone demethylase PHF8 is an oncogenic protein in human non-small cell lung cancer

    SciTech Connect

    Shen, Yuzhou; Pan, Xufeng; Zhao, Heng

    2014-08-15

    Highlights: • PHF8 overexpresses in human NSCLC and predicts poor survival. • PHF8 regulates lung cancer cell growth and transformation. • PHF8 regulates apoptosis in human lung cancer cells. • PHF8 promotes miR-21 expression in human lung cancer. • MiR-21 is critically essential for PHF8 function in human lung cancer cells. - Abstract: PHF8 is a JmjC domain-containing protein and erases repressive histone marks including H4K20me1 and H3K9me1/2. It binds to H3K4me3, an active histone mark usually located at transcription start sites (TSSs), through its plant homeo-domain, and is thus recruited and enriched in gene promoters. PHF8 is involved in the development of several types of cancer, including leukemia, prostate cancer, and esophageal squamous cell carcinoma. Herein we report that PHF8 is an oncogenic protein in human non-small cell lung cancer (NSCLC). PHF8 is up-regulated in human NSCLC tissues, and high PHF8 expression predicts poor survival. Our in vitro and in vivo evidence demonstrate that PHF8 regulates lung cancer cell proliferation and cellular transformation. We found that PHF8 knockdown induces DNA damage and apoptosis in lung cancer cells. PHF8 promotes miR-21 expression in human lung cancer, and miR-21 knockdown blocks the effects of PHF8 on proliferation and apoptosis of lung cancer cells. In summary, PHF8 promotes lung cancer cell growth and survival by regulating miR-21.

  18. Euphorbia mauritanica and Kedrostis hirtella extracts can induce anti-proliferative activities in lung cancer cells.

    PubMed

    Thafeni, Makhosazana A; Sayed, Yasien; Motadi, Lesetja R

    2012-12-01

    Cancer is a public health problem in the world accounting for most of the deaths. Currently, common treatment of cancer such as chemotherapy works by killing fast-growing cancer cells. Unfortunately, chemotherapy cannot tell the difference between cancer cells and fast-growing healthy cells, including red and white blood cells. As a result, one of the most serious potential side effects of some types of chemotherapy is a low white blood cell count that makes it unreliable (Parkin et al. [34]; Pauk et al. [3]). Even though intense research has been going on in recent years, successful therapeutic targets against this disease have been elusive. In this study, we evaluate the anti-proliferative activity of Euphorbia mauritanica and Kedrostis hirtella in lung cancer. In our assessment it was observed that E. mauritanica and K. hirtella were able to induce cell death at 5 μg/ml in A549 cells over 22 h and at 10 μg/ml over 24 h in the Lqr1 cell line. Molecular analysis of DNA fragmentation and Annexin V were used to examine the type of cell death induced by E. mauritanica and K. hirtella extracts. These results showed an increase in necrotic and apoptotic characteristics with both nuclear DNA fragmentation and smear. Therefore, these results suggest that E. mauritanica and K. hirtella may play a role in inducing cell death in lung cancer cells. However, further studies need to be conducted to ascertain these results. PMID:23086267

  19. Inhibition of curcumin on myeloid-derived suppressor cells is requisite for controlling lung cancer.

    PubMed

    Liu, Dan; You, Ming; Xu, Yujun; Li, Fanlin; Zhang, Dongya; Li, Xiujun; Hou, Yayi

    2016-10-01

    Lung cancer remains the leading cause of cancer mortality. Myeloid-derived suppressor cells (MDSCs) are potent immune-suppressive cells and present in most cancer patients. Recently, several studies have shown that curcumin inhibits the expansion of MDSCs in some cancers. However, it is not clear how curcumin modulates the suppressive function of MDSCs, and whether curcumin achieves anti-tumor effects via regulating the expansion of MDSCs in lung cancer. Here, our results showed that curcumin significantly inhibited tumor growth in a Lewis lung carcinoma (LLC) isogenic tumor model. Curcumin reduced the accumulation of MDSCs in spleen and tumor tissue in LLC isogenic model. And curcumin promoted the maturation and differentiation of MDSCs in tumor tissue. Notably, curcumin inhibited the expression level of immune suppressive factors of MDSCs, arginase-1 (Arg-1) and ROS, in purified MDSCs from tumor tissue in vivo. Expectedly, curcumin also inhibited the immunosuppressive function of isolated MDSCs from tumor tissue and spleen of tumor bearing mice in vitro. Moreover, curcumin decreased the level of IL-6 in the tumor tissue and serum from LLC-bearing mice. Taken together, curcumin indeed possesses anti-cancer effect and inhibits the accumulation and function of MDSCs. And curcumin reduces the level of IL-6 in tumor-bearing mice to impair the expansion and function of MDSCs. These results suggest that inhibition of MDSCs in tumor is requisite for controlling lung cancer. PMID:27497194

  20. COPD promotes migration of A549 lung cancer cells: the role of chemokine CCL21.

    PubMed

    Kuźnar-Kamińska, Barbara; Mikuła-Pietrasik, Justyna; Sosińska, Patrycja; Książek, Krzysztof; Batura-Gabryel, Halina

    2016-01-01

    Patients with COPD develop lung cancer more frequently than healthy smokers. At the same time, molecular mediators promoting various aspects of cancer cell progression are still elusive. In this report, we examined whether COPD can be coupled with increased migration of non-small-cell lung cancer cells A549 and, if so, whether this effect may be related to altered production and activity of chemokines CCL21, CXCL5, and CXCL12. The study showed that the migration of A549 cells through the polycarbonate membrane and basement membrane extract toward a chemotactic gradient elicited by serum from patients with COPD was markedly higher as compared with serum from healthy donors. The concentration of CCL21 and CXCL12, but not CXCL5, in serum from patients with COPD was also increased. Experiments in which CCL21- and CXCL12-dependent signaling was blocked revealed that increased migration of the cancer cells upon treatment with serum from patients with COPD was mediated exclusively by CCL21. Collectively, our results indicate that COPD may contribute to the progression of lung cancer via CCL21-dependent intensification of cancer cell migration. PMID:27307721

  1. Cancer stem cells and cisplatin-resistant cells isolated from non-small-lung cancer cell lines constitute related cell populations

    PubMed Central

    Lopez-Ayllon, Blanca D; Moncho-Amor, Veronica; Abarrategi, Ander; de Cáceres, Inmaculada Ibañez; Castro-Carpeño, Javier; Belda-Iniesta, Cristobal; Perona, Rosario; Sastre, Leandro

    2014-01-01

    Lung cancer is the top cause of cancer-related deceases. One of the reasons is the development of resistance to the chemotherapy treatment. In particular, cancer stem cells (CSCs), can escape treatment and regenerate the bulk of the tumor. In this article, we describe a comparison between cancer cells resistant to cisplatin and CSCs, both derived from the non-small-cell lung cancer cell lines H460 and A549. Cisplatin-resistant cells were obtained after a single treatment with the drug. CSCs were isolated by culture in defined media, under nonadherent conditions. The isolated CSCs were clonogenic, could be differentiated into adherent cells and were less sensitive to cisplatin than the original cells. Cisplatin resistant and CSCs were able to generate primary tumors and to metastasize when injected into immunodeficient Nu/Nu mice, although they formed smaller tumors with a larger latency than untreated cells. Notably, under appropriated proportions, CSCs synergized with differentiated cells to form larger tumors. CSCs also showed increased capacity to induce angiogenesis in Nu/Nu mice. Conversely, H460 cisplatin-resistant cells showed increased tendency to develop bone metastasis. Gene expression analysis showed that several genes involved in tumor development and metastasis (EGR1, COX2, MALAT1, AKAP12, ADM) were similarly induced in CSC and cisplatin-resistant H460 cells, in agreement with a close similarity between these two cell populations. Cells with the characteristic growth properties of CSCs were also isolated from surgical samples of 18 out of 44 lung cancer patients. A significant correlation (P = 0.028) was found between the absence of CSCs and cisplatin sensitivity. PMID:24961511

  2. Cancer stem cells and cisplatin-resistant cells isolated from non-small-lung cancer cell lines constitute related cell populations.

    PubMed

    Lopez-Ayllon, Blanca D; Moncho-Amor, Veronica; Abarrategi, Ander; Ibañez de Cáceres, Inmaculada; Castro-Carpeño, Javier; Belda-Iniesta, Cristobal; Perona, Rosario; Sastre, Leandro

    2014-10-01

    Lung cancer is the top cause of cancer-related deceases. One of the reasons is the development of resistance to the chemotherapy treatment. In particular, cancer stem cells (CSCs), can escape treatment and regenerate the bulk of the tumor. In this article, we describe a comparison between cancer cells resistant to cisplatin and CSCs, both derived from the non-small-cell lung cancer cell lines H460 and A549. Cisplatin-resistant cells were obtained after a single treatment with the drug. CSCs were isolated by culture in defined media, under nonadherent conditions. The isolated CSCs were clonogenic, could be differentiated into adherent cells and were less sensitive to cisplatin than the original cells. Cisplatin resistant and CSCs were able to generate primary tumors and to metastasize when injected into immunodeficient Nu/Nu mice, although they formed smaller tumors with a larger latency than untreated cells. Notably, under appropriated proportions, CSCs synergized with differentiated cells to form larger tumors. CSCs also showed increased capacity to induce angiogenesis in Nu/Nu mice. Conversely, H460 cisplatin-resistant cells showed increased tendency to develop bone metastasis. Gene expression analysis showed that several genes involved in tumor development and metastasis (EGR1, COX2, MALAT1, AKAP12, ADM) were similarly induced in CSC and cisplatin-resistant H460 cells, in agreement with a close similarity between these two cell populations. Cells with the characteristic growth properties of CSCs were also isolated from surgical samples of 18 out of 44 lung cancer patients. A significant correlation (P = 0.028) was found between the absence of CSCs and cisplatin sensitivity. PMID:24961511

  3. Pazopanib diminishes non-small cell lung cancer (NSCLC) growth and metastases in vivo

    PubMed Central

    Zhao, Honglin; Yang, Fan; Shen, Wang; Wang, Yuli; Li, Xuebing; You, Jiacong; Zhou, Qinghua

    2015-01-01

    Background Anti-angiogenesis has been demonstrated to have a critical role in lung cancer pathogenesis. Here, we characterized the effect of the small-molecule angiogenesis inhibitor pazopanib on non-small cell lung cancer (NSCLC) cells. Methods NSCLC cells were tested for viability and migration after incubation with varying concentrations of pazopanib. Further, the phosphorylation status of extracellular signal-regulated kinase, protein kinase B, and MEK were assessed in vitro. For in vivo testing, mice grafted with NSCLC cell lines L9981 and A549 were treated orally with pazopanib. Results Pazopanib inhibits signaling pathways in tumor cells, thus blocking NSCLC cell growth and migration in vitro and inducing tumor cell arrest at G0/G1 phase. We show that pazopanib could inhibit tumor cell growth, decrease metastases, and prolong survival in two mouse xenograft models of human NSCLC. Conclusion These preclinical studies of pazopanib show the possibility of clinical application and, ultimately, improvement in patient outcome. PMID:26273349

  4. Occupational lung cancer.

    PubMed

    Cone, J E

    1987-01-01

    The author addresses the attribution of lung cancer to cigarette smoking and the problems of confounding synergistic effects of occupational and other carcinogenic risk factors, as well as the divergent trends of declining smoking rates and increasing rates of lung cancer. He also reviews the existing literature to document associations between lung cancer and occupational exposures. Finally, interventions for prevention of occupational lung cancer are discussed. PMID:3303381

  5. Occupational lung cancer

    SciTech Connect

    Cone, J.E.

    1987-04-01

    The author addresses the attribution of lung cancer to cigarette smoking and the problems of confounding synergistic effects of occupational and other carcinogenic risk factors, as well as the divergent trends of declining smoking rates and increasing rates of lung cancer. He also reviews the existing literature to document associations between lung cancer and occupational exposures. Finally, interventions for prevention of occupational lung cancer are discussed.

  6. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

    PubMed Central

    Rizvi, Naiyer A.; Hellmann, Matthew D.; Snyder, Alexandra; Kvistborg, Pia; Makarov, Vladimir; Havel, Jonathan J.; Lee, William; Yuan, Jianda; Wong, Phillip; Ho, Teresa S.; Miller, Martin L.; Rekhtman, Natasha; Moreira, Andre L.; Ibrahim, Fawzia; Bruggeman, Cameron; Gasmi, Billel; Zappasodi, Roberta; Maeda, Yuka; Sander, Chris; Garon, Edward B.; Merghoub, Taha; Wolchok, Jedd D.; Schumacher, Ton N.; Chan, Timothy A.

    2016-01-01

    Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy. PMID:25765070

  7. MUC5AC interactions with integrin β4 enhances the migration of lung cancer cells through FAK signaling.

    PubMed

    Lakshmanan, I; Rachagani, S; Hauke, R; Krishn, S R; Paknikar, S; Seshacharyulu, P; Karmakar, S; Nimmakayala, R K; Kaushik, G; Johansson, S L; Carey, G B; Ponnusamy, M P; Kaur, S; Batra, S K; Ganti, A K

    2016-08-01

    MUC5AC is a secretory mucin aberrantly expressed in various cancers. In lung cancer, MUC5AC is overexpressed in both primary and metastatic lesions; however, its functional role is not well understood. The present study was aimed at evaluating mechanistic role of MUC5AC on metastasis of lung cancer cells. Clinically, the overexpression of MUC5AC was observed in lung cancer patient tissues and was associated with poor survival. In addition, the overexpression of Muc5ac was also observed in genetically engineered mouse lung adenocarcinoma tissues (Kras(G12D); Trp53(R172H/+); AdCre) in comparison with normal lung tissues. Our functional studies showed that MUC5AC knockdown resulted in significantly decreased migration in two lung cancer cell lines (A549 and H1437) as compared with scramble cells. Expression of integrins (α5, β1, β3, β4 and β5) was decreased in MUC5AC knockdown cells. As both integrins and MUC5AC have a von Willebrand factor domain, we assessed for possible interaction of MUC5AC and integrins in lung cancer cells. MUC5AC strongly interacted only with integrin β4. The co-localization of MUC5AC and integrin β4 was observed both in A549 lung cancer cells as well as genetically engineered mouse adenocarcinoma tissues. Activated integrins recruit focal adhesion kinase (FAK) that mediates metastatic downstream signaling pathways. Phosphorylation of FAK (Y397) was decreased in MUC5AC knockdown cells. MUC5AC/integrin β4/FAK-mediated lung cancer cell migration was confirmed through experiments utilizing a phosphorylation (Y397)-specific FAK inhibitor. In conclusion, overexpression of MUC5AC is a poor prognostic marker in lung cancer. MUC5AC interacts with integrin β4 that mediates phosphorylation of FAK at Y397 leading to lung cancer cell migration. PMID:26751774

  8. Amplification and expression of the c-myc oncogene in human lung cancer cell lines.

    PubMed

    Little, C D; Nau, M M; Carney, D N; Gazdar, A F; Minna, J D

    Genetic changes involving the c-myc oncogene have been observed in human tumours. In particular, the c-myc gene is translocated in Burkitt's lymphoma and is amplified in the human promyelocytic leukaemia cell line, HL-60, which contains double minute chromosomes (DMs). More recently, an amplified c-myc gene has been positioned on a chromosomal homogeneous staining region (HSR) in a human colon cancer cell line, COLO 320, with neuroendocrine properties. Furthermore, c-myc is expressed in increased amounts in some human tumour lines, and in some cases, human small cell lung cancers (SCLC) contain DMs and HSRs. These findings prompted us to study the c-myc gene and its RNA expression in a series of human lung cancer cell lines. We now report amplification and expression of the c-myc oncogene in a system other than B-cell lymphomas, namely human lung cancer. Of 18 human lung cancer cell lines tested, 8 showed an amplified 12.5-kilobase (kb) EcoRI c-myc DNA band. Of particular interest are five SCLC lines with a high degree of c-myc DNA amplification (20-76-fold) and greatly increased levels of c-myc RNA. All five lines reside in the variant class of SCLC (SCLC-V) characterized by altered morphology, lack of expression of some SCLC-differentiated functions and more malignant behaviour than pure SCLC. Three of the five lines which have been karyotyped also contain DMs or HSRs. The finding of a greatly amplified c-myc gene in all cell lines of the SCLC-V class examined strongly suggests a role for the c-myc gene in the phenotypic conversion and malignant behaviour of human lung cancer. PMID:6646201

  9. Regulatory mechanisms of betacellulin in CXCL8 production from lung cancer cells

    PubMed Central

    2014-01-01

    Background Betacellulin (BTC), a member of the epidermal growth factor (EGF) family, binds and activates ErbB1 and ErbB4 homodimers. BTC was expressed in tumors and involved in tumor growth progression. CXCL8 (interleukin-8) was involved in tumor cell proliferation via the transactivation of the epidermal growth factor receptor (EGFR). Materials and methods The present study was designed to investigate the possible interrelation between BTC and CXCL8 in human lung cancer cells (A549) and demonstrated the mechanisms of intracellular signals in the regulation of both functions. Bio-behaviors of A549 were assessed using Cell-IQ Alive Image Monitoring System. Results We found that BTC significantly increased the production of CXCL8 through the activation of the EGFR-PI3K/Akt-Erk signal pathway. BTC induced the resistance of human lung cancer cells to TNF-α/CHX-induced apoptosis. Treatments with PI3K inhibitors, Erk1/2 inhibitor, or Erlotinib significantly inhibited BTC-induced CXCL8 production and cell proliferation and movement. Conclusion Our data indicated that CXCL8 production from lung cancer cells could be initiated by an autocrine mechanism or external sources of BTC through the EGFR–PI3K–Akt–Erk pathway to the formation of inflammatory microenvironment. BTC may act as a potential target to monitor and improve the development of lung cancer inflammation. PMID:24629040

  10. Second primary cancer in survivors following concurrent chemoradiation for locally advanced non-small-cell lung cancer

    PubMed Central

    Takigawa, N; Kiura, K; Segawa, Y; Watanabe, Y; Kamei, H; Moritaka, T; Shibayama, T; Ueoka, H; Gemba, K; Yonei, T; Tabata, M; Shinkai, T; Hiraki, S; Takemoto, M; Kanazawa, S; Matsuo, K; Tanimoto, M

    2006-01-01

    Long-term cancer survivors risk development of second primary cancers (SPC). Vigilant follow-up may be required. We report outcomes of 92 patients who underwent chemoradiation for unresectable stage III non-small-cell lung cancer, with a median follow-up of 8.9 years. The incidence of SPC was 2.4 per 100 patient-years (95% confidence interval: 1.0–4.9). PMID:17031394

  11. CHMP4C Disruption Sensitizes the Human Lung Cancer Cells to Irradiation

    PubMed Central

    Li, Kang; Liu, Jianxiang; Tian, Mei; Gao, Gang; Qi, Xuesong; Pan, Yan; Ruan, Jianlei; Liu, Chunxu; Su, Xu

    2015-01-01

    Human lung cancer is highly invasive and the most malignant among human tumors. Adenocarcinoma as a specific type of non-small cell lung cancer occurs with high frequency and is also highly resistant to radiation therapy. Thus, how to avoid radiation resistance and improve radiotherapy effectiveness is a crucial question. In the present study, human lung cancer A549 and H1299 cells were irradiated using γ-rays from a Co60 irradiator. Protein expression was detected by Western blotting. Cell cycle and apoptosis were measured by flow cytometry. Surviving fraction was determined by colony formation assay. γH2AX and 53BP1 foci formation were examined by fluorescence microscopy. In the results, we show that CHMP4C, a subunit of Endosomal sorting complex-III (ESCRT-III), is involved in radiation-induced cellular response. Radiation-induced Aurora B expression enhances CHMP4C phosphorylation in non-small cell lung cancer (NSCLC) cells, maintaining cell cycle check-point and cellular viability as well as resisting apoptosis. CHMP4C depletion enhances cellular sensitivity to radiation, delays S-phase of cell cycle and reduces ionizing radiation (IR)-induced γH2AX foci formation. We found that Aurora B targets CHMP4C and inhibition of Aurora B exhibits similar effects with silencing of CHMP4C in radioresistance. We also confirm that CHMP4C phosphorylation is elevated after IR both in p53-positive and-negative cells, indicating that the close correlation between CHMP4C and Aurora B signaling pathway in mediating radiation resistance is not p53 dependent. Together, our work establishes a new function of CHMP4C in radiation resistance, which will offer a potential strategy for non-small cell lung cancer by disrupting CHMP4C. PMID:26712741

  12. CHMP4C Disruption Sensitizes the Human Lung Cancer Cells to Irradiation.

    PubMed

    Li, Kang; Liu, Jianxiang; Tian, Mei; Gao, Gang; Qi, Xuesong; Pan, Yan; Ruan, Jianlei; Liu, Chunxu; Su, Xu

    2016-01-01

    Human lung cancer is highly invasive and the most malignant among human tumors. Adenocarcinoma as a specific type of non-small cell lung cancer occurs with high frequency and is also highly resistant to radiation therapy. Thus, how to avoid radiation resistance and improve radiotherapy effectiveness is a crucial question. In the present study, human lung cancer A549 and H1299 cells were irradiated using γ-rays from a Co60 irradiator. Protein expression was detected by Western blotting. Cell cycle and apoptosis were measured by flow cytometry. Surviving fraction was determined by colony formation assay. γH2AX and 53BP1 foci formation were examined by fluorescence microscopy. In the results, we show that CHMP4C, a subunit of Endosomal sorting complex-III (ESCRT-III), is involved in radiation-induced cellular response. Radiation-induced Aurora B expression enhances CHMP4C phosphorylation in non-small cell lung cancer (NSCLC) cells, maintaining cell cycle check-point and cellular viability as well as resisting apoptosis. CHMP4C depletion enhances cellular sensitivity to radiation, delays S-phase of cell cycle and reduces ionizing radiation (IR)-induced γH2AX foci formation. We found that Aurora B targets CHMP4C and inhibition of Aurora B exhibits similar effects with silencing of CHMP4C in radioresistance. We also confirm that CHMP4C phosphorylation is elevated after IR both in p53-positive and-negative cells, indicating that the close correlation between CHMP4C and Aurora B signaling pathway in mediating radiation resistance is not p53 dependent. Together, our work establishes a new function of CHMP4C in radiation resistance, which will offer a potential strategy for non-small cell lung cancer by disrupting CHMP4C. PMID:26712741

  13. Gene expression profiling of cancer stem cell in human lung adenocarcinoma A549 cells

    PubMed Central

    Seo, Dong-Cheol; Sung, Ji-Min; Cho, Hee-Jung; Yi, Hee; Seo, Kun-Ho; Choi, In-Soo; Kim, Dong-Ku; Kim, Jin-Suk; El-Aty AM, Abd; Shin, Ho-Chul

    2007-01-01

    Background The studies on cancer-stem-cells (CSCs) have attracted so much attention in recent years as possible therapeutic implications. This study was carried out to investigate the gene expression profile of CSCs in human lung adenocarcinoma A549 cells. Results We isolated CSCs from A549 cell line of which side population (SP) phenotype revealed several stem cell properties. After staining the cell line with Hoechst 33342 dye, the SP and non-side population (non-SP) cells were sorted using flow cytometric analysis. The mRNA expression profiles were measured using an Affymetrix GeneChip® oligonucleotide array. Among the sixty one differentially expressed genes, the twelve genes inclusive three poor prognostic genes; Aldo-keto reductase family 1, member C1/C2 (AKR1C1/C2), Transmembrane 4 L six family member 1 nuclear receptor (TM4SF1), and Nuclear receptor subfamily 0, group B, member 1 (NR0B1) were significantly up-regulated in SP compared to non-SP cells. Conclusion This is the first report indicating the differences of gene expression pattern between SP and non-SP cells in A549 cells. We suggest that the up-regulations of the genes AKR1C1/C2, TM4SF1 and NR0B1 in SP of human adenocarcinoma A549 cells could be a target of poor prognosis in anti-cancer therapy. PMID:18034892

  14. Oncolytic newcastle disease virus triggers cell death of lung cancer spheroids and is enhanced by pharmacological inhibition of autophagy

    PubMed Central

    Hu, Lulu; Sun, Sulan; Wang, Tianpeng; Li, Yingchun; Jiang, Ke; Lin, Guibin; Ma, Yan; Barr, Martin P; Song, Fei; Zhang, Guirong; Meng, Songshu

    2015-01-01

    Lung cancer stem cells (CSCs) have recently been isolated from lung cancer patient samples and have been reported to be responsible for tumor initiation, treatment resistance and tumor recurrence. We have previously shown that oncolytic Newcastle disease virus (NDV), strain FMW (NDV/FMW) induces apoptosis in drug-resistant lung cancer cells. However, how NDV exerts its oncolytic effect on lung CSCs remains to be investigated. Here we show that NDV/FMW replicates in, and lyses CSC-enriched lung cancer spheroids and inhibits the 3D growth potential of lung cancer spheroid and agar colonies. We demonstrate that NDV/FMW triggers caspase-dependent apoptosis in lung cancer spheroids as shown by increased caspase-3 processing and Poly (ADP-ribose) polymerase (PARP) cleavage. Notably, NDV/FMW infection results in the degradation of microtubule-associated protein 1 light chain 3 (LC3) II and P62, two hallmarks of autophagy maturation, indicating that NDV/FMW promotes autophagy flux in lung cancer cell spheroids. This was further confirmed by the appearance of an increased number of double-membrane vesicles as detected by transmission electron microscopy. We also show that NDV/FMW promotes autophagy degradation in lung cancer spheroids via inhibition of the AKT/mTOR pathway. In addition, treatment of spheroids with the autophagy inhibitor, chloroquine increases NDV/FMW-induced cytotoxicity. Collectively, our data show that oncolytic NDV/FMW may be a potential strategy in targeting lung CSCs. PMID:26885450

  15. Arsenic trioxide inhibits cancer stem-like cells via down-regulation of Gli1 in lung cancer

    PubMed Central

    Chang, Ke-Jie; Yang, Meng-Hang; Zheng, Jin-Cheng; Li, Bing; Nie, Wei

    2016-01-01

    Cancer stem cells (CSCs) are responsible for the tumorigenesis and recurrence, so targeting CSCs is a potential effective method to cure cancers. Activated Hedgehog signaling pathway has been proved to be implicated in the maintenance of self-renewal of CSCs, and arsenic trioxide (As2O3) has been reported to inhibit Gli1, a key transcription factor of Hedgehog pathway. In this study, we evaluated whether As2O3 has inhibitory effects on cancer stem-like cells (CSLCs) in lung cancer and further explored the possible mechanism. CCK8 assay and colony formation assay were performed to demonstrate the ability of As2O3 to inhibit the growth of NCI-H460 and NCI-H446 cells, which represented non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), respectively. Tumor sphere formation assay was carried out to evaluate the effects of As2O3 on stem cell-like subpopulations. The expression of stem cell biomarkers CD133 and stem cell transcription factors such as Sox2 and Oct4 were detected. Moreover, the effects of As2O3 on expression of Gli1 and its target genes were observed. We found that As2O3 inhibited the cell proliferation and reduced the colony formation ability. Importantly, As2O3 decreased the formation of tumor spheres. The expression of stem cell biomarker CD133 and stem cell transcription factors such as Sox2 and Oct4 were markedly reduced by As2O3 treatment. Furthermore, As2O3 decreased the expression of Gli1, N-myc and GAS1. Our results suggested that As2O3 is a promising agent to inhibit CSLCs in lung cancer. In addition, the mechanism of CSLCs inhibition might involve Gli1 down-regulation. PMID:27158399

  16. Arsenic trioxide inhibits cancer stem-like cells via down-regulation of Gli1 in lung cancer.

    PubMed

    Chang, Ke-Jie; Yang, Meng-Hang; Zheng, Jin-Cheng; Li, Bing; Nie, Wei

    2016-01-01

    Cancer stem cells (CSCs) are responsible for the tumorigenesis and recurrence, so targeting CSCs is a potential effective method to cure cancers. Activated Hedgehog signaling pathway has been proved to be implicated in the maintenance of self-renewal of CSCs, and arsenic trioxide (As2O3) has been reported to inhibit Gli1, a key transcription factor of Hedgehog pathway. In this study, we evaluated whether As2O3 has inhibitory effects on cancer stem-like cells (CSLCs) in lung cancer and further explored the possible mechanism. CCK8 assay and colony formation assay were performed to demonstrate the ability of As2O3 to inhibit the growth of NCI-H460 and NCI-H446 cells, which represented non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), respectively. Tumor sphere formation assay was carried out to evaluate the effects of As2O3 on stem cell-like subpopulations. The expression of stem cell biomarkers CD133 and stem cell transcription factors such as Sox2 and Oct4 were detected. Moreover, the effects of As2O3 on expression of Gli1 and its target genes were observed. We found that As2O3 inhibited the cell proliferation and reduced the colony formation ability. Importantly, As2O3 decreased the formation of tumor spheres. The expression of stem cell biomarker CD133 and stem cell transcription factors such as Sox2 and Oct4 were markedly reduced by As2O3 treatment. Furthermore, As2O3 decreased the expression of Gli1, N-myc and GAS1. Our results suggested that As2O3 is a promising agent to inhibit CSLCs in lung cancer. In addition, the mechanism of CSLCs inhibition might involve Gli1 down-regulation. PMID:27158399

  17. Ligand independent aryl hydrocarbon receptor inhibits lung cancer cell invasion by degradation of Smad4.

    PubMed

    Lee, Chen-Chen; Yang, Wen-Hao; Li, Ching-Hao; Cheng, Yu-Wen; Tsai, Chi-Hao; Kang, Jaw-Jou

    2016-07-01

    The aryl hydrocarbon receptor (AhR) is a ligand-dependent-activated transcriptional factor that regulates the metabolism of xenobiotic and endogenous compounds. Although AhR plays a crucial role in air toxicant-induced carcinogenesis, AhR expression was shown to negatively regulate tumorigenesis. Therefore, in the present study, we investigated the effect of AhR without ligand treatment on cancer invasion in lung cancer cell lines. Lung cancer cells expressing lower levels of AhR showed higher invasion ability (H1299 cells) compared with cells expressing higher levels of AhR (A549 cells). Overexpression of AhR in H1299 cells inhibited the invasion ability. We found that vimentin expression was inhibited in AhR-overexpressing H1299 cells. Additionally, the expression of EMT-related transcriptional factors Snail and ID-1 decreased. Interestingly, we found that Smad4 degradation was induced in AhR-overexpressing H1299 cells. Our data showed that AhR could interact with Jun-activation domain binding protein (Jab1) and Smad4, which may cause degradation of Smad4 by the proteasome. Our data suggest that AhR affects the transforming growth factor-β signaling pathway by inducing Smad4 degradation by the proteasome and suppressing tumor metastasis via epithelial to mesenchymal transition reduction in lung cancer cells. PMID:27060206

  18. Recent advances in the treatment of non-small cell and small cell lung cancer.

    PubMed

    Stinchcombe, Thomas E

    2014-01-01

    Recent presentations at the American Society of Clinical Oncology (ASCO) meeting from 30 May to 3 June, 2014, will impact routine clinical care and the development of clinical trials in non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (ES-SCLC). Patients with activating epidermal growth factor receptor (EGFR) mutations, defined as exon 19 and exon 21 L858R point mutations, experience a high objective response rate and prolonged progression-free survival with EGFR tyrosine kinase inhibitors. However, inevitably, patients experience disease progression and the most common mechanism of acquired resistance is an EGFR exon 20 T790M mutation. Several agents (AZD9291, CO-1686 and HM61713) have demonstrated impressive activity in patients with T790M resistance mutations. Additional data on the efficacy of first-line therapy with afatinib and the combination of erlotinib and bevacizumab for patients with EGFR mutant NSCLC were presented. The results of a phase III trial of crizotinib compared to platinum-pemetrexed in the first-line setting, and a phase I trial and expansion cohort of ceritinib, provided additional efficacy and toxicity data for patients with anaplastic lymphoma kinase rearranged NSCLC. A phase III trial of cisplatin and gemcitabine, with and without necitumumab, revealed an improvement in overall survival with the addition of necitumumab in patients with squamous NSCLC. In the second-line setting, a phase III trial of docetaxel with ramucirumab or placebo revealed an improvement in overall survival with the addition of ramucirumab. In extensive stage small cell lung cancer phase III trials of consolidative thoracic radiation therapy and prophylactic cranial radiation failed to reveal an improvement in overall survival. PMID:25580271

  19. Micro RNA-98 interferes with expression interleukin-10 in peripheral B cells of patients with lung cancer

    PubMed Central

    Li, Yun; Rong, Jian; Qin, Jie; He, Jin-yuan; Chen, Hui-guo; Huang, Shao-hong

    2016-01-01

    Interleukin (IL)-10-producing B cells (B10 cells) plays an important role in the tumor tolerance. High frequency of peripheral B10 cell was reported in patients with lung cancer recently. Micro RNA (miR) regulates some gene expression. This study test a hypothesis that miR-98 suppresses the expression of IL-10 in B cells of subjects with lung cancer. The results showed that the levels of miR-98 were significantly less in peripheral B cells of patients with lung cancer than that in healthy subjects. IL-10 mRNA levels in peripheral B cells were significantly higher in lung cancer patients as compared with healthy controls. A negative correlation was identified between miR-98 and IL-10 in peripheral B cells. Serum IL-13 was higher in lung cancer patients than that in healthy controls. The levels of IL-13 were also negatively correlated with IL-10 in B cells. Exposure B10 cells to IL-13 in the culture or over expression of miR-98 reduced the expression of IL-10 in B cells. Administration with miR-98-laden liposomes inhibited the lung cancer growth in a mouse model. In conclusion, up regulation of miR-98 inhibits the expression of IL-10 in B cells, which may contribute to inhibit the lung cancer tolerance in the body. PMID:27605397

  20. Micro RNA-98 interferes with expression interleukin-10 in peripheral B cells of patients with lung cancer.

    PubMed

    Li, Yun; Rong, Jian; Qin, Jie; He, Jin-Yuan; Chen, Hui-Guo; Huang, Shao-Hong

    2016-01-01

    Interleukin (IL)-10-producing B cells (B10 cells) plays an important role in the tumor tolerance. High frequency of peripheral B10 cell was reported in patients with lung cancer recently. Micro RNA (miR) regulates some gene expression. This study test a hypothesis that miR-98 suppresses the expression of IL-10 in B cells of subjects with lung cancer. The results showed that the levels of miR-98 were significantly less in peripheral B cells of patients with lung cancer than that in healthy subjects. IL-10 mRNA levels in peripheral B cells were significantly higher in lung cancer patients as compared with healthy controls. A negative correlation was identified between miR-98 and IL-10 in peripheral B cells. Serum IL-13 was higher in lung cancer patients than that in healthy controls. The levels of IL-13 were also negatively correlated with IL-10 in B cells. Exposure B10 cells to IL-13 in the culture or over expression of miR-98 reduced the expression of IL-10 in B cells. Administration with miR-98-laden liposomes inhibited the lung cancer growth in a mouse model. In conclusion, up regulation of miR-98 inhibits the expression of IL-10 in B cells, which may contribute to inhibit the lung cancer tolerance in the body. PMID:27605397

  1. Inhibition of telomerase activity preferentially targets aldehyde dehydrogenase-positive cancer stem-like cells in lung cancer

    PubMed Central

    2011-01-01

    Background Mortality rates for advanced lung cancer have not declined for decades, even with the implementation of novel chemotherapeutic regimens or the use of tyrosine kinase inhibitors. Cancer Stem Cells (CSCs) are thought to be responsible for resistance to chemo/radiotherapy. Therefore, targeting CSCs with novel compounds may be an effective approach to reduce lung tumor growth and metastasis. We have isolated and characterized CSCs from non-small cell lung cancer (NSCLC) cell lines and measured their telomerase activity, telomere length, and sensitivity to the novel telomerase inhibitor MST312. Results The aldehyde dehydrogenase (ALDH) positive lung cancer cell fraction is enriched in markers of stemness and endowed with stem cell properties. ALDH+ CSCs display longer telomeres than the non-CSC population. Interestingly, MST312 has a strong antiproliferative effect on lung CSCs and induces p21, p27 and apoptosis in the whole tumor population. MST312 acts through activation of the ATM/pH2AX DNA damage pathway (short-term effect) and through decrease in telomere length (long-term effect). Administration of this telomerase inhibitor (40 mg/kg) in the H460 xenograft model results in significant tumor shrinkage (70% reduction, compared to controls). Combination therapy consisting of irradiation (10Gy) plus administration of MST312 did not improve the therapeutic efficacy of the telomerase inhibitor alone. Treatment with MST312 reduces significantly the number of ALDH+ CSCs and their telomeric length in vivo. Conclusions We conclude that antitelomeric therapy using MST312 mainly targets lung CSCs and may represent a novel approach for effective treatment of lung cancer. PMID:21827695

  2. Reversal of Aberrant Cancer Methylome and Transcriptome upon Direct Reprogramming of Lung Cancer Cells

    PubMed Central

    Mahalingam, Dashayini; Kong, Chiou Mee; Lai, Jason; Tay, Ling Lee; Yang, Henry; Wang, Xueying

    2012-01-01

    Recent reports on direct reprogramming of cancer cells (iPCs) which results in reduced tumorigenic potential has attributed the importance of epigenetics in tumorigenesis, but lacked genome-wide analysis. Here we describe successful generation of iPCs from non-small cell lung cancer (NSCLC) cell lines. Following reprogramming, they resembled embryonic stem and induced pluripotent stem cells in pluripotency markers expression, gene expression patterns and in vitro differentiation ability. Genome-wide methylation analysis revealed that aberrantly methylated promoters which were mostly developmental-associated genes and tumor suppressors; as well as commonly upregulated genes in NSCLC i.e. KRT19 and S100P were reversed in iPCs upon reprogramming. Also, the reversal of oncogenes and tumor suppressors status were partially explainable by DNA methylation. These findings suggest that DNA methylation patterns explain the downstream transcriptional effects, which potentially caused the reduced tumorigenicity in iPCs, thus providing evidence that reprogramming reverses the aberrantly dysregulated genes in NSCLC both epigenetically and transcriptionally. PMID:22912920

  3. Targeting Aromatase and Estrogen Signaling in Human Non-Small Cell Lung Cancer

    PubMed Central

    Márquez-Garbán, Diana C.; Chen, Hsiao-Wang; Goodglick, Lee; Fishbein, Michael C.; Pietras, Richard J.

    2009-01-01

    Lung cancer has become increasingly common in women, and gender differences in the physiology and pathogenesis of the disease have suggested a role for estrogens. In the lung recent data have shown local production of estrogens from androgens via the action of aromatase enzyme and higher levels of estrogen in tumor tissue as compared with surrounding normal lung tissue. High levels of aromatase expression are also maintained in metastases as compared with primary tumors. Consistent with these findings, clinical studies suggest that aromatase expression may be a useful predictive biomarker for prognosis in the management of non-small cell lung cancer (NSCLC), the most common form of lung malignancy. Low levels of aromatase associate with a higher probability of long-term survival in older women with early stage NSCLC. Treatment of lung NSCLC xenografts in vivo with an aromatase inhibitor (exemestane) alone or combined with standard cisplatin chemotherapy elicits a significant reduction in tumor progression as compared to paired controls. Further, lung cancer progression is also governed by complex interactions between estrogen and growth factor signaling pathways to stimulate the growth of NSCLC as well as tumor-associated angiogenesis. We find that combination therapy with the multitargeted growth factor receptor inhibitor vandetanib and the estrogen receptor antagonist fulvestrant inhibit tumor growth more effectively than either treatment administered alone. Thus, incorporation of antiestrogen treatment strategies in standard antitumor therapies for NSCLC may contribute to improved patient outcome, an approach that deserves to be tested in clinical trials. PMID:19250205

  4. Gold(III) compounds-mediated inhibition of lung cancer cell proliferation.

    PubMed

    Bostancioğlu, Rakibe B; Kaya, Murat; Koparal, Ayşe T; Benkli, Kadriye

    2016-03-01

    Research on chemotherapeutics for lung cancer is crucial for designing a new therapeutic strategy against malignant lung tumors. Although radiotherapy and chemotherapy, which are not selective for cancer cells and exert toxic effects on healthy cells, have a limited advantage, they are the primary treatment modalities for non-small lung cancer. In addition to cytotoxicity, resistance of chemotherapeutics results in failure of treatment. This is why it is of utmost importance to focus on the creation of new chemotherapeutics without toxicity for the successful treatment and improved survival of cancer patients. New gold(III) and Pt(II) compounds were synthesized with a heterocyclic ligand using 2-phenylimidazo[4,5-f][1,10]phenanthroline as a ligand and bis-1,4-di[([1,10] phenanthroline-5-il)amino]-2-buten as a bridge molecule. The characterization of the compounds was carried out using a variety of spectroscopic methods (H NMR, IR, MS, and elemental analysis). Their antiproliferative, antitumoral, and apoptotic activities were determined. IR spectra and NMR results confirmed the formation of dinuclear heterocyclic complexes for two metal complexes. Cytotoxicity studies on lung cancer cells (A549) and healthy cells (CHL) showed a marked increase in cytotoxicity with the use of gold(III) complexes, and especially [Au(L)B](PF6)2 showed higher cytotoxic and apoptotic features than cisplatin at lower concentrations in cancer cells. These findings have been supported by results from DAPI staining and colorimetric measurement of the caspase-3 enzyme in both cell lines. Compounds showed selective toxicity on the cancer cells. In the light of the high efficacy of our newly synthesized gold complexes, they might be good and promising anticancer agents compared with cisplatin. PMID:26825752

  5. The BMP Inhibitor Coco Reactivates Breast Cancer Cells at Lung Metastatic sites

    PubMed Central

    Gao, Hua; Chakraborty, Goutam; Lee-Lim, Ai Ping; Mo, Qianxing; Decker, Markus; Vonica, Alin; Shen, Ronglai; Brogi, Edi; Brivanlou, Ali H.; Giancotti, Filippo G.

    2012-01-01

    SUMMARY The mechanistic underpinnings of metastatic dormancy and reactivation are poorly understood. A gain-of-function cDNA screen reveals that Coco, a secreted antagonist of TGF-β ligands, induces dormant breast cancer cells to undergo reactivation in the lung. Mechanistic studies indicate that Coco exerts this effect by blocking lung-derived BMP ligands. Whereas Coco enhances the manifestation of traits associated with cancer stem cells, BMP signaling suppresses it. Coco induces a discrete gene expression signature, which is strongly associated with metastatic relapse to the lung but not to the bone or brain in patients. Experiments in mouse models suggest that these latter organs contain niches devoid of bioactive BMP. These findings reveal that metastasis-initiating cells need to overcome organ-specific anti-metastatic signals in order to undergo reactivation. PMID:22901808

  6. MG132 enhances the radiosensitivity of lung cancer cells in vitro and in vivo.

    PubMed

    Zhu, Wei; Liu, Jing; Nie, Jihua; Sheng, Wenjiong; Cao, Han; Shen, Wenhao; Dong, Aijing; Zhou, Jundong; Jiao, Yang; Zhang, Shuyu; Cao, Jianping

    2015-10-01

    Radiotherapy is a common treatment modality for lung cancer, however, radioresistance remains a fundamental barrier to attaining the maximal efficacy. Cancer cells take advantage of the ubiquitin-proteasome system (UPS) for increased proliferation and decreased apoptotic cell death. MG132 (carbobenzoxyl-leucinyl-leucinyl-leucinal‑H), a specific and selective reversible inhibitor of the 26S proteasome, has shown anticancer effect in multiple types of cancers. Previously, we have reported that MG132 enhances the anti‑growth and anti-metastatic effects of irradiation in lung cancer cells. However, whether MG132 can enhance the radiosensitivity in lung cancer cells in vitro and in vivo is still unknown. In this study, we found that MG132 increased apoptosis and dicentric chromosome ratio of A549 and H1299 cells treated by irradiation. Radiation-induced NF-κB expression and IκBα phosphorylation was attenuated in MG132 plus irradiation-treated cells. The in vivo model of H1299 xenografts of nude mice showed that the tumor size of MG132 plus irradiation treated xenografts was smaller than that of irradiation, MG132 or the control group. Moreover, MG132 plus irradiation group showed significant reduced Ki67 expression. Taken together, these results demonstrate that MG132 enhances the radiosensitivity through multiple mechanisms in vitro and in vivo. PMID:26238156

  7. A crucial requirement for Hedgehog signaling in small cell lung cancer

    PubMed Central

    Park, Kwon-Sik; Martelotto, Luciano G; Peifer, Martin; Sos, Martin L; Karnezis, Anthony N; Mahjoub, Moe R; Bernard, Katie; Conklin, Jamie F; Szczepny, Anette; Yuan, Jing; Guo, Ribo; Ospina, Beatrice; Falzon, Jeanette; Bennett, Samara; Brown, Tracey J; Markovic, Ana; Devereux, Wendy L; Ocasio, Cory A; Chen, James K; Stearns, Tim; Thomas, Roman K; Dorsch, Marion; Buonamici, Silvia; Watkins, D Neil; Peacock, Craig D; Sage, Julien

    2012-01-01

    Small-cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer for which there is no effective treatment1,2. Using a mouse model in which deletion of Rb1 and Trp53 in the lung epithelium of adult mice induces SCLC3,4, we found that the Hedgehog signaling pathway is activated in SCLC cells independently of the lung microenvironment. Constitutive activation of the Hedgehog signaling molecule Smoothened (Smo) promoted the clonogenicity of human SCLC in vitro and the initiation and progression of mouse SCLC in vivo. Reciprocally, deletion of Smo in Rb1 and Trp53-mutant lung epithelial cells strongly suppressed SCLC initiation and progression in mice. Furthermore, pharmacological blockade of Hedgehog signaling inhibited the growth of mouse and human SCLC, most notably following chemotherapy. These findings show a crucial cell-intrinsic role for Hedgehog signaling in the development and maintenance of SCLC and identify Hedgehog pathway inhibition as a therapeutic strategy to slow the progression of disease and delay cancer recurrence in individuals with SCLC. PMID:21983857

  8. Thromboxane synthase suppression induces lung cancer cell apoptosis via inhibiting NF-{kappa}B

    SciTech Connect

    Leung, Kin Chung; Li, Ming-Yue; Leung, Billy C.S.; Hsin, Michael K.Y.; Mok, Tony S.K.; Underwood, Malcolm J.; Chen, George G.

    2010-12-10

    Accumulating evidence shows that the inhibition of thromboxane synthase (TXS) induced apoptosis in cancer cells. TXS inhibitor 1-Benzylimidzole (1-BI) can trigger apoptosis in lung cancer cells but the mechanism is not fully defined. In this study, lung cancer cells were treated with 1-BI. In this study, the level of reactive oxygen species (ROS) was measured and NF-{kappa}B activity was determined in human lung cancer cells. The roles of ROS and NF-{kappa}B in 1-BI-mediated cell death were analyzed. The results showed that 1-BI induced ROS generation but decreased the activity of NF-{kappa}B by reducing phosphorylated I{kappa}B{alpha} (p-I{kappa}B{alpha}) and inhibiting the translocation of p65 into the nucleus. In contrast to 1-BI, antioxidant N-acetyl cysteine (NAC) stimulated cell proliferation and significantly protected the cells from 1-BI-mediated cell death by neutralizing ROS. Collectively, apoptosis induced by 1-BI is associated with the over-production of ROS and the reduction of NF-{kappa}B. Antioxidants can significantly block the inhibitory effect of 1-BI.

  9. Gefitinib in Treating Patients With Metastatic or Unresectable Head and Neck Cancer or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-01-11

    Anaplastic Thyroid Cancer; Insular Thyroid Cancer; Metastatic Parathyroid Cancer; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Parathyroid Cancer; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Thyroid Cancer; Recurrent Verrucous Carcinoma of the Larynx; Stage III Follicular Thyroid Cancer; Stage III Papillary Thyroid Cancer; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Larynx; Stage IIIB Non-small Cell Lung Cancer; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Non-small Cell Lung Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Adenoid Cystic Carcinoma of the Oral Cavity; Stage IVA Basal Cell Carcinoma of the Lip; Stage IVA Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Follicular Thyroid Cancer; Stage IVA Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IVA Lymphoepithelioma of the Oropharynx; Stage IVA Midline Lethal Granuloma of the Paranasal Sinus

  10. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer.

    PubMed

    Weiss, Jonathan; Sos, Martin L; Seidel, Danila; Peifer, Martin; Zander, Thomas; Heuckmann, Johannes M; Ullrich, Roland T; Menon, Roopika; Maier, Sebastian; Soltermann, Alex; Moch, Holger; Wagener, Patrick; Fischer, Florian; Heynck, Stefanie; Koker, Mirjam; Schöttle, Jakob; Leenders, Frauke; Gabler, Franziska; Dabow, Ines; Querings, Silvia; Heukamp, Lukas C; Balke-Want, Hyatt; Ansén, Sascha; Rauh, Daniel; Baessmann, Ingelore; Altmüller, Janine; Wainer, Zoe; Conron, Matthew; Wright, Gavin; Russell, Prudence; Solomon, Ben; Brambilla, Elisabeth; Brambilla, Christian; Lorimier, Philippe; Sollberg, Steinar; Brustugun, Odd Terje; Engel-Riedel, Walburga; Ludwig, Corinna; Petersen, Iver; Sänger, Jörg; Clement, Joachim; Groen, Harry; Timens, Wim; Sietsma, Hannie; Thunnissen, Erik; Smit, Egbert; Heideman, Daniëlle; Cappuzzo, Federico; Ligorio, Claudia; Damiani, Stefania; Hallek, Michael; Beroukhim, Rameen; Pao, William; Klebl, Bert; Baumann, Matthias; Buettner, Reinhard; Ernestus, Karen; Stoelben, Erich; Wolf, Jürgen; Nürnberg, Peter; Perner, Sven; Thomas, Roman K

    2010-12-15

    Lung cancer remains one of the leading causes of cancer-related death in developed countries. Although lung adenocarcinomas with EGFR mutations or EML4-ALK fusions respond to treatment by epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibition, respectively, squamous cell lung cancer currently lacks therapeutically exploitable genetic alterations. We conducted a systematic search in a set of 232 lung cancer specimens for genetic alterations that were therapeutically amenable and then performed high-resolution gene copy number analyses. We identified frequent and focal fibroblast growth factor receptor 1 (FGFR1) amplification in squamous cell lung cancer (n = 155), but not in other lung cancer subtypes, and, by fluorescence in situ hybridization, confirmed the presence of FGFR1 amplifications in an independent cohort of squamous cell lung cancer samples (22% of cases). Using cell-based screening with the FGFR inhibitor PD173074 in a large (n = 83) panel of lung cancer cell lines, we demonstrated that this compound inhibited growth and induced apoptosis specifically in those lung cancer cells carrying amplified FGFR1. We validated the FGFR1 dependence of FGFR1-amplified cell lines by FGFR1 knockdown and by ectopic expression of an FGFR1-resistant allele (FGFR1(V561M)), which rescued FGFR1-amplified cells from PD173074-mediated cytotoxicity. Finally, we showed that inhibition of FGFR1 with a small molecule led to significant tumor shrinkage in vivo. Thus, focal FGFR1 amplification is common in squamous cell lung cancer and associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients. PMID:21160078

  11. Frequent and Focal FGFR1 Amplification Associates With Therapeutically Tractable FGFR1 Dependency in Squamous-cell Lung Cancer

    PubMed Central

    Weiss, Jonathan; Sos, Martin L.; Seidel, Danila; Peifer, Martin; Zander, Thomas; Heuckmann, Johannes M.; Ullrich, Roland T.; Menon, Roopika; Maier, Sebastian; Soltermann, Alex; Moch, Holger; Wagener, Patrick; Fischer, Florian; Heynck, Stefanie; Koker, Mirjam; Schöttle, Jakob; Leenders, Frauke; Gabler, Franziska; Dabow, Ines; Querings, Silvia; Heukamp, Lukas C.; Balke-Want, Hyatt; Ansén, Sascha; Rauh, Daniel; Baessmann, Ingelore; Altmüller, Janine; Wainer, Zoe; Conron, Matthew; Wright, Gavin; Russell, Prudence; Solomon, Ben; Brambilla, Elisabeth; Brambilla, Christian; Lorimier, Philippe; Sollberg, Steinar; Brustugun, Odd Terje; Engel-Riedel, Walburga; Ludwig, Corinna; Petersen, Iver; Sänger, Jörg; Clement, Joachim; Groen, Harry; Timens, Wim; Sietsma, Hannie; Thunnissen, Erik; Smit, Egbert; Heideman, Daniëlle; Cappuzzo, Federico; Ligorio, Claudia; Damiani, Stefania; Hallek, Michael; Beroukhim, Rameen; Pao, William; Klebl, Bert; Baumann, Matthias; Buettner, Reinhard; Ernestus, Karen; Stoelben, Erich; Wolf, Jürgen; Nürnberg, Peter; Perner, Sven; Thomas, Roman K.

    2014-01-01

    Lung cancer remains one of the leading causes for cancer-related death in developed countries. In lung adenocarcinomas, EGFR mutations and EML4-ALK fusions are associated with response to EGFR and ALK inhibition. By contrast, therapeutically exploitable genetic alterations have been lacking in squamous-cell lung cancer. We conducted a systematic search for alterations that are therapeutically amenable and performed high-resolution gene-copy number analyses in a set of 232 lung cancer specimens. We identified frequent and focal FGFR1 amplification in squamous-cell lung cancer (n=155), but not in other lung cancer subtypes, and confirmed its presence in an independent cohort of squamous-cell lung cancer samples employing FISH (22% of cases). Using cell-based screening with the FGFR inhibitor (PD173074) in a large (n=83) panel of lung cancer cell lines, we demonstrated that this compound inhibited growth (p=0.0002) and induced apoptosis (p=0.008) specifically in those lung cancer cells carrying amplified FGFR1. We validated the dependency on FGFR1 of FGFR1-amplified cell lines by knockdown of FGFR1 and by ectopic expression of a resistance allele of FGFR1 (FGFR1V561M), which rescued FGFR1-amplified cells from PD173074-mediated cytotoxicity. Finally we showed that inhibition of FGFR1 with a small molecule led to significant tumor shrinkage in vivo. Focal FGFR1 amplification is common in squamous-cell lung cancer and associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients. PMID:21160078

  12. 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. PMID:27301194

  13. Investigating the Radioresistant Properties of Lung Cancer Stem Cells in the Context of the Tumor Microenvironment.

    PubMed

    Chan, Ryan; Sethi, Pallavi; Jyoti, Amar; McGarry, Ronald; Upreti, Meenakshi

    2016-02-01

    Lung cancer is the most common cause of cancer-related deaths worldwide and non-small cell lung cancer (NSCLC) accounts for ~85% of all lung cancer. While recent research has shown that cancer stem cells (CSC) exhibit radioresistant and chemoresistant properties, current cancer therapy targets the bulk of the tumor burden without accounting for the CSC and the contribution of the tumor microenvironment. CSC interaction with the stroma enhances NSCLC survival, thus limiting the efficacy of treatment. The aim of this study was to elucidate the role of CSC and the microenvironment in conferring radio- or chemoresistance in an in vitro tumor model for NSCLC. The novel in vitro three-dimensional (3D) NSCLC model of color-coded tumor tissue analogs (TTA) that we have developed is comprised of human lung adenocarcinoma cells, fibroblasts, endothelial cells and NSCLC cancer stem cells maintained in low oxygen conditions (5% O2) to recapitulate the physiologic conditions in tumors. Using this model, we demonstrate that a single 5 Gy radiation dose does not inhibit growth of TTA containing CSC and results in elevated expression of cytokines (TGF-α, RANTES, ENA-78) and factors (vimentin, MMP and TIMP), indicative of an invasive and aggressive phenotype. However, combined treatment of single dose or fractionated doses with cisplatin was found to either attenuate or decrease the proliferative effect that radiation exposure alone had on TTA containing CSC maintained in hypoxic conditions. In summary, we utilized a 3D NSCLC model, which had characteristics of the tumor microenvironment and tumor cell heterogeneity, to elucidate the multifactorial nature of radioresistance in tumors. PMID:26836231

  14. The Impact of Genomic Profiling for Novel Cancer Therapy--Recent Progress in Non-Small Cell Lung Cancer.

    PubMed

    Xie, Jingwu; Zhang, Xiaoli

    2016-01-20

    There is high expectation for significant improvements in cancer patient care after completion of the human genome project in 2003. Through pains-taking analyses of genomic profiles in cancer patients, a number of targetable gene alterations have been discovered, with some leading to novel therapies, such as activating mutations of EGFR, BRAF and ALK gene fusions. As a result, clinical management of cancer through targeted therapy has finally become a reality for a subset of cancers, such as lung adenocarcinomas and melanomas. In this review, we summarize how gene mutation discovery leads to new treatment strategies using non-small cell lung cancer (NSCLC) as an example. We also discuss possible future implications of cancer genome analyses. PMID:26842989

  15. Inoperable stage III non-small cell lung cancer: Current treatment and role of vinorelbine

    PubMed Central

    Provencio, Mariano; Isla, Dolores; Sánchez, Antonio; Cantos, Blanca

    2011-01-01

    Most lung cancer patients are diagnosed with a non-resectable disease; and around 40% in advanced stages. Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease with great variations in its clinical extent which presents a major therapeutic challenge. Although chemo-radiotherapy treatment has become the most widely used, there is currently no consensus on the best standard treatment and the experience of the therapy team plays an important role in the decision taking. We review the treatment of inoperable stage III NSCLC and the role of concomitant vinorelbine in this clinical scenario. PMID:22263088

  16. ER stress and autophagy are involved in the apoptosis induced by cisplatin in human lung cancer cells

    PubMed Central

    SHI, SHAOMIN; TAN, PING; YAN, BINGDI; GAO, RONG; ZHAO, JIANJUN; WANG, JING; GUO, JIA; LI, NING; MA, ZHONGSEN

    2016-01-01

    Cisplatin [cis-diamminedichloroplatinum II (CDDP)] is one of the most classical and effective chemotherapeutic drugs for the treatment of cancers including lung cancer. However, the presence of cisplatin resistance in cancer lowers its curative effect and limits its usage in the clinic. The aim of the present study was to investigate the underlying mechanisms of cisplatin resistance in lung cancer involving endoplasmic reticulum (ER) stress and autophagy. In the present study, we detected the effect of cisplatin on cell viability, ER stress and autophagy in lung cancer cell lines A549 and H460. We also tested the effects of ER stress and autophagy on apoptosis induced by cisplatin. The results showed that cisplatin induced apoptosis, ER stress and autophagy in lung cancer cell lines. In addition, the inhibition of ER stress by 4-phenylbutyric acid (4-PBA) or tauroursodeoxycholic acid sodium (TUDC) enhanced cisplatin-induced apoptosis in the human lung cancer cells. Meanwhile, combination treatment with the autophagic inhibitor 3-methyladenine (3-MA) or chloroquine (CQ) further increased the apoptosis induced by cisplatin in the human lung cancer cells. The present study provides a novel treatment strategy - cisplatin in combination with an autophagic inhibitor or an ER stress inhibitor leads to increased apoptosis in human lung cancer cells. PMID:26985651

  17. ER stress and autophagy are involved in the apoptosis induced by cisplatin in human lung cancer cells.

    PubMed

    Shi, Shaomin; Tan, Ping; Yan, Bingdi; Gao, Rong; Zhao, Jianjun; Wang, Jing; Guo, Jia; Li, Ning; Ma, Zhongsen

    2016-05-01

    Cisplatin [cis-diamminedichloroplatinum II (CDDP)] is one of the most classical and effective chemotherapeutic drugs for the treatment of cancers including lung cancer. However, the presence of cisplatin resistance in cancer lowers its curative effect and limits its usage in the clinic. The aim of the present study was to investigate the underlying mechanisms of cisplatin resistance in lung cancer involving endoplasmic reticulum (ER) stress and autophagy. In the present study, we detected the effect of cisplatin on cell viability, ER stress and autophagy in lung cancer cell lines A549 and H460. We also tested the effects of ER stress and autophagy on apoptosis induced by cisplatin. The results showed that cisplatin induced apoptosis, ER stress and autophagy in lung cancer cell lines. In addition, the inhibition of ER stress by 4-phenylbutyric acid (4-PBA) or tauroursodeoxycholic acid sodium (TUDC) enhanced cisplatin-induced apoptosis in the human lung cancer cells. Meanwhile, combination treatment with the autophagic inhibitor 3-methyladenine (3-MA) or chloroquine (CQ) further increased the apoptosis induced by cisplatin in the human lung cancer cells. The present study provides a novel treatment strategy - cisplatin in combination with an autophagic inhibitor or an ER stress inhibitor leads to increased apoptosis in human lung cancer cells. PMID:26985651

  18. TUCAN/CARDINAL/CARD8 and apoptosis resistance in non-small cell lung cancer cells

    PubMed Central

    Checinska, Agnieszka; Giaccone, Giuseppe; Hoogeland, Bas SJ; Ferreira, Carlos G; Rodriguez, Jose A; Kruyt, Frank AE

    2006-01-01

    Background Activation of caspase-9 in response to treatment with cytotoxic drugs is inhibited in NSCLC cells, which may contribute to the clinical resistance to chemotherapy shown in this type of tumor. The aim of the present study was to investigate the mechanism of caspase-9 inhibition, with a focus on a possible role of TUCAN as caspase-9 inhibitor and a determinant of chemosensitivity in NSCLC cells. Methods Caspase-9 processing and activation were investigated by Western blot and by measuring the cleavage of the fluorogenic substrate LEHD-AFC. Proteins interaction assays, and RNA interference in combination with cell viability and apoptosis assays were used to investigate the involvement of TUCAN in inhibition of caspase-9 and chemosensitivity NSCLC. Results Analysis of the components of the caspase-9 activation pathway in a panel of NSCLC and SCLC cells revealed no intrinsic defects. In fact, exogenously added cytochrome c and dATP triggered procaspase-9 cleavage and activation in lung cancer cell lysates, suggesting the presence of an inhibitor. The reported inhibitor of caspase-9, TUCAN, was exclusively expressed in NSCLC cells. However, interactions between TUCAN and procaspase-9 could not be demonstrated by any of the assays used. Furthermore, RNA interference-mediated down-regulation of TUCAN did not restore cisplatin-induced caspase-9 activation or affect cisplatin sensitivity in NSCLC cells. Conclusion These results indicate that procaspase-9 is functional and can undergo activation and full processing in lung cancer cell extracts in the presence of additional cytochrome c/dATP. However, the inhibitory protein TUCAN does not play a role in inhibition of procaspase-9 and in determining the sensitivity to cisplatin in NSCLC. PMID:16796750

  19. Local Therapy Indications in the Management of Patients with Oligometastatic Non-Small Cell Lung Cancer.

    PubMed

    Miller, Douglas A; Krasna, Mark J

    2016-07-01

    Advances in surgical, radiation, and interventional radiology therapies carry a reduction in morbidity associated with therapy. Aggressive management of patients with oligometastatic non-small cell lung cancer offers the potential for improved disease-free survival and quality of life compared with traditional systemic therapy alone. PMID:27261919

  20. Spontaneous pneumothorax due to bronchopleural fistula following reirradiation for locoregionally recurrent squamous cell lung cancer.

    PubMed

    Ota, Takayo; Suzumura, Tomohiro; Sugiura, Takamune; Hasegawa, Yoshikazu; Yonesaka, Kimio; Makihara, Masaru; Tsukuda, Hiroshi; Tada, Takuhito; Fukuoka, Masahiro

    2016-05-01

    Spontaneous pneumothorax following radiotherapy for pulmonary malignancy is an unusual clinical condition. Here, we report a case of a 78-year-old male suffering from dyspnea during radiotherapy for squamous cell lung cancer of the right main bronchus. Imaging studies and fiberoptic bronchoscopy revealed that pneumothorax was due to a bronchopleural fistula. PMID:27190612

  1. Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease.

    PubMed

    Hiley, Crispin T; Le Quesne, John; Santis, George; Sharpe, Rowena; de Castro, David Gonzalez; Middleton, Gary; Swanton, Charles

    2016-09-01

    Lung cancer diagnostics have progressed greatly in the previous decade. Development of molecular testing to identify an increasing number of potentially clinically actionable genetic variants, using smaller samples obtained via minimally invasive techniques, is a huge challenge. Tumour heterogeneity and cancer evolution in response to therapy means that repeat biopsies or circulating biomarkers are likely to be increasingly useful to adapt treatment as resistance develops. We highlight some of the current challenges faced in clinical practice for molecular testing of EGFR, ALK, and new biomarkers such as PDL1. Implementation of next generation sequencing platforms for molecular diagnostics in non-small-cell lung cancer is increasingly common, allowing testing of multiple genetic variants from a single sample. The use of next generation sequencing to recruit for molecularly stratified clinical trials is discussed in the context of the UK Stratified Medicine Programme and The UK National Lung Matrix Trial. PMID:27598680

  2. Beyond "second-line" in non-small cell lung cancer: therapy and supportive care.

    PubMed

    Martins, Renato G; Reynolds, Craig H; Riely, Gregory J

    2015-01-01

    Although there once was a single algorithm for the treatment of patients with advanced lung cancer, the modern treatment of advanced lung cancer has multiple treatment pathways that depend on multiple factors, including histology and molecular subtype of disease. New molecular targets, targeted agents, and modes of therapy for patients, including immunotherapy, are being identified at an accelerating pace. These advances are changing outcomes and the treatment landscape, but they also highlight situations with inadequate data to support the use of cytotoxic chemotherapy. In this article, we provide an overview of data regarding cytotoxic chemotherapy and targeted therapy and their value after second line, review the critical role of supportive care and palliative care, and emphasize the importance of advance care planning with our patients. Although this article focuses primarily on NSCLC, the comments about palliative care and advanced care planning also apply to patients with small cell lung cancer. PMID:25993204

  3. Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer

    PubMed Central

    Eruslanov, Evgeniy B.; Bhojnagarwala, Pratik S.; Quatromoni, Jon G.; Stephen, Tom Li; Ranganathan, Anjana; Deshpande, Charuhas; Akimova, Tatiana; Vachani, Anil; Litzky, Leslie; Hancock, Wayne W.; Conejo-Garcia, José R.; Feldman, Michael; Albelda, Steven M.; Singhal, Sunil

    2014-01-01

    Infiltrating inflammatory cells are highly prevalent within the tumor microenvironment and mediate many processes associated with tumor progression; however, the contribution of specific populations remains unclear. For example, the nature and function of tumor-associated neutrophils (TANs) in the cancer microenvironment is largely unknown. The goal of this study was to provide a phenotypic and functional characterization of TANs in surgically resected lung cancer patients. We found that TANs constituted 5%–25% of cells isolated from the digested human lung tumors. Compared with blood neutrophils, TANs displayed an activated phenotype (CD62LloCD54hi) with a distinct repertoire of chemokine receptors that included CCR5, CCR7, CXCR3, and CXCR4. TANs produced substantial quantities of the proinflammatory factors MCP-1, IL-8, MIP-1α, and IL-6, as well as the antiinflammatory IL-1R antagonist. Functionally, both TANs and neutrophils isolated from distant nonmalignant lung tissue were able to stimulate T cell proliferation and IFN-γ release. Cross-talk between TANs and activated T cells led to substantial upregulation of CD54, CD86, OX40L, and 4-1BBL costimulatory molecules on the neutrophil surface, which bolstered T cell proliferation in a positive-feedback loop. Together our results demonstrate that in the earliest stages of lung cancer, TANs are not immunosuppressive, but rather stimulate T cell responses. PMID:25384214

  4. Third CECOG consensus on the systemic treatment of non-small-cell lung cancer.

    PubMed

    Brodowicz, T; Ciuleanu, T; Crawford, J; Filipits, M; Fischer, J R; Georgoulias, V; Gridelli, C; Hirsch, F R; Jassem, J; Kosmidis, P; Krzakowski, M; Manegold, Ch; Pujol, J L; Stahel, R; Thatcher, N; Vansteenkiste, J; Minichsdorfer, C; Zöchbauer-Müller, S; Pirker, R; Zielinski, C C

    2012-05-01

    The current third consensus on the systemic treatment of non-small-cell lung cancer (NSCLC) builds upon and updates similar publications on the subject by the Central European Cooperative Oncology Group (CECOG), which has published such consensus statements in the years 2002 and 2005 (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer--update 2004. Lung Cancer 2005; 50: 129-137). The principle of all CECOG consensus is such that evidence-based recommendations for state-of-the-art treatment are given upon which all participants and authors of the manuscript have to agree (Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). This is of particular importance in diseases in which treatment options depend on very particular clinical and biologic variables (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer--update 2004. Lung Cancer 2005; 50: 129-137; Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). Since the publication of the last CECOG consensus on the medical treatment of NSCLC, a series of diagnostic tools for the characterization of biomarkers for personalized therapy for NSCLC as well as therapeutic options including adjuvant treatment, targeted therapy, and maintenance treatment have emerged and strongly influenced the field. Thus, the present third consensus was generated that not only readdresses previous disease-related issues but also expands toward recent developments in the management of NSCLC. It is the aim of the present consensus to summarize minimal quality-oriented requirements for individual patients with NSCLC in its various stages based upon levels of evidence in the light of a rapidly expanding array of individual therapeutic options. PMID:21940784

  5. The proangiogenic phenotype of natural killer cells in patients with non-small cell lung cancer.

    PubMed

    Bruno, Antonino; Focaccetti, Chiara; Pagani, Arianna; Imperatori, Andrea S; Spagnoletti, Marco; Rotolo, Nicola; Cantelmo, Anna Rita; Franzi, Francesca; Capella, Carlo; Ferlazzo, Guido; Mortara, Lorenzo; Albini, Adriana; Noonan, Douglas M

    2013-02-01

    The tumor microenvironment can polarize innate immune cells to a proangiogenic phenotype. Decidual natural killer (dNK) cells show an angiogenic phenotype, yet the role for NK innate lymphoid cells in tumor angiogenesis remains to be defined. We investigated NK cells from patients with surgically resected non-small cell lung cancer (NSCLC) and controls using flow cytometric and functional analyses. The CD56(+)CD16(-) NK subset in NSCLC patients, which represents the predominant NK subset in tumors and a minor subset in adjacent lung and peripheral blood, was associated with vascular endothelial growth factor (VEGF), placental growth factor (PIGF), and interleukin-8 (IL-8)/CXCL8 production. Peripheral blood CD56(+)CD16(-) NK cells from patients with the squamous cell carcinoma (SCC) subtype showed higher VEGF and PlGF production compared to those from patients with adenocarcinoma (AdC) and controls. Higher IL-8 production was found for both SCC and AdC compared to controls. Supernatants derived from NSCLC CD56(+)CD16(-) NK cells induced endothelial cell chemotaxis and formation of capillary-like structures in vitro, particularly evident in SCC patients and absent from controls. Finally, exposure to transforming growth factor-β(1) (TGFβ(1)), a cytokine associated with dNK polarization, upregulated VEGF and PlGF in peripheral blood CD56(+)CD16(-) NK cells from healthy subjects. Our data suggest that NK cells in NSCLC act as proangiogenic cells, particularly evident for SCC and in part mediated by TGFβ(1). PMID:23441128

  6. Hope and Disappointment: Covalent Inhibitors to Overcome Drug Resistance in Non-Small Cell Lung Cancer.

    PubMed

    Engel, Julian; Lategahn, Jonas; Rauh, Daniel

    2016-01-14

    In the last five years, the detailed understanding of how to overcome T790M drug resistance in non-small cell lung cancer (NSCLC) has culminated in the development of a third-generation of covalent EGFR inhibitors with excellent clinical outcomes. However, the emergence of a newly discovered acquired drug resistance challenges the concept of small molecule targeted cancer therapy in NSCLC. PMID:26819655

  7. Silencing of AP-4 inhibits proliferation, induces cell cycle arrest and promotes apoptosis in human lung cancer cells

    PubMed Central

    HU, XUANYU; GUO, WEI; CHEN, SHANSHAN; XU, YIZHUO; LI, PING; WANG, HUAQI; CHU, HEYING; LI, JUAN; DU, YUWEN; CHEN, XIAONAN; ZHANG, GUOJUN; ZHAO, GUOQIANG

    2016-01-01

    Activating enhancer-binding protein (AP)-4 is a member of the basic helix-loop-helix transcription factors, and is involved in tumor biology. However, the role of AP-4 in human lung cancer remains to be fully elucidated. In the present study, the expression of AP-4 in human lung cancer tissues and cells was investigated by reverse transcription-quantitative polymerase chain reaction, and it was observed that the level of AP-4 was increased in tumor tissues and cells compared with their normal counterparts. AP-4 expression was knocked down by transfection with a specific small interfering RNA (siRNA) in lung cancer cells, and this indicated that siRNA-mediated silencing of AP-4 inhibited cell proliferation, arrested the cell cycle at the G0/G1 phase and induced apoptosis by modulating the expression of p21 and cyclin D1. The results of the present study suggest that AP-4 may be an oncoprotein that has a significant role in lung cancer, and that siRNA-mediated silencing of AP-4 may have therapeutic potential as a strategy for the treatment of lung cancer. PMID:27313685

  8. Metastatic cancer to the lung

    MedlinePlus

    ... Bladder cancer Breast cancer Colon cancer Kidney cancer Neuroblastoma Prostate cancer Sarcoma Wilms tumor Symptoms Symptoms may ... Breast cancer Cancer Chemotherapy Colon cancer Lung cancer Neuroblastoma Prostate cancer Radiation therapy Wilms tumor Update Date ...

  9. Nintedanib Compared With Placebo in Treating Against Radiation-Induced Pneumonitis in Patients With Non-small Cell Lung Cancer That Cannot Be Removed by Surgery and Are Undergoing Chemoradiation Therapy

    ClinicalTrials.gov

    2016-04-27

    Radiation-Induced Pneumonitis; Stage IIA Non-Small Cell Lung Carcinoma; Stage IIB Non-Small Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer

  10. Neferine, an alkaloid from lotus seed embryo, inhibits human lung cancer cell growth by MAPK activation and cell cycle arrest.

    PubMed

    Poornima, Paramasivan; Weng, Ching Feng; Padma, Viswanadha Vijaya

    2014-01-01

    Neferine is the major bisbenzylisoquinoline alkaloid isolated from the seed embryo of a traditional medicinal plant Nelumbo nucifera (Lotus). Epidemiological studies have revealed the therapeutic potential of lotus seed embryo. Although several mechanisms have been proposed, a clear anticancer action mechanism of neferine on lung cancer cells is still not known. Lung cancer is the most common cause of cancer death in the world, and the patients with advanced stage of nonsmall lung cancer require adjunct chemotherapy after surgical resection for the eradication of cancer cells. In this study, the effects of neferine were evaluated and characterized in A549 cells. Neferine induced apoptosis in a dose-dependent manner with the hypergeneration of reactive oxygen species, activation of MAPKs, lipid peroxidation, depletion of cellular antioxidant pool, loss of mitochondrial membrane potential, and intracellular calcium accumulation. Furthermore, neferine treatment leads to the inhibition of nuclear factor kappaB and Bcl2, upregulation of Bax and Bad, release of cytochrome C, activation of caspase cascade, and DNA fragmentation. In addition, neferine could induce p53 and its effector protein p21 and downregulation of cell cycle regulatory protein cyclin D1 thereby inducing G1 cell cycle arrest. These results suggest a novel function of neferine as an apoptosis inducer in lung cancer cells. PMID:23983146

  11. Changes in Functional Lung Regions During the Course of Radiation Therapy and Their Potential Impact on Lung Dosimetry for Non-Small Cell Lung Cancer

    SciTech Connect

    Meng, Xue; Frey, Kirk; Matuszak, Martha; Paul, Stanton; Ten Haken, Randall; Yu, Jinming; Kong, Feng-Ming

    2014-05-01

    Purpose: To study changes in functional activity on ventilation (V)/perfusion (Q) single-photon emission computed tomography (SPECT) during radiation therapy (RT) and explore the impact of such changes on lung dosimetry in patients with non-small cell lung cancer (NSCLC). Methods and Materials: Fifteen NSCLC patients with centrally located tumors were enrolled. All patients were treated with definitive RT dose of ≥60 Gy. V/Q SPECT-CT scans were performed prior to and after delivery of 45 Gy of fractionated RT. SPECT images were used to define temporarily dysfunctional regions of lung caused by tumor or other potentially reversible conditions as B3. The functional lung (FL) was defined on SPECT by 2 separate approaches: FL1, a threshold of 30% of the maximum uptake of the patient's lung; and FL2, FL1 plus B3 region. The impact of changes in FL between initiation of RT and delivery of 45 Gy on lung dosimetry were analyzed. Results: Fourteen patients (93%) had larger FL2 volumes than FL1 pre-RT (P<.001). Dysfunctional lung became functional in 11 patients (73%) on V SPECT and in 10 patients (67%) on Q SPECT. The dosimetric parameters generated from CT-based anatomical lung had significantly lower values in FL1 than FL2, with a median reduction in the volume of lung receiving a dose of at least 20 Gy (V{sub 20}) of 3%, 5.6%, and mean lung dose of 0.95 and 1.55 on V and Q SPECT respectively. Conclusions: Regional ventilation and perfusion function improve significantly during RT in centrally located NSCLC. Lung dosimetry values vary notably between different definitions of functional lung.

  12. Magnolol induces apoptosis via caspase-independent pathways in non-small cell lung cancer cells.

    PubMed

    Tsai, Jong-Rung; Chong, Inn-Wen; Chen, Yung-Hsiang; Hwang, Jhi-Jhu; Yin, Wei-Hsian; Chen, Hsiu-Lin; Chou, Shah-Hwa; Chiu, Chien-Chih; Liu, Po-Len

    2014-04-01

    Magnolol, a hydroxylated biphenyl agent isolated from herbal planet Magnolia officinalis, is a component of traditional Asian herbal teas. It has been reported to have anti-microbial, anti-inflammatory, and anti-cancer activity. Non-small cell lung cancer (NSCLC) cell lines (A549, H441 and H520) and normal human bronchial epithelial cells (HBECs) were used to evaluate the cytotoxic effect of magnolol. We show that magnolol inhibited cellular proliferation, increased DNA fragmentation, and decreased mitochondrial membrane potential in all NSCLC cells, but had no cytotoxic effect on HBECs. Magnolol triggered the release of pro-apoptotic proteins: Bid, Bax and cytochrome c from mitochondria, but did not activate the caspase-3, -8, and -9, suggesting that magnolol induces apoptosis of NSCLC cell lines via a caspase-independent pathway. The caspase-independent pathway is mediated through the activation of nuclear translocation of apoptosis-inducing factor, endonuclease G and cleaved poly(ADP-ribose) polymerase, which played important roles in mediating cell death. Furthermore, magnolol inhibited PI3K/AKT and ERK1/2 activity, but up-regulated p38 and JNK activity in A549 cell lines. The results of this study provided a basis for understanding and developing magnolol as a novel treatment of NSCLC. PMID:23943503

  13. Trichosanthes kirilowii fruits inhibit non-small cell lung cancer cell growth through mitotic cell-cycle arrest.

    PubMed

    Ni, Lulu; Zhu, Xiaowen; Gong, Chenyuan; Luo, Yinbin; Wang, Lixin; Zhou, Wuxiong; Zhu, Shiguo; Li, Yan

    2015-01-01

    Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancer cases and the reported overall 5-year survival rate is less than 5%. Natural medicines have attracted much attention due to their lower toxicity and fewer side effects. Trichosanthes kirilowii Maxim (TKM) fruits are commonly used in cancer treatment in combination with other Chinese medicinal herbs. However, little is known about their biological functions and mechanisms in NSCLC cells. In this study, we investigated the efficacy of TKM fruits in NSCLC cells using cell proliferation, invasion, migration, and anchorage independent assays and a Xenograft NSCLC tumor model, and explored the possible biological mechanism by flow cytometric analysis, cDNA microarray and real-time PCR. Results showed that TKM fruits significantly suppressed NSCLC cell proliferation, migration, invasion, tumorigenicity and tumor growth, and significantly extended the survival time of NSCLC-bearing mice. Flow cytometric analysis showed that TKM fruits significantly induced G2-M arrest, necrosis and apoptosis in NSCLC cells. cDNA microarray analysis revealed that TKM fruits regulated the differential expression of 544 genes, and the differential expression of selected genes was also confirmed. Gene ontology (GO) analysis showed that 18 of first 20 biological processes were involved in cell cycle and mitosis. These results indicate that TKM fruits have certain inhibitory effect on NSCLC cells through cell-cycle and mitosis arrest, and suggest that TKM fruits may be an important resource for developing new antitumor drugs, and a potent natural product for treating patients with NSCLC. PMID:25779643

  14. Immune Checkpoint Blockade: A New Era for Non-Small Cell Lung Cancer.

    PubMed

    Califano, Raffaele; Kerr, Keith; Morgan, Robert David; Russo, Giuseppe Lo; Garassino, Marina; Morgillo, Floriana; Rossi, Antonio

    2016-09-01

    Despite better understanding of it's molecular biology, non-small cell lung cancer (NSCLC) remains a challenging disease to treat. Unfortunately, treatment options are still very limited and prognosis for advanced disease is poor. Immune surveillance plays a crucial role in a host's defence against tumour cells, and this is particular relevant for lung cancer due to it's high somatic mutational load, which increases the chances for the immune system to recognize cancer cells as 'non-self'. Novel immunotherapies are emerging as an effective treatment for this disease. In this review, we present the data on immune checkpoint inhibitors for NSCLC, describing their mechanism of action, data efficacy from recent clinical trials, and strategies to select patients more likely to benefit from these agents. PMID:27484062

  15. TRIM31 is downregulated in non-small cell lung cancer and serves as a potential tumor suppressor.

    PubMed

    Li, Hui; Zhang, Yi; Zhang, Yue; Bai, Xue; Peng, Yang; He, Ping

    2014-06-01

    The present study aims to investigate expression pattern and biological roles of TRIM31 in human non-small cell lung cancer (NSCLC). We examined TRIM31 expression in 116 NSCLC tissues and 20 corresponding normal lung tissues by immumohistochemistry. We found TRIM31 downregulation in 47 out of 116 (40.5 %) cancer samples, which correlated with tumor status (p=0.0132), advanced p-TNM stage (p=0.001), and nodal metastasis (p=0.0382). TRIM31 expression was lower in lung cancer cell lines than normal bronchial cell line HBE. Transfection of TRIM31 plasmid was performed in H157 and H1299 cells. TRIM31 overexpression inhibited cell growth rate and colony formation ability in both cell lines. In addition, expression of cell cycle regulator cyclin D1 and cyclin E were decreased after TRIM31 transfection. In conclusion, TRIM31 might serve as a tumor suppressor in non-small cell lung cancer. PMID:24566900

  16. CRKL promotes lung cancer cell invasion through ERK-MMP9 pathway.

    PubMed

    Lin, Fu; Chengyao, Xie; Qingchang, Li; Qianze, Dong; Enhua, Wang; Yan, Wang

    2015-06-01

    CRKL is recently defined as a new oncogene, which plays a role in the lung cancer progression. However, the potential mechanism of CRKL in human non-small cell lung cancer cell invasion is obscure. We investigated the potential mechanism of CRKL in lung cancer cell invasion using immunohistochemistry, plasmid transfection, Western blotting, real-time PCR, matrigel invasion assay, chromatin immunoprecipitation assay, and luciferase reporter assay. CRKL expression is higher in lymph node metastatic tumor compared with primary tumor. CRKL overexpression enhanced cell invasion and MMP9 expression in both HBE and H1299 cell lines. There was a significant correlation between CRKL overexpression and high MMP9 expression in primary tumors. MMP-9 antibody treatment significantly blocked cell invasion. CRKL overexpression also activated AP-1 luciferase reporter activity, ERK phosphorylation and association of c-fos to MMP9 promoter. Treatment with ERK inhibitor PD98059 in cells with CRKL transfection inhibited ERK activity, cell invasion, and MMP9 expression. These results suggested that overexpression of CRKL promoted cell invasion through upregulation of MMP9 expression and activation of ERK pathway. PMID:24664993

  17. Differential response to ablative ionizing radiation in genetically distinct non-small cell lung cancer cells.

    PubMed

    Oweida, Ayman; Sharifi, Zeinab; Halabi, Hani; Xu, Yaoxian; Sabri, Siham; Abdulkarim, Bassam

    2016-04-01

    Stereotactic ablative radiotherapy (SABR) has emerged as a highly promising treatment for medically inoperable early-stage non-small cell lung cancer patients. Treatment outcomes after SABR have been excellent compared to conventional fractionated radiotherapy (CFRT). However, the biological determinants of the response to ablative doses of radiation remain poorly characterized. Furthermore, there's little data on the cellular and molecular response of genetically distinct NSCLC subtypes to radiation. We assessed the response of 3 genetically distinct lung adenocarcinoma cell lines to ablative and fractionated ionizing radiation (AIR and FIR). We studied clonogenic survival, cell proliferation, migration, invasion, apoptosis and senescence. We also investigated the effect of AIR and FIR on the expression of pro-invasive proteins, epithelial-to-mesenchymal transition (EMT), extracellular signal-regulated kinases (ERK1/2) and the transmembrane receptor cMET. Our findings reveal that AIR significantly reduced cell proliferation and clonogenic survival compared to FIR in A549 cells only. This differential response was not observed in HCC827 or H1975 cells. AIR significantly enhanced the invasiveness of A549 cells, but not HCC827 or H1975 cells compared to FIR. Molecular analysis of pathways involved in cell proliferation and invasion revealed that AIR significantly reduced phosphorylation of ERK1/2 and upregulated cMET expression in A549 cells. Our results show a differential proliferative and invasive response to AIR that is dependent on genetic subtype and independent of intrinsic radioresistance. Further examination of these findings in a larger panel of NSCLC cell lines and in pre-clinical models is warranted for identification of biomarkers of tumor response to AIR. PMID:27096542

  18. High expression of HIF-2α and its anti-radiotherapy effect in lung cancer stem cells.

    PubMed

    Sun, J C; He, F; Yi, W; Wan, M H; Li, R; Wei, X; Wu, R; Niu, D L

    2015-01-01

    Hypoxia-inducible factor-2 alpha (HIF-2α) has been shown to regulate cell stemness, although the expression and effects of HIF-2α in lung cancer stem cells remained unclear. This study investigated HIF-2α expression in lung cancer stem cells, as well as the relationship between HIF-2α expression and radioresistance in lung cancer cells. Stem-like cells (CD133(+)) in the non-small-cell lung cancer cell line A549 were enriched by serum-free culture conditions, and CD133(+) cells were sorted via fluorescence-activated cell sorting. A549 cells were treated with middle-infrared radiation, and the level of HIF-2α expression was determined by a quantitative polymerase chain reaction assay and western blot analysis. The level of HIF-2α expression in tissue sections from 50 cases of clinically confirmed non-small-cell lung cancer was determined via immunohistochemical analysis, and its correlation with prognosis after radiotherapy was analyzed. HIF-2α levels in CD133(+) cells were significantly higher than those in CD133(-) cells (P = 0.032). However, after radiation treatment, these levels were significantly upregulated in both CD133(+) and CD133(-) cells (P = 0.031 and P = 0.023, respectively). After irradiation, the proportions of apoptotic, dead, and autophagic CD133(+) A549 cells were considerably lower than those of CD133(-) A549 cells (P < 0.05). Furthermore, the recovery of carcinoembryonic antigen to pre-radiation levels was more rapid in lung cancer patients with high levels of HIF-2α expression, and these patients had shorter survival times (P = 0.018). HIF-2α is highly expressed in lung cancer stem cells, which may lead to radioresistance. In conclusion, HIF-2α is a potential prognostic marker for lung cancer. PMID:26782458

  19. Capturing the metabolomic diversity of KRAS mutants in non-small-cell lung cancer cells

    PubMed Central

    Marabese, Mirko; Broggini, Massimo; Pastorelli, Roberta

    2014-01-01

    In non-small-cell lung cancer (NSCLC), one-fifth of patients have KRAS mutations, which are considered a negative predictive factor to first-line therapy. Evidence is emerging that not all KRAS mutations have the same biological activities and possible remodeling of cell metabolism by KRAS activation might complicate the scenario. An open question is whether different KRAS mutations at codon-12 affect cellular metabolism differently with possible implications for different responses to cancer treatments. We applied an explorative mass spectrometry-based untargeted metabolomics strategy to characterize the largest possible number of metabolites that might distinguish isogenic NSCLC cells overexpressing mutated forms of KRAS at codon-12 (G12C, G12D, G12V) and the wild-type. The glutamine deprivation assay and real-time PCR were used to confirm the involvement of some of the metabolic pathways highlighted. Cell clones indicated distinct metabolomic profiles in KRAS wild-type and mutants. Clones harboring different KRAS mutations at codon-12 also had different metabolic remodeling, such as a different redox buffering system and different glutamine-dependency not driven by the transcriptional state of enzymes involved in glutaminolysis. These findings indicate that KRAS mutations at codon-12 are associated with different metabolomic profiles that might affect the responses to cancer treatments. PMID:24952473

  20. Hypoxia-mediated autophagic flux inhibits silver nanoparticle-triggered apoptosis in human lung cancer cells

    PubMed Central

    Jeong, Jae-Kyo; Gurunathan, Sangiliyandi; Kang, Min-Hee; Han, Jae Woong; Das, Joydeep; Choi, Yun-Jung; Kwon, Deug-Nam; Cho, Ssang-Goo; Park, Chankyu; Seo, Han Geuk; Song, Hyuk; Kim, Jin-Hoi

    2016-01-01

    Solid tumors are frequently associated with resistance to chemotherapy because the fraction of hypoxic tumor cells is substantial. To understand the underlying mechanism of hypoxia on silver nanoparticle (AgNPs)-induced apoptosis, the expression of hypoxia-inducible factor (HIF)-1α, a hallmark of hypoxia, was measured in the presence and absence of AgNPs. The results showed that HIF-1α expression was upregulated after AgNPs treatment under both hypoxic and normoxic conditions. Cell viability assays showed that AgNPs promoted cell death in cancer cells but not in non-cancer cells, as cancer cells are slightly more acidic than normal cells. However, reactive oxygen species generation induced by AgNPs in lung cancer cells caused high susceptibility to oxidative stress, whereas pre-exposure to hypoxia blocked AgNPs-induced oxidative stress. Notably, HIF-1α inhibited AgNPs-induced mitochondria-mediated apoptosis by regulating autophagic flux through the regulation of ATG5, LC3-II, and p62. Further, cell viability after treatment of cancer cells with AgNPs under hypoxic conditions was lower in HIF-1α siRNA-transfected cells than in control siRNA-transfected cells, indicating that HIF-1α knockdown enhances hypoxia induced decrease in cell viability. Our results suggest that hypoxia-mediated autophagy may be a mechanism for the resistance of AgNPs-induced apoptosis and that strategies targeting HIF-1α may be used for cancer therapy. PMID:26867977

  1. Xanthohumol induces apoptosis and S phase cell cycle arrest in A549 non-small cell lung cancer cells

    PubMed Central

    Yong, Wai Kuan; Ho, Yen Fong; Malek, Sri Nurestri Abd

    2015-01-01

    Background: Xanthohumol, a major prenylated chalcone found in female hop plant, Humulus lupulus, was reported to have various chemopreventive and anti-cancer properties. However, its apoptotic effect on human alveolar adenocarcinoma cell line (A549) of non-small cell lung cancer (NSCLC) was unknown. Objective: This study aimed to investigate the effects of xanthohumol on apoptosis in A549 human NSCLC cells. Materials and Methods: A549 cell proliferation was determined by sulforhodamine B assay. Morphological changes of the cells were studied via phase contrast and fluorescent microscopy. Induction of apoptosis was assessed by Annexin-V fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) staining, DNA fragmentation (TUNEL) assay mitochondrial membrane potential assay, cell cycle analysis, and caspase activity studies. Results: Xanthohumol was found to decrease cell proliferation in A549 cells but had relatively low cytotoxicity on normal human lung fibroblast cell line (MRC-5). Typical cellular and nuclear apoptotic features were also observed in A549 cells treated with xanthohumol. Onset of apoptosis in A549 cells was further confirmed by externalization of phosphatidylserine, changes in mitochondrial membrane potential, and DNA fragmentation in the cells after treatment. Xanthohumol induced accumulation of cells in sub G1 and S phase based on cell cycle analysis and also increased the activities of caspase-3, -8, and -9. Conclusion: This work suggests that xanthohumol as an apoptosis inducer, may be a potent therapeutic compound for NSCLC. PMID:26664015

  2. Clinical test on circulating tumor cells in peripheral blood of lung cancer patients, based on novel immunomagnetic beads.

    PubMed

    Wang, Bo; Wang, Bin; Zhang, Daoyun; Guo, Hongyin; Zhang, Lianbin; Zhou, Wenpeng

    2016-05-01

    This paper aims to establish a novel and highly sensitive method to detect circulating tumor cells (CTCs) in the peripheral blood of patients with lung cancer. This therefore enables the discovery of invisible micrometastasis in the early stage of lung cancer, leading to better prognostic assessments of lung cancer and detection of the post-operative tumor recurrence and metastasis, treatment options, and evaluation of curative effects. In this research study, various lung cancer cells were mixed with adult blood samples to simulate blood samples of tumor patients. With novel test methods, CTCs in peripheral blood of lung cancer patients were calculated, after the reaction between the cells obtained from the mix and EpCAM (epithelial cell adhesion molecule) antibodies which were marked by immunomagnetic beads. The results showed that 18 out of 42 (42.9%) lung cancer patients had a positive CTCs, which increased with tumor enlargement or metastasis. CTCs were not detected in a total of 20 blood samples from healthy volunteers. This indicated that the technology of novel immunomagnetic bead-enrichment could effectively separate and identify CTCs in peripheral blood of lung cancer patients, which is of great clinical value for prognostic assessments and treatment guidance of lung cancer. PMID:25682839

  3. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer.

    PubMed

    Hodgkinson, Cassandra L; Morrow, Christopher J; Li, Yaoyong; Metcalf, Robert L; Rothwell, Dominic G; Trapani, Francesca; Polanski, Radoslaw; Burt, Deborah J; Simpson, Kathryn L; Morris, Karen; Pepper, Stuart D; Nonaka, Daisuke; Greystoke, Alastair; Kelly, Paul; Bola, Becky; Krebs, Matthew G; Antonello, Jenny; Ayub, Mahmood; Faulkner, Suzanne; Priest, Lynsey; Carter, Louise; Tate, Catriona; Miller, Crispin J; Blackhall, Fiona; Brady, Ged; Dive, Caroline

    2014-08-01

    Small-cell lung cancer (SCLC), an aggressive neuroendocrine tumor with early dissemination and dismal prognosis, accounts for 15-20% of lung cancer cases and ∼200,000 deaths each year. Most cases are inoperable, and biopsies to investigate SCLC biology are rarely obtainable. Circulating tumor cells (CTCs), which are prevalent in SCLC, present a readily accessible 'liquid biopsy'. Here we show that CTCs from patients with either chemosensitive or chemorefractory SCLC are tumorigenic in immune-compromised mice, and the resultant CTC-derived explants (CDXs) mirror the donor patient's response to platinum and etoposide chemotherapy. Genomic analysis of isolated CTCs revealed considerable similarity to the corresponding CDX. Most marked differences were observed between CDXs from patients with different clinical outcomes. These data demonstrate that CTC molecular analysis via serial blood sampling could facilitate delivery of personalized medicine for SCLC. CDXs are readily passaged, and these unique mouse models provide tractable systems for therapy testing and understanding drug resistance mechanisms. PMID:24880617

  4. Chidamide alleviates TGF-β-induced epithelial-mesenchymal transition in lung cancer cell lines.

    PubMed

    Lin, Sheng-Hao; Wang, Bing-Yen; Lin, Ching-Hsiung; Chien, Peng-Ju; Wu, Yueh-Feng; Ko, Jiunn-Liang; Chen, Jeremy J W

    2016-07-01

    Transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition is a critical process in the initiation of metastasis of various types of cancer. Chidamide is a class I histone deacetylase inhibitor with anti-tumor activity. This study investigated the effects of chidamide on TGF-β-mediated suppression of E-cadherin expression in adenocarcinomic lung epithelial cells and the molecular mechanisms involved in these effects. Western blot analysis, confocal microscopy, Quantitative methyl-specific PCR and bisulfite sequencing were used to evaluate the effects of different treatments on chidamide ameliorating TGF-β induced-E-cadherin loss. H3 acetylation binding to the promoter of E-cadherin was detected by chromatin immunoprecipitations (CHIP). We found that chidamide reduced the level of lung cancer cell migration observed using a Boyden chamber assay (as an indicator of metastatic potential). Chidamide inhibited TGF-β-induced SMAD2 phosphorylation and attenuated TGF-β-induced loss of E-cadherin expression in lung cancer cells by Western blotting and confocal microscopy, respectively. Quantitative methyl-specific PCR and bisulfite sequencing revealed that TGF-β-enhanced E-cadherin promoter methylation was ameliorated in cells treated with chidamide. We demonstrated that histone H3 deacetylation within the E-cadherin promoter was required for TGF-β-induced E-cadherin loss; cell treatment with chidamide increased the H3 acetylation detected by CHIP. Taken together, our results demonstrate that TGF-β suppressed E-cadherin expression by regulating promoter methylation and histone H3 acetylation. Chidamide significantly enhanced E-cadherin expression in TGF-β-treated cells and inhibited lung cancer cell migration. These findings indicate that chidamide has a potential therapeutic use due to its capacity to prevent cancer cell metastasis. PMID:27188428

  5. Lung cancer

    MedlinePlus

    ... any symptoms. Symptoms depend on the type of cancer you have, but may include: Chest pain Cough that does not go away Coughing up blood Fatigue Losing weight without trying Loss of appetite Shortness of breath ...

  6. Digitoxin and a synthetic monosaccharide analog inhibit cell viability in lung cancer cells

    SciTech Connect

    Elbaz, Hosam A.; Stueckle, Todd A.; Wang, Hua-Yu Leo; O'Doherty, George A.; Lowry, David T.; Sargent, Linda M.; Wang, Liying; Dinu, Cerasela Zoica; Rojanasakul, Yon

    2012-01-01

    Mechanisms of digitoxin-inhibited cell growth and induced apoptosis in human non-small cell lung cancer (NCI-H460) cells remain unclear. Understanding how digitoxin or derivate analogs induce their cytotoxic effect below therapeutically relevant concentrations will help in designing and developing novel, safer and more effective anti-cancer drugs. In this study, NCI-H460 cells were treated with digitoxin and a synthetic analog D6-MA to determine their anti-cancer activity. Different concentrations of digitoxin and D6-MA were used and the subsequent changes in cell morphology, viability, cell cycle, and protein expressions were determined. Digitoxin and D6-MA induced dose-dependent apoptotic morphologic changes in NCI-H460 cells via caspase-9 cleavage, with D6-MA possessing 5-fold greater potency than digitoxin. In comparison, non-tumorigenic immortalized bronchial and small airway epithelial cells displayed significantly less apoptotic sensitivity compared to NCI-H460 cells suggesting that both digitoxin and D6-MA were selective for NSCLC. Furthermore, NCI-H460 cells arrested in G(2)/M phase following digitoxin and D6-MA treatment. Post-treatment evaluation of key G2/M checkpoint regulatory proteins identified down-regulation of cyclin B1/cdc2 complex and survivin. Additionally, Chk1/2 and p53 related proteins experienced down-regulation suggesting a p53-independent cell cycle arrest mechanism. In summary, digitoxin and D6-MA exert anti-cancer effects on NCI-H460 cells through apoptosis or cell cycle arrest, with D6-MA showing at least 5-fold greater potency relative to digitoxin. -- Highlights: ► Digitoxin and synthetic analog D6-MA induced apoptotic morphologic changes in NCI-H460 cells in a dose-dependent manner. ► Apoptotic cell death induced by analog was 5-fold more potent when compared to digitoxin. ► NCI-H460 cells arrested in G(2)/M phase following digitoxin (≥ 5 nM) and analog (≥ 1 nM) treatment. ► Digitoxin inhibited the expression of cyclin

  7. IARS2 silencing induces non-small cell lung cancer cells proliferation inhibition, cell cycle arrest and promotes cell apoptosis.

    PubMed

    Yin, J; Liu, W; Li, R; Liu, J; Zhang, Y; Tang, W; Wang, K

    2016-01-01

    The purpose of this study was to investigate the potential role of Ileucyl-tRNA synthetase (IARS2) silencing in non-small cell lung cancer (NSCLC). The silencing of IARS2 in H1299 cells and A549 cells were performed by lentivirus encoding shRNAs. The efficiency of IARS2 silencing was detected by quantitative real time PCR and western blot. The effects of IARS2 silencing on cell growth, cell apoptosis, cell cycle and cell colony formation ability were assessed by cells counting, MTT assay, flow cytometer analysis and soft agar colony formation assay, respectively. Compared with negative control group, IARS2 was significantly knockdown by transfection with lentivirus encoding shRNA of IARS2. The IARS2 silencing significantly inhibited the cells proliferation and cells colony formation ability, induced cell cycle arrest at G1/S phase and promoted cell apoptosis. IARS2 silencing induced NSCLC cells growth inhibition, cell cycle arrest and promoted cell apoptosis. These results suggest that IARS2 may be a novel target for the treatment of NSCLC. PMID:26639235

  8. Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer treatment.

    PubMed

    El-Osta, Hazem; Shahid, Kamran; Mills, Glenn M; Peddi, Prakash

    2016-01-01

    Lung cancer is the major cause for cancer-related death in the US. Although advances in chemotherapy and targeted therapy have improved the outcome of metastatic non-small-cell lung cancer, its prognosis remains dismal. A deeper understanding of the complex interaction between the immune system and tumor microenvironment has identified immune checkpoint inhibitors as new avenue of immunotherapy. Rather than acting directly on the tumor, these therapies work by removing the inhibition exerted by tumor cell or other immune cells on the immune system, promoting antitumoral immune response. To date, two programmed death-1 inhibitors, namely nivolumab and pembrolizumab, have received the US Food and Drug Administration approval for the treatment of advanced non-small-cell lung cancer that failed platinum-based chemotherapy. This manuscript provides a brief overview of the pathophysiology of cancer immune evasion, summarizes pertinent data on completed and ongoing clinical trials involving checkpoint inhibitors, discusses the different strategies to optimize their function, and outlines various challenges that are faced in this promising yet evolving field. PMID:27574451

  9. Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer treatment

    PubMed Central

    El-Osta, Hazem; Shahid, Kamran; Mills, Glenn M; Peddi, Prakash

    2016-01-01

    Lung cancer is the major cause for cancer-related death in the US. Although advances in chemotherapy and targeted therapy have improved the outcome of metastatic non-small-cell lung cancer, its prognosis remains dismal. A deeper understanding of the complex interaction between the immune system and tumor microenvironment has identified immune checkpoint inhibitors as new avenue of immunotherapy. Rather than acting directly on the tumor, these therapies work by removing the inhibition exerted by tumor cell or other immune cells on the immune system, promoting antitumoral immune response. To date, two programmed death-1 inhibitors, namely nivolumab and pembrolizumab, have received the US Food and Drug Administration approval for the treatment of advanced non-small-cell lung cancer that failed platinum-based chemotherapy. This manuscript provides a brief overview of the pathophysiology of cancer immune evasion, summarizes pertinent data on completed and ongoing clinical trials involving checkpoint inhibitors, discusses the different strategies to optimize their function, and outlines various challenges that are faced in this promising yet evolving field. PMID:27574451

  10. Pharmacogenomic Approach to Identify Drug Sensitivity in Small-Cell Lung Cancer

    PubMed Central

    Wildey, Gary; Chen, Yanwen; Lent, Ian; Stetson, Lindsay; Pink, John; Barnholtz-Sloan, Jill S.; Dowlati, Afshin

    2014-01-01

    There are currently no molecular targeted approaches to treat small-cell lung cancer (SCLC) similar to those used successfully against non-small-cell lung cancer. This failure is attributable to our inability to identify clinically-relevant subtypes of this disease. Thus, a more systematic approach to drug discovery for SCLC is needed. In this regard, two comprehensive studies recently published in Nature, the Cancer Cell Line Encyclopedia and the Cancer Genome Project, provide a wealth of data regarding the drug sensitivity and genomic profiles of many different types of cancer cells. In the present study we have mined these two studies for new therapeutic agents for SCLC and identified heat shock proteins, cyclin-dependent kinases and polo-like kinases (PLK) as attractive molecular targets with little current clinical trial activity in SCLC. Remarkably, our analyses demonstrated that most SCLC cell lines clustered into a single, predominant subgroup by either gene expression or CNV analyses, leading us to take a pharmacogenomic approach to identify subgroups of drug-sensitive SCLC cells. Using PLK inhibitors as an example, we identified and validated a gene signature for drug sensitivity in SCLC cell lines. This gene signature could distinguish subpopulations among human SCLC tumors, suggesting its potential clinical utility. Finally, circos plots were constructed to yield a comprehensive view of how transcriptional, copy number and mutational elements affect PLK sensitivity in SCLC cell lines. Taken together, this study outlines an approach to predict drug sensitivity in SCLC to novel targeted therapeutics. PMID:25198282

  11. Dopamine D2 receptor agonists inhibit lung cancer progression by reducing angiogenesis and tumor infiltrating myeloid derived suppressor cells.

    PubMed

    Hoeppner, Luke H; Wang, Ying; Sharma, Anil; Javeed, Naureen; Van Keulen, Virginia P; Wang, Enfeng; Yang, Ping; Roden, Anja C; Peikert, Tobias; Molina, Julian R; Mukhopadhyay, Debabrata

    2015-01-01

    We sought to determine whether Dopamine D2 Receptor (D2R) agonists inhibit lung tumor progression and identify subpopulations of lung cancer patients that benefit most from D2R agonist therapy. We demonstrate D2R agonists abrogate lung tumor progression in syngeneic (LLC1) and human xenograft (A549) orthotopic murine models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells. Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D2R expression and tumor stage. Lung cancer patients with a smoking history exhibited greater levels of D2R in lung endothelium. Our results suggest D2R agonists may represent a promising individualized therapy for lung cancer patients with high levels of endothelial D2R expression and a smoking history. PMID:25226814

  12. Dopamine D2 Receptor Agonists Inhibit Lung Cancer Progression by Reducing Angiogenesis and Tumor Infiltrating Myeloid Derived Suppressor Cells

    PubMed Central

    Hoeppner, Luke H.; Wang, Ying; Sharma, Anil; Javeed, Naureen; Van Keulen, Virginia P.; Wang, Enfeng; Yang, Ping; Roden, Anja C.; Peikert, Tobias; Molina, Julian R.; Mukhopadhyay, Debabrata

    2014-01-01

    We sought to determine whether Dopamine D2 Receptor (D2R) agonists inhibit lung tumor progression and identify subpopulations of lung cancer patients that benefit most from D2R agonist therapy. We demonstrate D2R agonists abrogate lung tumor progression in syngeneic (LLC1) and human xenograft (A549) orthotopic murine models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells. Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D2R expression and tumor stage. Lung cancer patients with a smoking history exhibited greater levels of D2R in lung endothelium. Our results suggest D2R agonists may represent a promising individualized therapy for lung cancer patients with high levels of endothelial D2R expression and a smoking history. PMID:25226814

  13. Progesterone and estrogen receptor expression and activity in human non-small cell lung cancer

    PubMed Central

    Marquez-Garban, Diana C.; Mah, Vei; Alavi, Mohammad; Maresh, Erin L.; Chen, Hsiao-Wang; Bagryanova, Lora; Horvath, Steve; Chia, David; Garon, Edward; Goodglick, Lee; Pietras, Richard J.

    2011-01-01

    Lung cancer is the most common cause of cancer mortality in male and female patients in the US. Although it is clear that tobacco smoking is a major cause of lung cancer, about half of all women with lung cancer worldwide are never-smokers. Despite a declining smoking population, the incidence of non-small cell lung cancer (NSCLC), the predominant form of lung cancer, has reached epidemic proportions particularly in women. Emerging data suggest that factors other than tobacco, namely endogenous and exogenous female sex hormones, have a role in stimulating NSCLC progression. Aromatase, a key enzyme for estrogen biosynthesis, is expressed in NSCLC. Clinical data show that women with high levels of tumor aromatase (and high intratumoral estrogen) have worse survival than those with low aromatase. The present and previous studies also reveal significant expression and activity of estrogen receptors (ERα, ERβ) in both extranuclear and nuclear sites in most NSCLC. We now report further on the expression of progesterone receptor (PR) transcripts and protein in NSCLC. PR transcripts were significantly lower in cancerous as compared to non-malignant tissue. Using immunohistochemistry, expression of PR was observed in the nucleus and/or extranuclear compartments in the majority of human tumor specimens examined. Combinations of estrogen and progestins administered in vitro cooperate in promoting tumor secretion of vascular endothelial growth factor and, consequently, support tumor-associated angiogenesis. Further, dual treatment with estradiol and progestin increased the numbers of putative tumor stem/progenitor cells. Thus, ER- and/or PR-targeted therapies may offer new approaches to manage NSCLC. PMID:21600232

  14. Downregulated TIPE2 is associated with poor prognosis and promotes cell proliferation in non-small cell lung cancer

    SciTech Connect

    Li, Yuexia; Li, Xiaohui; Liu, Gang; Sun, Rongqing; Wang, Lirui; Wang, Jing; Wang, Hongmin

    2015-01-30

    Highlights: • TIPE2 is down-regulated in NSCLC tissues. • TIPE2 inhibits NSCLC cell proliferation, colony formation and invasion. • TIPE2 reduces the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. - Abstract: The present study aims to investigate the expression pattern of TIPE2 protein and its clinical significance in human non-small cell lung cancer (NSCLC). We investigated the expression levels of TIPE2 in 96 NSCLC tumor samples by immunohistochemistry and then analyzed its clinical significance. Furthermore, the role of TIPE2 on the biological properties of the NSCLC cell line H1299 and A549 was experimentally tested in vitro and in vivo. We found that the expression level of TIPE2 was significantly higher in normal lung tissues compared with NSCLC tissues (P < 0.001), and TIPE2 downregulation was significantly correlated with advanced TNM stage (P = 0.006). TIPE2 expression was lower in lung cancer cell lines than normal bronchial cell line HBE. Transfection of TIPE2 plasmid was performed in H1299 and A549 cells. TIPE2 overexpression inhibited lung cancer cell proliferation, colony formation and cell invasive in vitro, and prevented lung tumor growth in vivo. In addition, TIPE2 transfection reduced the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. Taken together, our results demonstrate that TIPE2 might serve as a tumor suppressor in NSCLC progression.

  15. Pyrogallol induces G2-M arrest in human lung cancer cells and inhibits tumor growth in an animal model.

    PubMed

    Yang, Chih-Jen; Wang, Chuan-Sheng; Hung, Jen-Yu; Huang, Hurng-Wern; Chia, Yi-Chen; Wang, Pei-Hui; Weng, Ching-Feng; Huang, Ming-Shyan

    2009-11-01

    Pyrogallol, a catechin compound, is an active component of Emblica officinalis extracts and has an anti-proliferative effect on some human cancer cell lines. In our preliminary study, pyrogallol had highly cytotoxic effect on human lung cancer cell lines and less effect on human bronchial epithelium cell line. This study was performed to investigate the beneficial effect of pyrogallol on human lung cancer cell lines - H441 (lung adenocarcinoma) and H520 (lung squamous cell carcinoma). The MTT (cytotoxic) data showed the inhibition growth of lung cancer cells followed pyrogallol treatment. The cell cycle of lung cancer cells was arrested in G2/M phase using flow cytometry. Using Western blot analysis, the cell cycle related proteins - cyclin B1 and Cdc25c were decreased in a time-dependent manner and the phosphorylated Cdc2 (Thr14) was increased within 4h pyrogallol treatment. Moreover, the higher cleavage of poly (ADP)-ribose polymerase (PARP), the increased of Bax concurrent with the decreased of Bcl-2 indicated that pyrogallol treatment resulted in apoptosis of lung cancer cells. The cell apoptosis was also directly demonstrated using Annexin V-FITC and TUNEL stain. Additionally, the tumoricidal effect of pyrogallol was measured using a xenograft nude mice model. After 5 weeks of pyrogallol treatment could cause the regression of tumor. Taken in vitro and in vivo studies together, these results suggest that pyrogallol can be developed as a promising anti-lung cancer drug particular for the non-small cell lung cancer (NSCLC). PMID:19233505

  16. Downregulating microRNA-144 mediates a metabolic shift in lung cancer cells by regulating GLUT1 expression

    PubMed Central

    LIU, MIN; GAO, JUN; HUANG, QIN; JIN, YANFENG; WEI, ZHONGHUA

    2016-01-01

    Lung cancer is the leading cause of cancer-associated mortality worldwide. Increasing evidence has found that cancer metabolism alternations represent a critical hallmark for lung cancer. There is an urgent requirement to understand and dissect the molecular mechanisms underlying cancer metabolism for lung cancer therapy. It remains largely unknown whether the deregulation of miRNAs contributes to the cancer metabolism. The present study aimed to investigate the role of miR-144 in lung cancer. Glucose uptake rate and lactate production assays demonstrated that miR-144 expression is decreased and therefore enhances the aerobic metabolism in lung cancer cells. In addition, western blot analysis revealed that miR-144 performs this function by increasing the expression of glucose transporter 1 (GLUT1), leading to an increase in glucose uptake and lactate production. Furthermore, cell viability assays demonstrated that the altered metabolism induced by miR-144 results in the rapid growth of cancer cells. In conclusion, these results identify miR-144 as a molecular switch involved in the orchestration of the Warburg effect in lung cancer cells via targeting the expression of GLUT1. PMID:27313692

  17. ASAP3 expression in non-small cell lung cancer: association with cancer development and patients' clinical outcome.

    PubMed

    Fan, Chuifeng; Tian, Yuan; Miao, Yuan; Lin, Xuyong; Zhang, Xiupeng; Jiang, Guiyang; Luan, Lan; Wang, Enhua

    2014-02-01

    ASAP3 belongs to Arf-specific GTPase-activating proteins which regulate Arfs by stimulating their intrinsic GTP hydrolysis. ASAP3 expression and the clinical significance in malignant tumors are largely unknown. In this study, we examined ASAP3 expression in non-small cell lung cancer (NSCLC) to find out its clinicopathological significance. Immunohistochemistry shows elevated expression of ASAP3 in cancer tissues (54.8 % (57/104)) compared to normal lung tissues (18.0 % (9/50)) (p < 0.05). Increased ASAP3 expression was associated with poor differentiation, lymph node metastasis, and advanced TNM stages in NSCLC (p < 0.05). Survival analysis reveals that ASAP3 expression contributes to patients' poor clinical outcome (p < 0.05). We also examined ASAP3 expression in several lung cancer cell lines using Western blotting. We downregulated ASAP3 expression in LTE cell which has a relative high level of ASAP3 expression using siRNA and found that reduced ASAP3 leads to significant inhibition of cancer cell invasion (p < 0.05). These data indicate that ASAP3 is elevated in NSCLC and may contribute to cancer development and patients' poor clinical outcome, which is possibly due to its critical roles in regulating cancer invasion. PMID:24078447

  18. Calcium-dependent growth regulation of small cell lung cancer cells by neuropeptides.

    PubMed

    Gudermann, Thomas; Roelle, Susanne

    2006-12-01

    Approximately 15-25% of all primary cancers of the lung are classified histologically as small cell lung carcinoma (SCLC), a subtype characterized by rapid growth and a poor prognosis. Neuropeptide hormones like bombesin/gastrin-releasing peptide, bradykinin or galanin are the principal mitogenic stimuli of this tumour entity. The mitogenic signal is transmitted into the cell via heptahelical neuropeptide hormone receptors, which couple to the heterotrimeric G proteins of the Gq/11 familiy. Subsequent activation of phospholipase Cbeta (PLCbeta) entails the activation of protein kinase C and the elevation of the intracellular calcium concentration. There is mounting evidence to support the notion that calcium mobilization is the key event that initiates different mitogen-activated protein kinase cascades. Neuropeptide-dependent proliferation of SCLC cells relies on parallel activation of the Gq/11/PLCbeta/Ras/extracellular signal-regulated kinase and the c-jun N-terminal kinase pathways, while selective engagement of either signalling cascade alone results in growth arrest and differentiation or apoptotic cell death. Basic experimental research has the potential to identify and validate novel therapeutic targets located at critical points of convergence of different mitogenic signal transduction pathways. In the case of SCLC, targeting the distinct components of the Ca2+ influx pathway as well as critical Ca2+-dependent cellular effectors may be rewarding in this regard. PMID:17158754

  19. Preferential killing of human lung cancer cell lines with mitochondrial dysfunction by nonthermal dielectric barrier discharge plasma

    PubMed Central

    Panngom, K; Baik, K Y; Nam, M K; Han, J H; Rhim, H; Choi, E H

    2013-01-01

    The distinctive cellular and mitochondrial dysfunctions of two human lung cancer cell lines (H460 and HCC1588) from two human lung normal cell lines (MRC5 and L132) have been studied by dielectric barrier discharge (DBD) plasma treatment. This cytotoxicity is exposure time-dependent, which is strongly mediated by the large amount of H2O2 and NOx in culture media generated by DBD nonthermal plasma. It is found that the cell number of lung cancer cells has been reduced more than that of the lung normal cells. The mitochondrial vulnerability to reactive species in H460 may induce distinctively selective responses. Differential mitochondrial membrane potential decrease, mitochondrial enzymatic dysfunction, and mitochondrial morphological alteration are exhibited in two cell lines. These results suggest the nonthermal plasma treatment as an efficacious modality in lung cancer therapy. PMID:23703387

  20. Secondary osteosarcoma developing 10 years after chemoradiotherapy for non-small-cell lung cancer.

    PubMed

    Yagishita, Shigehiro; Horinouchi, Hidehito; Yorozu, Takashi; Kitazono, Satoru; Mizugaki, Hidenori; Kanda, Shintaro; Fujiwara, Yutaka; Nokihara, Hiroshi; Yamamoto, Noboru; Mori, Taisuke; Tsuta, Koji; Sumi, Minako; Tamura, Tomohide

    2014-02-01

    A 53-year-old female patient was admitted with pain and a progressively enlarging mass in the right upper chest. Chest computed tomography revealed a mass lesion in the region of the right upper ribs. Ten years prior to this admission, the patient had undergone right lobectomy for lung adenocarcinoma. One year after the surgery, follow-up computed tomography had revealed tumor recurrence in the mediastinal and supraclavicular lymph nodes, and the patient had been treated by chemoradiotherapy. Thereafter, regular follow-up had revealed no evidence of recurrence of the non-small-cell lung cancer. Histopathological findings revealed proliferation of spindle-shaped malignant tumor cells in a background of osteoid, consistent with the diagnosis of osteosarcoma. The location of the tumor was consistent with the radiation field. Based on the clinicopathological findings, the patient was diagnosed as having secondary osteosarcoma occurring as a result of the chemoradiotherapy administered previously for the recurrent non-small-cell lung cancer. Unfortunately, the patient died of rapid progression of the osteosarcoma within a week of admission to the hospital. The autopsy revealed contiguous invasion by the tumor of the heart, with massive thrombus formation. The peripheral pulmonary arteries were diffusely occluded by metastatic tumors. Our case serves to highlight the risk of development of secondary sarcoma as a life-threatening late complication after chemoradiotherapy for locally advanced non-small-cell lung cancer, even after complete cure of the primary tumor. PMID:24338556

  1. Prognostic and predictive value of MET deregulation in non-small cell lung cancer

    PubMed Central

    Toschi, Luca; Gianoncelli, Letizia; Baretti, Marina; Santoro, Armando

    2015-01-01

    Recent progress in cancer biology has led to the discovery of increasing number of oncogene alterations that have dramatically changed the paradigm of lung cancer treatment. MET is a tyrosine kinase receptor for the hepatocyte growth factor (HGF) that is deregulated in several malignancies, including non-small cell lung cancer (NSCLC). Abnormal MET-HGF signaling pathway activation can occur via different mechanisms, including HGF and/or MET overexpression, MET gene amplification, mutations or rearrangements. MET protein overexpression and increased MET gene number have been identified as poor prognostic factors in several series of surgically resected NSCLC making this receptor an attractive target for cancer treatment. Several clinical trials have recently evaluated the activity of a variety of anti-MET strategies in NSCLC patients with or without molecular selection with a variable degree of success, underscoring the need of establishing the best predictive biomarker for the identification of responding patients. PMID:25992382

  2. Gender-related disparities in non-small cell lung cancer.

    PubMed

    Paggi, Marco G; Vona, Rosa; Abbruzzese, Claudia; Malorni, Walter

    2010-12-01

    Epidemiological studies clearly outline some disparities in cancer onset, progression as well as prognosis and therapeutic response between sexes. In particular, in lung cancer, the leading cause of cancer death, at least in Western countries, a gender disparity appears now to emerge, especially for non-small cell lung cancer (NSCLC). Such a disparity is apparently due to a variety of mechanisms, ranging from genetic and epigenetic differences to gender-specific lifestyle as well as to behavioral causes and, clearly, to sex hormones activity. Here we briefly recapitulate gender differences in terms of risk factors, histopathological features and pathogenetic mechanisms in NSCLC, and hypothesize that a gender-oriented pharmacology could beneficially impact on innovative therapeutic strategies. PMID:20826048

  3. HOXA11 hypermethylation is associated with progression of non-small cell lung cancer.

    PubMed

    Hwang, Jung-Ah; Lee, Bo Bin; Kim, Yujin; Park, Seong-Eun; Heo, Kyun; Hong, Seung-Hyun; Kim, Young-Ho; Han, Joungho; Shim, Young Mog; Lee, Yeon-Su; Kim, Duk-Hwan

    2013-12-01

    This study was aimed at understanding the functional significance of HOXA11 hypermethylation in non-small cell lung cancer (NSCLC). HOXA11 hypermethylation was characterized in six lung cancer cell lines, and its clinical significance was analyzed using formalin-fixed paraffin-embedded tissues from 317 NSCLC patients, and Ki-67 expression was analyzed using immunohistochemistry. The promoter region of HOXA11 was highly methylated in six lung cancer cell lines, but not in normal bronchial epithelial cells. The loss of expression was restored by treatment of the cells with a demethylating agent, 5-aza-2'-deoxycytidine (5-Aza-dC). Transient transfection of HOXA11 into H23 lung cancer cells resulted in the inhibition of cell migration and proliferation. HOXA11 hypermethylation was found in 218 (69%) of 317 primary NSCLCs. HOXA11 hypermethylation was found at a higher prevalence in squamous cell carcinoma than in adenocarcinoma (74% vs. 63%, respectively). HOXA11 hypermethylation was associated with Ki-67 proliferation index (P = 0.03) and pT stage (P = 0.002), but not with patient survival. Patients with pT2 and pT3 stages were 1.85 times (95% confidence interval [CI] = 1.04-3.29; P = 0.04) and 5.47 times (95% CI = 1.18-25.50; P = 0.01), respectively, more likely to show HOXA11 hypermethylation than those with pT1 stage, after adjusting for age, sex, and histology. In conclusion, the present study suggests that HOXA11 hypermethylation may contribute to the progression of NSCLC by promoting cell proliferation or migration. PMID:24259349

  4. RNAi-mediated silencing of praline-rich gene causes growth reduction in human lung cancer cells.

    PubMed

    Zhao, Qingbo

    2015-01-01

    Lung cancer ranks among one of the most frequent causes of cancer death in the world. Here, we investigated PRR11, one novel gene, with no functional annotation, was found to be over-expressed in lung cancer patients suggesting its potential implication in tumorigenesis. Furthermore, high PRR11 levels predict shorter survival of lung cancer patients. In this study, we investigated the therapeutic potential of PRR11 in lung cancer using the technique of RNA silencing via small interfering RNA (siRNA). Synthetic siRNA duplexes against PRR11 were introduced into 3 lung cancer cell lines, which subsequently resulted in a significant depletion in PRR11 expression in the cells. We found that the targeted depletion of PRR11 caused a dramatic cell cycle arrest followed by massive apoptotic cell death, and eventually resulted in a significant decrease in growth and viability of all 2 lung cancer cell lines. In summary, our study strongly suggests that PRR11 may serve as a potential therapeutic target in human lung cancer. PMID:25973065

  5. 244-MPT overcomes gefitinib resistance in non-small cell lung cancer cells.

    PubMed

    Zhang, Yi; Yao, Ke; Shi, Chengcheng; Jiang, Yanan; Liu, Kangdong; Zhao, Song; Chen, Hanyong; Reddy, Kanamata; Zhang, Chengjuan; Chang, Xiaoyu; Ryu, Joohyun; Bode, Ann M; Dong, Ziming; Dong, Zigang

    2015-12-29

    The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer(NSCLC). Several EGFR tyrosine kinase inhibitors(TKIs), such as gefitinib, have been used as effective clinical therapies for patients with NSCLC. Unfortunately, acquired resistance to gefitinib commonly occurs after 6-12 months of treatment. The resistance is associated with the appearance of the L858R/T790M double mutation of the EGFR. In our present study, we discovered a compound,referred to as 244-MPT, which could suppress either gefitinib-sensitive or -resistant lung cancer cell growth and colony formation, and also suppressed the kinase activity of both wildtype and double mutant (L858R/T790M) EGFR. The underlying mechanism reveals that 244-MPT could interact with either the wildtype or double-mutant EGFR in an ATP-competitive manner and inhibit activity. Treatment with 244-MPT could substantially reduce the phosphorylation of EGFR and its downstream signaling pathways, including Akt and ERK1/2 in gefitinib-sensitive and -resistant cell lines. It was equally effective in suppressing EGFR phosphorylation and downstream signaling in NL20 cells transfected with wildtype, single-mutant (L858R) or mutant (L858R/T790M) EGFR. 244-MPT could also induce apoptosis in a gefitinib-resistant cell line and strongly suppress gefitinib-resistant NSCLC tumor growth in a xenograft mouse model. In addition, 244-MPT could effectively reduce the size of tumors in a gefitinib-resistant NSCLC patient-derived xenograft (PDX) SCID mouse model. Overall, 244-MPT could overcome gefitinib-resistance by directly targeting the EGFR. PMID:26517520

  6. 244-MPT overcomes gefitinib resistance in non-small cell lung cancer cells

    PubMed Central

    Liu, Kangdong; Zhao, Song; Chen, Hanyong; Reddy, Kanamata; Zhang, Chengjuan; Chang, Xiaoyu; Ryu, Joohyun; Bode, Ann M.; Dong, Ziming; Dong, Zigang

    2015-01-01

    The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer(NSCLC). Several EGFR tyrosine kinase inhibitors(TKIs), such as gefitinib, have been used as effective clinical therapies for patients with NSCLC. Unfortunately, acquired resistance to gefitinib commonly occurs after 6–12 months of treatment. The resistance is associated with the appearance of the L858R/T790M double mutation of the EGFR. In our present study, we discovered a compound,referred to as 244-MPT, which could suppress either gefitinib-sensitive or -resistant lung cancer cell growth and colony formation, and also suppressed the kinase activity of both wildtype and double mutant (L858R/T790M) EGFR. The underlying mechanism reveals that 244-MPT could interact with either the wildtype or double-mutant EGFR in an ATP-competitive manner and inhibit activity. Treatment with 244-MPT could substantially reduce the phosphorylation of EGFR and its downstream signaling pathways, including Akt and ERK1/2 in gefitinib-sensitive and -resistant cell lines. It was equally effective in suppressing EGFR phosphorylation and downstream signaling in NL20 cells transfected with wildtype, single-mutant (L858R) or mutant (L858R/T790M) EGFR. 244-MPT could also induce apoptosis in a gefitinib-resistant cell line and strongly suppress gefitinib-resistant NSCLC tumor growth in a xenograft mouse model. In addition, 244-MPT could effectively reduce the size of tumors in a gefitinib-resistant NSCLC patient-derived xenograft (PDX) SCID mouse model. Overall, 244-MPT could overcome gefitinib-resistance by directly targeting the EGFR. PMID:26517520

  7. Identification of Serum Peptidome Signatures of Non-Small Cell Lung Cancer

    PubMed Central

    Klupczynska, Agnieszka; Swiatly, Agata; Hajduk, Joanna; Matysiak, Jan; Dyszkiewicz, Wojciech; Pawlak, Krystian; Kokot, Zenon J.

    2016-01-01

    Due to high mortality rates of lung cancer, there is a need for identification of new, clinically useful markers, which improve detection of this tumor in early stage of disease. In the current study, serum peptide profiling was evaluated as a diagnostic tool for non-small cell lung cancer patients. The combination of the ZipTip technology with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) for the analysis of peptide pattern of cancer patients (n = 153) and control subjects (n = 63) was presented for the first time. Based on the observed significant differences between cancer patients and control subjects, the classification model was created, which allowed for accurate group discrimination. The model turned out to be robust enough to discriminate a new validation set of samples with satisfactory sensitivity and specificity. Two peptides from the diagnostic pattern for non-small cell lung cancer (NSCLC) were identified as fragments of C3 and fibrinogen α chain. Since ELISA test did not confirm significant differences in the expression of complement component C3, further study will involve a quantitative approach to prove clinical utility of the other proteins from the proposed multi-peptide cancer signature. PMID:27043541

  8. Identification of Serum Peptidome Signatures of Non-Small Cell Lung Cancer.

    PubMed

    Klupczynska, Agnieszka; Swiatly, Agata; Hajduk, Joanna; Matysiak, Jan; Dyszkiewicz, Wojciech; Pawlak, Krystian; Kokot, Zenon J

    2016-01-01

    Due to high mortality rates of lung cancer, there is a need for identification of new, clinically useful markers, which improve detection of this tumor in early stage of disease. In the current study, serum peptide profiling was evaluated as a diagnostic tool for non-small cell lung cancer patients. The combination of the ZipTip technology with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) for the analysis of peptide pattern of cancer patients (n = 153) and control subjects (n = 63) was presented for the first time. Based on the observed significant differences between cancer patients and control subjects, the classification model was created, which allowed for accurate group discrimination. The model turned out to be robust enough to discriminate a new validation set of samples with satisfactory sensitivity and specificity. Two peptides from the diagnostic pattern for non-small cell lung cancer (NSCLC) were identified as fragments of C3 and fibrinogen α chain. Since ELISA test did not confirm significant differences in the expression of complement component C3, further study will involve a quantitative approach to prove clinical utility of the other proteins from the proposed multi-peptide cancer signature. PMID:27043541

  9. CDK-associated Cullin 1 promotes cell proliferation with activation of ERK1/2 in human lung cancer A549 cells

    SciTech Connect

    Chen, Tian Jun; Gao, Fei; Yang, Tian; Thakur, Asmitanand; Ren, Hui; Li, Yang; Zhang, Shuo; Wang, Ting; Chen, Ming Wei

    2013-07-19

    Highlights: •CDK-associated Cullin 1 (CAC1) expression increases in human lung carcinoma. •CAC1 promotes the proliferation of lung cancer A549 cells. •CAC1 promotes human lung cancer A549 cell proliferation with activation of ERK1/2. -- Abstract: Lung cancer is one of the most common causes of cancer-related death in the world, but the mechanisms remain unknown. In this study, we investigated the expression of CDK-associated Cullin 1 (CAC1) in lung cancer, the effect of CAC1 on the proliferation of human lung cancer A549 cells, and the activation of signaling pathways of mitogen-activated protein kinases (MAPKs). Results showed that CAC1 expression was higher levels in human lung carcinoma than normal lung tissue, and CAC1 siRNA reduced the proliferation of lung cancer A549 cells by decreasing cell activity and cell division in vitro. The proportion of cells treated with CAC1 siRNA increased in the G1 phase and decreased in the S and G2/M phase, indicative of G1 cell cycle arrest. Furthermore, the proportions of early/late apoptosis in lung cancer A549 cells were enhanced with CAC1 siRNA treatment. It was also found that activation of extracellular signal-regulated protein kinase (ERK) and p38 signaling pathways were involved in the proliferation of A549 cells. After CAC1 siRNA treatment, p-ERK1/2 levels decreased, and meanwhile p-p38 level increased, A549 cell proliferation increased when ERK1/2 signaling is activated by PMA. Our findings demonstrated that CAC1 promoted the proliferation of human lung cancer A549 cells with activation of ERK1/2 signaling pathways, suggesting a potential cure target for treatment of human lung cancer.

  10. 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

  11. Genetic and Prognostic Differences of Non-small Cell Lung Cancer between Elderly Patients and Younger Counterparts.

    PubMed

    Suda, Kenichi; Tomizawa, Kenji; Mizuuchi, Hiroshi; Ito, Simon; Kitahara, Hirokazu; Shimamatsu, Shinichiro; Kohno, Mikihiro; Yoshida, Tsukihisa; Okamoto, Tatsuro; Maehara, Yoshihiko; Yatabe, Yasushi; Mitsudomi, Tetsuya

    2012-12-01

    Many elderly patients suffer from lung cancers, but it is not clear if their lung cancers differ from those of younger patients. In this study, we compared genetic and prognostic characteristics of lung cancers of patients aged ≥75 years with those of patients aged ≤ 64 years. In the genetic analysis, we explored 292 surgically treated non-squamous cell lung cancers with known mutational status of epidermal growth factor (EGFR) and anaplastic lymphoma kinase (ALK). In the prognostic analysis, we retrospectively analyzed 405 surgically treated non-small cell lung cancers (NSCLCs) before the era of routine clinical application of post-surgical adjuvant chemotherapy. Postsurgical recurrence-free survival (RFS) was compared between elderly patients and younger counterparts. The genetic analysis showed elderly non-squamous cell lung cancer patients to have higher prevalence of EGFR mutations (53.1 % vs 42.0%, P = 0.15) and lower prevalence of the ALK translocation (0 % vs 4.5%, P = 0.23) than their younger counterparts. The prognostic analysis showed postsurgical RFS was similar between the elderly NSCLC patients and the younger patients. However in multivariate analysis, adjusting for gender, smoking status, pathological stage, and histology, elderly patients had significantly worse prognoses (HR 1.57, 95% CI, 1.08-2.29; P = 0.02) compared with younger patients. These results suggest differences in genetic and prognostic aspects between elderly lung cancer patients and younger lung cancer patients. PMID:23251849

  12. Genetic and Prognostic Differences of Non-small Cell Lung Cancer between Elderly Patients and Younger Counterparts

    PubMed Central

    Suda, Kenichi; Tomizawa, Kenji; Mizuuchi, Hiroshi; Ito, Simon; Kitahara, Hirokazu; Shimamatsu, Shinichiro; Kohno, Mikihiro; Yoshida, Tsukihisa; Okamoto, Tatsuro; Maehara, Yoshihiko; Yatabe, Yasushi; Mitsudomi, Tetsuya

    2012-01-01

    Many elderly patients suffer from lung cancers, but it is not clear if their lung cancers differ from those of younger patients. In this study, we compared genetic and prognostic characteristics of lung cancers of patients aged ≥75 years with those of patients aged ≤ 64 years. In the genetic analysis, we explored 292 surgically treated non-squamous cell lung cancers with known mutational status of epidermal growth factor (EGFR) and anaplastic lymphoma kinase (ALK). In the prognostic analysis, we retrospectively analyzed 405 surgically treated non-small cell lung cancers (NSCLCs) before the era of routine clinical application of post-surgical adjuvant chemotherapy. Postsurgical recurrence-free survival (RFS) was compared between elderly patients and younger counterparts. The genetic analysis showed elderly non-squamous cell lung cancer patients to have higher prevalence of EGFR mutations (53.1 % vs 42.0%, P = 0.15) and lower prevalence of the ALK translocation (0 % vs 4.5%, P = 0.23) than their younger counterparts. The prognostic analysis showed postsurgical RFS was similar between the elderly NSCLC patients and the younger patients. However in multivariate analysis, adjusting for gender, smoking status, pathological stage, and histology, elderly patients had significantly worse prognoses (HR 1.57, 95% CI, 1.08–2.29; P = 0.02) compared with younger patients. These results suggest differences in genetic and prognostic aspects between elderly lung cancer patients and younger lung cancer patients. PMID:23251849

  13. Inhibitory Effects of Metabolites of 5-Demethylnobiletin on Human Nonsmall Cell Lung Cancer Cells.

    PubMed

    Song, Mingyue; Charoensinphon, Noppawat; Wu, Xian; Zheng, Jinkai; Gao, Zili; Xu, Fei; Wang, Minqi; Xiao, Hang

    2016-06-22

    5-Demethylnobiletin is a unique flavonoid found in citrus fruits with potential chemopreventive effects against human cancers. We previously identified three metabolites of 5DN, namely 5,4'-didemethylnobiletin (M1), 5,3',4'- tridemethylnobiletin (M2), and 5,3'-didemethylnobiletin (M3) in mice fed 5DN. Herein, we investigated the inhibitory effects of these three metabolites on NSCLC cells. Our results demonstrated that M1, M2, and especially M3 showed stronger inhibition on the growth and colony formation of H460 and H1299 cells compared to 5DN. Three metabolites significantly inhibited the tumorsphere formation of A549 cells. Flow cytometry analysis showed that all metabolites induced cell cycle arrest and cellular apoptosis, and these effects were also stronger than that of 5DN. The inhibitory effects of these metabolites were associated with their ability to modulate the key signaling proteins related to cell proliferation and apoptosis. Overall, our results provided a basis for utilizing 5DN and its metabolites for chemoprevention of lung cancer. PMID:27219898

  14. Vascular Endothelial Growth Factor A Regulates the Secretion of Different Angiogenic Factors in Lung Cancer Cells.

    PubMed

    Frezzetti, Daniela; Gallo, Marianna; Roma, Cristin; D'Alessio, Amelia; Maiello, Monica R; Bevilacqua, Simona; Normanno, Nicola; De Luca, Antonella

    2016-07-01

    Vascular endothelial growth factor A (VEGFA) is one of the main mediators of angiogenesis in non-small cell lung cancer (NSCLC). Recently, it has been described an autocrine feed-forward loop in NSCLC cells in which tumor-derived VEGFA promoted the secretion of VEGFA itself, amplifying the proangiogenic signal. In order to investigate the role of VEGFA in lung cancer progression, we assessed the effects of recombinant VEGFA on proliferation, migration, and secretion of other angiogenic factors in A549, H1975, and HCC827 NSCLC cell lines. We found that VEGFA did not affect NSCLC cell proliferation and migration. On the other hand, we demonstrated that VEGFA not only produced a strong and persistent increase of VEGFA itself but also significantly induced the secretion of a variety of angiogenic factors, including follistatin (FST), hepatocyte growth factor (HGF), angiopoietin-2 (ANGPT2), granulocyte-colony stimulating factor (G-CSF), interleukin (IL)-8, leptin (LEP), platelet/endothelial cell adhesion molecule 1 (PECAM-1), and platelet-derived growth factor bb (PDGF-BB). PI3K/AKT, RAS/ERK, and STAT3 signalling pathways were found to mediate the effects of VEGFA in NSCLC cell lines. We also observed that VEGFA regulation mainly occurred at post-transcriptional level and that NSCLC cells expressed different isoforms of VEGFA. Collectively, our data suggested that VEGFA contributes to lung cancer progression by inducing a network of angiogenic factors, which might offer potential for therapeutic intervention. PMID:26542886

  15. Computational discovery of pathway-level genetic vulnerabilities in non-small-cell lung cancer

    PubMed Central

    Young, Jonathan H.; Peyton, Michael; Seok Kim, Hyun; McMillan, Elizabeth; Minna, John D.; White, Michael A.; Marcotte, Edward M.

    2016-01-01

    Motivation: Novel approaches are needed for discovery of targeted therapies for non-small-cell lung cancer (NSCLC) that are specific to certain patients. Whole genome RNAi screening of lung cancer cell lines provides an ideal source for determining candidate drug targets. Results: Unsupervised learning algorithms uncovered patterns of differential vulnerability across lung cancer cell lines to loss of functionally related genes. Such genetic vulnerabilities represent candidate targets for therapy and are found to be involved in splicing, translation and protein folding. In particular, many NSCLC cell lines were especially sensitive to the loss of components of the LSm2-8 protein complex or the CCT/TRiC chaperonin. Different vulnerabilities were also found for different cell line subgroups. Furthermore, the predicted vulnerability of a single adenocarcinoma cell line to loss of the Wnt pathway was experimentally validated with screening of small-molecule Wnt inhibitors against an extensive cell line panel. Availability and implementation: The clustering algorithm is implemented in Python and is freely available at https://bitbucket.org/youngjh/nsclc_paper. Contact: marcotte@icmb.utexas.edu or jon.young@utexas.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26755624

  16. Transferrin synthesis by small cell lung cancer cells acts as an autocrine regulator of cellular proliferation.

    PubMed Central

    Vostrejs, M; Moran, P L; Seligman, P A

    1988-01-01

    Since transferrin is required for cellular proliferation, we investigated transferrin synthesis by a small cell lung cancer line (NCI-H510) that survives in serum-free media without added transferrin. Immunoassays for human transferrin demonstrated that these cells contained immunoreactive human transferrin. Immunofluorescence studies showed that the protein is expressed on the surface of cells, presumably bound to transferrin receptor. Media conditioned by NCI-H510 cells support proliferation of human leukemic cells that would not survive in media lacking transferrin. [35S]Methionine incorporation documented transferrin synthesis by NCI-H510 cells as well as three other small cell lines. Transferrin synthesis by NCI-H510 cells increased more than 10-fold when cells entered active phases of the cell cycle, and this increase was seen before large increases in transferrin-receptor expression. Further experiments examining the effects of agents that affect iron metabolism show that the addition of transferrin-iron or hemin to the media is associated with a more rapid initial rate of proliferation and lower rates of transferrin synthesis than control cells. Gallium salts, which inhibit iron uptake, inhibited proliferation of these cells. If the cells recovered from this effect, transferrin synthesis remained greatly increased compared to control. We conclude that transferrin synthesis by these malignant cells is ultimately related to an iron requirement for cellular proliferation. It appears that this synthesized transferrin acts as part of an important autocrine mechanism permitting proliferation of these cells, and perhaps permitting tumor cell growth in vivo in areas not well vascularized. Images PMID:2839550

  17. Role of immunotherapy in the treatment of advanced non-small-cell lung cancer.

    PubMed

    Rijavec, Erika; Genova, Carlo; Alama, Angela; Barletta, Giulia; Sini, Claudio; Pronzato, Paolo; Coco, Simona; Dal Bello, Maria Giovanna; Savarino, Graziana; Truini, Anna; Boccardo, Francesco; Grossi, Francesco

    2014-01-01

    After several decades of modest results with nonspecific immune stimulants, immunotherapy has become an exciting approach in the treatment of cancer. Although non-small-cell lung cancer has not been considered an immunogenic disease for very long, a better understanding of tumor immunology and the identification of new targets have led to the development of many clinical trials of immune-based therapies for this neoplasm. Promising results from many clinical trials suggest that immunotherapy could be an effective strategy in the management of advanced non-small-cell lung cancer. Further studies are required to help clinicians in the selection of patients who are more likely to benefit from immunotherapy strategies by the identification of biomarkers and to understand when the combination of immunotherapy with other agents should be recommended. PMID:24328411

  18. New molecular targeted therapies for advanced non-small-cell lung cancer

    PubMed Central

    Méndez, Míriam; Custodio, Ana; Provencio, Mariano

    2011-01-01

    Non-small-cell lung cancer (NSCLC) is a uniformly fatal disease and most patients will present with advanced stage. Treatment outcomes remain unsatisfactory, with low long-term survival rates. Standard treatment, such as palliative chemotherapy and radiotherapy, offers a median survival not exceeding 1 year. Hence, considerable efforts have started to be made in order to identify new biological agents which may safely and effectively be administered to advanced NSCLC patients. Two cancer cell pathways in particular have been exploited, the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR) pathways. However, novel targeted therapies that interfere with other dysregulated pathways in lung cancer are already in the clinic. This review outlines the most promising research approaches to the treatment of NSCLC, discussed according to the specific molecular pathway targeted. PMID:22263060

  19. Targeting PD-L1 for non-small-cell lung cancer.

    PubMed

    Feld, Emily; Horn, Leora

    2016-06-01

    Lung cancer is the leading cause of cancer-related death worldwide. For decades, cytotoxic chemotherapy has been the mainstay of treatment for the majority of patients, yet median survival remains poor and side effects from chemotherapy are not trivial. Immune checkpoint inhibitors, which exert antitumor effects by inhibiting negative T-cell regulators, are changing the landscape of treatment options for patients with non-small-cell lung cancer (NSCLC). The anti-PD-1 antibodies nivolumab and pembrolizumab are approved by the US FDA for treatment of patients with NSCLC and other tumor types. Additional agents are in clinical development. This review provides an update on the PD-1 and PD-L1 immune checkpoint inhibitors currently being evaluated in NSCLC patients. PMID:27197542

  20. The Distribution of Human Stem Cell–like Memory T Cell in Lung Cancer

    PubMed Central

    Hong, Hai; Gu, Yong; Sheng, Si Yuan; Lu, Chuan Gang; Zou, Jian Yong

    2016-01-01

    Human stem cell–like memory T (Tscm) cells are long-lived, self-renewing memory lymphocytes that can differentiate into effector cells and mediate strong antitumour response in murine model. The distribution and function of Tscm cells in human lung cancer remain unknown. In this study, we investigated the properties of human Tscm cells in the blood and lymph node of non–small cell lung cancer (NSCLC) patients. There were more CD4+ Tscm cells in blood from NSCLC patients than from healthy donors, fewer CD4+ and CD8+ TSCM cells in blood than in lymph node from NSCLC patients. To further analyze their properties, we stimulated peripheral blood mononuclear cells from NSCLC patients by mitogens to examine cytokine production. Our data suggest that both CD4 and CD8 Tscm cells in blood produced interferon-γ significantly increased in NSCLC patients compare with healthy subjects. In addition, fewer Tscm cells produced interferon-γ in lymph node than in blood from NSCLC patients. Our results strongly suggest that the distribution and function of CD4 Tscm cells in NSCLC patients is upregulated. Understanding of the properties of stem-like memory T cells will supply a good rationale for designing the new adoptive immunotherapy in cancer. PMID:27244531

  1. Downregulated TIPE2 is associated with poor prognosis and promotes cell proliferation in non-small cell lung cancer.

    PubMed

    Li, Yuexia; Li, Xiaohui; Liu, Gang; Sun, Rongqing; Wang, Lirui; Wang, Jing; Wang, Hongmin

    2015-01-30

    The present study aims to investigate the expression pattern of TIPE2 protein and its clinical significance in human non-small cell lung cancer (NSCLC). We investigated the expression levels of TIPE2 in 96 NSCLC tumor samples by immunohistochemistry and then analyzed its clinical significance. Furthermore, the role of TIPE2 on the biological properties of the NSCLC cell line H1299 and A549 was experimentally tested in vitro and in vivo. We found that the expression level of TIPE2 was significantly higher in normal lung tissues compared with NSCLC tissues (P<0.001), and TIPE2 downregulation was significantly correlated with advanced TNM stage (P=0.006). TIPE2 expression was lower in lung cancer cell lines than normal bronchial cell line HBE. Transfection of TIPE2 plasmid was performed in H1299 and A549 cells. TIPE2 overexpression inhibited lung cancer cell proliferation, colony formation and cell invasive in vitro, and prevented lung tumor growth in vivo. In addition, TIPE2 transfection reduced the anti-apoptotic Bcl-XL protein and mesenchymal marker N-cadherin expression. Taken together, our results demonstrate that TIPE2 might serve as a tumor suppressor in NSCLC progression. PMID:25542151

  2. Adrenal Insufficiency Associated with Small Cell Lung Cancer: A Case Report and Literature Review.

    PubMed

    Noguchi, Shingo; Torii, Ryo; Shimabukuro, Ikuko; Yamasaki, Kei; Kido, Takashi; Yoshii, Chiharu; Mukae, Hiroshi; Yatera, Kazuhiro

    2016-06-01

    A 78-year-old Japanese man with fatigue, appetite loss, skin hyperpigmentation, hypotension and hypoglycemia, visited our hospital to evaluate an abnormal chest X-ray and adrenal gland swelling in echography in February 2015. Chest computed tomography showed a mass lesion in the right lower lobe and bilateral adrenal swellings, and small cell lung cancer (SCLC) with bilateral adrenal metastasis was diagnosed after bronchoscopy. According to low levels of serum cortisol, elevated adrenocorticotropic hormone (ACTH) and rapid ACTH test, the diagnosis of adrenal insufficiency associated with SCLC was made. Treatment with hydrocortisone (20 mg/day) was started in addition to systemic chemotherapy with carboplatin and etoposide. The patient's symptoms were slightly improved, however, systemic chemotherapy was discontinued according to the patient's request after 1 course of chemotherapy. Thereafter, he received only supportive care, and his general condition gradually worsened and he ultimately died in August 2015. Adrenal insufficiency associated with SCLC, which is caused by tissue destruction more than 90% of the adrenal glands, is rare although adrenal metastasis is not rare in patients with lung cancer. The findings such as general fatigue, appetite loss, hypotension, and hyponatremia are often got follow up as findings of advanced cancer, but appropriate therapy for adrenal insufficiency, supplement of the adrenal corticosteroid hormone, may lead to a significant improvement in the symptoms and quality of life in clinical practice of lung cancer. Therefore, physicians must consider potential adrenal insufficiency in lung cancer patients with bilateral adrenal metastasis. PMID:27302729

  3. RESISTANCE TO PLATINUM-BASED CHEMOTHERAPY IN LUNG CANCER CELL LINES

    PubMed Central

    Chen, Jianli; Emara, Nashwa; Solomides, Charalambos; Parekh, Hemant; Simpkins, Henry

    2010-01-01

    Purpose A series of six lung cancer cell lines of different cell origin (including small cell and mesothelioma) were characterized immunohistochemically and the role of a series of protein candidates previously implicated in drug resistance investigated. Methods These include colony-forming and cell growth assays, immunohistochemistry, siRNA knockouts, Real Time PCR, and Western blots. Results No correlation was found with AKT, HO-1, HO-2, GRP78, 14-3-3zeta and ERCC1 levels and cisplatin nor oxaliplatin cytotoxicity but an association was observed with levels of the enzyme, dihydrodiol dehydrogenase (DDH); an enzyme previously implicated in the development of platinum resistance. The relationship appeared to hold true for those cell lines derived from lung epithelial primary tumors but not for the neuroendocrine/small cell and mesothelioma cell lines. siRNA knockouts to DDH-1 and DDH-2 were prepared with the cell line exhibiting the greatest resistance to cisplatin (A549) resulting in marked decreases in the DDH isoforms as assessed by Real Time PCR, western blot and enzymatic activity. The DDH-1 knockout was far more sensitive to cisplatin than the DDH-2 knockout. Conclusion Thus, sensitivity to cisplatin appeared to be associated with DDH levels in epithelial lung cancer cell lines with the DDH-1 isoform producing the greatest effect. Results in keeping with transfection experiments with ovarian and other cell lines. PMID:20953859

  4. Prognostic significance of CT-emphysema score in patients with advanced squamous cell lung cancer

    PubMed Central

    Kim, Young Saing; Ahn, Hee Kyung; Cho, Eun Kyung; Jeong, Yu Mi; Kim, Jeong Ho

    2016-01-01

    Background Although emphysema is a known independent risk factor of lung cancer, no study has addressed the prognostic impact of computed tomography (CT)-emphysema score in advanced stage lung cancer. Methods For 84 consecutive patients with stage IIIB and IV squamous cell lung cancer that underwent palliative chemotherapy, severity of emphysema was semi-quantitatively scored using baseline chest CT images according to the Goddard scoring system (possible scores range, 0–24). The cutoff of high CT-emphysema score was determined using the maximum chi-squared test and the prognostic significance of the high CT-emphysema score was evaluated using Kaplan-Meier analysis and Cox proportional hazards analysis. Results The median CT-emphysema score was 5 (range, 0–22). Patients with a high CT-emphysema score (≥4) tended to have poorer overall survival (OS) (median: 6.3 vs. 13.7 months) than those with a score of <4 (P=0.071). Multivariable analysis revealed that a higher CT-emphysema score was a significant independent prognostic factor for poor OS [hazard ratio (HR) =2.06; 95% confidence interval (CI), 1.24–3.41; P=0.005), along with no response to first-line therapy (P=0.009) and no second-line therapy (P<0.001). Conclusions CT-emphysema score is significantly associated with poor prognosis in patients with advanced squamous cell lung cancer.

  5. Genomic profiling toward precision medicine in non-small cell lung cancer: getting beyond EGFR

    PubMed Central

    Richer, Amanda L; Friel, Jacqueline M; Carson, Vashti M; Inge, Landon J; Whitsett, Timothy G

    2015-01-01

    Lung cancer remains the leading cause of cancer-related mortality worldwide. The application of next-generation genomic technologies has offered a more comprehensive look at the mutational landscape across the different subtypes of non-small cell lung cancer (NSCLC). A number of recurrent mutations such as TP53, KRAS, and epidermal growth factor receptor (EGFR) have been identified in NSCLC. While targeted therapeutic successes have been demonstrated in the therapeutic targeting of EGFR and ALK, the majority of NSCLC tumors do not harbor these genomic events. This review looks at the current treatment paradigms for lung adenocarcinomas and squamous cell carcinomas, examining genomic aberrations that dictate therapy selection, as well as novel therapeutic strategies for tumors harboring mutations in KRAS, TP53, and LKB1 which, to date, have been considered “undruggable”. A more thorough understanding of the molecular alterations that govern NSCLC tumorigenesis, aided by next-generation sequencing, will lead to targeted therapeutic options expected to dramatically reduce the high mortality rate observed in lung cancer. PMID:25897257

  6. A bibenzyl from Dendrobium ellipsophyllum inhibits migration in lung cancer cells.

    PubMed

    Chaotham, Chatchai; Chanvorachote, Pithi

    2015-10-01

    Metastatic cancer cells have been shown to have aggressive behaviors accounting for the high incidence of chemotherapeutic failure and mortality. Because migration and invasion are crucial behaviors for cancer cell dissemination, promising compounds exhibiting potential antimigration effects are of interest for metastasis-based therapeutic approaches. This study aimed to evaluate the activity of a bibenzyl, 4,5,4'-trihydroxy-3,3'-dimethoxybibenzyl (TDB), isolated from Dendrobium ellipsophyllum Tang and Wang, in the suppression of migration in human lung cancer cells. TDB at nontoxic concentrations (1 and 5 µM) significantly inhibited the motility of lung cancer cells in scratch-wound assay. Chemotaxis-induced migration and invasion assays also revealed that the cell motility dramatically diminished in the cells treated with 1-5 µM TDB. Western blot analysis provided the underlying molecular mechanism, showing that TDB reduced such cell migration and invasion by decreasing migration-regulating proteins, including integrins αv, α4, β1, β3 and β5, as well as downstream signaling proteins, such as activated focal adhesion kinase (pFAK), activated Ras-related C3 botulinum toxin substrate 1 (Rac1-GTP) and cell division control protein 42 (Cdc42). As the presence of cellular protrusion, called filopodia, has been indicated as a hallmark of migrating cells, we showed that the reduction of the mentioned proteins correlated well with the disappearance of filopodia. In summary, this study demonstrates the promising activity of TDB and its mechanism in the inhibition of lung cancer cell migration, which might be useful for encouraging the development of this compound for antimetastatic approaches. PMID:26109451

  7. Effect of plasmid-mediated RNA interference targeting telomerase reverse transcriptase on lung cancer cells.

    PubMed

    Ge, Linhu; Deng, Zhansheng; Zhang, Yangde; Shao, Wenlong; Qiu, Yuan; Cui, Dong; Huang, Donghai

    2011-12-01

    In the present study, a plasmid-mediated siRNA interference vector targeting the hTERT gene was constructed and stably transfected into H1299 lung cancer cells. Using real-time quantitative fluorescent PCR technology, western blotting and flow cytometry-based cell cycle profiling, the silencing effect of this vector and its inhibitory effect on proliferation in lung cancer cells were explored. Based upon the results of our previous study, a pair of siRNA sequences was selected, and a DNA template primer was designed and synthesized. After cloning of the template primer into the promoter of the pGenesil-1.1 expression vector, the constructed interference vector was validated using enzyme digestion and gene sequencing. The recombinant interference vector and empty vector were separately transfected into H1299 lung cancer cells with cationic liposomes, and stable monoclonally transfected cells were obtained after selection with G418. After stable transfection, hTERT mRNA and protein expression levels were detected using real-time RT-PCR technology and western blotting. Using the MTT method and a colony formation assay, the growth and proliferation of the stably transfected lung cancer cells were determined. Changes in the cell cycle profile of the stably transfected lung cancer cells were detected using flow cytometry. An interference vector targeting the hTERT gene (pGenesil.1-hTERT) was successfully constructed. Enzyme digestion and gene sequencing confirmed that the sequence insertion met the criteria of the design. After transfection of H1299 cells with pGenesil.1-hTERT or an empty vector, the stably transfected monoclonal cell lines H1299-pGenesil.1-hTERT and H1299-pGenesil.1 were obtained. Compared to the control cells transfected with the empty vector, the H1299-pGenesil.1-hTERT cells had significantly lower mRNA expression of hTERT (93.97±0.83% inhibition, with P<0.001). The protein expression of hTERT in H1299-pGenesil.1-hTERT cells was significantly lower

  8. FGFR1 promotes the stem cell-like phenotype of FGFR1-amplified non-small cell lung cancer cells through the Hedgehog pathway

    PubMed Central

    Ji, Wenxiang; Yu, Yongfeng; Li, Ziming; Wang, Guan; Li, Fan; Xia, Weiliang; Lu, Shun

    2016-01-01

    Cancer stem cell-like phenotype is critical for tumor formation and treatment resistance. FGFR1 is found to be amplified in non-small cell lung cancer, particularly in the lung squamous cell cancer (LSCC). Whether FGFR1 contributes to the maintenance of stem cell-like phenotype of FGFR1-amplified lung cancer cells remains elusive. In this study, treatment with FGFR1 inhibitor AZD4547 suppressed the growth of tumor spheres and reduced ALDH positive proportion in FGFR1-amplified lung cancer cells in vitro, as well as inhibited the growth of oncospheres and parental cells in xenograft models. Knockdown of FGFR1 recaptured the similar effect as AZD4547 in vitro. Furthermore, activation of FGFR1 and subsequently its downstream ERK signaling enhanced the expression and transcriptional activity of GLI2, which could be blocked by FGFR1 inhibitor/silencing or ERK inhibitor. Knockdown of GLI2 directly inhibited the stem-like phenotype of FGFR1-amilified cells, whereas overexpression of GLI2 sufficiently rescued the phenotype caused by FGFR1 knockdown. Notably we also identified a correlation between FGFR1 and GLI2 expressions from clinical data, as well as an inverse relationship with progression free survival (PFS). Together our study suggests that the FGFR1/GLI2 axis promotes the lung cancer stem cell-like phenotype. These results support a rational strategy of combination of FGFR1 and GLI inhibitors for treatment of FGFR1-amplified lung cancers, especially LSCC. PMID:26936993

  9. Identification of a long non-coding RNA gene, growth hormone secretagogue receptor opposite strand, which stimulates cell migration in non-small cell lung cancer cell lines.

    PubMed

    Whiteside, Eliza J; Seim, Inge; Pauli, Jana P; O'Keeffe, Angela J; Thomas, Patrick B; Carter, Shea L; Walpole, Carina M; Fung, Jenny N T; Josh, Peter; Herington, Adrian C; Chopin, Lisa K

    2013-08-01

    The molecular mechanisms involved in non‑small cell lung cancer tumourigenesis are largely unknown; however, recent studies have suggested that long non-coding RNAs (lncRNAs) are likely to play a role. In this study, we used public databases to identify an mRNA-like, candidate long non-coding RNA, GHSROS (GHSR opposite strand), transcribed from the antisense strand of the ghrelin receptor gene, growth hormone secretagogue receptor (GHSR). Quantitative real-time RT-PCR revealed higher expression of GHSROS in lung cancer tissue compared to adjacent, non-tumour lung tissue. In common with many long non-coding RNAs, GHSROS is 5' capped and 3' polyadenylated (mRNA-like), lacks an extensive open reading frame and harbours a transposable element. Engineered overexpression of GHSROS stimulated cell migration in the A549 and NCI-H1299 non-small cell lung cancer cell lines, but suppressed cell migration in the Beas-2B normal lung-derived bronchoepithelial cell line. This suggests that GHSROS function may be dependent on the oncogenic context. The identification of GHSROS, which is expressed in lung cancer and stimulates cell migration in lung cancer cell lines, contributes to the growing number of non-coding RNAs that play a role in the regulation of tumourigenesis and metastatic cancer progression. PMID:23722988

  10. Antiproliferative effect of Toona sinensis leaf extract on non-small-cell lung cancer.

    PubMed

    Yang, Chih-Jen; Huang, Yu-Jung; Wang, Cheng-Yuan; Wang, Pei-Hui; Hsu, Hseng-Kuang; Tsai, May-Jywan; Chen, Yu-Chu; Bharath Kumar, V; Huang, Ming-Shyan; Weng, Ching-Feng

    2010-06-01

    Toona sinensis (TS), which is also known as Cedrela sinensis, belongs to Meliaceae family, the compounds identified from this TS leaves possess a wide range of biologic functions, such as hypoglycemic effects, anti-LDL glycative activity, antioxidant activities, and inhibition of sudden acute respiratory syndrome (SARS) coronavirus replication. However, their effect against cancer cells is not well explored. In this study, to understand the cytotoxic effect and molecular mechanism stimulated by TSL-1 (TS leaf extract fraction) we employed three different non-small-cell lung cancer (NSCLC) cell lines: H441 cells (lung adenocarcinoma), H661 cells (lung large cell carcinoma) and H520 cells (lung squamous cell carcinoma). IC50 value was varied between these three cell lines, the least IC(50) value was observed in TSL-1-treated H661cells. Exposure of NSCLC cells to TSL-1 caused cell-cycle arrest in subG1 phase and caused apoptosis. Moreover, TSL-1 treatment decreased the cell-cycle regulators; cyclin D1 and CDK4 proteins by up regulating p27 expression in a dose-dependent manner. Thus, the TSL-1-induced apoptosis was further confirmed by cell morphology, subG1 peak accumulation, poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) cleavage, propidium iodide (PI)-Annexin-V double staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. The decreased Bcl2 protein level was concurrent with an increased Bax protein level in all 3 cell lines. Additionally, the tumoricidal effect of TSL-1 was measured using a xenograft model, after 5 weeks of TSL-1 treatment by various regimen caused regression of tumor. Taken together both these in vitro and in vivo studies revealed that TSL-1 is a potent inhibitor against NSCLC growth and our provoking result suggest that TSL-1 can be a better nutriceutical as a singlet or along with doublet agents (taxane, vinorelbine, and gemcitabine) for treating NSCLC. PMID:20478545

  11. Treatment with HIF-1α Antagonist PX-478 Inhibits Progression and Spread of Orthotopic Human Small Cell Lung Cancer and Lung Adenocarcinoma in Mice

    PubMed Central

    Jacoby, Jörg J.; Erez, Baruch; Korshunova, Maria V.; Williams, Ryan R.; Furutani, Kazuhisa; Takahashi, Osamu; Kirkpatrick, Lynn; Lippman, Scott M.; Powis, Garth; O’Reilly, Michael S.; Herbst, Roy S.

    2011-01-01

    Introduction PX-478 is a potent small-molecule inhibitor of HIF-1α. In preclinical studies, it had antitumor activity against various solid tumors in subcutaneous xenografts but had no measurable activity against a non-small cell lung cancer (NSCLC) xenograft. To determine the effectiveness of PX-478 against lung tumors, we investigated HIF-1α expression in several lung cancer cell lines, both in vitro and in vivo, and treated orthotopic mouse models of human lung cancer with PX-478. Methods Cells from two human lung adenocarcinoma cell models (PC14-PE6 and NCI-H441) or two human small cell lung cancer (SCLC) models (NCI-H187 and NCI-N417) were injected into the left lungs of nude mice and were randomized 16 to 18 days after injection with daily oral treatment with PX-478 or vehicle for 5 days. Results In the PC14-PE6 NSCLC model, treatment with 20 mg/kg PX-478 significantly reduced the median primary lung tumor volume by 87% (p = 0.005) compared with the vehicle-treated group. PX-478 treatment also markedly reduced mediastinal metastasis and prolonged survival. Similar results were obtained in a second NSCLC model. In SCLC models, PX-478 was even more effective. In the NCI-H187 model, the median primary lung tumor volume was reduced by 99% (p = 0.0001). The median survival duration was increased by 132%. In the NCI-N417 model, the median primary lung tumor volume was reduced by 97% (p = 0.008). Conclusions We demonstrated that the PX-478, HIF-1α inhibitor, had significant antitumor activity against two orthotopic models of lung adenocarcinomas and two models of SCLC. These results suggest the inclusion of lung cancer patients in phase I clinical trials of PX-478. PMID:20512076

  12. Role of ATG10 expression quantitative trait loci in non-small cell lung cancer survival.

    PubMed

    Xie, Kaipeng; Liang, Cheng; Li, Qin; Yan, Caiwang; Wang, Cheng; Gu, Yayun; Zhu, Meng; Du, Fangzhi; Wang, Hui; Dai, Juncheng; Liu, Xiao'an; Jin, Guangfu; Shen, Hongbing; Ma, Hongxia; Hu, Zhibin

    2016-10-01

    The aim of this article was to evaluate whether genetic variants in autophagy-related genes affect the overall survival (OS) of non-small cell lung cancer (NSCLC) patients. We analyzed 14 single nucleotide polymorphisms (SNPs) in core autophagy-related genes for OS in 1,001 NSCLC patients. Three promising SNPs in ATG10 were subsequently annotated by the expression quantitative trait loci (eQTL) and methylation quantitative trait loci (meQTL) analyses based on Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. We observed that the variants of rs10514231, rs1864182 and rs1864183 were associated with poor lung cancer survival (HR = 1.33, 95% CI = 1.07-1.65; HR = 1.43, 95% CI = 1.13-1.81; HR = 1.38, 95% CI = 1.14-1.68, respectively) and positively correlated with ATG10 expression (all p < 0.05) from GTEx and TCGA datasets. The elevated expression of ATG10 may predict shorter survival time in lung cancer patients in TCGA dataset (HR = 2.10, 95% CI = 1.33-3.29). Moreover, the variants of rs10514231 and rs1864182 were associated with the increased methylation levels of cg17942617 (meQTL), which in turn contributed to the elevated ATG10 expression and decreased survival time. Further functional assays revealed that ATG10 facilitated lung cancer cell proliferation and migration. Our findings suggest that eQTL/meQTL variations of ATG10 could influence lung cancer survival through regulating ATG10 expression. PMID:27225307

  13. Role of Chemokines in Non-Small Cell Lung Cancer: Angiogenesis and Inflammation

    PubMed Central

    Rivas-Fuentes, Selma; Salgado-Aguayo, Alfonso; Pertuz Belloso, Silvana; Gorocica Rosete, Patricia; Alvarado-Vásquez, Noé; Aquino-Jarquin, Guillermo

    2015-01-01

    Non-small cell lung cancer (NSCLC) is one of the most common types of aggressive cancer. The tumor tissue, which shows an active angiogenesis, is composed of neoplastic and stromal cells, and an abundant inflammatory infiltrate. Angiogenesis is important to support tumor growth, while infiltrating cells contribute to the tumor microenvironment through the secretion of growth factors, cytokines and chemokines, important molecules in the progression of the disease. Chemokines are important in development, activation of the immune response, and physiological angiogenesis. Chemokines have emerged as important regulators in the pathophysiology of cancer. These molecules are involved in the angiogenesis/angiostasis balance and in the recruitment of tumor infiltrating hematopoietic cells. In addition, chemokines promote tumor cell survival, as well as the directing and establishment of tumor cells to metastasis sites. The findings summarized here emphasize the central role of chemokines as modulators of tumor angiogenesis and their potential role as therapeutic targets in the inflammatory process of NSCLC angiogenesis. PMID:26316890

  14. The potential diagnostic power of circulating tumor cell analysis for non-small-cell lung cancer.

    PubMed

    Ross, Kirsty; Pailler, Emma; Faugeroux, Vincent; Taylor, Melissa; Oulhen, Marianne; Auger, Nathalie; Planchard, David; Soria, Jean-Charles; Lindsay, Colin R; Besse, Benjamin; Vielh, Philippe; Farace, Françoise

    2015-01-01

    In non-small-cell lung cancer (NSCLC), genotyping tumor biopsies for targetable somatic alterations has become routine practice. However, serial biopsies have limitations: they may be technically difficult or impossible and could incur serious risks to patients. Circulating tumor cells (CTCs) offer an alternative source for tumor analysis that is easily accessible and presents the potential to identify predictive biomarkers to tailor therapies on a personalized basis. Examined here is our current knowledge of CTC detection and characterization in NSCLC and their potential role in EGFR-mutant, ALK-rearranged and ROS1-rearranged patients. This is followed by discussion of the ongoing issues such as the question of CTC partnership as diagnostic tools in NSCLC. PMID:26564313

  15. Cyclophosphamide or Denileukin Diftitox Followed By Expanding a Patient's Own T Cells in the Laboratory in Treating Patients With HER-2/Neu Overexpressing Metastatic Breast Cancer, Ovarian Cancer, or Non-Small Cell Lung