Science.gov

Sample records for adenosquamous cell lung

  1. Molecular profiling of lung adenosquamous carcinoma: hybrid or genuine type?

    PubMed Central

    Vassella, Erik; Langsch, Stephanie; Dettmer, Matthias S.; Schlup, Cornelia; Neuenschwander, Maja; Frattini, Milo; Gugger, Mathias; Schäfer, Stephan C.

    2015-01-01

    Lung adenosquamous carcinoma is a particular subtype of non-small cell lung carcinoma that is defined by the coexistence of adenocarcinoma and squamous cell carcinoma components. The aim of this study was to assess the mutational profile in each component of 16 adenosquamous carcinoma samples from a Caucasian population by a combination of next generation sequencing using the cancer hotspot panel as well as the colon and lung cancer panel and FISH. Identified mutations were confirmed by Sanger sequencing of DNA from cancer cells of each component collected by Laser Capture microdissection. Mutations typical for adenocarcinoma as well as squamous cell carcinoma were identified. Driver mutations were predominantly in the trunk suggesting a monoclonal origin of adenosquamous carcinoma. Most remarkably, EGFR mutations and mutations in the PI3K signaling pathway, which accounted for 30% and 25% of tumors respectively, were more prevalent while KRAS mutations were less prevalent than expected for a Caucasian population. Surprisingly, expression of classifier miR-205 was intermediate between that of classical adenocarcinoma and squamous cell carcinoma suggesting that adenosquamous carcinoma is a transitional stage between these tumor types. The high prevalence of therapy-relevant targets opens new options of therapeutic intervention for adenosquamous carcinoma patients. PMID:26068980

  2. Successful pemetrexed-containing chemotherapy for epidermal growth factor receptor mutation-positive adenosquamous cell carcinoma of the lung: A case report

    PubMed Central

    WATANABE, HIROKO; TAMURA, TOMOHIRO; KAGOHASHI, KATSUNORI; KAWAGUCHI, MIO; KURISHIMA, KOICHI; SATOH, HIROAKI

    2016-01-01

    Pemetrexed-containing chemotherapy has shown promise in the treatment of non-small-cell lung cancer (NSCLC). However, although adenosquamous cell lung cancer (ASCLC) is a type of NSCLC, the availability of studies investigating its response to pemetrexed-containing chemotherapy is limited. A 66-year-old woman was referred to Mito Medical Center, University of Tsukuba with hemoptysis and a chest computed tomography (CT) scan revealed a large cavitary mass in the lower lobe of the left lung. The patient underwent left lower lobectomy and mediastinal lymph node dissection. The tumor was staged as pT2bN2M0. An epidermal growth factor receptor (EGFR) exon 19 deletion was identified in the adenocarcinomatous as well as the squamous cell carcinomatous components. Despite gefitinib therapy for pulmonary metastases, the patient developed cavitary metastases in both lungs. Therefore, treatment with pemetrexed-containing chemotherapy was initiated. A chest CT scan revealed significant regression of the metastatic lesions in both lungs, with thinning of the walls. The patient remains well and recurrence-free 19 months after the initiation of pemetrexed-containing chemotherapy. Therefore, the clinical response of EGFR mutation-positive ASCLC to pemetrexed-containing chemotherapy was promising, suggesting pemetrexed to be one of the key drugs for this subset of ASCLC patients. PMID:27073680

  3. 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

  4. 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

  5. TPD52L1-ROS1, a new ROS1 fusion variant in lung adenosquamous cell carcinoma identified by comprehensive genomic profiling.

    PubMed

    Zhu, Viola Weijia; Upadhyay, Daya; Schrock, Alexa B; Gowen, Kyle; Ali, Siraj M; Ou, Sai-Hong Ignatius

    2016-07-01

    Crizotinib was approved for the treatment of ROS1-rearranged non-small cell lung cancer (NSCLC) patients in the US on 11 March, 2016. Interestingly no one companion diagnostic test (CDx) has been approved simultaneously with this approval of crizotinib. Hence, an ideal and adequate CDx will have to be able to identify ROS1 fusions without the knowledge of the fusion partners to ROS1, and as to date there are 13 fusion partners reported for ROS1 in NSCLC. Here we report a novel TPD52L1-ROS1 fusion variant in NSCLC. This novel TPD52L1-ROS1 fusion variant is generated by the fusion of exons 1-3 of TPD52L1 on chromosome 6q22-23 to the exons 33-43 of ROS1 on chromosome 6q22, likely from an intra-chromosomal deletion and subsequent fusion event similar to the generation of EML4-ALK. The predicted TPD52L1-ROS1 protein product contains 655 amino acids comprising of the N-terminal amino acids 1-95 of TPD52L1 and C-terminal amino acids of 1789-2348 of ROS1. In summary, TPD52L1-ROS1 is a novel ROS1 fusion variant in NSCLC identified by comprehensive genomic profiling and should be included in any ROS1 detecting assays that depend on identifying the corresponding fusion partners, such as reverse transcriptase-polymerase chain reaction (RT-PCR). PMID:27237027

  6. Screening for major driver oncogene alterations in adenosquamous lung carcinoma using PCR coupled with next-generation and Sanger sequencing methods

    PubMed Central

    Shi, Xiaohua; Wu, Huanwen; Lu, Junliang; Duan, Huanli; Liu, Xuguang; Liang, Zhiyong

    2016-01-01

    We investigated the frequency of major driver oncogenes in lung adenosquamous cell carcinoma (ASC) cases. Frequency of EGFR, K-Ras, B-Raf, PIK3CA, DDR2, ALK, and PDGFRA gene mutations was examined in 56 patients using next-generation sequencing, polymerase chain reaction, and Sanger sequencing. Macrodissection or microdissection was performed in 37 cases to separate the adenomatous and squamous components of ASC. The overall mutation rate was 64.29%, including 55.36%, 7.14%, and 1.79% for EGFR, K-Ras, and B-Raf mutations, respectively. PIK3CA mutation was detected in three cases; all involved coexisting EGFR mutations. Of the 37 cases, 34 were convergent in two components, while three showed EGFR mutations in the glandular components and three showed PIK3CA mutations in the squamous components. With respect to EGFR mutations, the number of young female patients, nonsmokers, and those with positive pleural invasion was higher in the mutation-positive group than that in the mutation-negative. K-Ras mutation was significantly associated with smoking. Overall survival in the different EGFR mutation groups differed significantly. The frequency and clinicopathological characteristics of EGFR- and K-Ras-mutated adenosquamous lung carcinoma were similar to that noted in Asian adenocarcinomas patients. The high convergence mutation rate in both adenomatous and squamous components suggests monoclonality in ASC. PMID:26923333

  7. 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

  8. 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

  9. 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

  10. 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

  11. A case of adenosquamous cell carcinoma of the gallbladder with markedly elevated PTHrP and G-CSF levels.

    PubMed

    Ueda, Kaoru; Kinoshita, Akiyoshi; Akasu, Takafumi; Hagiwara, Noriko; Yokota, Takeharu; Imai, Nami; Iwaku, Akira; Fushiya, Nao; Koike, Kazuhiko; Nishino, Hirokazu

    2016-09-01

    A 76-year-old woman was referred to our hospital with anorexia. Computed tomography revealed a tumor lesion measuring 110mm in the liver at S4/5 with calcification and swelling of a paraaortic lymph node. The gallbladder was not visualized. Histological examination of a biopsy specimen from the liver tumor revealed squamous cell and undifferentiated carcinomas, and several tumor markers were elevated. Therefore, we diagnosed the patient with gallbladder adenosquamous cell carcinoma T3N2M0 stage III. Because the serum parathyroid hormone-related protein (PTHrP) and granulocyte-colony stimulating factor (G-CSF) levels were significantly elevated, we suspected that PTHrP and G-CSF production occurred because of adenosquamous cell carcinoma in the gallbladder. We initiated chemotherapy with S-1. PMID:27593366

  12. Adenosquamous Cell Carcinoma of the Rectum in a Girl: First Case Reported and Review of the Literature.

    PubMed

    García, Natalia Á; Hernando Cubero, Jorge; Alonso Orduña, Vicente; Torrecilla Idoipe, Nerea; Calvo Escribano, Carlota; Fernandez Atuán, Rafael

    2015-08-01

    Adenosquamous carcinoma is a rare colorectal tumor with few cases described in the literature; no children have been reported. A 12-year-old-girl presented tenesmus, diarrhea, and iron deficiency anemia. Intestinal bowel disease was suspected, colonoscopy and biopsy were performed and the diagnosis was a squamous cell carcinoma. Chemoradiation therapy based on last colorectal cancer guidelines was started. Complete regression of the primary tumor was observed with lymph node progression. The pathology report of the lymphadenectomy revealed metastasis of adenosquamous carcinoma, although there was not any adenomatous component in the first biopsy. The patient presented progression with liver metastases, despite stable local disease due to response to first-line treatment of the squamous component. PMID:26181422

  13. Spindle and kinetochore associated complex subunit 1 regulates the proliferation of oral adenosquamous carcinoma CAL-27 cells in vitro

    PubMed Central

    2013-01-01

    Background The prognosis of oral squamous cell carcinoma is very poor due to local recurrence and metastasis. This study explores the molecular events involved in oral carcinoma with the goal of developing novel therapeutic strategies. The mitotic spindle is a complex mechanical apparatus required for the accurate segregation of sister chromosomes during mitosis. Spindle and kinetochore associated complex subunit 1 (SKA1) is a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation. In recent years, much attention has been focused on determining how SKA proteins interact with each other, as well as their biological role in cancer cells. However, the precise role of SKA1 in oral carcinoma remains unknown. Methods In order to investigate the role of SKA1 in oral cancer, we employed lentivirus-mediated shRNA to silence SKA1 expression in the CAL-27 human oral adenosquamous carcinoma cell line. Results Depletion of SKA1 in CAL-27 cells significantly decreased cell proliferation, as determined by MTT and colony formation assays. These results strongly demonstrate that reduced SKA1 protein levels may cause inhibition of tumor formation. The shRNA-mediated depletion of SKA1 also led to G2/M phase cell cycle arrest and apoptosis. Conclusion This is the first report to show that SKA1 plays an important role in the progression of oral adenosqamous carcinoma. Thus, silencing of SKA1 by RNAi might be a potential therapy for this disease. PMID:23962337

  14. 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 ...

  15. 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 ...

  16. 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

  17. Metastatic gallbladder adenosquamous carcinoma to the skin†

    PubMed Central

    Lupinacci, Renato Micelli; Santana, André; Dias, André Roncon

    2014-01-01

    Cutaneous metastasis (CM) is an uncommon manifestation of visceral malignancies. Adenosquamous carcinoma of the gallbladder is a rare variation in gallbladder carcinoma (GBC), associated with worse prognosis. We present the case of a 56-year-old woman who presented with an inflamed lump on her abdominal wall. Computed tomography (CT) revealed a large mass from the gallbladder invading the abdominal wall. She underwent liver resection with regional lymphadenectomy. Pathology analysis revealed a 12-cm pT3N0 GBC. Hospital discharge occurred at post-operative Day 20. She recurred and died 10 months after surgery. Survival after the diagnosis of CM is dismal. The present case was a diagnostic trap. First, the patient's skin lesion presented as a cutaneous abscess and biopsy revealed a squamous cell cancer. A CT scan suggested a continuous mass involving the abdominal wall. CM was only suspected during surgery when no continuity between the tumour and the abdominal wall was identified. PMID:25480835

  18. Lung Cell Oxidant Injury

    PubMed Central

    Suttorp, Norbert; Simon, Lawrence M.

    1982-01-01

    The oxidant damage of lung tissue during in vivo hyperoxic exposure appears to be amplified by neutrophils that release toxic amounts of oxygen metabolites. In our studies cloned lung epithelial cells (L2 cells), lung fibroblasts, and pulmonary artery endothelial cells were cultured under either ambient (Po2 ∼ 140 torr) or hyperoxic (Po2 ∼ 630 torr) conditions for 48 h (24 h for endothelial cells). After cultivation, phorbol myristate acetate- or opsonized zymosan-stimulated neutrophils were added to the cultivated monolayers for 4 h, and lung cell damage was quantitated using 51Cr release as an index. The data show that stimulated neutrophils are able to injure the three lung cell lines tested, with endothelial cells being highly susceptible to this injury and L2 cells being slightly more susceptible than lung fibroblasts. The studies also demonstrate that all three lung cell lines exposed to sustained hyperoxia are more susceptible to neutrophil-mediated cytotoxicity than their time-matched air controls. Hydrogen peroxide was the main toxic oxygen metabolite because catalase (2,500 U/ml) completely protected the target cells. Equivalent quantities of hydrogen peroxide generated by glucose oxidase instead of by neutrophils gave a similar degree of target cell injury. Superoxide dismutase at high concentrations (250 μg/ml) provided some protection. Other systems that detoxify oxygen metabolites were without protective effect. These findings indicate that the increase in susceptibility of lung cells to neutrophil-mediated oxidant damage is a toxic effect of hyperoxia on lung cells. This specific manifestation of oxygen damage provides insight into the integration between primary mechanisms (oxygen exposure) and secondary mechanisms (release of oxygen metabolites by neutrophils) with respect to the cellular basis for pulmonary oxygen toxicity. PMID:6284800

  19. 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 ...

  20. Intracardiac Metastasis From Non-Small Cell Lung Cancer

    PubMed Central

    Verma, Vivek; Talmon, Geoffrey A.; Zhen, Weining K.

    2015-01-01

    A 56-year-old female with history of stage IIA adenosquamous lung carcinoma treated 13 months prior to presentation with lobectomy, mediastinal lymph node dissection, and adjuvant chemotherapy, presented for several weeks of worsening dyspnea. Exam was non-focal aside from tachycardia. Computed tomography of the chest revealed a large 4 cm × 5 cm mass in the bilateral ventricular myocardium. There was also evidence of metastatic disease elsewhere in the body, including a supraclavicular lymph node that was positive for metastatic adenosquamous lung carcinoma. She started whole heart radiotherapy and was to commence chemotherapy but passed away. This report discusses important aspects of diagnosis of this not uncommon condition that many oncologists may come across. We also discuss differential diagnosis of an isolated intracardiac mass as first-diagnosis presentations, and discuss the great importance of multidisciplinary cardio-oncologic management and clinical prioritization. PMID:26258073

  1. CD10/NEP in non-small cell lung carcinomas. Relationship to cellular proliferation.

    PubMed Central

    Ganju, R K; Sunday, M; Tsarwhas, D G; Card, A; Shipp, M A

    1994-01-01

    The cell surface metalloproteinase CD10/neutral endopeptidase 24.11 (NEP) hydrolyzes a variety of peptide substrates and reduces cellular responses to specific peptide hormones. Because CD10/NEP modulates peptide-mediated proliferation of small cell carcinomas of the lung (SCLC) and normal fetal bronchial epithelium, we evaluated the enzyme's expression in non-small cell lung carcinomas (NSCLC). Bronchoalveolar and large cell carcinoma cell lines had low levels of CD10/NEP expression whereas squamous, adenosquamous, and adenocarcinoma cell lines had higher and more variable levels of the cell surface enzyme. Regional variations in CD10/NEP immunostaining in primary NSCLC specimens prompted us to correlate CD10/NEP expression with cell growth. In primary carcinomas of the lung, clonal NSCLC cell lines and SV40-transformed fetal airway epithelium, subsets of cells expressed primarily CD10/NEP or the proliferating cell nuclear antigen (PCNA). Cultured airway epithelial cells had the lowest levels of CD10/NEP expression when the highest percentage of cells were actively dividing; in addition, these cells grew more rapidly when cell surface CD10/NEP was inhibited. NSCLC cell lines had receptors for a variety of mitogenic peptides known to be CD10/NEP substrates, underscoring the functional significance of growth-related variability in CD10/NEP expression. Images PMID:7962523

  2. Ciliated Adenosquamous Carcinoma: Expanding the Phenotypic Diversity of Human Papillomavirus-Associated Tumors.

    PubMed

    Radkay-Gonzalez, Lisa; Faquin, William; McHugh, Jonathan B; Lewis, James S; Tuluc, Madalina; Seethala, Raja R

    2016-06-01

    This study describes a unique subset of ciliated, human papillomavirus (HPV) related, adenosquamous carcinomas (AsqCA) of the head and neck that in contrast to most AsqCA, often show areas with lower grade cytonuclear features. They are comprised of largely non-keratinizing squamous cell carcinoma components with cystic change, gland formation, mucin production, and cilia in tumor cells. Seven cases of ciliated AsqCA were retrieved. Site distribution was as follows: palatine tonsil-3/7, base of tongue-1/7, and neck (unknown primary site)-3/7. Despite the occasional resemblance to mucoepidermoid carcinoma (MEC), the tumors showed focal keratinizing morphology and atypia, and all tumors were negative for MAML2 rearrangements. Oropharyngeal and neck tumors were uniformly p16 positive and showed punctate staining by in situ hybridization for high risk HPV DNA. There were two distant metastases (lung), and one tumor related death. Thus, ciliated AsqCA are HPV-associated lesions that pose unique pitfalls, closely mimicking MEC and other salivary gland tumors. These tumors add to the list of those which defy the dogma that ciliated epithelium always equates to a benign process. PMID:26411881

  3. 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

  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. Codon 12 Ki-ras mutation in non-small-cell lung cancer: comparative evaluation in tumoural and non-tumoural lung.

    PubMed Central

    Urban, T.; Ricci, S.; Lacave, R.; Antoine, M.; Kambouchner, M.; Capron, F.; Bernaudin, J. F.

    1996-01-01

    Ki-ras activation by point mutation on codon 12 has been reported in non-small-cell lung carcinomas and in various models of experimental lung tumours induced by chemical carcinogens. The cellular targets for carcinogenic compounds of tobacco smoke are usually considered to be the cells of the bronchial mucosa or alveolar epithelium. However, little is known about preneoplastic events in bronchopulmonary carcinogenesis. The hypothesis of the presence of widespread target cells containing Ki-ras mutation was investigated by evaluating concurrent neoplastic and non-neoplastic bronchial and alveolar samples from 51 patients with non-small-cell lung carcinomas. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method used can detect one cell with a mutation on codon 12 among 10(2) normal cells. In tumour samples, a mutation was detected in 20% of adenocarcinomas, but in none of the adenosquamous or squamous cell carcinomas. No mutation was detected in the non-neoplastic bronchial or parenchymal samples. When using an enriched PCR-RFLP method detecting one mutated allele among 10(3) normal alleles a mutation was detected in 23% of adenocarcinomas. In conclusion, Ki-ras activation by mutation on codon 12 was not observed in non-neoplastic bronchial or parenchymal tissues in patients with bronchopulmonary cancers and does not appear to be a genetic event present in non-malignant epithelial target cells exposed to tobacco smoke. Images Figure 1 Figure 2 Figure 3 PMID:8855973

  6. Adenosquamous carcinoma arising from a thyroglossal duct cyst: A case report

    PubMed Central

    CHANG, YU-SUNG; SU, HSIN-HAO; HO, SZU-PEI

    2016-01-01

    The current study describes a case of adenosquamous carcinoma originating from a thyroglossal duct cyst (TGDC). A 77-year-old man presented with an asymptomatic mass in the left mid-neck, which was soft and mobile on palpation. Fine-needle aspiration was performed, but cytology did not detect any malignant cells. Computed tomography demonstrated a single cystic lesion in the left lobe of the thyroid gland; therefore, surgery was performed on the suspected thyroid cyst. However, it was identified intraoperatively that the lesion was separated from the thyroid gland and instead adhered to an additional hyoid bone; therefore, the Sistrunk procedure was performed. Histopathological examination of the resected tumor confirmed the diagnosis of adenosquamous carcinoma originating from a TGDC. Carcinoma arising from a TGDC is rare, and accounts for 1% of all TGDC cases. The most common subtype of carcinoma associated with TGDC is papillary carcinoma, whilst adenosquamous carcinoma developing from a TGDC is extremely rare, with only one case currently reported in the literature. Although a consensus for the management of this disease has not yet been established, adequate surgical excision with long-term follow-up is currently the preferred treatment. PMID:27073536

  7. [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

  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. Stem Cells and Lung Regeneration

    PubMed Central

    El-Badrawy, Mohammad K.; Shalabi, Nesrein M.; Mohamed, Mie A.; Ragab, Amany; Abdelwahab, Heba Wagih

    2016-01-01

    Background:Tissues such as the lung, liver, and pancreas that have a low steady-state cell turnover yet can respond robustly after injury to replace damaged cells. The airway epithelium is exposed to inhaled particles and pathogens that may lead to the development of a many infectious and inflammatory respiratory diseases. Lung transplantation is an accepted modality of treatment for end-stage lung diseases. Since the early 1990 s, more than 26,000 lung transplants have been performed at centers worldwide. However, the availability of donor tissues and organs is limited, which presents a serious limitation for widespread transplantation surgery. The appearance of bioengineered lung and tracheal tissue transplants is considered a promising alternative to the classical transplantation of donor organ/tissue. Stem cells therapy arises as a new therapeutic approach, with a wide application potential. PMID:27426083

  10. 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 ...

  11. 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 ...

  12. 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

  13. Regulation of neutrophil gelatinase-associated lipocalin expression by C/EBPβ in lung carcinoma cells

    PubMed Central

    ZHANG, PI-XIAN; CHANG, JING-XIA; XIE, JIAN-JUN; YUAN, HUA-MIN; DU, ZE-PENG; ZHANG, FA-REN; LÜ, ZHUO; XU, LI-YAN; LI1, EN-MIN

    2012-01-01

    Neutrophil gelatinase-associated lipocalin (NGAL), a member of the lipocalin family, has been found to be overexpressed in a variety of tumors, including lung adenocarcinomas. However, the mechanism by which NGAL expression is regulated in lung carcinoma needs further evaluation. In this study, immunohistochemistry was employed to analyze the expression of NGAL in lung carcinoma tissue samples, including lung squamous carcinomas, adenocarcinomas, adenosquamous carcinomas and bronchial alveolar cell carcinomas. The results showed that NGAL was expressed in 82.61% (19/23) of the samples. RT-PCR and immunofluorescent staining showed that NGAL was localized to the cytoplasm in lung carcinoma cell lines. To explore the transcriptional regulation mechanism of NGAL basal expression in lung carcinoma, a 1515-bp fragment (−1431 to +84) of the NGAL promoter region was cloned and a series of deletion and mutation constructs were generated. These constructs were analyzed using the luciferase reporter assay. The results indicated that the cis-acting elements important for the basal activity of NGAL transcription were likely located between −152 and −141. Further analysis using site-directed mutagenesis and the luciferase reporter assay suggested that the C/EBP binding sites were responsible for the activity of the NGAL promoter. Finally, the binding ability and specificity of the transcription factors were determined by electrophoretic mobility-shift assay (EMSA). The results showed that C/EBPβ was able to bind to the −152 and −141 segments. Taken together, these findings suggest that NGAL is expressed in lung carcinomas and that NGAL expression is mediated by the binding of C/EBPβ to the −152 and −141 segment of the NGAL promoter. PMID:23162623

  14. Antisense bcl-2 treatment increases programmed cell death in non-small cell lung cancer cell lines.

    PubMed

    Koty, P P; Zhang, H; Levitt, M L

    1999-02-01

    Programmed cell death (PCD) is a genetically regulated pathway that is altered in many cancers. This process is, in part, regulated by the ratio of PCD inducers (Bax) or inhibitors (Bcl-2). An abnormally high ratio of Bcl-2 to Bax prevents PCD, thus contributing to resistance to chemotherapeutic agents, many of which are capable of inducing PCD. Non-small cell lung cancer (NSCLC) cells demonstrate resistance to these PCD-inducing agents. If Bcl-2 prevents NSCLC cells from entering the PCD pathway, then reducing the amount of endogenous Bcl-2 product may allow these cells to spontaneously enter the PCD pathway. Our purpose was to determine the effects of bcl-2 antisense treatment on the levels of programmed cell death in NSCLC cells. First, we determined whether bcl-2 and bax mRNA were expressed in three morphologically distinct NSCLC cell lines: NCI-H226 (squamous), NCI-H358 (adenocarcinoma), and NCI-H596 (adenosquamous). Cells were then exposed to synthetic antisense bcl-2 oligonucleotide treatment, after which programmed cell death was determined, as evidenced by DNA fragmentation. Bcl-2 protein expression was detected immunohistochemically. All three NSCLC cell lines expressed both bcl-2 and bax mRNA and had functional PCD pathways. Synthetic antisense bcl-2 oligonucleotide treatment resulted in decreased Bcl-2 levels, reduced cell proliferation, decreased cell viability, and increased levels of spontaneous PCD. This represents the first evidence that decreasing Bcl-2 in three morphologically distinct NSCLC cell lines allows the cells to spontaneously enter a PCD pathway. It also indicates the potential therapeutic use of antisense bcl-2 in the treatment of NSCLC. PMID:10217615

  15. Intraluminal superior vena cava metastasis from adenosquamous carcinoma of the duodenum: A case report

    PubMed Central

    TAKAYOSHI, KOTOE; ARIYAMA, HIROSHI; TAMURA, SHINGO; YODA, SHUNSUKE; ARITA, TAKESHI; YAMAGUCHI, TOSHIHIRO; OZONO, KEIGO; YAMAMOTO, HIDETAKA; INADOMI, KYOKO; KUMAGAI, HOZUMI; TANAKA, MAMORU; OKUMURA, YUTA; SAGARA, KOSUKE; NIO, KENTA; NAKANO, MICHITAKA; ARITA, SHUJI; KUSABA, HITOSHI; ODASHIRO, KEITA; ODA, YOSHINAO; AKASHI, KOICHI; BABA, EISHI

    2016-01-01

    In 2013, a 76-year-old male with a cardiac pacemaker was diagnosed with adenosquamous carcinoma of the duodenum. Subsequently, a pancreatoduodenectomy and lymph node dissection were performed, and 12 cycles of adjuvant chemotherapy (modified FOLFOX6 regimen), which consisted of fluorouracil, leucovorin and oxaliplatin, were administered via a central venous catheter. At 5 months after the completion of adjuvant chemotherapy, the patient experienced the sudden onset of severe pain at the back right of the ear, edema of the right side of the face and right jugular vein dilatation. Computed tomography (CT) revealed filling defects in the superior vena cava (SVC) and right brachiocephalic vein, indicating catheter-induced venous thrombosis. Although the catheter was removed and anti-coagulation therapy, aspiration of the thrombosis and ballooning dilatation were performed immediately, the patient's symptoms were not ameliorated. Notably, histological examination following thrombus aspiration revealed metastatic cancer cells, and fluorodeoxyglucose-positron emission tomography/CT identified metabolically active nodules in the SVC at locations consistent with the initial duodenal tumors detected by CT and in the first thoracic vertebrae. The tumor thrombus rapidly increased in size and resulted in worsening dyspnea. Subsequently, radiotherapy was performed, followed by chemotherapy, which relieved the systemic symptoms and suppressed the tumor growth. Adenosquamous carcinoma of the duodenum is extremely rare, and to the best of our knowledge, intraluminal SVC metastasis as a result of adenosquamous carcinoma of the duodenum has not been reported previously. The placement of a cardiac pacemaker, central venous catheter and tumor cells possessing high metastatic potential are hypothesized to have contributed to this rare case of metastasis. PMID:26870254

  16. Characteristics and Outcomes of Adenosquamous Carcinoma of the Pancreas

    PubMed Central

    Simone, Christine G.; Zuluaga Toro, Tania; Chan, Ellie; Feely, Michael M.; Trevino, Jose G.

    2013-01-01

    ABSTRACT BACKGROUND: Adenosquamous carcinoma of the pancreas (ASCAP) is a rare histologic type of pancreatic carcinoma that constitutes 1% to 4% of all pancreatic exocrine malignancies. It has a clinical presentation similar to that of adenocarcinoma of the pancreas (ACP), but may have a worse overall prognosis, with most patients surviving for less than 2 years. METHODS: This was an institutional, retrospective, cohort analysis of 237 patients who underwent resection of pancreatic cancer with curative intent. RESULTS: Of the 237 cases examined, we identified 7 (2.9%) with histologically confirmed ASCAP. Demographics, comorbidities, risk factors, presenting symptoms, survival data, tumor characteristics, and types of treatment for each patient were included in the analysis. Risk factors for development of ASCAP were not conclusive. Although human papilloma virus (HPV) has been implicated in other squamous cell cancers, in our cohort, its involvement in ASCAP was 0%. Presurgical fine-needle aspiration failed to identify the invasive squamous cell component in all cases. In this cohort analysis, overall survival ranged from 3 to 25 months, with 2 patients surviving more than 20 months after surgical resection. With a median follow-up of 2.9 years, our data demonstrate a trend to worse median overall survival for ASCAP than for ACP (8.2 vs. 20.4 months; P = .23), with a limited number of long-term survivors. CONCLUSIONS: Although recommended, adjuvant treatment was inconsistently provided for patients in this ASCAP cohort. Published data show variability in overall survival, but our findings support that surgical resection is one of the few options for control of this rare, poorly understood pancreatic malignancy. Further research is necessary to define risk factors and adjuvant and neoadjuvant treatments, to help improve patient outcomes. PMID:23936547

  17. Effect of suramin on squamous differentiation and apoptosis in three human non-small-cell lung cancer cell lines.

    PubMed

    Lokshin, A; Levitt, M L

    1996-01-01

    Non-small cell lung cancer (NSCLC) is fatal in approximately 90% of all cases due to the failure of systemic therapy, secondary to resistance to chemotherapy. In such malignancies new therapeutic paradigms are needed. One such approach takes advantage of normal physiologic growth regulatory mechanisms, such as terminal cellular differentiation or apoptosis. Suramin, as an antineoplastic drug, has shown efficacy in the treatment of prostate cancer and is capable of promoting differentiation in several human cancer cell lines. Little is known about the differentiating effects of suramin in lung cancer. In the present investigation we evaluated the ability of suramin to induce cross-linked envelope (CLE) formation, as a common marker for squamous differentiation and apoptosis, in three representative human non-small cell lung cancer cell lines: NCI-H226 (squamous), NCI-H358 (bronchoalveolar [adenocarcinoma]), and NCI-H596 (adenosquamous). Among agents that we have tested, suramin demonstrated the unique ability to induce spontaneous CLE formation in the two cell lines with squamous features, NCI-H226 and NCI-H596. Suramin induced CLE formation was accompanied by DNA fragmentation, a marker for apoptosis, in NCI-H596 and NCI-H358, but not in NCI-H226. Stimulation of CLE formation by suramin correlated with the rapid induction of both type II transglutaminase (TG) activity and involucrin expression. These parameters were protein synthesis independent, suggesting posttranslational mechanisms of suramin activity. Induction of differentiation/apoptosis markers by suramin did not correlate with its effect on growth. Modulation of signal transduction is a likely candidate mechanism for suramin activity in lung cancer. The relationship between growth, squamous differentiation, and apoptosis is considered. PMID:8806101

  18. Stem Cells in the Lung

    PubMed Central

    Liu, Xiaoming; Driskell, Ryan R.; Engelhardt, John F.

    2007-01-01

    The lung is composed of two major anatomically distinct regions—the conducting airways and gas-exchanging airspaces. From a cell biology standpoint, the conducting airways can be further divided into two major compartments, the tracheobronchial and bronchiolar airways, while the alveolar regions of the lung make up the gas-exchanging airspaces. Each of these regions consists of distinct epithelial cell types with unique cellular physiologies and stem cell compartments. This chapter focuses on model systems with which to study stem cells in the adult tracheobronchial airways, also referred to as the proximal airway of the lung. Important in such models is an appreciation for the diversity of stem cell niches in the conducting airways that provide localized environmental signals to both maintain and mobilize stem cells in the setting of airway injury and normal cellular turnover. Because cellular turnover in airways is relatively slow, methods for analysis of stem cells in vivo have required prior injury to the lung. In contrast, ex vivo and in vitro models for analysis of airway stem cells have used genetic markers to track lineage relationships together with reconstitution systems that mimic airway biology. Over the past decades, several widely acceptable methods have been developed and used in the characterization of adult airway stem/ progenitor cells. These include localization of label-retaining cells (LRCs), retroviral tagging of epithelial cells seeded into xenografts, air–liquid interface cultures to track clonal proliferative potential, and multiple transgenic mouse models. This chapter reviews the biologic context and use of these models while providing detailed methods for several of the more broadly useful models for studying adult airway stem/progenitor cell types. PMID:17141060

  19. 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 ...

  20. The omega-hydroxy palmitic acid induced apoptosis in human lung carcinoma cell lines H596 and A549.

    PubMed

    Abe, Akihisa; Yamane, Mototeru; Yamada, Hiroyuki; Sugawara, Isamu

    2002-02-01

    We have found that omega-hydroxy palmitic acid (16-hydroxy palmitic acid, omega-HPA) has both cell growth inhibiting and cell death inducing actions on human lung adenosquamous carcinoma cell line H596 and adenocarcinoma cell line A549. Further, these effects were dose- and time-dependent in both cell lines. However, in squamous carcinoma cell line H226, omega-HPA had no cytotoxic effect. On the other hand, in the human small cell lung carcinoma (SCLC) cell line H128, this compound showed weak cytotoxicity. The sensitivity toward omega-HPA was higher in H596 cells than in A549 cells. In both H596 and A549 cells, cell growth was inhibited to 24.4 and 9.4%, respectively, by treatment with 100 microM omega-HPA for 12 h. In the 24 h treatment cells, growth inhibition was increased to 100 and 38.1%, respectively. In cytotoxicity experiments, the number of dead cells increased with incubation times in the presence of omega-HPA: on three days incubation with 100 microM omega-HPA, viability was 0 and 13.5%, respectively, in H596 and A549 cells. Further, the fragmentation of DNA to oligonucleosomal-sized ladder fragments, which is an index of apoptosis, was observed in both cell lines on treatment with omega-HPA. Therefore, it is assumed that these cell deaths induced by omega-HPA, were apoptosis in these cell lines. Since the number of dead cells following treatment with omega-HPA decreased by treatment with omega-HPA in combination with Z-VAD-fmk, a caspase family inhibitor, it is thought that apoptotic cell death was related to caspase activity. PMID:12186781

  1. Fever as a first manifestation of advanced gastric adenosquamous carcinoma: A case report

    PubMed Central

    Ajoodhea, Harsha; Zhang, Ren-Chao; Xu, Xiao-Wu; Jin, Wei-Wei; Chen, Ke; He, Yong-Tao; Mou, Yi-Ping

    2014-01-01

    Gastric adenosquamous carcinoma (ASC) is a rare type of gastric cancer. It is a mixed neoplasm, consisting of glandular cells and squamous cells. It is often diagnosed at an advanced stage, thus carrying a poor prognosis. We describe a case of a 73-year-old male, who presented with refractory fever and an intra-abdominal mass on imaging. He underwent a laparoscopic exploration followed by a successful totally laparoscopic total gastrectomy with D2 lymphadenectomy for gastric cancer. Postoperative pathology revealed primary gastric ASC (T4aN0M0). The patient received adjuvant radiotherapy and chemotherapy with S1 and is alive 20 mo after surgery without recurrence. This is the first case of advanced gastric ASC with fever as the initial presentation treated with totally laparoscopic total gastrectomy reported in the English literature. PMID:25110448

  2. Dendritic cells in lung immunopathology.

    PubMed

    Cook, Peter C; MacDonald, Andrew S

    2016-07-01

    Dendritic cells (DCs) lie at the heart of the innate immune system, specialised at recognising danger signals in many forms including foreign material, infection or tissue damage and initiating powerful adaptive immune and inflammatory responses. In barrier sites such as the lung, the instrumental role that DCs play at the interface between the environment and the host places them in a pivotal position in determining the severity of inflammatory disease. The past few years has seen a significant increase in our fundamental understanding of the subsets of DCs involved in pulmonary immunity, as well as the mechanisms by which they are activated and which they may use to coordinate downstream inflammation and pathology. In this review, we will summarise current understanding of the multi-faceted role that DCs play in the induction, maintenance and regulation of lung immunopathology, with an emphasis on allergic pulmonary disease. PMID:27256370

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

    PubMed

    Schilders, Kim A A; Eenjes, Evelien; van Riet, Sander; Poot, André A; Stamatialis, Dimitrios; Truckenmüller, Roman; Hiemstra, Pieter S; Rottier, Robbert J

    2016-01-01

    Inspired by the increasing burden of lung associated diseases in society and an growing demand to accommodate patients, great efforts by the scientific community produce an increasing stream of data that are focused on delineating the basic principles of lung development and growth, as well as understanding the biomechanical properties to build artificial lung devices. In addition, the continuing efforts to better define the disease origin, progression and pathology by basic scientists and clinicians contributes to insights in the basic principles of lung biology. However, the use of different model systems, experimental approaches and readout systems may generate somewhat conflicting or contradictory results. In an effort to summarize the latest developments in the lung epithelial stem cell biology, we provide an overview of the current status of the field. We first describe the different stem cells, or progenitor cells, residing in the homeostatic lung. Next, we focus on the plasticity of the different cell types upon several injury-induced activation or repair models, and highlight the regenerative capacity of lung cells. Lastly, we summarize the generation of lung mimics, such as air-liquid interface cultures, organoids and lung on a chip, that are required to test emerging hypotheses. Moreover, the increasing collaboration between distinct specializations will contribute to the eventual development of an artificial lung device capable of assisting reduced lung function and capacity in human patients. PMID:27107715

  4. Stem cells and repair of lung injuries

    PubMed Central

    Neuringer, Isabel P; Randell, Scott H

    2004-01-01

    Fueled by the promise of regenerative medicine, currently there is unprecedented interest in stem cells. Furthermore, there have been revolutionary, but somewhat controversial, advances in our understanding of stem cell biology. Stem cells likely play key roles in the repair of diverse lung injuries. However, due to very low rates of cellular proliferation in vivo in the normal steady state, cellular and architectural complexity of the respiratory tract, and the lack of an intensive research effort, lung stem cells remain poorly understood compared to those in other major organ systems. In the present review, we concisely explore the conceptual framework of stem cell biology and recent advances pertinent to the lungs. We illustrate lung diseases in which manipulation of stem cells may be physiologically significant and highlight the challenges facing stem cell-related therapy in the lung. PMID:15285789

  5. 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

  6. Adult stem cells underlying lung regeneration

    PubMed Central

    2012-01-01

    Despite the massive toll in human suffering imparted by degenerative lung disease, including COPD, idiopathic pulmonary fibrosis and ARDS, the scientific community has been surprisingly agnostic regarding the potential of lung tissue and, in particular, the alveoli, to regenerate. However, there is circumstantial evidence in humans and direct evidence in mice that ARDS triggers robust regeneration of lung tissue rather than irreversible fibrosis. The stem cells responsible for this remarkable regenerative process has garnered tremendous attention, most recently yielding a defined set of cloned human airway stem cells marked by p63 expression but with distinct commitment to differentiated cell types typical of the upper or lower airways, the latter of which include alveoli-like structures in vitro and in vivo. These recent advances in lung regeneration and distal airway stem cells and the potential of associated soluble factors in regeneration must be harnessed for therapeutic options in chronic lung disease. PMID:22333577

  7. 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 ...

  8. 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

  9. Adult stem cells for chronic lung diseases.

    PubMed

    Mora, Ana L; Rojas, Mauricio

    2013-10-01

    Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are chronic, progressive and lethal lung diseases. The incidence of IPF and COPD increases with age, independent of exposure to common environmental risk factors. At present, there is limited understanding of the relationship between ageing and the development of chronic lung diseases. One hypothesis is that chronic injury drives to exhaustion the local and systemic repair responses in the lung. These changes are accentuated during ageing where there is a progressive accumulation of senescent cells. Recently, stem cells have emerged as a critical reparative mechanism for lung injury. In this review, we discuss the repair response of bone marrow-derived mesenchymal stem cells (B-MSC) after lung injury and how their function is affected by ageing. Our own work has demonstrated a protective role of B-MSC in several animal models of acute and chronic lung injury. We recently demonstrated the association, using animal models, between age and an increase in the susceptibility to develop severe injury and fibrosis. At the same time, we have identified functional differences between B-MSC isolated from young and old animals. Further studies are required to understand the functional impairment of ageing B-MSC, ultimately leading to a rapid stem cell depletion or fatigue, interfering with their ability to play a protective role in lung injury. The elucidation of these events will help in the development of rational and new therapeutic strategies for COPD and IPF. PMID:23648014

  10. Marrow cells as progenitors of lung tissue.

    PubMed

    Fine, Alan

    2004-01-01

    There is accumulating evidence showing that marrow-derived cells can engraft as differentiated epithelial cells of various tissues, including the lung. These findings challenge long-held views regarding the basic biology of stem cells. Elucidating the fundamental mechanisms controlling these processes is the major challenge of this field. Regardless, these experiments suggest new strategies for the treatment of chronic diseases. PMID:14757420

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

    PubMed

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

    2016-04-01

    Lung tissue exposure to ionizing irradiation can invariably occur during the treatment of a variety of cancers leading to increased risk of radiation-induced lung disease (RILD). Mesenchymal stem cells (MSCs) possess the potential to differentiate into epithelial cells. However, cell culture methods of primary type II pneumocytes are slow and cannot provide a sufficient number of cells to regenerate damaged lungs. Moreover, effects of ablative radiation doses on the ability of MSCs to differentiate in vitro into lung cells have not been investigated yet. Therefore, an in vitro coculture system was used, where MSCs were physically separated from dissociated lung tissue obtained from either healthy or high ablative doses of 16 or 20 Gy whole thorax irradiated rats. Around 10±5% and 20±3% of cocultured MSCs demonstrated a change into lung-specific Clara and type II pneumocyte cells when MSCs were cocultured with healthy lung tissue. Interestingly, in cocultures with irradiated lung biopsies, the percentage of MSCs changed into Clara and type II pneumocytes cells increased to 40±7% and 50±6% at 16 Gy irradiation dose and 30±5% and 40±8% at 20 Gy irradiation dose, respectively. These data suggest that MSCs to lung cell differentiation is possible without cell fusion. In addition, 16 and 20 Gy whole thorax irradiation doses that can cause varying levels of RILD, induced different percentages of MSCs to adopt lung cell phenotype compared with healthy lung tissue, providing encouraging outlook for RILD therapeutic intervention for ablative radiotherapy prescriptions. PMID:26200842

  12. 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

  13. Mesenchymal stem cells and inflammatory lung diseases.

    PubMed

    Iyer, S S; Co, C; Rojas, M

    2009-03-01

    Mesenchymal stem cells (MSCs) are emerging as a therapeutic modality in various inflammatory disease states. A number of ongoing randomized Phase I/II clinical trials are evaluating the effects of allogeneic MSC infusion in patients with multiple sclerosis, graft-versus-host disease, Crohn's disease, and severe chronic myocardial ischemia. MSCs are also being considered as a potential therapy in patients with inflammatory lung diseases. Several studies, including our own, have demonstrated compelling benefits from the administration of MSCs in animal models of lung injury. These studies are leading to growing interest in the therapeutic use of MSCs in inflammatory lung diseases. In this Review, we describe how the immunoregulatory effects of MSCs can confer substantial protection in the setting of lung diseases such as acute lung injury, chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. We also address potential pitfalls related to the therapeutic use of MSCs in fibrotic lung diseases such as idiopathic pulmonary fibrosis. In addition, we identify emerging areas for MSC- based therapies in modulating oxidative stress and in attenuating inflammation in alcohol-related acute lung injury. PMID:19352305

  14. Stem cells--potential for repairing damaged lungs and growing human lungs for transplant.

    PubMed

    Bishop, Anne E; Rippon, Helen J

    2006-08-01

    Repair or regeneration of defective lung epithelium would be of great therapeutic potential. It is estimated by the British Lung Foundation that 1 in 7 people in the UK is affected by a lung disease and that 1 in 4 admissions to children's wards are as a result of respiratory problems. Potential cellular sources for the regeneration of lung tissue in vivo or lung tissue engineering in vitro include endogenous pulmonary epithelial stem cells, extrapulmonary circulating stem cells and embryonic stem cells. This article discusses the potential role of each of these stem cell types in future approaches to the treatment of lung injury and disease. PMID:16856797

  15. 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

  16. Obstructive jaundice in small cell lung carcinoma.

    PubMed

    Mokhtar Pour, Ali; Masir, Noraidah; Isa, Mohd Rose

    2015-08-01

    Small cell lung carcinoma (SCLC) commonly metastasizes to distant organs. However, metastasis to the pancreas is not a common event. Moreover, obstructive jaundice as a first clinical presentation of SCLC is extremely unusual. This case reports a 51-year-old male with SCLC, manifesting with obstructive jaundice as the initial clinical presentation. Endoscopic retrograde cholangiopancreatograghy (ERCP) and abdominal computed tomography (CT) scan showed a mass at the head of the pancreas. The patient underwent pancreatoduodenectomy (Whipple procedure). Histopathology revealed a chromogranin- A-positive poorly-differentiated neuroendocrine carcinoma of the pancreas. No imaging study of the lung was performed before surgery. A few months later, a follow-up CT revealed unilateral lung nodules with ipsilateral hilar nodes. A lung biopsy was done and histopathology reported a TTF- 1-positive, chromogranin A-positive, small cell carcinoma of the lung. On review, the pancreatic tumour was also TTF-1-positive. He was then treated with combination chemotherapy (cisplatin, etoposide). These findings highlight that presentation of a mass at the head of pancreas could be a manifestation of a metastatic tumour from elsewhere such as the lung, and thorough investigations should be performed before metastases can be ruled out. PMID:26277673

  17. Lung function in sickle cell disease.

    PubMed

    Koumbourlis, Anastassios C

    2014-03-01

    Although some of the most severe complications of Sickle Cell Disease (SCD) tend to be acute and severe (e.g. acute chest syndrome, stroke etc.), the chronic ones can be equally debilitating. Prominent among them is the effect that the disease has on lung growth and function. For many years the traditional teaching has been that SCD is associated with the development of a restrictive lung defect. However, there is increasing evidence that this is not a universal finding and that at least during childhood and adolescence, the majority of the patients have a normal or obstructive pattern of lung function. The following article reviews the current knowledge on the effects of SCD on lung growth and function. Special emphasis is given to the controversies among the published articles in the literature and discusses possible causes for these discrepancies. PMID:24268618

  18. Volcanic ash: toxicity to isolated lung cells.

    PubMed

    Castranova, V; Bowman, L; Shreve, J M; Jones, G S; Miles, P R

    1982-02-01

    Samples of volcanic ash from Mount St. Helens were collected from Spokane, Washington, after the major eruption of May 18, 1980. The toxicity of ash to the lung was estimated by monitoring the effects of in vitro and in vivo exposure on various physiological parameters of isolated lung cells. Volcanic ash had little effect on O2 consumption of rabbit type II pneumocytes, O2 consumption or superoxide release of resting rat alveolar macrophages, or membrane integrity of rat alveolar macrophages. Ash also caused no significant lipid peroxidation in rat lung microsomes. However, volcanic ash did inhibit superoxide anion release from zymosan-stimulated rat alveolar macrophages. Since superoxide is an antibacterial substance, this result suggests that exposure to volcanic ash may adversely affect the ability of alveolar macrophages to protect the lung from infection. PMID:6281450

  19. 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

  20. Clear cell carcinoma of the lung.

    PubMed Central

    Edwards, C; Carlile, A

    1985-01-01

    Six tumours of the lung initially classified as clear cell carcinoma, were studied. Examination of further material by light and electron microscopy showed adenocarcinomatous differentiation in three cases and squamous differentiation in two. One case showed the features of a large cell anaplastic carcinoma. The clear appearance of the cytoplasm in paraffin sections was due to accumulations of glycogen that were partially removed during processing. It is concluded that clear cell carcinoma is not a single and separate entity. Images PMID:4031101

  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. 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

  3. The lung in sickle cell disease.

    PubMed

    Knight, J; Murphy, T M; Browning, I

    1999-09-01

    Sickle cell disease is the most common inherited disorder in African-Americans. Although the primary defect is hematological, the changes in the erythrocytes lead to a vasculopathy with multiorgan injury. The pulmonary complications, i.e., acute chest syndrome and chronic sickle cell lung disease, are significant causes of morbidity and mortality. The pulmonary manifestations result from a unique constellation of factors which come into play in sickle cell disease. Based on the growing understanding of the molecular and cellular biology of sickle cell disease, new therapies are being developed that are likely to ameliorate the natural history of this disease and its complications. PMID:10495338

  4. Adenosquamous carcinoma of the floor of the mouth and lower alveolus: a radiation-induced lesion

    SciTech Connect

    Siar, C.H.; Ng, K.H.

    1987-02-01

    A case of adenosquamous carcinoma of the floor of the mouth and alveolus that occurred following radiation therapy is described. The possible role of radiation in the etiology of this lesion is discussed, and the complex histopathologic features of this neoplasm are emphasized.

  5. Stem Cells and Regenerative Medicine in Lung Biology and Diseases

    PubMed Central

    Lau, Allison N; Goodwin, Meagan; Kim, Carla F; Weiss, Daniel J

    2012-01-01

    A number of novel approaches for repair and regeneration of injured lung have developed over the past several years. These include a better understanding of endogenous stem and progenitor cells in the lung that can function in reparative capacity as well as extensive exploration of the potential efficacy of administering exogenous stem or progenitor cells to function in lung repair. Recent advances in ex vivo lung engineering have also been increasingly applied to the lung. The current status of these approaches as well as initial clinical trials of cell therapies for lung diseases are reviewed below. PMID:22395528

  6. Clinical Behaviors and Outcomes for Adenocarcinoma or Adenosquamous Carcinoma of Cervix Treated by Radical Hysterectomy and Adjuvant Radiotherapy or Chemoradiotherapy

    SciTech Connect

    Huang, Yi-Ting; Wang, Chun-Chieh; Tsai, Chien-Sheng; Lai, Chyong-Huey; Chang, Ting-Chang; Chou, Hung-Hsueh; Lee, Steve P.; Hong, Ji-Hong

    2012-10-01

    Purpose: To compare clinical behaviors and treatment outcomes between patients with squamous cell carcinoma (SCC) and adenocarcinoma/adenosquamous carcinoma (AC/ASC) of the cervix treated with radical hysterectomy (RH) and adjuvant radiotherapy (RT) or concurrent chemoradiotherapy (CCRT). Methods and Materials: A total of 318 Stage IB-IIB cervical cancer patients, 202 (63.5%) with SCC and 116 (36.5%) with AC/ASC, treated by RH and adjuvant RT/CCRT, were included. The indications for RT/CCRT were deep stromal invasion, positive resection margin, parametrial invasion, or lymph node (LN) metastasis. Postoperative CCRT was administered in 65 SCC patients (32%) and 80 AC/ASC patients (69%). Patients with presence of parametrial invasion or LN metastasis were stratified into a high-risk group, and the rest into an intermediate-risk group. The patterns of failure and factors influencing survival were evaluated. Results: The treatment failed in 39 SCC patients (19.3%) and 39 AC/ASC patients (33.6%). The 5-year relapse-free survival rates for SCC and AC/ASC patients were 83.4% and 66.5%, respectively (p = 0.000). Distant metastasis was the major failure pattern in both groups. After multivariate analysis, prognostic factors for local recurrence included younger age, parametrial invasion, AC/ASC histology, and positive resection margin; for distant recurrence they included parametrial invasion, LN metastasis, and AC/ASC histology. Compared with SCC patients, those with AC/ASC had higher local relapse rates for the intermediate-risk group but a higher distant metastasis rate for the high-risk group. Postoperative CCRT tended to improve survival for intermediate-risk but not for high-risk AC/ASC patients. Conclusions: Adenocarcinoma/adenosquamous carcinoma is an independent prognostic factor for cervical cancer patients treated by RH and postoperative RT. Concurrent chemoradiotherapy could improve survival for intermediate-risk, but not necessarily high-risk, AC/ASC patients.

  7. Intratumor Heterogeneity of ALK-Rearrangements and Homogeneity of EGFR-Mutations in Mixed Lung Adenocarcinoma

    PubMed Central

    Marino, Federica Zito; Liguori, Giuseppina; Aquino, Gabriella; La Mantia, Elvira; Bosari, Silvano; Ferrero, Stefano; Rosso, Lorenzo; Gaudioso, Gabriella; De Rosa, Nicla; Scrima, Marianna; Martucci, Nicola; La Rocca, Antonello; Normanno, Nicola; Morabito, Alessandro; Rocco, Gaetano; Botti, Gerardo; Franco, Renato

    2015-01-01

    Background Non Small Cell Lung Cancer is a highly heterogeneous tumor. Histologic intratumor heterogeneity could be ‘major’, characterized by a single tumor showing two different histologic types, and ‘minor’, due to at least 2 different growth patterns in the same tumor. Therefore, a morphological heterogeneity could reflect an intratumor molecular heterogeneity. To date, few data are reported in literature about molecular features of the mixed adenocarcinoma. The aim of our study was to assess EGFR-mutations and ALK-rearrangements in different intratumor subtypes and/or growth patterns in a series of mixed adenocarcinomas and adenosquamous carcinomas. Methods 590 Non Small Cell Lung Carcinomas tumor samples were revised in order to select mixed adenocarcinomas with available tumor components. Finally, only 105 mixed adenocarcinomas and 17 adenosquamous carcinomas were included in the study for further analyses. Two TMAs were built selecting the different intratumor histotypes. ALK-rearrangements were detected through FISH and IHC, and EGFR-mutations were detected through IHC and confirmed by RT-PCR. Results 10/122 cases were ALK-rearranged and 7 from those 10 showing an intratumor heterogeneity of the rearrangements. 12/122 cases were EGFR-mutated, uniformly expressing the EGFR-mutated protein in all histologic components. Conclusion Our data suggests that EGFR-mutations is generally homogeneously expressed. On the contrary, ALK-rearrangement showed an intratumor heterogeneity in both mixed adenocarcinomas and adenosquamous carcinomas. The intratumor heterogeneity of ALK-rearrangements could lead to a possible impact on the therapeutic responses and the disease outcomes. PMID:26422230

  8. A hidden residential cell in the lung.

    PubMed

    Rothenberg, Marc E

    2016-09-01

    Eosinophils are classically known as proinflammatory cells, as they are equipped with a variety of preformed cytotoxic mediators and have been shown to definitively contribute to asthma. The connection between eosinophils and asthma development has led to a new class of asthma therapeutics based on blocking eosinophils with humanized antibodies that neutralize IL-5, a potent eosinophil growth, activation, and survival factor. Yet, recent studies have led to an increasing appreciation that eosinophils have a variety of homeostatic functions, including immunomodulation. In this issue of the JCI, Mesnil et al. identify a notable population of lung-resident eosinophils and demonstrate that, compared with traditional eosinophils, these cells have distinct characteristics, including nuclear structure, surface markers, IL-5 independence, and immunoregulatory function that is capable of polarizing adaptive immune responses, at least in vitro. Thus, these results reinforce a key homeostatic role for this enigmatic cell population, particularly in residing and regulating immunity in the lung. PMID:27548525

  9. 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

  10. DETECTION OF HUMAN LUNG EPITHELIA CELL GROWTH FACTORS PRODUCED BY A LUNG CARCINOMA CELL LINE: USE IN CULTURE OF PRIMARY SOLID LUNG TUMORS

    EPA Science Inventory

    Serum-free medium conditioned for 72 h by a human undifferentiated adenocarcinoma of lung, Cal u 6, stimulated the colony formation of normal human bronchial epithelial cells, newly cultured cells from human solid lung tumors, and established human lung tumor cell lines, includin...

  11. 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- ...

  12. 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

  13. Spontaneous regression in advanced squamous cell lung carcinoma

    PubMed Central

    Park, Yeon Hee; Park, Bo Mi; Park, Se Yeon; Choi, Jae Woo; Kim, Sun Young; Kim, Ju Ock; Jung, Sung Soo; Park, Hee Sun; Moon, Jae Young

    2016-01-01

    Spontaneous regression of malignant tumors is rare especially of lung tumor and biological mechanism of such remission has not been addressed. We report the case of a 79-year-old Korean patient with non-small cell lung cancer, squamous cell cancer with a right hilar tumor and multiple lymph nodes, lung to lung metastasis that spontaneously regressed without any therapies. He has sustained partial remission state for one year and eight months after the first histological diagnosis. PMID:27076978

  14. Generation of Mouse Lung Epithelial Cells

    PubMed Central

    Kasinski, Andrea L.; Slack, Frank J.

    2016-01-01

    Although in vivo models are excellent for assessing various facets of whole organism physiology, pathology, and overall response to treatments, evaluating basic cellular functions, and molecular events in mammalian model systems is challenging. It is therefore advantageous to perform these studies in a refined and less costly setting. One approach involves utilizing cells derived from the model under evaluation. The approach to generate such cells varies based on the cell of origin and often the genetics of the cell. Here we describe the steps involved in generating epithelial cells from the lungs of KrasLSL-G12D/+; p53LSL-R172/+ mice (Kasinski and Slack, 2012). These mice develop aggressive lung adenocarcinoma following cre-recombinase dependent removal of a stop cassette in the transgenes and subsequent expression of Kra-G12D and p53R172. While this protocol may be useful for the generation of epithelial lines from other genetic backgrounds, it should be noted that the Kras; p53 cell line generated here is capable of proliferating in culture without any additional genetic manipulation that is often needed for less aggressive backgrounds.

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

    PubMed

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

    2016-01-01

    The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases. PMID:26797607

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

    PubMed Central

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

    2016-01-01

    The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases. PMID:26797607

  17. Human embryonic stem cells and lung regeneration

    PubMed Central

    Varanou, A; Page, C P; Minger, S L

    2008-01-01

    Human embryonic stem cells are pluripotent cells derived from the inner cell mass of preimplantation stage embryos. Their unique potential to give rise to all differentiated cell types has generated great interest in stem cell research and the potential that it may have in developmental biology, medicine and pharmacology. The main focus of stem cell research has been on cell therapy for pathological conditions with no current methods of treatment, such as neurodegenerative diseases, cardiac pathology, retinal dysfunction and lung and liver disease. The overall aim is to develop methods of application either of pure cell populations or of whole tissue parts to the diseased organ under investigation. In the field of pulmonary research, studies using human embryonic stem cells have succeeded in generating enriched cultures of type II pneumocytes in vitro. On account of their potential of indefinite proliferation in vitro, embryonic stem cells could be a source of an unlimited supply of cells available for transplantation and for use in gene therapy. Uncovering the ability to generate such cell types will expand our understanding of biological processes to such a degree that disease understanding and management could change dramatically. PMID:18724383

  18. Breathing life into the lung stem cell field.

    PubMed

    Fine, Alan

    2009-06-01

    In this issue of Cell Stem Cell, Rawlins et al. (2009) use an elegant lineage-tracing system to circumvent technical obstacles that have long limited advances in lung stem cell research and, as a result, definitively clarify the role of Clara cells in lung growth, homeostasis, and repair. PMID:19497272

  19. Preconditioning allows engraftment of mouse and human embryonic lung cells, enabling lung repair in mice.

    PubMed

    Rosen, Chava; Shezen, Elias; Aronovich, Anna; Klionsky, Yael Zlotnikov; Yaakov, Yasmin; Assayag, Miri; Biton, Inbal Eti; Tal, Orna; Shakhar, Guy; Ben-Hur, Herzel; Shneider, David; Vaknin, Zvi; Sadan, Oscar; Evron, Shmuel; Freud, Enrique; Shoseyov, David; Wilschanski, Michael; Berkman, Neville; Fibbe, Willem E; Hagin, David; Hillel-Karniel, Carmit; Krentsis, Irit Milman; Bachar-Lustig, Esther; Reisner, Yair

    2015-08-01

    Repair of injured lungs represents a longstanding therapeutic challenge. We show that human and mouse embryonic lung tissue from the canalicular stage of development (20-22 weeks of gestation for humans, and embryonic day 15-16 (E15-E16) for mouse) are enriched with progenitors residing in distinct niches. On the basis of the marked analogy to progenitor niches in bone marrow (BM), we attempted strategies similar to BM transplantation, employing sublethal radiation to vacate lung progenitor niches and to reduce stem cell competition. Intravenous infusion of a single cell suspension of canalicular lung tissue from GFP-marked mice or human fetal donors into naphthalene-injured and irradiated syngeneic or SCID mice, respectively, induced marked long-term lung chimerism. Donor type structures or 'patches' contained epithelial, mesenchymal and endothelial cells. Transplantation of differentially labeled E16 mouse lung cells indicated that these patches were probably of clonal origin from the donor. Recipients of the single cell suspension transplant exhibited marked improvement in lung compliance and tissue damping reflecting the energy dissipation in the lung tissues. Our study provides proof of concept for lung reconstitution by canalicular-stage human lung cells after preconditioning of the pulmonary niche. PMID:26168294

  20. 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

  1. Isolation and Characterization of Distal Lung Progenitor Cells

    PubMed Central

    Driscoll, Barbara; Kikuchi, Alex; Lau, Allison N.; Lee, Jooeun; Reddy, Raghava; Jesudason, Edwin; Kim, Carla F.; Warburton, David

    2013-01-01

    The majority of epithelial cells in the distal lung of rodents and humans are quiescent in vivo, yet certain cell populations retain an intrinsic capacity to proliferate and differentiate in response to lung injury or in appropriate culture settings, thus giving them properties of stem/progenitor cells. Here, we describe the isolation of two such populations from adult mouse lung: alveolar epithelial type 2 cells (AEC2), which can generate alveolar epithelial type 1 cells, and bronchioalveolar stem cells (BASCs), which in culture can reproduce themselves, as well as generate a small number of other distal lung epithelial cell types. These primary epithelial cells are typically isolated using enzyme digestion, mechanical disruption, and serial filtration. AEC2 and BASCs are distinguished from other distal lung cells by expression of specific markers as detected by fluorescence-activated cell sorting, immunohistochemistry, or a combination of both of these techniques. PMID:22610556

  2. Prognostic markers in resectable non-small cell lung cancer: a multivariate analysis

    PubMed Central

    Pelletier, Marc P.; deB. Edwardes, Michael D.; Michel, René P.; Halwani, Fawaz; Morin, Jean E.

    2001-01-01

    Objective To identify the prognostic significance of certain clinical, cellular and immunologic markers in resectable non-small cell lung cancer (NSCLC). Design A cohort of patients with resectable NSCLC was prospectively followed up for 8 years (100% follow-up). Setting A university hospital in a large Canadian city. Patients One hundred and thirteen consecutive patients who underwent surgical resection of primary NSCLC. Main outcome measures Presence of peritumoral B lymphocytes (identified with antibody to CD20) and T lymphocytes (antibody to CD43), along with tumour markers (carcinoembryonic antigen [CEA], keratin, cytokeratin, S-100 protein, vimentin, chromogranin) and other factors such as age, sex, cell type, American Joint Committee on Cancer (AJCC) stage, histologic grade, DNA ploidy and S-phase fraction were correlated with survival. Results The mean age of patients in the study was 66.0 years; 60% were male. Histologic types of the tumours were: adenocarcinoma 57 (50.4%), squamous cell 47 (41.6%), adenosquamous 6 (5.3%) and large cell 3 (2.6%). AJCC stages were: I 66 (58.4%), II 20 (17.7%) and III 27 (23.9%). Histologic grades were: I (well differentiated) 31 (27.4%), II 50 (44.2%), III 29 (25.7%) and IV 3 (2.6%). Survival was 85% at 1 year (95% confidence interval [CI] 76%–90%), 44% at 5 years (95% CI 34%–53%) and 34% at 10 years (95% CI 22%–46%). Multivariate analyses using the Cox proportional hazards model for survival confirmed AJCC stage (p < 0.001) in all histologic subtypes to be the strongest factor of independent prognostic significance. It also revealed the presence of CD20-stained B lymphocytes (p = 0.04) in the peritumoral region of all tumours to be a positive prognostic factor. This relation was especially strong for nonsquamous cell carcinomas (p < 0.001). For squamous cell carcinomas, the immunohistochemical presence of CEA was of marginally negative prognostic value (p = 0.04). DNA ploidy and a high S-phase fraction showed no

  3. 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

  4. 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

  5. Cell-derived microparticles and the lung.

    PubMed

    Nieri, Dario; Neri, Tommaso; Petrini, Silvia; Vagaggini, Barbara; Paggiaro, Pierluigi; Celi, Alessandro

    2016-09-01

    Cell-derived microparticles are small (0.1-1 μm) vesicles shed by most eukaryotic cells upon activation or during apoptosis. Microparticles carry on their surface, and enclose within their cytoplasm, molecules derived from the parental cell, including proteins, DNA, RNA, microRNA and phospholipids. Microparticles are now considered functional units that represent a disseminated storage pool of bioactive effectors and participate both in the maintenance of homeostasis and in the pathogenesis of diseases. The mechanisms involved in microparticle generation include intracellular calcium mobilisation, cytoskeleton rearrangement, kinase phosphorylation and activation of the nuclear factor-κB. The role of microparticles in blood coagulation and inflammation, including airway inflammation, is well established in in vitro and animal models. The role of microparticles in human pulmonary diseases, both as pathogenic determinants and biomarkers, is being actively investigated. Microparticles of endothelial origin, suggestive of apoptosis, have been demonstrated in the peripheral blood of patients with emphysema, lending support to the hypothesis that endothelial dysfunction and apoptosis are involved in the pathogenesis of the disease and represent a link with cardiovascular comorbidities. Microparticles also have potential roles in patients with asthma, diffuse parenchymal lung disease, thromboembolism, lung cancer and pulmonary arterial hypertension. PMID:27581826

  6. Properties of Adult Lung Stem and Progenitor Cells.

    PubMed

    Bertoncello, Ivan

    2016-12-01

    The last decade has seen significant progress in understanding the organisation of regenerative cells in the adult lung. Cell-lineage tracing and in vitro clonogenic assays have enabled the identification and characterisation of endogenous lung epithelial stem and progenitor cells. Selective lung injury models, and genetically engineered mice have revealed highly conserved gene networks, factors, signalling pathways, and cellular interactions important in maintaining lung homeostasis and regulating lung regeneration and repair following injury. This review describes the current models of lung epithelial stem and progenitor cell organisation in adult mice, and the impediments encountered in translational studies aiming to identify and characterise their human homologs. J. Cell. Physiol. 231: 2582-2589, 2016. © 2016 Wiley Periodicals, Inc. PMID:27062064

  7. Surgical resection of splenic metastasis from the adenosquamous gallbladder carcinoma: A case report

    PubMed Central

    Utsumi, Masashi; Aoki, Hideki; Kunitomo, Tomoyoshi; Mushiake, Yutaka; Kanaya, Nobuhiko; Yasuhara, Isao; Arata, Takashi; Katsuda, Kou; Tanakaya, Kohji; Takeuchi, Hitoshi

    2016-01-01

    Introduction Splenic metastasis of gallbladder carcinoma is extremely rare. Specific anatomical, histological, and functional properties of spleen are believed to be responsible for the rarity of solitary splenic metastasis. Presentation of case We present the case of a 62-year-old female who developed metachronous splenic metastasis of adenosquamous carcinoma of the gallbladder. We performed central bisegmentectomy of the liver for gallbladder carcinoma. The patient subsequently presented 3 months later with isolated splenic metastasis and liver metastasis. Splenectomy and partial hepatectomy was performed at this time. Histological examination confirmed metastatic adenosquamous carcinoma of the gallbladder. No signs of recurrence were observed at 3 months after the second surgery. Discussion Although splenectomy provides a potential means of radical treatment in patients with isolated splenic metastases, it should be performed with caution as splenic metastatic lesions may represent the initial clinical manifestation of systemic metastases at multiple sites. In this case, radical surgery was performed following the confirmation of no new unresectable metastatic lesions or systemic dissemination. Conclusion This is the first report on the adenosquamous splenic metastasis from the gallbladder carcinoma. Curative resection may be the treatment of choice for prolonging survival in patients with the splenic metastasis of gallbladder carcinoma. PMID:26852359

  8. Rituximab efficiently depletes B cells in lung tumors and normal lung tissue

    PubMed Central

    Joly-Battaglini, Albane; Hammarström, Clara; Stankovic, Branislava; Aamodt, Henrik; Stjärne, Johan; Brustugun, Odd Terje; Helland, Åslaug; Øynebråten, Inger; Corthay, Alexandre

    2016-01-01

    Rituximab is a monoclonal antibody that targets the CD20 B-cell-specific antigen and is widely used as therapy for B-cell lymphoma. Since rituximab depletes both malignant and normal B cells, it is increasingly being used to treat various conditions in which normal B cells have a pathogenic role, such as rheumatoid arthritis and multiple sclerosis. It is well-established that rituximab efficiently eliminates B cells in blood, lymph nodes, and spleen. In contrast, the effect of rituximab in non-lymphoid tissues remains poorly documented and is debated. Here, we report a rheumatoid arthritis patient who was treated with rituximab before receiving thoracic surgery for non-small cell lung cancer. Using flow cytometry and immunohistochemistry, we show that rituximab efficiently depleted CD20-positive B cells in a primary lung tumor, in lung-associated lymph nodes, and in normal lung tissue. We conclude that rituximab may be very efficient at depleting normal B cells in the lungs. This property of rituximab may potentially be exploited for the treatment of conditions in which pathogenic B cells reside in the lungs. On the other hand, the clearance of lung B cells may provide an explanation for the rare cases of severe non-infectious pulmonary toxicity of rituximab. PMID:27081474

  9. Alpha-1 Antitrypsin and Lung Cell Apoptosis.

    PubMed

    Serban, Karina A; Petrache, Irina

    2016-04-01

    Discovery of alpha-1 antitrypsin (A1AT) as the principal circulating inhibitor of neutrophil elastase was critical to the appreciation of protease/antiprotease imbalance involvement in the pathogenesis of emphysema. Additional targets of A1AT have been uncovered, along with their contribution to alveolar wall destruction induced by cigarette smoke exposure. We highlight in this report mechanisms of A1AT antiapoptotic effects on structural lung endothelial cells. This function was largely dependent on uptake of the protein from the circulation via clathrin- and, in part, caveolae-mediated endocytosis and on specific interactions with cysteine proteases such as capsase-3, -6, and -7. Exposures to cigarette smoke diminished A1AT intracellular uptake and its anticaspase action, suggesting that even in A1AT-suficient individuals, cigarette smoke may weaken the serpin's endothelial prosurvival effect. In addition, cigarette smoke exposure or genetic mutations known to induce posttranslational modifications such as oxidation or polymerization may alter A1AT bidirectional intracellular traffic in endothelial cells and thus determine its functional bioavailability in certain lung compartments. Uncovering and harnessing the A1AT canonical and noncanonical mechanisms will advance our understanding of the pathogenesis of emphysema and may provide means to improve the effectiveness of therapies in both A1AT-sufficient and A1AT-deficient individuals. PMID:27115949

  10. 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

  11. EGFR Mutations in Surgically Resected Fresh Specimens from 697 Consecutive Chinese Patients with Non-Small Cell Lung Cancer and Their Relationships with Clinical Features

    PubMed Central

    Lai, Yuanyang; Zhang, Zhipei; Li, Jianzhong; Sun, Dong; Zhou, Yong’an; Jiang, Tao; Han, Yong; Huang, Lijun; Zhu, Yifang; Li, Xiaofei; Yan, Xiaolong

    2013-01-01

    We aimed to reveal the true status of epidermal growth factor receptor (EGFR) mutations in Chinese patients with non-small cell lung cancer (NSCLC) after lung resections. EGFR mutations of surgically resected fresh tumor samples from 697 Chinese NSCLC patients were analyzed by Amplification Refractory Mutation System (ARMS). Correlations between EGFR mutation hotspots and clinical features were also explored. Of the 697 NSCLC patients, 235 (33.7%) patients had tyrosine kinase inhibitor (TKIs) sensitive EGFR mutations in 41 (14.5%) of the 282 squamous carcinomas, 155 (52.9%) of the 293 adenocarcinomas, 34 (39.5%) of the 86 adenosquamous carcinomas, one (9.1%) of the 11 large-cell carcinomas, 2 (11.1%) of the 18 sarcomatoid carcinomas, and 2 (28.6%) of the 7 mucoepidermoid carcinomas. TKIs sensitive EGFR mutations were more frequently found in female patients (p < 0.001), non-smokers (p = 0.047) and adenocarcinomas (p < 0.001). The rates of exon 19 deletion mutation (19-del), exon 21 L858R point mutation (L858R), exon 21 L861Q point mutation (L861Q), exon 18 G719X point mutations (G719X, including G719C, G719S, G719A) were 43.4%, 48.1%, 1.7% and 6.8%, respectively. Exon 20 T790M point mutation (T790M) was detected in 3 squamous carcinomas and 3 adenocarcinomas and exon 20 insertion mutation (20-ins) was detected in 2 patients with adenocarcinoma. Our results show the rates of EGFR mutations are higher in all types of NSCLC in Chinese patients. 19-del and L858R are two of the more frequent mutations. EGFR mutation detection should be performed as a routine postoperative examination in Chinese NSCLC patients. PMID:24351833

  12. Epidermal growth factor receptor gene mutation status and its association with clinical characteristics and tumor markers in non-small-cell lung cancer patients in Northwest China

    PubMed Central

    ABDURAHMAN, ABLAJAN; ANWAR, JURAT; TURGHUN, ABDUGHENI; NIYAZ, MADINIYET; ZHANG, LIWEI; AWUT, IDIRIS

    2015-01-01

    This study was conducted to investigate the mutation status of epidermal growth factor receptor (EGFR) and its association with clinical characteristics and tumor markers in non-small-cell lung cancer (NSCLC) patients from the Xinjiang Uygur Autonomous Region in China. We enrolled 51 cases of NSCLC patients who received radical surgical treatment in the First Affiliated Hospital of Xinjiang Medical University. Quantitative polymerase chain reaction was applied to detect exons 18, 19, 20 and 21 of the EGFR gene in tumor tissues. Multiple tumor markers, including carcinoembryonic antigen (CEA), were assessed preoperatively. The EGFR-positive rate was 49.02% (25/51), with a mutation rate of 8% (2/25) in exon 18, 52% (13/51) in exon 19, 40% (10/51) in exon 21 and no mutations in exon 20. The positive mutation rate in men and women was 37.5% (12/32) and 68.42%, respectively (13/19), with a statistically significantly higher rate in women (P<0.05). There were also statistically significant differences among adenocarcinoma, adenosquamous carcinoma and squamous cell carcinoma cases (P<0.05), while no statistically significant differences were observed in adenocarcinoma cases regarding degree of differentiation, lymph node metastasis and TNM stage (P>0.05). There was a statistically significant association between the EGFR gene mutation status and the preoperative serum CEA level (P<0.05). The mutation rate of the EGFR gene was 68.42% in female lung adenocarcinoma patients, which supports the application of targeted therapy in such cases. However, whether it is possible to obtain information regarding targeted therapy through measuring the level of serum CEA for NSCLC patients with unknown EGFR mutation status requires further investigation through related studies including a higher number of cases. PMID:26171194

  13. Harnessing the potential of lung stem cells for regenerative medicine.

    PubMed

    McQualter, Jonathan L; Anthony, Desiree; Bozinovski, Steven; Prêle, Cecilia M; Laurent, Geoffrey J

    2014-11-01

    In response to recurrent exposure to environmental insults such as allergens, pollution, irritants, smoke and viral/bacterial infection, the epithelium of the lung is continually damaged. Homeostasis of the lung requires a balance between immune regulation and promotion of tissue regeneration, which requires the co-ordinated proliferation and differentiation of stem and progenitor cells. In this review we reflect on the current understanding of lung epithelial stem and progenitor cells and advocate a model hierarchy in which self-renewing multipotent lung epithelial stem cells give rise to lineage restricted progenitor cells that repopulate airway and alveolar epithelial cell lineages during homeostasis and repair. We also discuss the role of mesenchymal progenitor cells in maintaining the structural integrity of the lung and propose a model in which mesenchymal cells act as the quintessential architects of lung regeneration by providing molecular signals, such as FGF-10, to regulate the fate and specificity of epithelial stem and progenitor cells. Moreover, we discuss the current status and future prospects for translating lung stem cell therapies to the clinic to replace, repair, or regenerate diseased lung tissue. This article is part of a directed issue entitled: Regenerative Medicine: the challenge of translation. PMID:25450456

  14. 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

  15. Amine-containing cells of the lung.

    PubMed

    Pack, R J; Widdicombe, J G

    1984-11-01

    In many vertebrates, including mammals, there are amine-containing cells in the walls of the airways and the lungs. Despite a plethora of names for these cells, there is a general agreement about their structure. They occur singly or in groups (NEBs), but the functional distinction between the two types of distribution is uncertain. In spite of ultrastructural similarities, the cells may be physiologically heterogenous. The cells are characterised by their staining characteristics and content of electron-dense-core vesicles, which are believed to contain a biogenic amine. They also have additional cytoplasmic features common to other sensory paraganglia. They may be more numerous in certain species and also in the neonate. The NEBs may be innervated with afferent and/or efferent nerves, though physiological evidence of their innervation is scanty. The most popular hypothesis is that they can be stimulated by hypoxia to release mediators or to induce reflex activity. In the healthy animal, the amine-cells may control local ventilation/perfusion (V/Q) ratios via an action on the pulmonary vasculature. In disease, they may cause pulmonary hypertension. They can also give rise to three forms of tumour. Their full significance has yet to be established. PMID:6083878

  16. Carboplatin and Paclitaxel With or Without Bevacizumab and/or Cetuximab in Treating Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2015-09-01

    Recurrent Large Cell Lung Carcinoma; Recurrent Lung Adenocarcinoma; Recurrent Squamous Cell Lung Carcinoma; Stage IV Large Cell Lung Carcinoma; Stage IV Lung Adenocarcinoma; Stage IV Squamous Cell Lung Carcinoma

  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. LZTFL1 suppresses lung tumorigenesis by maintaining differentiation of lung epithelial cells

    PubMed Central

    Wei, Q; Chen, Z-H; Wang, L; Zhang, T; Duan, L; Behrens, C; Wistuba, I I; Minna, J D; Gao, B; Luo, J-H; Liu, Z P

    2016-01-01

    Lung cancer is the leading cause of cancer-related death in the United States, and metastatic behavior is largely responsible for this mortality. Mutations in multiple ‘driver' oncogenes and tumor suppressors are known to contribute to the lung tumorigenesis and in some cases represent therapeutic targets. Leucine Zipper Transcription Factor-like 1 (LZTFL1) is located in the chromosome region 3p21.3 where allelic loss and genetic alterations occur early and frequently in lung cancers. Previously, we found that LZTFL1 is downregulated in epithelial tumors, including lung cancer, and functions as a tumor suppressor in gastric cancers. However, the functional role of LZTFL1 in lung oncogenesis is undefined. We show here that downregulation of LZTFL1 expression in non-small cell lung cancer is associated with recurrence and poor survival, whereas re-expression of LZTFL1 in lung tumor cells inhibited extravasation/colonization of circulating tumor cells to the lung and inhibited tumor growth in vivo. Mechanistically, we found that LZTFL1 is expressed in ciliated human bronchial epithelial cells (HBECs) and its expression correlates with HBEC differentiation. LZTFL1 inhibits transforming growth factor β-activated mitogen-activated protein kinase and hedgehog signaling. Alteration of intracellular levels of LZTFL1 resulted in changes of expression of genes associated with epithelial-to-mesenchymal transition (EMT). We conclude that LZTFL1 inhibits lung tumorigenesis, possibly by maintaining epithelial cell differentiation and/or inhibition of signalings that lead to EMT and suggest that reactivation of LZTFL1 expression in tumor cells may be a novel lung cancer therapeutic approach. PMID:26364604

  19. LZTFL1 suppresses lung tumorigenesis by maintaining differentiation of lung epithelial cells.

    PubMed

    Wei, Q; Chen, Z-H; Wang, L; Zhang, T; Duan, L; Behrens, C; Wistuba, I I; Minna, J D; Gao, B; Luo, J-H; Liu, Z P

    2016-05-19

    Lung cancer is the leading cause of cancer-related death in the United States, and metastatic behavior is largely responsible for this mortality. Mutations in multiple 'driver' oncogenes and tumor suppressors are known to contribute to the lung tumorigenesis and in some cases represent therapeutic targets. Leucine Zipper Transcription Factor-like 1 (LZTFL1) is located in the chromosome region 3p21.3 where allelic loss and genetic alterations occur early and frequently in lung cancers. Previously, we found that LZTFL1 is downregulated in epithelial tumors, including lung cancer, and functions as a tumor suppressor in gastric cancers. However, the functional role of LZTFL1 in lung oncogenesis is undefined. We show here that downregulation of LZTFL1 expression in non-small cell lung cancer is associated with recurrence and poor survival, whereas re-expression of LZTFL1 in lung tumor cells inhibited extravasation/colonization of circulating tumor cells to the lung and inhibited tumor growth in vivo. Mechanistically, we found that LZTFL1 is expressed in ciliated human bronchial epithelial cells (HBECs) and its expression correlates with HBEC differentiation. LZTFL1 inhibits transforming growth factor β-activated mitogen-activated protein kinase and hedgehog signaling. Alteration of intracellular levels of LZTFL1 resulted in changes of expression of genes associated with epithelial-to-mesenchymal transition (EMT). We conclude that LZTFL1 inhibits lung tumorigenesis, possibly by maintaining epithelial cell differentiation and/or inhibition of signalings that lead to EMT and suggest that reactivation of LZTFL1 expression in tumor cells may be a novel lung cancer therapeutic approach. PMID:26364604

  20. 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

  1. 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

  2. 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

  3. Prognostic significance of the combined score of endothelial expression of nucleolin and CD31 in surgically resected non-small cell lung cancer.

    PubMed

    Zhao, Hongyun; Huang, Yan; Xue, Cong; Chen, Yang; Hou, Xue; Guo, Ying; Zhao, Liping; Hu, Zhi huang; Huang, Yujie; Luo, Yongzhang; Zhang, Li

    2013-01-01

    Nucleolin is implicated to play a role in angiogenesis, a vital process in tumor growth and metastasis. However, the presence and clinical relevance of nucleolin in human non small cell lung cancer (NSCLC) remains largely unknown. In this study, we explored the expression and prognostic implication of nucleolin in surgically resected NSCLC patients. A cohort of 146 NSCLC patients who underwent surgical resection was selected for tissue microarray. In this tissue microarray, nucleolin expression was measured by immunofluorescence. Staining for CD31, a marker of endothelial cells, was performed to mark blood vessels. A Cox proportional hazards model was used to assess the prognostic significance of nucleolin. Nucleolin expression was observed in 34.2% of all patients, and 64.1% in high CD31 expression patients. The disease-free survival (DFS) was significantly shorter in patients with high nucleolin (CD31(hi)NCL(hi)) compared to patients with low tumor blood vessels (CD31(lo)NCL(lo)) (5 ys of DFS 24% vs 64%, p = 0.002). Such a difference was demonstrated in the following stratified analyses: stage I (p<0.001), squamous cell carcinoma and adenosquamous cell carcinoma (p = 0.028), small tumor (<5 cm, p = 0.008), and surgery alone (p = 0.015). Multivariate analysis further revealed that nucleolin expression independently predicted for worse survival (p = 0.003). This study demonstrates that nucleolin is associated with the clinical outcomes in postoperative NSCLC patients. Thus, the expression levels of nucleolin may provide a new prognostic marker to identify patients at higher risk for treatment failure, especially in some subgroups. PMID:23382938

  4. Tracking the Clonal Evolution of Adenosquamous Carcinoma, a Rare Variant of Intraductal Papillary Mucinous Neoplasm of the Pancreas.

    PubMed

    Matsuzaka, Suguru; Karasaki, Hidenori; Ono, Yusuke; Ogata, Munehiko; Oikawa, Kensuke; Tamakawa, Susumu; Chiba, Shin-Ichi; Muraki, Miho; Yokochi, Tomoki; Funakoshi, Hiroshi; Kono, Toru; Nagashima, Kazuo; Mizukami, Yusuke

    2016-07-01

    Adenosquamous carcinoma (ASC) is an uncommon variant of pancreatic neoplasm. We sought to trace the mode of tumor progression using specimens of ASC associated with intraductal papillary mucinous neoplasm (IPMN) of the pancreas. A resected specimen of the primary pancreatic ASC, developed in a 72-year-old man, was subjected to mutation profiling using amplicon-targeted sequencing and digital polymerase chain reaction. DNA was isolated from each histological compartment including noninvasive IPMN, squamous cell carcinoma (SCC), and adenocarcinoma (AC). Histologically, an IPMN with a large mural nodule was identified. The invasive tumor predominantly consisted of SCC, and a smaller AC was found around the lesion. Squamous metaplasias were sporadically distributed within benign IPMNs. Mutation alleles KRAS and GNAS were identified in all specimens of IPMN including the areas of squamous metaplasia. In addition, these mutations were found in SCC and AC. Clear transition from flat/low-papillary IPMN to SCC indicated a potent invasion front, and the SCC compartment was genetically unique, because the area has a higher frequency of mutation KRAS. The invasive tumors with distinct histological appearances shared the form of noninvasive IPMN as a common precursor, rather than de novo cancer, suggesting the significance of a genetic profiling scheme of tumors associated with IPMN. PMID:27295533

  5. 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

  6. 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

  7. Mechanobiology in Lung Epithelial Cells: Measurements, Perturbations, and Responses

    PubMed Central

    Waters, Christopher M.; Roan, Esra; Navajas, Daniel

    2015-01-01

    Epithelial cells of the lung are located at the interface between the environment and the organism and serve many important functions including barrier protection, fluid balance, clearance of particulate, initiation of immune responses, mucus and surfactant production, and repair following injury. Because of the complex structure of the lung and its cyclic deformation during the respiratory cycle, epithelial cells are exposed to continuously varying levels of mechanical stresses. While normal lung function is maintained under these conditions, changes in mechanical stresses can have profound effects on the function of epithelial cells and therefore the function of the organ. In this review, we will describe the types of stresses and strains in the lungs, how these are transmitted, and how these may vary in human disease or animal models. Many approaches have been developed to better understand how cells sense and respond to mechanical stresses, and we will discuss these approaches and how they have been used to study lung epithelial cells in culture. Understanding how cells sense and respond to changes in mechanical stresses will contribute to our understanding of the role of lung epithelial cells during normal function and development and how their function may change in diseases such as acute lung injury, asthma, emphysema, and fibrosis. PMID:23728969

  8. 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

  9. Plasmacytoid Dendritic Cells Control Lung Inflammation and Monocyte Recruitment in Indirect Acute Lung Injury in Mice

    PubMed Central

    Venet, Fabienne; Huang, Xin; Chung, Chun-Shiang; Chen, Yaping; Ayala, Alfred

    2010-01-01

    Indirect acute lung injury (ALI, not caused by a direct insult to the lung) represents the first organ dysfunction in trauma patients, with nonpulmonary sepsis being the most common cause of indirect ALI. Dendritic cells (DCs) are thought to participate in a number of inflammatory lung diseases; however, their role in indirect ALI is currently not established. Using a clinically relevant model of indirect ALI induced in mice by hemorrhagic shock followed 24 hours later by polymicrobial septic challenge, we report that mature DC numbers were markedly increased in the lung during indirect ALI. DC depletion induced a significant increase in indirect ALI severity, which was associated with enhanced lung and plasma proinflammatory cytokine concentration and recruitment of proinflammatory CD115+ monocytes in response to increased lung monocyte chemotactic protein-1 production. Among the different DC subpopulations, plasmacytoid DCs, which were induced and activated in the lung during indirect ALI, were responsible for this effect because their specific depletion reproduced the observations made in DC-depleted mice. As the recruitment of monocytes to the lung plays a central deleterious role in the pathophysiology of indirect ALI, our data therefore position plasmacytoid DCs as important regulators of acute lung inflammation. PMID:20042672

  10. Stage IB2 adenosquamous cervical cancer diagnosed at 19-weeks' gestation.

    PubMed

    Peculis, Luiza D; Ius, Yvette; Campion, Michael; Friedlander, Michael; Hacker, Neville

    2015-02-01

    Neoadjuvant chemotherapy (NACT) for advanced cervical cancer in pregnancy has been shown to increase operability and be effective against spread of disease. In all reported cases of advanced disease, residual tumour has been found at surgery following NACT. We present a case of a 27-year old diagnosed with stage IB2 adenosquamous cervical carcinoma at 19-weeks' gestation who was treated with NACT. Following caesarean section and radical hysterectomy, histopathology showed no evidence of residual tumour in the cervix and negative pelvic lymph nodes. PMID:25470742

  11. The relationship between microvessel count and the expression of vascular endothelial growth factor, p53, and K-ras in non-small cell lung cancer.

    PubMed Central

    Kang, Y. H.; Kim, K. S.; Yu, Y. K.; Lim, S. C.; Kim, Y. C.; Park, K. O.

    2001-01-01

    Using immunohistochemical staining, we studied the relationship between the microvessel count (MC) and the expression of K-ras, mutant p53 protein, and vascular endothelial growth factor (VEGF) in 61 surgically resected non-small cell lung cancers (NSCLC) (42 squamous cell carcinoma, 14 adenocarcinoma, 2 large cell carcinoma, 2 adenosquamous carcinoma, and 1 mucoepidermoid carcinoma). MC of the tumors with lymph node (LN) metastasis was significantly higher than that of tumors without LN metastasis (66.1+/-23.1 vs. 33.8+/-13.1, p<0.05). VEGF was positive in 54 patients (88.5%). MC was 58.1+/-25.2 (mean+/-S.D.) in a x200 field, and it was significantly higher in VEGF(+) tumors than in VEGF(-) tumors (61.4+/-23.7 vs. 32.9+/-23.8, p<0.05). VEGF expression was higher in K-ras-positive or mutant p53-positive tumors than in negative tumors (p<0.05). MC was significantly higher in K-ras(+) tumors than in K-ras(-) tumors, although it did not differ according to the level of mutant p53 protein expression. Survival did not differ with VEGF, mutant p53, or K-ras expression, or the level of MC. In conclusion, there is a flow of molecular alterations from K-ras and p53, to VEGF expression, leading to angiogenesis and ultimately lymph node metastasis. Correlations between variables in close approximation and the lack of prognostic significance of individual molecular alterations suggest that tumorigenesis and metastasis are multifactorial processes. PMID:11511786

  12. 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

  13. 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

  14. Identification of differentially expressed genes between lung adenocarcinoma and lung squamous cell carcinoma by gene expression profiling.

    PubMed

    Lu, Chaojing; Chen, Hezhong; Shan, Zhengxiang; Yang, Lixin

    2016-08-01

    The present study aimed to identify the differentially expressed genes (DEGs) between lung adenocarcinoma and normal lung tissues, and between lung squamous cell carcinoma and normal lung tissues, with the purpose of identifying potential biomarkers for the treatment of lung cancer. The gene expression profile (GSE6044) was downloaded from the Gene Expression Omnibus database, which included data from 10 lung adenocarcinoma samples, 10 lung squamous cell carcinoma samples, and five matched normal lung tissue samples. After data processing, DEGs were identified using the Student's t‑test adjusted via the Benjamini‑Hochberg method. Subsequently, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the DEGs was performed using the Database for Annotation, Visualization and Integrated Discovery, and a global network was constructed. A total of 95 upregulated and 241 downregulated DEGs were detected in lung adenocarcinoma samples, and 204 upregulated and 285 downregulated DEGs were detected in lung squamous cell carcinoma samples, as compared with the normal lung tissue samples. The DEGs in the lung squamous cell carcinoma group were enriched in the following three pathways: Hsa04110, Cell cycle; hsa03030, DNA replication; and hsa03430, mismatch repair. However, the DEGs in the lung adenocarcinoma group were not significantly enriched in any specific pathway. Subsequently, a global network of lung cancer was constructed, which consisted of 341 genes and 1,569 edges, of which the top five genes were HSP90AA1, BCL2, CDK2, KIT and HDAC2. The expression trends of the above genes were different in lung adenocarcinoma and lung squamous cell carcinoma when compared with normal tissues. Therefore, these genes were suggested to be crucial genes for differentiating lung adenocarcinoma and lung squamous cell carcinoma. PMID:27356570

  15. Identification of differentially expressed genes between lung adenocarcinoma and lung squamous cell carcinoma by gene expression profiling

    PubMed Central

    Lu, Chaojing; Chen, Hezhong; Shan, Zhengxiang; Yang, Lixin

    2016-01-01

    The present study aimed to identify the differentially expressed genes (DEGs) between lung adenocarcinoma and normal lung tissues, and between lung squamous cell carcinoma and normal lung tissues, with the purpose of identifying potential biomarkers for the treatment of lung cancer. The gene expression profile (GSE6044) was downloaded from the Gene Expression Omnibus database, which included data from 10 lung adenocarcinoma samples, 10 lung squamous cell carcinoma samples, and five matched normal lung tissue samples. After data processing, DEGs were identified using the Student's t-test adjusted via the Benjamini-Hochberg method. Subsequently, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the DEGs was performed using the Database for Annotation, Visualization and Integrated Discovery, and a global network was constructed. A total of 95 upregulated and 241 downregulated DEGs were detected in lung adenocarcinoma samples, and 204 upregulated and 285 downregulated DEGs were detected in lung squamous cell carcinoma samples, as compared with the normal lung tissue samples. The DEGs in the lung squamous cell carcinoma group were enriched in the following three pathways: Hsa04110, Cell cycle; hsa03030, DNA replication; and hsa03430, mismatch repair. However, the DEGs in the lung adenocarcinoma group were not significantly enriched in any specific pathway. Subsequently, a global network of lung cancer was constructed, which consisted of 341 genes and 1,569 edges, of which the top five genes were HSP90AA1, BCL2, CDK2, KIT and HDAC2. The expression trends of the above genes were different in lung adenocarcinoma and lung squamous cell carcinoma when compared with normal tissues. Therefore, these genes were suggested to be crucial genes for differentiating lung adenocarcinoma and lung squamous cell carcinoma. PMID:27356570

  16. Mast cells in airway diseases and interstitial lung disease.

    PubMed

    Cruse, Glenn; Bradding, Peter

    2016-05-01

    Mast cells are major effector cells of inflammation and there is strong evidence that mast cells play a significant role in asthma pathophysiology. There is also a growing body of evidence that mast cells contribute to other inflammatory and fibrotic lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. This review discusses the role that mast cells play in airway diseases and highlights how mast cell microlocalisation within specific lung compartments and their cellular interactions are likely to be critical for their effector function in disease. PMID:25959386

  17. Trichinella spiralis: killing of newborn larvae by lung cells.

    PubMed

    Falduto, Guido H; Vila, Cecilia C; Saracino, María P; Calcagno, Marcela A; Venturiello, Stella M

    2015-02-01

    The migratory stage of Trichinella spiralis, the newborn larva (NBL), travels along the pulmonary microvascular system on its way to the skeletal muscle cells. The present work studies the capability of lung cells to kill NBL. For this purpose, in vitro cytotoxicity assays were performed using NBL, lung cell suspensions from Wistar rats, rat anti-NBL surface sera, and fresh serum as complement source. The cytotoxic activity of lung cells from rats infected on day 6 p.i. was compared with that from noninfected rats. Two and 20 h-old NBL (NBL2 and NBL20) were used as they had shown to exhibit different surface antigens altering their biological activity. Sera antibodies were analyzed by indirect immunofluorescence assay, and cell populations used in each assay were characterized by histological staining. The role of IgE in the cytotoxic attack against NBL was analyzed using heated serum. The FcεRI expression on cell suspensions was examined by flow cytometry. Results showed that lung cells were capable of killing NBL by antibody-dependent cell-mediated cytotoxicity (ADCC). Lung cells from infected animals yielded the highest mortality percentages of NBL, with NBL20 being the most susceptible to such attack. IgE yielded a critical role in the cytotoxic attack. Regarding the analysis of cell suspensions, cells from infected rats showed an increase in the percentage of eosinophils, neutrophils, and the number of cells expressing the FcεRI receptor. We conclude that lung cells are capable of killing NBL in the presence of specific antibodies, supporting the idea that the lung is one of the sites where the NBL death occurs due to ADCC. PMID:25416332

  18. 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

  19. 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

  20. Therapeutic effect of lung mixed culture-derived epithelial cells on lung fibrosis.

    PubMed

    Tanaka, Kensuke; Fujita, Tetsuo; Umezawa, Hiroki; Namiki, Kana; Yoshioka, Kento; Hagihara, Masahiko; Sudo, Tatsuhiko; Kimura, Sadao; Tatsumi, Koichiro; Kasuya, Yoshitoshi

    2014-11-01

    Cell-based therapy is recognized as one of potential therapeutic options for lung fibrosis. However, preparing stem/progenitor cells is complicated and not always efficient. Here, we show easily prepared cell populations having therapeutic capacity for lung inflammatory disease that are named as 'lung mixed culture-derived epithelial cells' (LMDECs). LMDECs expressed surfactant protein (SP)-C and gave rise to type I alveolar epithelial cells (AECs) in vitro and in vivo that partly satisfied type II AEC-like characteristics. An intratracheal delivery of not HEK 293 cells but LMDECs to the lung ameliorated bleomycin (BLM)-induced lung injury. A comprehensive analysis of bronchoalveolar fluid by western blot array revealed that LMDEC engraftment could improve the microenvironment in the BLM-instilled lung in association with stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 signaling axis. SDF-1 enhanced both migration activity and differentiating efficiency of LMDECs. Further classification of LMDECs by flow cytometric study showed that a major population of LMDECs (LMDEC(Maj), 84% of total LMDECs) was simultaneously SP-C(+), CD44(+), CD45(+), and hematopoietic cell lineage(+) and that LMDECs included bronchioalveolar stem cells (BASCs) showing SP-C(+)Clara cell secretory protein(+)stem cell antigen (Sca)1(+) as a small population (1.8% of total LMDECs). CD44(+)-sorted LMDEC(Maj) and Sca1(+)-sorted LMDECs equally ameliorated fibrosis induced by BLM like LMDECs did. However, infiltrated neutrophils were observed in Sca1(+)-sorted LMDEC-treated alveoli that was not typical in LMDEC(Maj)- or LMDEC-treated alveoli. These findings suggest that the protective effect of LMDECs against BLM-induced lung injury depends greatly on that of LMDEC(Maj). Furthermore, the cells expressing both alveolar epithelial and hematopoietic cell lineage markers (SP-C(+)CD45(+)) that have characteristics corresponding to LMDEC(Maj) were observed in the alveoli of lung and

  1. Mesenchymal stem cell therapy in lung disorders: pathogenesis of lung diseases and mechanism of action of mesenchymal stem cell.

    PubMed

    Inamdar, Ajinkya C; Inamdar, Arati A

    2013-10-01

    Lung disorders such as asthma, acute respiratory distress syndrome (ARDS), chronic obstructive lung disease (COPD), and interstitial lung disease (ILD) show a few common threads of pathogenic mechanisms: inflammation, aberrant immune activity, infection, and fibrosis. Currently no modes of effective treatment are available for ILD or emphysema. Being anti-inflammatory, immunomodulatory, and regenerative in nature, the administration of mesenchymal stem cells (MSCs) has shown the capacity to control immune dysfunction and inflammation in the lung. The intravenous infusion of MSCs, the common mode of delivery, is followed by their entrapment in lung vasculature before MSCs reach to other organ systems thus indicating the feasible and promising approach of MSCs therapy for lung diseases. In this review, we discuss the mechanistic basis for MSCs therapy for asthma, ARDS, COPD, and ILD. PMID:23992090

  2. Chemoprevention of lung squamous cell carcinoma by ginseng.

    PubMed

    Pan, Jing; Zhang, Qi; Li, Kezhen; Liu, Qian; Wang, Yian; You, Ming

    2013-06-01

    Ginseng has been used as a medicinal herb to maintain physical vitality for thousands of years, and it has also been shown to be a nonorgan-specific cancer preventive agent by several epidemiologic studies. However, the chemopreventive effects of Korea white ginseng (KWG) in lung squamous cell carcinoma (SCC) have not been tested. In this study, we investigated the chemopreventive activity of KWG in a mouse lung SCC model. N-nitroso-trischloroethylurea (NTCU) was used to induce lung tumors in female Swiss mice, and KWG was given orally. KWG significantly reduced the percentage of lung SCCs from 26.5% in the control group to 9.1% in the KWG group and in the meantime, increased the percentage of normal bronchial and hyperplasia. KWG was also found to greatly reduce squamous cell lung tumor area from an average of 9.4% in control group to 1.5% in the KWG group. Treatment with KWG decreased Ki-67 staining, suggesting that the lung tumor inhibitory effects of KWG were partly through inhibition of proliferation. High-performance liquid chromatography/mass spectrometry identified 10 ginsenosides from KWG extracts, Rb1 and Rd being the most abundant as detected in mouse blood and lung tissue. The tumor inhibitory effects of KWG are mediated by inhibition of activator protein (AP-1), as showed by in vitro study conducted on AP-1/NF-κB-dependent mouse non-small cell lung carcinoma cell lines. Western blotting of lung tissues also indicated that NTCU upregulated AP-1 through phosphorylation of c-jun-NH2-kinase, which was downregulated by KWG in concurrence with its chemoprevention function. These results suggest that KWG could be a potential chemopreventive agent for lung SCC. PMID:23550152

  3. Looking for the elusive lung stem cell niche.

    PubMed

    Banerjee, Ena Ray

    2014-01-01

    This discourse contains three perspectives on various aspects of Stem Cell Biology and tools available to study and translate into Regenerative Medicine. The lung incessantly faces onslaught of the environment, constantly undergoes oxidative stress, and is an important organ of detoxification. In degenerative diseases and inflammation, the lung undergoes irreversible remodeling that is difficult to therapeutically address and/or transplant a dying tissue. The other difficulty is to study its development and regenerative aspects to best address the aforementioned problems. This perspective therefore addresses- firstly, review of types of stem cells, their pathway of action and models in invertebrate organisms vis-a-vis microenvironment and its dynamics; secondly, stem cells in higher organisms and niche; and lastly data and inference on a novel approach to study stem cell destruction patterns in an injury model and information on putative lung stem cell niche. Stem cells are cryptic cells known to retain certain primitive characteristics making them akin to ancient cells of invertebrates, developmental stages in invertebrates and vertebrates and pliant cells of complex creatures like mammals that demonstrate stimulus-specific behavious, whether to clonally propagate or to remain well protected and hidden within specialized niches, or mobilize and differentiate into mature functionally operative cells to house-keep, repair injury or make new tissues. In lung fibrosis, alveolar epithelium degenerates progressively. In keeping with the goal of regenerative medicine, various models and assays to evaluate long and short term identity of stem cells and their niches is the subject of this perspective. We also report identification and characterization of functional lung stem cells to clarify how stem cell niches counteract this degenerative process. Inferences drawn from this injury model of lung degeneration using a short term assay by tracking side population cells and a

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

    SciTech Connect

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

    2007-12-31

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

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

    PubMed

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

    2008-06-01

    Lung injuries are leading causes of morbidity and mortality worldwide. Pulmonary diseases such as asthma or chronic obstructive pulmonary disease characterized by loss of lung elasticity, small airway tethers, and luminal obstruction with inflammatory mucoid secretions, or idiopathic pulmonary fibrosis characterized by excessive matrix deposition and destruction of the normal lung architecture, have essentially symptomatic treatments and their management is costly to the health care system.Regeneration of tissue by stem cells from endogenous, exogenous, and even genetically modified cells is a promising novel therapy. The use of adult stem cells to help with lung regeneration and repair could be a newer technology in clinical and regenerative medicine. In fact, different studies have shown that bone marrow progenitor cells contribute to repair and remodeling of lung in animal models of progressive pulmonary hypertension.Therefore, lung stem cell biology may provide novel approaches to therapy and could represent a great promise for the future of molecular medicine. In fact, several diseases can be slowed or even blocked by stem cell transplantation. PMID:19124369

  6. 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

  7. Glucocorticoids decrease Treg cell numbers in lungs of allergic mice.

    PubMed

    Olsen, P C; Kitoko, J Z; Ferreira, T P; de-Azevedo, C T; Arantes, A C; Martins, Μ A

    2015-01-15

    Glucocorticoids have been the hallmark anti-inflammatory drug used to treat asthma. It has been shown that glucocorticoids ameliorate asthma by increasing numbers and activity of Tregs, in contrast recent data show that glucocorticoid might have an opposite effect on Treg cells from normal mice. Since Tregs are target cells that act on the resolution of asthma, the aim of this study was to elucidate the effect of glucocorticoid treatment on lung Tregs in mouse models of asthma. Allergen challenged mice were treated with either oral dexamethasone or nebulized budesonide. Broncoalveolar lavage and airway hyperresponsiveness were evaluated after allergenic challenge. Lung, thymic and lymph node cells were phenotyped on Treg through flow cytometry. Lung cytokine secretion was detected by ELISA. Although dexamethasone inhibited airway inflammation and hyperresponsiveness, improving resolution, we have found that both dexamethasone and budesonide induce a reduction of Treg numbers on lungs and lymphoid organs of allergen challenged mice. The reduction of lung Treg levels was independent of mice strain or type of allergen challenge. Our study also indicates that both glucocorticoids do not increase Treg activity through production of IL-10. Glucocorticoid systemic or localized treatment induced thymic atrophy. Taken together, our results demonstrate that glucocorticoids decrease Treg numbers and activity in different asthma mouse models, probably by reducing thymic production of T cells. Therefore, it is possible that glucocorticoids do not have beneficial effects on lung populations of Treg cells from asthmatic patients. PMID:25499819

  8. 27-Hydroxycholesterol accelerates cellular senescence in human lung resident cells.

    PubMed

    Hashimoto, Yuichiro; Sugiura, Hisatoshi; Togo, Shinsaku; Koarai, Akira; Abe, Kyoko; Yamada, Mitsuhiro; Ichikawa, Tomohiro; Kikuchi, Takashi; Numakura, Tadahisa; Onodera, Katsuhiro; Tanaka, Rie; Sato, Kei; Yanagisawa, Satoru; Okazaki, Tatsuma; Tamada, Tsutomu; Kikuchi, Toshiaki; Hoshikawa, Yasushi; Okada, Yoshinori; Ichinose, Masakazu

    2016-06-01

    Cellular senescence is reportedly involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). We previously showed that 27-hydroxycholesterol (27-OHC) is elevated in the airways of COPD patients compared with those in healthy subjects. The aim of this study was to investigate whether lung fibroblasts of COPD patients are senescent and to determine the effects of 27-OHC on senescence of lung resident cells, including fibroblasts and airway epithelial cells. Localization of senescence-associated proteins and sterol 27-hydroxylase was investigated in the lungs of COPD patients by immunohistochemical staining. To evaluate whether 27-OHC accelerates cellular senescence, lung resident cells were exposed to 27-OHC. Senescence markers and fibroblast-mediated tissue repair were investigated in the 27-OHC-treated cells. Expression of senescence-associated proteins was significantly enhanced in lung fibroblasts of COPD patients. Similarly, expression of sterol 27-hydroxylase was significantly upregulated in lung fibroblasts and alveolar macrophages in these patients. Treatment with the concentration of 27-OHC detected in COPD airways significantly augmented expression of senescence-associated proteins and senescence-associated β-galactosidase activity, and delayed cell growth through the prostaglandin E2-reactive nitrogen species pathway. The 27-OHC-treated fibroblasts impaired tissue repair function. Fibroblasts from lungs of COPD patients showed accelerated senescence and were more susceptible to 27-OHC-induced cellular senescence compared with those of healthy subjects. In conclusion, 27-OHC accelerates cellular senescence in lung resident cells and may play a pivotal role in cellular senescence in COPD. PMID:27036870

  9. Long-Term Outcome and Prognostic Factors for Adenocarcinoma/Adenosquamous Carcinoma of Cervix After Definitive Radiotherapy

    SciTech Connect

    Huang, Yi-Ting; Wang, Chun-Chieh; Tsai, Chien-Sheng; Lai, Chyong-Huey; Chang, Ting-Chang; Chou, Hung-Hsueh; Hsueh, Swei; Chen, Chien-Kuang; Lee, Steve P.; Hong, Ji-Hong

    2011-06-01

    Purpose: To study the outcomes of patients with adenocarcinoma/adenosquamous carcinoma (AC/ASC) of the cervix primarily treated with radiotherapy (RT), identify the prognostic factors, and evaluate the efficacy of concurrent chemoradiotherapy (CCRT) or salvage surgery. Methods and Materials: A total of 148 patients with Stage I-IVA AC/ASC of cervix after full-course definitive RT were included. Of the 148 patients, 77% had advanced stage disease. Treatment failure was categorized as either distant or local failure. Local failure was further separated into persistent tumor or local relapse after complete remission. The effectiveness of CCRT with cisplatin and/or paclitaxel was examined, and the surgical salvage rate for local failure was reviewed. Results: The 5-year relapse-free survival rate was 68%, 38%, 49%, 30%, and 0% for those with Stage IB/IIA nonbulky, IB/IIA bulky, IIB, III, and IVA disease, respectively, and appeared inferior to that of those with squamous cell carcinoma of the cervix treated using the same RT protocol. Incomplete tumor regression after RT, a low hemoglobin level, and positive lymph node metastasis were independent poor prognostic factors for relapse-free survival. CCRT with weekly cisplatinum did not improve the outcome for our AC/ASC patients. Salvage surgery rescued 30% of patients with persistent disease. Conclusion: Patients with AC/ASC of the cervix primarily treated with RT had inferior outcomes compared to those with squamous cell carcinoma. Incomplete tumor regression after RT was the most important prognostic factor for local failure. Salvage surgery for patients with persistent tumor should be encouraged for selected patients. Our results did not demonstrate a benefit of CCRT with cisplatin for this disease.

  10. TRIM72 modulates caveolar endocytosis in repair of lung cells.

    PubMed

    Nagre, Nagaraja; Wang, Shaohua; Kellett, Thomas; Kanagasabai, Ragu; Deng, Jing; Nishi, Miyuki; Shilo, Konstantin; Oeckler, Richard A; Yalowich, Jack C; Takeshima, Hiroshi; Christman, John; Hubmayr, Rolf D; Zhao, Xiaoli

    2016-03-01

    Alveolar epithelial and endothelial cell injury is a major feature of the acute respiratory distress syndrome, in particular when in conjunction with ventilation therapies. Previously we showed [Kim SC, Kellett T, Wang S, Nishi M, Nagre N, Zhou B, Flodby P, Shilo K, Ghadiali SN, Takeshima H, Hubmayr RD, Zhao X. Am J Physiol Lung Cell Mol Physiol 307: L449-L459, 2014.] that tripartite motif protein 72 (TRIM72) is essential for amending alveolar epithelial cell injury. Here, we posit that TRIM72 improves cellular integrity through its interaction with caveolin 1 (Cav1). Our data show that, in primary type I alveolar epithelial cells, lack of TRIM72 led to significant reduction of Cav1 at the plasma membrane, accompanied by marked attenuation of caveolar endocytosis. Meanwhile, lentivirus-mediated overexpression of TRIM72 selectively increases caveolar endocytosis in rat lung epithelial cells, suggesting a functional association between these two. Further coimmunoprecipitation assays show that deletion of either functional domain of TRIM72, i.e., RING, B-box, coiled-coil, or PRY-SPRY, abolishes the physical interaction between TRIM72 and Cav1, suggesting that all theoretical domains of TRIM72 are required to forge a strong interaction between these two molecules. Moreover, in vivo studies showed that injurious ventilation-induced lung cell death was significantly increased in knockout (KO) TRIM72(KO) and Cav1(KO) lungs compared with wild-type controls and was particularly pronounced in double KO mutants. Apoptosis was accompanied by accentuation of gross lung injury manifestations in the TRIM72(KO) and Cav1(KO) mice. Our data show that TRIM72 directly and indirectly modulates caveolar endocytosis, an essential process involved in repair of lung epithelial cells through removal of plasma membrane wounds. Given TRIM72's role in endomembrane trafficking and cell repair, we consider this molecule an attractive therapeutic target for patients with injured lungs. PMID

  11. The in vitro generation of lung and airway progenitor cells from human pluripotent stem cells

    PubMed Central

    Huang, Sarah X L; Green, Michael D; de Carvalho, Ana Toste; Mumau, Melanie; Chen, Ya-Wen; D’Souza, Sunita L.; Snoeck, Hans-Willem

    2015-01-01

    Lung and airway epithelial cells generated in vitro from human pluripotent stem cells have applications in regenerative medicine, modeling of lung disease, drug screening and studies of human lung development. Here we describe a strategy for directed differentiation of human pluripotent stem cells into developmental lung progenitors, and their subsequent differentiation into predominantly distal lung epithelial cells. The protocol entails four stages that recapitulate lung development and takes approximately 50 days. First, definitive endoderm is induced in the presence of high concentrations of Activin A. Subsequently, lung-biased anterior foregut endoderm is specified by sequential inhibition of BMP, TGF-β and Wnt signaling. Anterior foregut endoderm is then ventralized by applying Wnt, BMP, FGF and RA signaling to obtain lung and airway progenitors. Finally, these are further differentiated into more mature epithelial cells types using Wnt, FGF, c-AMP and glucocorticoid agonism. This protocol is conducted in defined conditions, does not involve genetic manipulation of the cells, and results in cultures where the majority of the cells express markers of various lung and airway epithelial cells, with a predominance of cells identifiable as functional type II alveolar epithelial cells. PMID:25654758

  12. 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.

  13. Control of regulatory T cells and airway tolerance by lung macrophages and dendritic cells.

    PubMed

    Duan, Wei; Croft, Michael

    2014-12-01

    Airway tolerance, a state of immunological surveillance, suppresses the development of lung inflammatory disorders that are driven by various pathological effector cells of the immune system. Tolerance in the lung to inhaled antigens is primarily mediated by regulatory T cells (Treg cells) that can inhibit effector T cells via a myriad of mechanisms. Accumulating evidence suggests that regulatory antigen-presenting cells are critical for generating Treg cells and/or maintaining the suppressive environment in the lung. This review focuses on the control of airway tolerance by Treg cells and the role of regulatory lung tissue and alveolar macrophages, and lung and lymph node dendritic cells, in contributing to airway tolerance that is associated with suppression of allergic asthmatic disease. PMID:25525738

  14. 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

  15. Obstructive Jaundice from Metastatic Squamous Cell Carcinoma of the Lung.

    PubMed

    Seth, Abhishek; Palmer, Thomas R; Campbell, Jason

    2016-01-01

    Obstructive jaundice from metastatic lung cancer is extremely rare. Most reported cases have had small cell cancer of lung or adenocarcinoma of lung as primary malignancy metastasizing to the biliary system. We report the case of a patient presenting with symptoms of obstructive jaundice found to have metastatic involvement of hepatobiliary system from squamous cell cancer (SCC) of lung. ERCP (endoscopic retrograde cholangiopancreatography) with biliary stenting is the procedure of choice in such patients. Our case is made unique by the fact that technical difficulties made it difficult for the anesthesiologists to intubate the patient for an ERCP. As a result percutaneous transhepatic cholangiogram (PTC) with internal-external biliary drainage was performed. PMID:27389381

  16. Adrenomedullin regulates club cell recovery following lung epithelial injury.

    PubMed

    García-Sanmartín, Josune; Larrayoz, Ignacio M; Martínez, Alfredo

    2016-06-01

    The equilibrium between lung epithelium damage and recovery in the context of chronic injury is at the basis of numerous lung diseases, including lung cancer and COPD. Understanding the contribution of growth factors and other molecular intermediates to this crosstalk may help in devising new therapeutic approaches. To better understand the contribution of adrenomedullin (AM) to lung homeostasis, we built club cell-specific conditional knockout (KO) mice for AM and subjected them to naphthalene injury. Untreated KO mice had lower levels of club cell 10 KDa protein (CC10) immunoreactivity than their wild type (WT) littermates in both terminal and regular bronchioles. Naphthalene injury resulted in a rapid necrosis of club cells followed by a progressive recovery of the epithelium. Club cells proliferated at higher rates in the KO mice and at 21 days post-injury the club cell coverage of the main bronchioles was higher and more homogeneous than in the WT animals. In conclusion, the paracrine/autocrine influence of AM in club cells subtly modulates their proliferation and spreading kinetics during lung epithelium recovery. PMID:26661726

  17. Interplay of macrophages and T cells in the lung vasculature.

    PubMed

    Gerasimovskaya, Evgenia; Kratzer, Adelheid; Sidiakova, Asya; Salys, Jonas; Zamora, Martin; Taraseviciene-Stewart, Laimute

    2012-05-15

    In severe pulmonary arterial hypertension (PAH), vascular lesions are composed of phenotypically altered vascular and inflammatory cells that form clusters or tumorlets. Because macrophages are found in increased numbers in intravascular and perivascular space in human PAH, here we address the question whether macrophages play a role in pulmonary vascular remodeling and whether accumulation of macrophages in the lung vasculature could be compromised by the immune system. We used the mouse macrophage cell line RAW 264.7 because these cells are resistant to apoptosis, have high proliferative capacity, and resemble cells in the plexiform lesions that tend to pile up instead of maintaining a monolayer. Cells were characterized by immunocytochemistry with cell surface markers (Lycopersicon Esculentum Lectin, CD117, CD133, FVIII, CD31, VEGFR-2, and S100). Activated, but not quiescent, T cells were able to suppress RAW 264.7 cell proliferative and migration activity in vitro. The carboxyfluorescein diacetate-labeled RAW 264.7 cells were injected into the naïve Sprague Dawley (SD) rat and athymic nude rat. Twelve days later, cells were found in the lung vasculature of athymic nude rats that lack functional T cells, contributing to vascular remodeling. No labeled RAW 264.7 cells were detected in the lungs of immune-competent SD rats. Our data demonstrate that T cells can inhibit in vitro migration and in vivo accumulation of macrophage-like cells. PMID:22387295

  18. Zinc modulates cytokine-induced lung epithelial cell barrier permeability.

    PubMed

    Bao, Shenying; Knoell, Daren L

    2006-12-01

    Apoptosis plays a causative role in acute lung injury in part due to epithelial cell loss. We recently reported that zinc protects the lung epithelium during inflammatory stress whereas depletion of intracellular zinc enhances extrinsic apoptosis. In this investigation, we evaluated the relationship between zinc, caspase-3, and cell-to-cell contact via proteins that form the adherens junction complex. Cell adhesion proteins are directly responsible for formation of the mechanical barrier of the lung epithelium. We hypothesized that exposure to inflammatory cytokines, in conjunction with zinc deprivation, would induce caspase-3, leading to degradation of junction proteins, loss of cell-to-cell contact, and compromised barrier function. Primary human upper airway and type I/II alveolar epithelial cultures were obtained from multiple donors and exposed to inflammatory stimuli that provoke extrinsic apoptosis in addition to depletion of intracellular zinc. We observed that zinc deprivation combined with tumor necrosis factor-alpha, interferon-gamma, and Fas receptor ligation accelerates caspase-3 activation, proteolysis of E-cadherin and beta-catenin, and cellular apoptosis, leading to increased paracellular leak across monolayers of both upper airway and alveolar lung epithelial cultures. Zinc supplementation inhibited apoptosis and paracellular leak, whereas caspase inhibition was less effective. We conclude that zinc is a vital factor in the lung epithelium that protects against death receptor-mediated apoptosis and barrier dysfunction. Furthermore, our findings suggest that although caspase-3 inhibition reduces lung epithelial apoptosis it does not prevent mechanical dysfunction. These findings facilitate future studies aimed at developing therapeutic strategies to prevent acute lung injury. PMID:16844947

  19. 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.

  20. Mast cells and their activation in lung disease.

    PubMed

    Virk, Harvinder; Arthur, Greer; Bradding, Peter

    2016-08-01

    Mast cells and their activation contribute to lung health via innate and adaptive immune responses to respiratory pathogens. They are also involved in the normal response to tissue injury. However, mast cells are involved in disease processes characterized by inflammation and remodeling of tissue structure. In these diseases mast cells are often inappropriately and chronically activated. There is evidence for activation of mast cells contributing to the pathophysiology of asthma, pulmonary fibrosis, and pulmonary hypertension. They may also play a role in chronic obstructive pulmonary disease, acute respiratory distress syndrome, and lung cancer. The diverse mechanisms through which mast cells sense and interact with the external and internal microenvironment account for their role in these diseases. Newly discovered mechanisms of redistribution and interaction between mast cells, airway structural cells, and other inflammatory cells may offer novel therapeutic targets in these disease processes. PMID:26845625

  1. Aerosol-Based Cell Therapy for Treatment of Lung Diseases.

    PubMed

    Kardia, Egi; Halim, Nur Shuhaidatul Sarmiza Abdul; Yahaya, Badrul Hisham

    2016-01-01

    Aerosol-based cell delivery technique via intratracheal is an effective route for delivering transplant cells directly into the lungs. An aerosol device known as the MicroSprayer(®) Aerosolizer is invented to transform liquid into an aerosol form, which then can be applied via intratracheal administration for drug delivery. The device produces a uniform and concentrated distribution of aerosolized liquid. Using the capability of MicroSprayer(®) Aerosolizer to transform liquid into aerosol form, our group has designed a novel method of cell delivery using an aerosol-based technique. We have successfully delivered skin-derived fibroblast cells and airway epithelial cells into the airway of a rabbit with minimum risk of cell loss and have uniformly distributed the cells into the airway. This chapter illustrates the application of aerosol device to deliver any type of cells for future treatment of lung diseases. PMID:27062596

  2. 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

  3. Mixed adenocarcinoma, sarcomatoid carcinoma and adenosquamous carcinoma of the prostate: A case report

    PubMed Central

    ZHANG, ZHONGFU; WANG, YADONG; ZHAO, QING; LI, GANHONG; ZHAO, XINGQI; LI, JUN; LI, XIANXIN

    2014-01-01

    Adenosquamous carcinoma (ASC) and sarcomatoid carcinoma (SC) of the prostate are rare, but highly aggressive tumors. The occurrence of mixed carcinomas in the prostate is even more rarely reported. The present study reports the case of a 62-year-old male who was diagnosed with prostatic adenocarcinoma accompanied by multiple bone metastases, as shown by a needle biopsy and skeletal computed tomography scan. The patient was treated with hormonal therapy, but thereafter, specimens from a transurethral resection of the prostate (TURP) were found to be composed of three histologically distinct elements: ASC, SC and adenocarcinoma. The level of p53 was evaluated by immunohistochemistry in detail, and it was found that this was significantly increased in the TURP samples compared with the needle biopsy samples. The abnormal level of p53 was likely associated with the prognosis of the patient; the patient succumbed to prostate carcinoma two months after the confirmation of the diagnosis. PMID:25295118

  4. 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

  5. MOLECULAR AND CYTOGENETIC ANALYSIS OF LUNG TUMOR CELL LINES

    EPA Science Inventory

    We have measured the levels of amplification of oncogenes and tumor marker genes or other genes of interest in nine human lung tumor cell lines in comparison to normal human bronchial epithelial cells or normal blood lymphocytes to test the hypothesis that aberrant amplification ...

  6. Nerve growth factor enhances Clara cell proliferation after lung injury.

    PubMed

    Sonar, S S; Schwinge, D; Kilic, A; Yildirim, A O; Conrad, M L; Seidler, K; Müller, B; Renz, H; Nockher, W A

    2010-07-01

    The lung epithelia facilitate wound closure by secretion of various cytokines and growth factors. Nerve growth factor (NGF) has been well described in airway inflammation; however, its likely role in lung repair has not been examined thus far. To investigate the repair function of NGF, experiments were performed in vitro using cultured alveolar epithelial cells and in vivo using a naphthalene-induced model of Clara epithelial cell injury. Both in vitro and in vivo experiments revealed airway epithelial cell proliferation following injury to be dependent on NGF and the expression of its receptor, tropomyosin-receptor-kinase A. Additionally, NGF also augmented in vitro migration of alveolar type II cells. In vivo, transgenic mice over-expressing NGF in Clara cells (NGFtg) did not reveal any proliferation or alteration in Clara cell phenotype. However, following Clara cell specific injury, proliferation was increased in NGFtg and impaired upon inhibition of NGF. Furthermore, NGF also promoted the expression of collagen I and fibronectin in vitro and in vivo during repair, where significantly higher levels were measured in re-epithelialising NGFtg mice. Our study demonstrates that NGF promotes the proliferation of lung epithelium in vitro and the renewal of Clara cells following lung injury in vivo. PMID:20075049

  7. AIRWAY CELL AND NUCLEAR DEPTH DISTRIBUTION IN HUMAN RAT LUNGS

    EPA Science Inventory

    To predict the critical cells that are subject to injury from inhaled radon and other alpha particle sources it is necessary to calculate the dose absorbed by the different cells in the lungs. n order to provide information necessary to make these dose determinations, the airway ...

  8. LungGENS’: a web-based tool for mapping single-cell gene expression in the developing lung

    PubMed Central

    Du, Yina; Guo, Minzhe; Whitsett, Jeffrey A; Xu, Yan

    2015-01-01

    We developed LungGENS (Lung Gene Expression iN Single-cell), a web-based bioinformatics resource for querying single-cell gene expression databases by entering a gene symbol or a list of genes or selecting a cell type of their interest. Gene query provides quantitative RNA expression of the gene of interest in each lung cell type. Cell type query returns associated selective gene signatures and genes encoding cell surface markers and transcription factors in interactive heatmap and tables. LungGENS will be broadly applicable in respiratory research, providing a cell-specific RNA expression resource at single-cell resolution. LungGENS is freely available for non-commercial use at https://research.cchmc.org/pbge/lunggens/default.html. PMID:26130332

  9. 'LungGENS': a web-based tool for mapping single-cell gene expression in the developing lung.

    PubMed

    Du, Yina; Guo, Minzhe; Whitsett, Jeffrey A; Xu, Yan

    2015-11-01

    We developed LungGENS (Lung Gene Expression iN Single-cell), a web-based bioinformatics resource for querying single-cell gene expression databases by entering a gene symbol or a list of genes or selecting a cell type of their interest. Gene query provides quantitative RNA expression of the gene of interest in each lung cell type. Cell type query returns associated selective gene signatures and genes encoding cell surface markers and transcription factors in interactive heatmap and tables. LungGENS will be broadly applicable in respiratory research, providing a cell-specific RNA expression resource at single-cell resolution. LungGENS is freely available for non-commercial use at https://research.cchmc.org/pbge/lunggens/default.html. PMID:26130332

  10. Low-grade adenosquamous carcinoma of the breast: A diagnostic and clinical challenge.

    PubMed

    Tan, Qing Ting; Chuwa, Esther Wee Lee; Chew, Sung Hock; Lim-Tan, Soo Kim; Lim, Swee Ho

    2015-07-01

    Adenosquamous carcinoma of the breast (ASBC) is a rare variant of metaplastic breast cancer with both glandular as well as squamous differentiation. Their lack of distinct imaging characteristics, sometimes subtle histological characteristics and overlapping features with other benign lesions pose a diagnostic challenge. Unlike other forms of metaplastic breast cancer, low-grade adenosquamous carcinoma (LGAC) tends to follow an indolent course with favourable prognosis. We reviewed eight cases of LGAC in our institution from June 2005 to March 2014. In six cases, LGAC was only found after excisional biopsy. In our patients, LGAC frequently co-existed with other forms of breast pathology. Two patients had incidental findings of LGAC alongside their primary malignant tumour (adenoid cystic carcinoma and invasive ductal carcinoma in one, four foci between 0.5 and 4.0 mm within a radial sclerosing lesion adjacent to a malignant phyllodes tumour in the other). A further four patients had LGAC within a complex sclerosing lesion. One patient had a focus of LGAC within a fibroadenoma. One had a focus of LGAC within a benign phyllodes tumour. None of the patients had evidence of nodal involvement. A high degree of suspicion is recommended as such lesions tend to be incidental histological findings within benign tumours or within complex sclerosing lesions. Although the risk of nodal and distant metastasis is low, the potential for local recurrence necessitates aggressive local excision with margin clearance. The role of axillary dissection has yet to be defined and routine sentinel node biopsy and axillary clearance may not be necessary in view of rarity of nodal metastasis in literature. Benefit from adjuvant radiotherapy or chemotherapy is not clearly defined. All eight patients in our study have shown no evidence of recurrence after definitive surgery but longer periods of surveillance is required. PMID:25986061

  11. An observational study of giant cell interstitial pneumonia and lung fibrosis in hard metal lung disease

    PubMed Central

    Tanaka, Junichi; Moriyama, Hiroshi; Terada, Masaki; Takada, Toshinori; Suzuki, Eiichi; Narita, Ichiei; Kawabata, Yoshinori; Yamaguchi, Tetsuo; Hebisawa, Akira; Sakai, Fumikazu; Arakawa, Hiroaki

    2014-01-01

    Background Hard metal lung disease has various pathological patterns including giant cell interstitial pneumonia (GIP) and usual interstitial pneumonia (UIP). Although the UIP pattern is considered the prominent feature in advanced disease, it is unknown whether GIP finally progresses to the UIP pattern. Objectives To clarify clinical, pathological and elemental differences between the GIP and UIP patterns in hard metal lung disease. Methods A cross-sectional study of patients from 17 institutes participating in the 10th annual meeting of the Tokyo Research Group for Diffuse Parenchymal Lung Diseases, 2009. Nineteen patients (seven female) diagnosed with hard metal lung disease by the presence of tungsten in lung specimens were studied. Results Fourteen cases were pathologically diagnosed as GIP or centrilobular inflammation/fibrosing. The other five cases were the UIP pattern or upper lobe fibrosis. Elemental analyses of lung specimens of GIP showed tungsten throughout the centrilobular fibrotic areas. In the UIP pattern, tungsten was detected in the periarteriolar area with subpleural fibrosis, but no association with centrilobular fibrosis or inflammatory cell infiltration. The GIP group was younger (43.1 vs 58.6 years), with shorter exposure duration (73 vs 285 months; p<0.01), lower serum KL-6 (398 vs 710 U/mL) and higher lymphocyte percentage in bronchoalveolar lavage fluid (31.5% vs 3.22%; p<0.05) than the fibrosis group. Conclusions The UIP pattern or upper lobe fibrosis is remarkably different from GIP in distribution of hard metal elements, associated interstitial inflammation and fibrosis, and clinical features. In hard metal lung disease, the UIP pattern or upper lobe fibrosis may not be an advanced form of GIP. PMID:24674995

  12. 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

  13. Lung epithelial cells modulate the inflammatory response of alveolar macrophages.

    PubMed

    Rubovitch, Vardit; Gershnabel, Shoham; Kalina, Moshe

    2007-12-01

    The goal of this study was to examine the effect of alveolar epithelial cells on inflammatory responses in macrophages. Lung epithelial cells (either rat RLE-6TN or human A549 cells) reduced LPS-induced NO production in alveolar macrophages (AM) in a contact-independent mechanism. The inhibitory effect of the epithelial cells was present already at the transcriptional level: LPS-induced inducible NO synthase (iNOS) expression was significantly smaller. Surfactant protein A (SP-A)-induced NO production by alveolar macrophages was also reduced in the presence of A549 cells, though, by a different kinetics. LPS-induced interleukin-6 (IL-6) production (another inflammatory pathway) by alveolar macrophages was also reduced in the presence of RLE-6TN cells. These data suggest a role for lung epithelial cells in the complicated modulation of inflammatory processes, and provide an insight into the mechanism underlying. PMID:17851743

  14. 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

  15. 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.

  16. 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

  17. The Epithelial Cell in Lung Health and Emphysema Pathogenesis

    PubMed Central

    Mercer, Becky A.; Lemaître, Vincent; Powell, Charles A.; D’Armiento, Jeanine

    2009-01-01

    Cigarette smoking is the primary cause of the irreversible lung disease emphysema. Historically, inflammatory cells such as macrophages and neutrophils have been studied for their role in emphysema pathology. However, recent studies indicate that the lung epithelium is an active participant in emphysema pathogenesis and plays a critical role in the lung’s response to cigarette smoke. Tobacco smoke increases protease production and alters cytokine expression in isolated epithelial cells, suggesting that these cells respond potently even in the absence of a complete inflammatory program. Tobacco smoke also acts as an immunosuppressant, reducing the defense function of airway epithelial cells and enhancing colonization of the lower airways. Thus, the paradigm that emphysema is strictly an inflammatory-cell based disease is shifting to consider the involvement of resident epithelial cells. Here we review the role of epithelial cells in lung development and emphysema. To better understand tobacco-epithelial interactions we performed microarray analyses of RNA from human airway epithelial cells exposed to smoke extract for 24 hours. These studies identified differential regulation of 425 genes involved in diverse biological processes, such as apoptosis, immune function, cell cycle, signal transduction, proliferation, and antioxidants. Some of these genes, including VEGF, glutathione peroxidase, IL-13 receptor, and cytochrome P450, have been previously reported to be altered in the lungs of smokers. Others, such as pirin, cathepsin L, STAT1, and BMP2, are shown here for the first time to have a potential role in smoke-associated injury. These data broaden our understanding of the importance of epithelial cells in lung health and cigarette smoke-induced emphysema. PMID:19662102

  18. Endotoxin suppresses surfactant synthesis in cultured rat lung cells

    SciTech Connect

    Li, J.J.; Sanders, R.L.; McAdam, K.P.; Gelfand, J.A.; Burke, J.F.

    1989-02-01

    Pulmonary complications secondary to postburn sepsis are a major cause of death in burned patients. Using an in vitro organotypic culture system, we examined the effect of E. coli endotoxin (LPS) on lung cell surfactant synthesis. Our results showed that E. coli endotoxin (1.0, 2.5, 10 micrograms LPS/ml) was capable of suppressing the incorporation of /sup 3/H-choline into de novo synthesized surfactant, lamellar bodies (LB), and common myelin figures (CMF) at 50%, 68%, and 64%, respectively. In a similar study, we were able to show that LPS also inhibited /sup 3/H-palmitate incorporation by cultured lung cells. LPS-induced suppression of surfactant synthesis was reversed by hydrocortisone. Our results suggest that LPS may play a significant role in reducing surfactant synthesis by rat lung cells, and thus contribute to the pathogenesis of sepsis-related respiratory distress syndrome (RDS) in burn injury.

  19. 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

  20. 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

  1. Generation of leukotrienes by purified human lung mast cells.

    PubMed Central

    MacGlashan, D W; Schleimer, R P; Peters, S P; Schulman, E S; Adams, G K; Newball, H H; Lichtenstein, L M

    1982-01-01

    Although mediator release from mast cells and basophils plays a central role in the pathogenesis of human allergic disease, biochemical studies have been restricted to rat peritoneal mast cells and basophilic leukemia cells because they could be easily purified. We have used two new techniques of cell separation to purify human lung mast cells to 98% homogeneity. Lung cell suspensions were obtained by dispersion of chopped lung tissue with proteolytic enzymes. Mast cells were then purified from the suspensions by countercurrent centrifugal elutriation and affinity chromatography. The purified mast cells released both histamine and slow-reacting substance of anaphylaxis (SRS-A) (leukotriene C and D) during stimulation with goat anti-human IgE antibody. Moreover, these preparations were able to generate significant quantities of SRS-A (32 +/- 7 x 10(-17) LTD mole-equivalents/mast cell) at all stages of purification, indicating that a secondary cell is not necessary for the antigen-induced release of SRS. Images PMID:7119113

  2. 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

  3. 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

  4. 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.

  5. Lung epithelial cell death induced by oil-dispersant mixtures.

    PubMed

    Wang, He; Shi, Yongli; Major, Danielle; Yang, Zhanjun

    2012-08-01

    The dispersants used in oil spill disasters are claimed to be safe, but increased solubility of high-molecular-weight components in crude oil is of public health concern. The water-accommodated fractions (WAF) of crude oil mixed with dispersants may become airborne and cause lung epithelial damage when inhaled. This study was designed to examine the cell death and related death pathways of lung epithelial cells in response to WAF. Cultured A549 cells were treated for 2 or 24h with different concentrations of WAF. The WAF was prepared by mixing each of the dispersants (Corexit EC9527A, Corexit EC9500A and Corexit EC9580A) with crude oil for extraction with PBS. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide MTT assay, lactate dehydrogenase assay, morphology and cleaved caspase 9 protein, and microtubule-associated protein 1 light chain 3 were all used to measure cell viability, necrosis, apoptosis and autophagy quantitation, respectively. Results showed that the WAF of oil-dispersant mixtures caused cell death in the lung epithelial cells, in a dose-dependent manner, with the major cellular pathways of necrosis and apoptosis involved. Autophagy also occurred in cells exposed to WAF mixtures at lower concentrations before any detectable cell death, indicating greater sensitivity to WAF exposure. The three types of cell behavior, namely necrosis, apoptosis and autophagy, may play different roles in oil spill-related respiratory disorders. PMID:22504303

  6. 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

  7. [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

  8. The putative role of mast cells in lung transplantation.

    PubMed

    Jungraithmayr, W

    2015-03-01

    Mast cells (MCs) were primarily recognized as effector cells of allergy. These cells are acting predominantly at the interface between the host and the external environment, such as skin, gastrointestinal and the respiratory tract. Only recently, MCs have gained increased recognition as cells of functional plasticity with immune-regulatory properties that influence both the innate and the adaptive immune response in inflammatory disorders, cancer and transplantation. Through the secretion of both proinflammatory and antiinflammatory mediators, MCs can either ameliorate or deteriorate the course and outcome in lung transplantation. Recent research from other models recognized the immune-protective activity of MCs including its role as an important source of IL-10 and TGF-β for the modulation of alloreactive T cell responses or assistance in Treg activity. This paper summarizes the current understanding of MCs in lung transplantation and discusses MC-mediated immune-mechanisms by which the outcome of the engrafted organ is modulated. PMID:25693471

  9. Silencing Aurora-A with siRNA inhibits cell proliferation in human lung adenocarcinoma cells.

    PubMed

    Zhong, Ning; Shi, Shunbin; Wang, Hongzhen; Wu, Guangzhou; Wang, Yunliang; Ma, Qiang; Wang, Hongwei; Liu, Yuanhua; Wang, Jinzhi

    2016-09-01

    Aurora kinase A (AURKA) is an oncogenic serine/threonine kinase, it plays important roles in tumorigenesis and chemoresistance. In this study, we investigated the expression of AURKA in lung adenocarcinoma tissues, the role of small interference RNA targeting AURKA on growth, cell cycle, and apoptosis of lung adenocarcinoma cell lines in vitro. The AURKA is highly expressed in lung adenocarcinoma tissues and human lung adenocarcinoma cell lines. Lentivirus-mediated short hairpin RNA (shRNA) was used to knock down AURKA expression in human lung adenocarcinoma cell lines H1299 and A549. The results indicated that depletion of AURKA could inhibit cell growth, cause cell cycle arrest and apoptosis. The potential mechanisms of AURKA inhibition induced cell cycle arrest and apoptosis are associated with downregulated RAF-1, CCND2, CCND3, CDK4, PAK4, EGFR and upregulated WEE1 expression. Furthermore, AURKA knockdown cooperated with vincristine (VCR) to repress A549 cell proliferation. Therefore, AURKA plays important roles in the proliferation of human lung adenocarcinoma cells, which suggests that AURKA could be a promising tool for lung adenocarcinoma therapy. PMID:27571708

  10. 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

  11. Diversity of epithelial stem cell types in adult lung.

    PubMed

    Li, Feng; He, Jinxi; Wei, Jun; Cho, William C; Liu, Xiaoming

    2015-01-01

    Lung is a complex organ lined with epithelial cells. In order to maintain its homeostasis and normal functions following injuries caused by varied extraneous and intraneous insults, such as inhaled environmental pollutants and overwhelming inflammatory responses, the respiratory epithelium normally undergoes regenerations by the proliferation and differentiation of region-specific epithelial stem/progenitor cells that resided in distinct niches along the airway tree. The importance of local epithelial stem cell niches in the specification of lung stem/progenitor cells has been recently identified. Studies using cell differentiating and lineage tracing assays, in vitro and/or ex vivo models, and genetically engineered mice have suggested that these local epithelial stem/progenitor cells within spatially distinct regions along the pulmonary tree contribute to the injury repair of epithelium adjacent to their respective niches. This paper reviews recent findings in the identification and isolation of region-specific epithelial stem/progenitor cells and local niches along the airway tree and the potential link of epithelial stem cells for the development of lung cancer. PMID:25810726

  12. Diversity of Epithelial Stem Cell Types in Adult Lung

    PubMed Central

    Li, Feng; He, Jinxi; Wei, Jun; Cho, William C.; Liu, Xiaoming

    2015-01-01

    Lung is a complex organ lined with epithelial cells. In order to maintain its homeostasis and normal functions following injuries caused by varied extraneous and intraneous insults, such as inhaled environmental pollutants and overwhelming inflammatory responses, the respiratory epithelium normally undergoes regenerations by the proliferation and differentiation of region-specific epithelial stem/progenitor cells that resided in distinct niches along the airway tree. The importance of local epithelial stem cell niches in the specification of lung stem/progenitor cells has been recently identified. Studies using cell differentiating and lineage tracing assays, in vitro and/or ex vivo models, and genetically engineered mice have suggested that these local epithelial stem/progenitor cells within spatially distinct regions along the pulmonary tree contribute to the injury repair of epithelium adjacent to their respective niches. This paper reviews recent findings in the identification and isolation of region-specific epithelial stem/progenitor cells and local niches along the airway tree and the potential link of epithelial stem cells for the development of lung cancer. PMID:25810726

  13. Loss of lysophosphatidic acid receptor-3 enhances cell migration in rat lung tumor cells

    SciTech Connect

    Hayashi, Mai; Okabe, Kyoko; Yamawaki, Yasuna; Teranishi, Miki; Honoki, Kanya; Mori, Toshio; Fukushima, Nobuyuki; Tsujiuchi, Toshifumi

    2011-02-18

    Research highlights: {yields} Loss of the Lpar3 expression due to aberrant DNA methylation occurred in rat lung tumor cells. {yields} The Lpar3 inhibited cell migration of rat lung tumor cells. {yields} The Lpar3 may act as a negative regulator of rat lung tumor cells. -- Abstract: Lysophosphatidic acid (LPA) indicates several biological effects, such as cell proliferation, differentiation and migration. LPA interacts with G protein-coupled transmembrane LPA receptors. In our previous report, we detected that loss of the LPA receptor-1 (Lpar1) expression is due to its aberrant DNA methylation in rat tumor cell lines. In this study, to assess an involvement of the other LPA receptor, Lpar3, in the pathogenesis of rat lung tumor cells, we measured the expression levels of the Lpar3 gene and its DNA methylation status by reverse transcription (RT)-polymerase chain reaction (PCR) and bisulfite sequencing analyses, respectively. RLCNR lung adenocarcinoma cells showed reduced expression of the Lpar3, compared with normal lung tissues. In the 5' upstream region of the Lpar3, normal lung tissues were unmethylated. By contrast, RLCNR cells were highly methylated, correlating with reduced expressions of the Lpar3. Based on these results, we generated the Lpar3-expressing RLCNR-a3 cells and measured the cell migration ability. Interestingly, the cell migration of RLCNR-a3 cells was significantly lower than that of RLCNR cells. This study suggests that loss of the Lpar3 due to aberrant DNA methylation may be involved in the progression of rat lung tumor cells.

  14. From Here to There, Progenitor Cells and Stem Cells Are Everywhere in Lung Vascular Remodeling.

    PubMed

    Heise, Rebecca L; Link, Patrick A; Farkas, Laszlo

    2016-01-01

    The field of stem cell biology, cell therapy, and regenerative medicine has expanded almost exponentially, in the last decade. Clinical trials are evaluating the potential therapeutic use of stem cells in many adult and pediatric lung diseases with vascular component, such as bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), or pulmonary arterial hypertension (PAH). Extensive research activity is exploring the lung resident and circulating progenitor cells and their contribution to vascular complications of chronic lung diseases, and researchers hope to use resident or circulating stem/progenitor cells to treat chronic lung diseases and their vascular complications. It is becoming more and more clear that progress in mechanobiology will help to understand the various influences of physical forces and extracellular matrix composition on the phenotype and features of the progenitor cells and stem cells. The current review provides an overview of current concepts in the field. PMID:27583245

  15. From Here to There, Progenitor Cells and Stem Cells Are Everywhere in Lung Vascular Remodeling

    PubMed Central

    Heise, Rebecca L.; Link, Patrick A.; Farkas, Laszlo

    2016-01-01

    The field of stem cell biology, cell therapy, and regenerative medicine has expanded almost exponentially, in the last decade. Clinical trials are evaluating the potential therapeutic use of stem cells in many adult and pediatric lung diseases with vascular component, such as bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), or pulmonary arterial hypertension (PAH). Extensive research activity is exploring the lung resident and circulating progenitor cells and their contribution to vascular complications of chronic lung diseases, and researchers hope to use resident or circulating stem/progenitor cells to treat chronic lung diseases and their vascular complications. It is becoming more and more clear that progress in mechanobiology will help to understand the various influences of physical forces and extracellular matrix composition on the phenotype and features of the progenitor cells and stem cells. The current review provides an overview of current concepts in the field. PMID:27583245

  16. 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

  17. RESPONSES OF LUNG CELLS TO METALS IN MANUFACTURED NANOPARTICLES

    EPA Science Inventory

    In vitro assays with lung epithelial cells were used to compare pairs of micron-sized and nano-sized particles with the same nominal chemical composition for cytotoxicity and induction of the proinflammatory cytokine IL-6.  Results suggested ...

  18. 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

  19. Expression of Carcinoembryonic Cell Adhesion Molecule 6 and Alveolar Epithelial Cell Markers in Lungs of Human Infants with Chronic Lung Disease.

    PubMed

    Gonzales, Linda W; Gonzalez, Robert; Barrette, Anne Marie; Wang, Ping; Dobbs, Leland; Ballard, Philip L

    2015-12-01

    The membrane protein carcinoembryonic antigen cell adhesion molecule (CEACAM6) is expressed in the epithelium of various tissues, participating in innate immune defense, cell proliferation and differentiation, with overexpression in gastrointestinal tract, pancreatic and lung tumors. It is developmentally and hormonally regulated in fetal human lung, with an apparent increased production in preterm infants with respiratory failure. To further examine the expression and cell localization of CEACAM6, we performed immunohistochemical and biochemical studies in lung specimens from infants with and without chronic lung disease. CEACAM6 protein and mRNA were increased ~4-fold in lungs from infants with chronic lung disease as compared with controls. By immunostaining, CEACAM6 expression was markedly increased in the lung parenchyma of infants and children with a variety of chronic lung disorders, localizing to hyperplastic epithelial cells with a ~7-fold elevated proliferative rate by PCNA staining. Some of these cells also co-expressed membrane markers of both type I and type II cells, which is not observed in normal postnatal lung, suggesting they are transitional epithelial cells. We suggest that CEACAM6 is both a marker of lung epithelial progenitor cells and a contributor to the proliferative response after injury due to its anti-apoptotic and cell adhesive properties. PMID:26374831

  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. Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness

    PubMed Central

    Ruiz de Garibay, Gorka; Herranz, Carmen; Llorente, Alicia; Boni, Jacopo; Serra-Musach, Jordi; Mateo, Francesca; Aguilar, Helena; Gómez-Baldó, Laia; Petit, Anna; Vidal, August; Climent, Fina; Hernández-Losa, Javier; Cordero, Álex; González-Suárez, Eva; Sánchez-Mut, José Vicente; Esteller, Manel; Llatjós, Roger; Varela, Mar; López, José Ignacio; García, Nadia; Extremera, Ana I.; Gumà, Anna; Ortega, Raúl; Plà, María Jesús; Fernández, Adela; Pernas, Sònia; Falo, Catalina; Morilla, Idoia; Campos, Miriam; Gil, Miguel; Román, Antonio; Molina-Molina, María; Ussetti, Piedad; Laporta, Rosalía; Valenzuela, Claudia; Ancochea, Julio; Xaubet, Antoni; Casanova, Álvaro; Pujana, Miguel Angel

    2015-01-01

    Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM. PMID:26167915

  2. Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness.

    PubMed

    Ruiz de Garibay, Gorka; Herranz, Carmen; Llorente, Alicia; Boni, Jacopo; Serra-Musach, Jordi; Mateo, Francesca; Aguilar, Helena; Gómez-Baldó, Laia; Petit, Anna; Vidal, August; Climent, Fina; Hernández-Losa, Javier; Cordero, Álex; González-Suárez, Eva; Sánchez-Mut, José Vicente; Esteller, Manel; Llatjós, Roger; Varela, Mar; López, José Ignacio; García, Nadia; Extremera, Ana I; Gumà, Anna; Ortega, Raúl; Plà, María Jesús; Fernández, Adela; Pernas, Sònia; Falo, Catalina; Morilla, Idoia; Campos, Miriam; Gil, Miguel; Román, Antonio; Molina-Molina, María; Ussetti, Piedad; Laporta, Rosalía; Valenzuela, Claudia; Ancochea, Julio; Xaubet, Antoni; Casanova, Álvaro; Pujana, Miguel Angel

    2015-01-01

    Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM. PMID:26167915

  3. 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

  4. ADAM23 is downregulated in side population and suppresses lung metastasis of lung carcinoma cells.

    PubMed

    Ota, Masahide; Mochizuki, Satsuki; Shimoda, Masayuki; Abe, Hitoshi; Miyamae, Yuka; Ishii, Ken; Kimura, Hiroshi; Okada, Yasunori

    2016-04-01

    Cancer cells contain a small population of cancer stem cells or cancer initiating cells, which can be enriched in the side population (SP) after fluorescence activated cell sorting. To examine the members of the ADAM, ADAMTS and MMP gene families related to phenotypes of the SP and the main population (MP), we screened the expression of all the members in the propagated SP and MP of A549 lung adenocarcinoma cells, and found that the relative expression ratio of ADAM23 in the MP to the SP is most highly increased, but none of them are increased in the SP. A similar result on the ADAM23 expression was obtained with another cell line, Calu-3 cells. Overexpression of ADAM23 inhibited colony formation, cell adhesion and migration, and knockdown of ADAM23 by shRNA showed the reverse effects. ADAM23-mediated suppression of colony formation, cell adhesion and migration was greatly reduced by treatment with neutralizing anti-ADAM23 antibody, anti-αvβ3 integrin antibody and/or ADAM23 disintegrin peptide. Expression of cancer stem cell-related genes, including AKRC1/2, TM4SF1 and NR0B1, was increased by knockdown of ADAM23. In addition, lung metastasis of A549 transfectants with different levels of ADAM23 expression was negatively regulated by the ADAM23 expression levels. Our data provide evidence that ADAM23 plays a role in suppression of cancer cell progression through interaction with αvβ3 integrin, and suggest that downregulation of ADAM23 in SP cells may contribute toward providing a cancer stem cell phenotype by facilitating the activity of integrin αvβ3. PMID:26800504

  5. Vitamin D inhibition of lung adenocarcinoma cell proliferation in vitro.

    PubMed

    Li, Rong; Lou, Yuqing; Zhang, Weiyan; Dong, Qianggang; Han, Baohui

    2014-11-01

    Vitamin D has the capability to inhibit tumor cell proliferation and promote tumor cell apoptosis but whether this mechanism exists in lung adenocarcinoma cells remains to be studied. Our objective is to explore whether vitamin D has the capability to inhibit lung adenocarcinoma cell proliferation and synergize with cisplatin. Our method was to explore the effect of different concentrations of 1,25(OH)2D3 with or without cisplatin on lung adenocarcinoma cells by detecting cell proliferation rates at different time points. 1,25(OH)2D3 was capsulated with nanomaterial before acting on lung adenocarcinoma cells, and cell proliferation rates at different time points were detected with the CCK-8 method. When vitamin D was applied at a concentration of 1 × 10(-7) and 1 × 10(-6) mol/L on A549, PC9, SPC-A1, and H1650 cells for 72 h, no inhibition occurred on cell proliferation. Between the concentrations of 1 × 10(-5) and 0.5 × 10(-5) mol/L, inhibition on cell proliferation increased with drug action time. Between the concentration of 2.5 × 10(-5) and 0.03 × 10(-5) mol/L, inhibition on cell proliferation increased with increasing drug concentration. Analysis using bivariate correlations showed that the correlation coefficient of the proliferation inhibition rate and drug content was 0.580 (p < 0.0001). The correlation coefficient of proliferation inhibition rate and the drug action time was 0.379 (p = 0.01). The combined use of vitamin D and dichlorodiammine-platinum(II) (DDP) significantly increased the inhibition rate on A549 cell proliferation, which peaked after culturing for 96 h (Table 4). Further analysis using bivariate correlations showed that the correlation coefficient between proliferation inhibition rate and DDP concentration was 0.319 (p < 0.0001). The correlation coefficient of the proliferation inhibition rate and vitamin D concentration was 0.269 (p < 0.0001). The correlation coefficient of proliferation inhibition and drug action time was 0.221(p

  6. 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

  7. Epithelial cell apoptosis causes acute lung injury masquerading as emphysema.

    PubMed

    Mouded, Majd; Egea, Eduardo E; Brown, Matthew J; Hanlon, Shane M; Houghton, A McGarry; Tsai, Larry W; Ingenito, Edward P; Shapiro, Steven D

    2009-10-01

    Theories of emphysema traditionally revolved around proteolytic destruction of extracellular matrix. Models have recently been developed that show airspace enlargement with the induction of pulmonary cell apoptosis. The purpose of this study was to determine the mechanism by which a model of epithelial cell apoptosis caused airspace enlargement. Mice were treated with either intratracheal microcystin (MC) to induce apoptosis, intratracheal porcine pancreatic elastase (PPE), or their respective vehicles. Mice from all groups were inflated and morphometry was measured at various time points. Physiology measurements were performed for airway resistance, tissue elastance, and lung volumes. The groups were further analyzed by air-saline quasistatic measurements, surfactant staining, and surfactant functional studies. Mice treated with MC showed evidence of reversible airspace enlargement. In contrast, PPE-treated mice showed irreversible airspace enlargement. The airspace enlargement in MC-treated mice was associated with an increase in elastic recoil due to an increase in alveolar surface tension. PPE-treated mice showed a loss of lung elastic recoil and normal alveolar surface tension, a pattern more consistent with human emphysema. Airspace enlargement that occurs with the MC model of pulmonary epithelial cell apoptosis displays physiology distinct from human emphysema. Reversibility, restrictive physiology due to changes in surface tension, and alveolar enlargement associated with heterogeneous alveolar collapse are most consistent with a mild acute lung injury. Inflation near total lung capacity gives the appearance of enlarged alveoli as neighboring collapsed alveoli exert tethering forces. PMID:19188661

  8. 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

  9. 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

  10. 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.

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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.

  16. Cell-associated bacteria in the human lung microbiome

    PubMed Central

    2014-01-01

    Background Recent studies have revealed that bronchoalveolar lavage (BAL) fluid contains previously unappreciated communities of bacteria. In vitro and in vivo studies have shown that host inflammatory signals prompt bacteria to disperse from cell-associated biofilms and adopt a virulent free-living phenotype. The proportion of the lung microbiota that is cell-associated is unknown. Results Forty-six BAL specimens were obtained from lung transplant recipients and divided into two aliquots: ‘whole BAL’ and ‘acellular BAL,’ the latter processed with a low-speed, short-duration centrifugation step. Both aliquots were analyzed via bacterial 16S rRNA gene pyrosequencing. The BAL specimens represented a wide spectrum of lung health, ranging from healthy and asymptomatic to acutely infected. Bacterial signal was detected in 52% of acellular BAL aliquots, fewer than were detected in whole BAL (96%, p ≤ 0.0001). Detection of bacteria in acellular BAL was associated with indices of acute infection [BAL neutrophilia, high total bacterial (16S) DNA, low community diversity, p < 0.01 for all] and, independently, with low relative abundance of specific taxonomic groups (p < 0.05). When whole and acellular aliquots from the same bronchoscopy were directly compared, acellular BAL contained fewer bacterial species (p < 0.05); whole and acellular BAL similarity was positively associated with evidence of infection and negatively associated with relative abundance of several prominent taxa (p < 0.001). Acellular BAL contained decreased relative abundance of Prevotella spp. (p < 0.05) and Pseudomonas fluorescens (p < 0.05). Conclusions We present a novel methodological and analytical approach to the localization of lung microbiota and show that prominent members of the lung microbiome are cell-associated, potentially via biofilms, cell adhesion, or intracellularity. PMID:25206976

  17. 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

  18. 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

  19. 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

  20. 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.

  1. 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

  2. Adenosquamous carcinoma of the pancreas: Molecular characterization of 23 patients along with a literature review

    PubMed Central

    Borazanci, Erkut; Millis, Sherri Z; Korn, Ron; Han, Haiyong; Whatcott, Clifford J; Gatalica, Zoran; Barrett, Michael T; Cridebring, Derek; Von Hoff, Daniel D

    2015-01-01

    Adenosquamous carcinoma of the pancreas (ASCP) is a rare entity. Like adenocarcinoma of the pancreas, overall survival is poor. Characteristics of ASCP include central tumor necrosis, along with osteoclasts and hypercalcemia. Various theories exist as to why this histological subtype exists, as normal pancreas tissue has no benign squamous epithelium. Due to the rarity of this disease, limited molecular analysis has been performed, and those reports indicate unique molecular features of ASCP. In this paper, we characterize 23 patients diagnosed with ASCP through molecular profiling using immunohistochemistry staining, fluorescent in situ hybridization, chromogenic in situ hybridization, and gene sequencing, Additionally, we provide a comprehensive literature review of what is known to date of ASCP. Molecular characterization revealed overexpression in MRP1 (80%), MGMT (79%), TOP2A (75), RRM1 (42%), TOPO1 (42%), PTEN (45%), CMET (40%), and C-KIT (10%) among others. One hundred percent of samples tested were positive for KRAS mutations. This analysis shows heretofore unsuspected leads to be considered for treatments of this rare type of exocrine pancreas cancer. Molecular profiling may be appropriate to provide maximum information regarding the patient’s tumor. Further work should be pursued to better characterize this disease. PMID:26380056

  3. Vitamin D-responsive SGPP2 variants associated with lung cell expression and lung function

    PubMed Central

    2013-01-01

    Background Vitamin D is associated with lung health in epidemiologic studies, but mechanisms mediating observed associations are poorly understood. This study explores mechanisms for an effect of vitamin D in lung through an in vivo gene expression study, an expression quantitative trait loci (eQTL) analysis in lung tissue, and a population-based cohort study of sequence variants. Methods Microarray analysis investigated the association of gene expression in small airway epithelial cells with serum 25(OH)D in adult non-smokers. Sequence variants in candidate genes identified by the microarray were investigated in a lung tissue eQTL database, and also in relation to cross-sectional pulmonary function in the Health, Aging, and Body Composition (Health ABC) study, stratified by race, with replication in the Framingham Heart Study (FHS). Results 13 candidate genes had significant differences in expression by serum 25(OH)D (nominal p < 0.05), and a genome-wide significant eQTL association was detected for SGPP2. In Health ABC, SGPP2 SNPs were associated with FEV1 in both European- and African-Americans, and the gene-level association was replicated in European-American FHS participants. SNPs in 5 additional candidate genes (DAPK1, FSTL1, KAL1, KCNS3, and RSAD2) were associated with FEV1 in Health ABC participants. Conclusions SGPP2, a sphingosine-1-phosphate phosphatase, is a novel vitamin D-responsive gene associated with lung function. The identified associations will need to be followed up in further studies. PMID:24274704

  4. Decreased Laminin Expression by Human Lung Epithelial Cells and Fibroblasts Cultured in Acellular Lung Scaffolds from Aged Mice

    PubMed Central

    Godin, Lindsay M.; Sandri, Brian J.; Wagner, Darcy E.; Meyer, Carolyn M.; Price, Andrew P.; Akinnola, Ifeolu; Weiss, Daniel J.; Panoskaltsis-Mortari, Angela

    2016-01-01

    The lung changes functionally and structurally with aging. However, age-related effects on the extracellular matrix (ECM) and corresponding effects on lung cell behavior are not well understood. We hypothesized that ECM from aged animals would induce aging-related phenotypic changes in healthy inoculated cells. Decellularized whole organ scaffolds provide a powerful model for examining how ECM cues affect cell phenotype. The effects of age on ECM composition in both native and decellularized mouse lungs were assessed as was the effect of young vs old acellular ECM on human bronchial epithelial cells (hBECs) and lung fibroblasts (hLFs). Native aged (1 year) lungs demonstrated decreased expression of laminins α3 and α4, elastin and fibronectin, and elevated collagen, compared to young (3 week) lungs. Proteomic analyses of decellularized ECM demonstrated similar findings, and decellularized aged lung ECM contained less diversity in structural proteins compared to young ECM. When seeded in old ECM, hBECs and hLFs demonstrated lower gene expression of laminins α3 and α4, respectively, as compared to young ECM, paralleling the laminin deficiency of aged ECM. ECM changes appear to be important factors in potentiating aging-related phenotypes and may provide clues to mechanisms that allow for aging-related lung diseases. PMID:26954258

  5. Fibroblast Growth Factor-10 (FGF-10) Mobilizes Lung-resident Mesenchymal Stem Cells and Protects Against Acute Lung Injury

    PubMed Central

    Tong, Lin; Zhou, Jian; Rong, Linyi; Seeley, Eric J.; Pan, Jue; Zhu, Xiaodan; Liu, Jie; Wang, Qin; Tang, Xinjun; Qu, Jieming; Bai, Chunxue; Song, Yuanlin

    2016-01-01

    FGF-10 can prevent or reduce lung specific inflammation due to traumatic or infectious lung injury. However, the exact mechanisms are poorly characterized. Additionally, the effect of FGF-10 on lung-resident mesenchymal stem cells (LR-MSCs) has not been studied. To better characterize the effect of FGF-10 on LR-MSCs, FGF-10 was intratracheally delivered into the lungs of rats. Three days after instillation, bronchoalveolar lavage was performed and plastic-adherent cells were cultured, characterized and then delivered therapeutically to rats after LPS intratracheal instillation. Immunophenotyping analysis of FGF-10 mobilized and cultured cells revealed expression of the MSC markers CD29, CD73, CD90, and CD105, and the absence of the hematopoietic lineage markers CD34 and CD45. Multipotency of these cells was demonstrated by their capacity to differentiate into osteocytes, adipocytes, and chondrocytes. Delivery of LR-MSCs into the lungs after LPS injury reduced the inflammatory response as evidenced by decreased wet-to-dry ratio, reduced neutrophil and leukocyte recruitment and decreased inflammatory cytokines compared to control rats. Lastly, direct delivery of FGF-10 in the lungs of rats led to an increase of LR-MSCs in the treated lungs, suggesting that the protective effect of FGF-10 might be mediated, in part, by the mobilization of LR-MSCs in lungs. PMID:26869337

  6. Multicolor fluorescence in situ hybridization and comparative genomic hybridization reveal molecular events in lung adenocarcinomas and squamous cell lung carcinomas.

    PubMed

    Shen, Hua; Gao, Wen; Wu, Yu-jie; Qiu, Hai-rong; Shu, Yong-qian

    2009-07-01

    We have used the molecular cytogenetic techniques of multicolor fluorescence in situ hybridization (M-FISH) and comparative genomic hybridization (CGH) to analyze two established lung cancer cell lines (A549, H520), 80 primary lung adenocarcinoma samples and 80 squamous cell lung carcinoma samples in order to identify common chromosomal aberrations. M-FISH revealed numerous complex chromosomal rearrangements. Chromosomes 5, 6, 11, 12, and 17 were most frequently involved in interchromosomal translocations. CGH revealed regions on 1q, 2p, 3q, 5p, 5q, 7p, 8q, 11q, 12q, 14q, 16p, 17p, 19q, 20q, 21q and 22q to be commonly over-represented and regions on 2q, 3p, 4p, 5q, 7q, 8p, 9p, 13q, 14q, and 17p to be under-represented. In lung adenocarcinomas the most common gains were found in 16p13 (50%); while in squamous cell lung carcinomas the common gains were found in 17q21 (45%) and these alterations were observed to be associated with their specific pathological subtype. In conclusion, the present study contributes to the molecular biological characterization in lung adenocarcinomas and squamous cell lung carcinomas and through evaluation of molecular events to the recently emergent focus on novel markers for lung cancer treatment. PMID:18848758

  7. 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

  8. 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

  9. Bone marrow-derived cells contribute to NDEA-induced lung squamous cell carcinoma.

    PubMed

    Luo, Dan; Liu, Dengqun; Zhou, Xiangdong; Yang, Shiming; Tang, Chunlan; Liu, Guoxiang

    2013-02-01

    Bone marrow-derived stem cells (BMDCs) have the ability to differentiate into lung epithelial cells in response to damage; however, their role in squamous cell carcinoma (SCC) formation is unknown. This study aimed to determine whether BMDC-derived lung epithelial cells could contribute to SCC formation. A model of lung SCC induced with N-nitrosodiethylamine (NDEA) in recipient female mice transplanted with green fluorescent protein (GFP)-positive BMDCs from male donors was established. Incorporation of BMDCs in lung tissue was determined using immunohistochemistry and immunofluorescence to detect GFP expression and fluorescence in situ hybridization to Y chromosomes. BMDC appeared at three stages of lung SCC progression: metaplasia, dysplasia, and carcinoma. There was a significantly higher proportion of GFP-positive (GFP(+)) cells within SCC than was found in metaplasia and dysplasia 16 weeks post-transplantation (both P < 0.017); GFP(+) BMDCs were also observed in clusters within several SCC nests. Furthermore, most GFP(+) cells in SCC were pancytokeratin-positive (PCK(+)) epithelial cells, and some exhibited proliferative activity as determined by Ki67 staining (9.7 ± 3.92 %). The presence of GFP(+)Ki67(+)PCK(+) cells within SCC nests suggested that some donor BMDCs differentiated into proliferating epithelial cells. Finally, analysis of p63 expression, a marker of SCC cells, indicated that the presence of GFP(+)p63(+) cells (green) in inner parts of the SCC. These findings strongly suggest that BMDC-derived lung epithelial cells could participate in lung SCC formation and partially contribute to tumor growth, which might have significant potential implications for both clinical cancer therapy using BMDCs. PMID:23055190

  10. Lung Epithelial Cell-Specific Expression of Human Lysosomal Acid Lipase Ameliorates Lung Inflammation and Tumor Metastasis in Lipa(-/-) Mice.

    PubMed

    Zhao, Ting; Ding, Xinchun; Du, Hong; Yan, Cong

    2016-08-01

    Lysosomal acid lipase (LAL), a key enzyme in the metabolic pathway of neutral lipids, has a close connection with inflammation and tumor progression. One major manifestation in LAL-deficient (Lipa(-/-)) mice is an increase of tumor growth and metastasis associated with expansion of myeloid-derived suppressor cells. In the lung, LAL is highly expressed in alveolar type II epithelial cells. To assess how LAL in lung epithelial cells plays a role in this inflammation-related pathogenic process, lung alveolar type II epithelial cell-specific expression of human LAL (hLAL) in Lipa(-/-) mice was established by crossbreeding of CCSP-driven rtTA transgene and (TetO)7-CMV-hLAL transgene into Lipa(-/-) mice (CCSP-Tg/KO). hLAL expression in lung epithelial cells not only reduced tumor-promoting myeloid-derived suppressor cells in the lung, but also down-regulated the synthesis and secretion of tumor-promoting cytokines and chemokines into the bronchoalveolar lavage fluid of Lipa(-/-) mice. hLAL expression reduced the immunosuppressive functions of bronchoalveolar lavage fluid cells, inhibited bone marrow cell transendothelial migration, and inhibited endothelial cell proliferation and migration in Lipa(-/-) mice. As a result, hLAL expression in CCSP-Tg/KO mice corrected pulmonary damage, and inhibited tumor cell proliferation and migration in vitro, and tumor metastasis to the lung in vivo. These results support a concept that LAL is a critical metabolic enzyme in lung epithelial cells that regulates lung homeostasis, immune response, and tumor metastasis. PMID:27461363

  11. 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

  12. 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

  13. Proteome Profiling in Lung Injury after Hematopoietic Stem Cell Transplantation.

    PubMed

    Bhargava, Maneesh; Viken, Kevin J; Dey, Sanjoy; Steinbach, Michael S; Wu, Baolin; Jagtap, Pratik D; Higgins, LeeAnn; Panoskaltsis-Mortari, Angela; Weisdorf, Daniel J; Kumar, Vipin; Arora, Mukta; Bitterman, Peter B; Ingbar, David H; Wendt, Chris H

    2016-08-01

    Pulmonary complications due to infection and idiopathic pneumonia syndrome (IPS), a noninfectious lung injury in hematopoietic stem cell transplant (HSCT) recipients, are frequent causes of transplantation-related mortality and morbidity. Our objective was to characterize the global bronchoalveolar lavage fluid (BALF) protein expression of IPS to identify proteins and pathways that differentiate IPS from infectious lung injury after HSCT. We studied 30 BALF samples from patients who developed lung injury within 180 days of HSCT or cellular therapy transfusion (natural killer cell transfusion). Adult subjects were classified as having IPS or infectious lung injury by the criteria outlined in the 2011 American Thoracic Society statement. BALF was depleted of hemoglobin and 14 high-abundance proteins, treated with trypsin, and labeled with isobaric tagging for relative and absolute quantification (iTRAQ) 8-plex reagent for two-dimensional capillary liquid chromatography (LC) and data dependent peptide tandem mass spectrometry (MS) on an Orbitrap Velos system in higher-energy collision-induced dissociation activation mode. Protein identification employed a target-decoy strategy using ProteinPilot within Galaxy P. The relative protein abundance was determined with reference to a global internal standard consisting of pooled BALF from patients with respiratory failure and no history of HSCT. A variance weighted t-test controlling for a false discovery rate of ≤5% was used to identify proteins that showed differential expression between IPS and infectious lung injury. The biological relevance of these proteins was determined by using gene ontology enrichment analysis and Ingenuity Pathway Analysis. We characterized 12 IPS and 18 infectious lung injury BALF samples. In the 5 iTRAQ LC-MS/MS experiments 845, 735, 532, 615, and 594 proteins were identified for a total of 1125 unique proteins and 368 common proteins across all 5 LC-MS/MS experiments. When comparing IPS to

  14. Role of Innate Lymphoid Cells in Lung Disease.

    PubMed

    Marashian, Sayed Mehran; Mortaz, Esmaeil; Jamaati, Hamid Reza; Alavi-Moghaddam, Mostafa; Kiani, Arda; Abedini, Atefeh; Garssen, Johan; Adcock, Ian M; Velayati, Ali Akbar

    2015-08-01

    Innate lymphoid cells (ILCs) are identified as novel population of hematopoietic cells which protect the body by coordinating the innate immune response against a wide range of threats including infections, tissue damages and homeostatic disturbances. ILCs, particularly ILC2 cells, are found throughout the body including the brain. ILCs are morphologically similar to lymphocytes, express and release high levels of T-helper (Th)1, Th2 and Th17 cytokines but do not express classical cell-surface markers that are associated with other immune cell lineages. Three types of ILCs (ILC1, 2 & 3) have been reported depending upon the cytokines produced. ILC1 cells encompass natural killer (NK) cells and interferon (IFN)-g releasing cells; ILC2 cells release the Th2 cytokines, IL-5, IL-9 and IL-13 in response to IL-25 and IL-33; and ILC3 cells which release IL-17 and IL-22. ILC2 cells have been implicated inmucosal reactions occurring in animal models of allergic asthma and virus-induced lung disorders resulting in the regulation of airway remodeling and tissue homeostasis. There is evidence for increased ILC2 cell numbers in allergic responses in man but little is known about the role of ILCs in chronic obstructive pulmonary disease (COPD). Further understanding of the characteristics of ILCs such as their origin, location and phenotypes and function would help to clarify the role of these cells in the pathogenesis of various lung diseases. In this review we will focus on the role of ILC2 cells and consider their origin, function,location and possible role in the pathogenesis of the chronic inflammatory disorders such as asthma and COPD. PMID:26547702

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

    PubMed Central

    Berika, Mohamed; Elgayyar, Marwa E.; El-Hashash, Ahmed H. K.

    2014-01-01

    New insights have been added to identification, behavior and cellular properties of embryonic and tissue-specific stem cells over the last few years. The modes of stem cell division, asymmetric vs. symmetric, are tightly regulated during development and regeneration. The proper choice of a stem cell to divide asymmetrically or symmetrically has great consequences for development and disease because inappropriate asymmetric division disrupts organ morphogenesis, whereas uncontrolled symmetric division induces tumorigenesis. Therefore, understanding the behavior of lung stem cells could identify innovative solutions for restoring normal morphogenesis and/or regeneration of different organs. In this concise review, we describe recent studies in our laboratory about the mode of division of lung epithelial stem cells. We also compare asymmetric cell division (ACD) in the lung stem cells with other tissues in different organisms. PMID:25364740

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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.

  1. Endogenous lung stem cells: what is their potential for use in regenerative medicine?

    PubMed

    Bertoncello, Ivan; McQualter, Jonathan L

    2010-06-01

    Advances in stem cell technologies in recent years have generated considerable interest in harnessing the potential of adult and embryonic stem cells in regenerative medicine. Stem cell-based therapies are a particularly attractive option for the treatment of intractable lung diseases for which current therapies are essentially palliative. Proof-of-principle experiments in animal models demonstrate the efficacy of exogenous stem cells in mediating lung repair by attenuating fibrotic responses to injury, but also suggest that their ability to contribute to lung epithelial regeneration and repair is limited. Consequently, attention has turned to endogenous lung stem cells as targets or vehicles for the delivery of lung regenerative therapies. In this article, we discuss the potential and promise of endogenous lung stem cells in regenerative medicine, and the problems and challenges faced by researchers and clinicians in harnessing their potential to repair the lung. PMID:20524918

  2. 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

  3. The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells

    PubMed Central

    Gomez-Casal, Roberto; Bhattacharya, Chitralekha; Epperly, Michael W.; Basse, Per H.; Wang, Hong; Wang, Xinhui; Proia, David A.; Greenberger, Joel S.; Socinski, Mark A.; Levina, Vera

    2015-01-01

    The molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibitor, was evaluated in human lung adenocarcinoma (AC) cells for its ability to potentiate the effects of IR treatment in both in vitro and in vivo. The cytotoxic effects of ganetespib included; G2/M cell cycle arrest, inhibition of DNA repair, apoptosis induction, and promotion of senescence. All of these antitumor effects were both concentration- and time-dependent. Both pretreatment and post-radiation treatment with ganetespib at low nanomolar concentrations induced radiosensitization in lung AC cells in vitro. Ganetespib may impart radiosensitization through multiple mechanisms: such as down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and promotion of cellular senescence. In vivo, ganetespib reduced growth of T2821 tumor xenografts in mice and sensitized tumors to IR. Tumor irradiation led to dramatic upregulation of β-catenin expression in tumor tissues, an effect that was mitigated in T2821 xenografts when ganetespib was combined with IR treatments. These data highlight the promise of combining ganetespib with IR therapies in the treatment of AC lung tumors. PMID:26010604

  4. The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells.

    PubMed

    Gomez-Casal, Roberto; Bhattacharya, Chitralekha; Epperly, Michael W; Basse, Per H; Wang, Hong; Wang, Xinhui; Proia, David A; Greenberger, Joel S; Socinski, Mark A; Levina, Vera

    2015-01-01

    The molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibitor, was evaluated in human lung adenocarcinoma (AC) cells for its ability to potentiate the effects of IR treatment in both in vitro and in vivo. The cytotoxic effects of ganetespib included; G2/M cell cycle arrest, inhibition of DNA repair, apoptosis induction, and promotion of senescence. All of these antitumor effects were both concentration- and time-dependent. Both pretreatment and post-radiation treatment with ganetespib at low nanomolar concentrations induced radiosensitization in lung AC cells in vitro. Ganetespib may impart radiosensitization through multiple mechanisms: such as down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and promotion of cellular senescence. In vivo, ganetespib reduced growth of T2821 tumor xenografts in mice and sensitized tumors to IR. Tumor irradiation led to dramatic upregulation of β-catenin expression in tumor tissues, an effect that was mitigated in T2821 xenografts when ganetespib was combined with IR treatments. These data highlight the promise of combining ganetespib with IR therapies in the treatment of AC lung tumors. PMID:26010604

  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. 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

  8. 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

  9. 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

  10. 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

  11. Mesenchymal stem cell therapy and lung diseases.

    PubMed

    Akram, Khondoker M; Samad, Sohel; Spiteri, Monica; Forsyth, Nicholas R

    2013-01-01

    Mesenchymal stem cells (MSCs), a distinct population of adult stem cells, have amassed significant interest from both medical and scientific communities. An inherent multipotent differentiation potential offers a cell therapy option for various diseases, including those of the musculoskeletal, neuronal, cardiovascular and pulmonary systems. MSCs also secrete an array of paracrine factors implicated in the mitigation of pathological conditions through anti-inflammatory, anti-apoptotic and immunomodulatory mechanisms. The safety and efficacy of MSCs in human application have been confirmed through small- and large-scale clinical trials. However, achieving the optimal clinical benefit from MSC-mediated regenerative therapy approaches is entirely dependent upon adequate understanding of their healing/regeneration mechanisms and selection of appropriate clinical conditions. MSC-mediated acute alveolar injury repair. A cartoon depiction of an injured alveolus with associated inflammation and AEC apoptosis. Proposed routes of MSC delivery into injured alveoli could be by either intratracheal or intravenous routes, for instance. Following delivery a proposed mechanism of MSC action is to inhibit/reduce alveolar inflammation by abrogation of IL-1_-depenedent Tlymphocyte proliferation and suppression of TNF-_ secretion via macrophage activation following on from stimulation by MSC-secreted IL-1 receptor antagonist (IL-1RN). The inflammatory environment also stimulates MSC to secrete prostaglandin-E2 (PGE2) which can stimulate activated macrophages to secrete the anti-inflammatory cytokine IL-10. Inhibition of AEC apoptosis following injury can also be promoted via MSC stimulated up-regulation of the anti-apoptotic Bcl-2 gene. MSC-secreted KGF can stimulate AECII proliferation and migration propagating alveolar epithelial restitution. Alveolar structural engraftment of MSC is a rare event. PMID:22772131

  12. 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

  13. 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

  14. Sp3 regulates fas expression in lung epithelial cells.

    PubMed Central

    Pang, H; Miranda, K; Fine, A

    1998-01-01

    By transducing an apoptotic signal in immune effector cells, Fas has been directly implicated in the control of immunological activity. Expression and functional results, however, have also suggested a role for Fas in regulating cell turnover in specific epithelial populations. To characterize factors responsible for Fas expression in epithelial cells, approximately 3 kb of the 5' flanking region of the mouse Fas gene was isolated. By rapid amplification of cDNA ends and primer extension, transcriptional start sites were identified within 50 bp upstream of the translation start site. Transient transfection of promoter-luciferase constructs in a mouse lung epithelial cell line, MLE-15, localized promoter activity to the first 77 bp of upstream sequence. By using a 60 bp DNA probe (-18 to -77) in electrophoretic mobility-shift assays, three shifted complexes were found. Incubation with excess cold Sp1 oligonucleotide or an anti-Sp3 antibody inhibited complex formation. Site-directed mutagenesis of the Sp1 site resulted in 60-70% loss of promoter activity. In Drosophila SL-2 cells, promoter activity was markedly increased by co-transfection of an Sp3 expression construct. These results show that the Sp3 protein is involved in regulating Fas gene expression in lung epithelial cells. PMID:9639581

  15. Guinea Pig Lung Lavage Cells After Intranasal BCG Sensitization

    PubMed Central

    Terai, T.; Ganguly, Rama; Waldman, Robert H.

    1979-01-01

    Recent studies have suggested that intranasal administration of antigen can induce local cell-mediated immunity in lung lavage cells. The present study was designed to examine the changes in composition of lung lavage cells and their capacity to produce the lymphokine migration inhibitory factor after intranasal immunization with BCG in guinea pigs. Results indicate that guinea pigs responded to respiratory tract BCG infection with an increase in immunocompetent cells in the bronchoalveolar tract and with production of migration inhibitory factor. After local pulmonary BCG administration, the total number of cells increased as compared with that of the uninfected animals, the increase being statistically significant within 2 weeks. This marked increase in the total cell population is due to a more than doubling of the number of macrophages in the lavage fluid. Animals also developed at this time positive delayed hypersensitivity to intradermally administered purified protein derivative. A significant increase in the total lymphoid cells and macrophage population was observed again at 6 weeks after sensitization, suggesting that the response is biphasic in nature. At 6 weeks, however, there was also a significant rise in total lymphocytes and T cell population in addition to macrophage numbers. This increase in T cells correlated with an increase in production of migration inhibitory factor in the presence of purified protein derivative. These data suggest that the immune response of the respiratory tract after BCG challenge involves increased recruitment of immunocompetent cells locally at the site of infection and that these cells are capable of producing effector molecules in terms of the elaboration of migration inhibitory factor. PMID:387595

  16. 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

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

    SciTech Connect

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

    2007-12-01

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

  18. Unresectable Squamous Cell Carcinoma of the Lung: An Outcomes Study

    SciTech Connect

    Newlin, Heather E.; Iyengar, Meera; Morris, Christopher G.; Olivier, Kenneth

    2009-06-01

    Purpose: To report survival and control rates in patients with inoperable squamous cell carcinoma (SCC). Methods and Materials: Two hundred seventy-five patients with inoperable squamous cell carcinoma of the lung (Stages I-IIIB) who received radiotherapy alone or combined with chemotherapy given with curative intent at University of Florida between 1963 and 2006 were retrospectively analyzed. Results: Overall survival (OS) at 5 years for Stages I, II, and III was 10%, 14%, and 7% (p = 0.0034); local-regional control at 5 years was 51%, 38%, and 29% (p = 0.0003); and freedom from metastases at 5 years was 81%, 60%, and 65% (p = 0.0689), respectively. Patients who received doses {>=} 65 Gy had improved cause-specific survival (CSS), OS, and metastasis-free survival at 5 years compared with those who received doses < 65 Gy. Five-year regional control was significantly improved with twice-daily vs. once-daily treatment (37% vs. 14%, p = 0.02). Chemotherapy significantly improved 5-year regional control (36% for patients who received chemotherapy vs. 13% for those who did not; p = 0.01). Conclusions: Dose escalation, accelerated fractionation, and combined modality therapies improve outcomes in SCC of the lung. Our review of the literature highlights the different natural history for SCC vs. other non-small cell lung cancers and emphasizes the importance of tailoring treatment strategies to individual patients. At University of Florida, we have begun treating unresectable Stage III patients with SCC of the lung using 69.6 Gy twice daily with concurrent chemotherapy.

  19. 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.

  20. Efficacy of platinum chemotherapy agents in the adjuvant setting for adenosquamous carcinoma of the pancreas

    PubMed Central

    Wild, Aaron T.; Dholakia, Avani S.; Fan, Katherine Y.; Kumar, Rachit; Moningi, Shalini; Rosati, Lauren M.; Laheru, Daniel A.; Zheng, Lei; De Jesus-Acosta, Ana; Ellsworth, Susannah G.; Hacker-Prietz, Amy; Voong, Khinh R.; Tran, Phuoc T.; Hruban, Ralph H.; Pawlik, Timothy M.; Wolfgang, Christopher L.

    2015-01-01

    Background Pancreatic adenosquamous carcinoma (PASC) accounts for only 1-4% of all exocrine pancreatic cancers and carries a particularly poor prognosis. This retrospective study was performed to determine whether inclusion of a platinum agent as part of adjuvant therapy is associated with improved survival in patients with resected PASC. Methods Records of all patients who underwent pancreatic resection at Johns Hopkins Hospital from 1986 to 2012 were reviewed to identify those with PASC. Multivariable Cox proportional hazards modeling was used to assess for significant associations between patient characteristics and survival. Results In total, 62 patients (1.1%) with resected PASC were identified among 5,627 cases. Median age was 68 [interquartile range (IQR), 57-77] and 44% were female. Multivariate analysis revealed that, among all patients (n=62), the following factors were independently predictive of poor survival: lack of adjuvant therapy [hazard ratio (HR) =3.6; 95% confidence interval (CI), 1.8-7.0; P<0.001], margin-positive resection (HR =3.5; 95% CI, 1.8-6.8; P<0.001), lymph node involvement (HR =3.5; 95% CI, 1.5-8.2; P=0.004), and age (HR =1.0; 95% CI, 1.0-1.1; P=0.035). There were no significant differences between patients who did and did not receive adjuvant therapy following resection (all P>0.05). A second multivariable model included only those patients who received adjuvant therapy (n=39). Lack of inclusion of a platinum agent in the adjuvant regimen (HR =2.4; 95% CI, 1.0-5.8; P=0.040) and larger tumor diameter (HR =1.3; 95% CI, 1.0-1.6; P=0.047) were independent predictors of inferior survival. Conclusions Addition of a platinum agent to adjuvant regimens for resected PASC may improve survival among these high-risk patients, though collaborative prospective investigation is needed. PMID:25830031

  1. 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

  2. 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

  3. 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

  4. 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

  5. SOX2 suppresses CDKN1A to sustain growth of lung squamous cell carcinoma

    PubMed Central

    Fukazawa, Takuya; Guo, Minzhe; Ishida, Naomasa; Yamatsuji, Tomoki; Takaoka, Munenori; Yokota, Etsuko; Haisa, Minoru; Miyake, Noriko; Ikeda, Tomoko; Okui, Tatsuo; Takigawa, Nagio; Maeda, Yutaka; Naomoto, Yoshio

    2016-01-01

    Since the SOX2 amplification was identified in lung squamous cell carcinoma (lung SCC), SOX2 transcriptional downstream targets have been actively investigated; however, such targets are often cell line specific. Here, in order to identify highly consensus SOX2 downstream genes in lung SCC cells, we used RNA-seq data from 178 lung SCC specimens (containing tumor and tumor-associated cells) and analyzed the correlation between SOX2 and previously-reported SOX2-controlled genes in lung SCC. In addition, we used another RNA-seq dataset from 105 non-small cell lung cancer cell lines (NSCLC; including 4 lung SCC cell lines) and again analyzed the correlation between SOX2 and the reported SOX2-controlled genes in the NSCLC cell lines (no tumor-associated cells). We combined the two analyses and identified genes commonly correlated with SOX2 in both datasets. Among the 99 genes reported as SOX2 downstream and/or correlated genes, we found 4 negatively-correlated (e.g., CDKN1A) and 11 positively-correlated genes with SOX2. We used biological studies to demonstrate that CDKN1A was suppressed by SOX2 in lung SCC cells. G1 cell cycle arrest induced by SOX2 siRNA was rescued by CDKN1A siRNA. These results indicate that the tumorigenic effect of SOX2 in lung SCC cells is mediated in part by suppression of CDKN1A. PMID:26846300

  6. 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

  7. [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

  8. 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.

  9. 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

  10. Micro FT-IR Characterization Of Human Lung Tumor Cells

    NASA Astrophysics Data System (ADS)

    Benedetti, Enzo; Teodori, L.; Vergamini, Piergiorgio; Trinca, M. L.; Mauro, F.; Salvati, F.; Spremolla, Giuliano

    1989-12-01

    FT-IR spectroscopy has opened up a new approach to the analytical study of cell transformation. Investigations carried out in normal and leukemic lymphocytes have evidenced an increase in DNA with respect to proteic components in neoplastic cells.(1) The evaluation of the ratio of the integrated areas(A) of the bands at 1080 cm-1 (mainly DNA) and at 1540 cm-1 (proteic components) has allowed us to establish a parameter which indicates, for values above 1.5, the neoplastic nature of cells. Recently, this approach has been applied to the study of human lung tumor cells. Several monocellular suspension procedures of the tissue fragment (mechanical and/or chemical) were tested to obtain reproducible and reliable spectra able to differentiate clearly between normal and patological cells. Chemical treatment (EDTA, Pepsin, Collagenase, etc.) produced additional bands in the spectra of the cells causing distortion of the profiles of some absorptions, and as a result, mechanical treatment was preferred. The normal and neoplastic cells homogeneously distributed by cytospin preparation on BaF2 windows were examined by means of FT-IR microscopy. An examination of several microareas of each sample yielded reproducible spectra, with values of the A 1080 cm-1 / A 1540 cm-1 parameter within a very narrow range for each sample, even if certain differences still remained among the different cases, in good agreement with the results obtained for leukemic cells.(1) The value of this parameter was found to be lower for cells isolated from the normal area of lung, than in the case of those corresponding to the tumoral area, meaning that an increase occurs in DNA with respect to the proteic components. These insights, which provide a basis to obtain indications at the molecular level, can open up new possibilities in clinical practice, in order to obtain diagnosis confirmation, to detect early stages of disease and to offer additional indications in cases of dubious interpretation.

  11. Somatic growth and lung function in sickle cell disease.

    PubMed

    Catanzaro, Tina; Koumbourlis, Anastassios C

    2014-03-01

    Somatic growth is a key indicator of overall health and well-being with important prognostic implications in the management of chronic disease. Worldwide studies of growth in children and adults with SCD have predominantly shown delayed growth (especially in terms of body weight) that is gradual and progressive in nature. However, more recent studies have shown that a substantial number of patients with SCD have normal weight gain whereas some are even obese. Height in patients with SCD is not universally affected even among those with suboptimal weight gain, whereas some achieve the same or greater height than healthy controls. The relationship between somatic growth and lung function in SCD is not yet clearly defined. As a group, patients with SCD tend to have lower lung volumes compared with healthy controls. These findings are similar across the age spectrum and across ethnic/racial lines regardless of the differences in body weight. Several mechanisms and risk factors have been proposed to explain these findings. These include malnutrition, racial differences and socioeconomic status. In addition, there are structural changes of the thorax (specifically the anterio-posterior chest diameter and anterio-posterior to lateral chest ratio) specific to sickle cell disease, that potentially interfere with normal lung growth. Although, caloric and protein intake have been shown to improve both height and weight, the composition of an optimal diet remains unclear. The following article reviews the current knowledge and controversies regarding somatic growth and its relationship with lung function in sickle cell disease (SCD) as well as the role of specific deficiencies of certain micronutrients. PMID:24268619

  12. Lung dendritic cells facilitate extrapulmonary bacterial dissemination during pneumococcal pneumonia

    PubMed Central

    Rosendahl, Alva; Bergmann, Simone; Hammerschmidt, Sven; Goldmann, Oliver; Medina, Eva

    2013-01-01

    Streptococcus pneumoniae is a leading cause of bacterial pneumonia worldwide. Given the critical role of dendritic cells (DCs) in regulating and modulating the immune response to pathogens, we investigated here the role of DCs in S. pneumoniae lung infections. Using a well-established transgenic mouse line which allows the conditional transient depletion of DCs, we showed that ablation of DCs resulted in enhanced resistance to intranasal challenge with S. pneumoniae. DCs-depleted mice exhibited delayed bacterial systemic dissemination, significantly reduced bacterial loads in the infected organs and lower levels of serum inflammatory mediators than non-depleted animals. The increased resistance of DCs-depleted mice to S. pneumoniae was associated with a better capacity to restrict pneumococci extrapulmonary dissemination. Furthermore, we demonstrated that S. pneumoniae disseminated from the lungs into the regional lymph nodes in a cell-independent manner and that this direct way of dissemination was much more efficient in the presence of DCs. We also provide evidence that S. pneumoniae induces expression and activation of matrix metalloproteinase-9 (MMP-9) in cultured bone marrow-derived DCs. MMP-9 is a protease involved in the breakdown of extracellular matrix proteins and is critical for DC trafficking across extracellular matrix and basement membranes during the migration from the periphery to the lymph nodes. MMP-9 was also significantly up-regulated in the lungs of mice after intranasal infection with S. pneumoniae. Notably, the expression levels of MMP-9 in the infected lungs were significantly decreased after depletion of DCs suggesting the involvement of DCs in MMP-9 production during pneumococcal pneumonia. Thus, we propose that S. pneumoniae can exploit the DC-derived proteolysis to open tissue barriers thereby facilitating its own dissemination from the local site of infection. PMID:23802100

  13. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas.

    PubMed

    Campbell, Joshua D; Alexandrov, Anton; Kim, Jaegil; Wala, Jeremiah; Berger, Alice H; Pedamallu, Chandra Sekhar; Shukla, Sachet A; Guo, Guangwu; Brooks, Angela N; Murray, Bradley A; Imielinski, Marcin; Hu, Xin; Ling, Shiyun; Akbani, Rehan; Rosenberg, Mara; Cibulskis, Carrie; Ramachandran, Aruna; Collisson, Eric A; Kwiatkowski, David J; Lawrence, Michael S; Weinstein, John N; Verhaak, Roel G W; Wu, Catherine J; Hammerman, Peter S; Cherniack, Andrew D; Getz, Gad; Artyomov, Maxim N; Schreiber, Robert; Govindan, Ramaswamy; Meyerson, Matthew

    2016-06-01

    To compare lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SqCC) and to identify new drivers of lung carcinogenesis, we examined the exome sequences and copy number profiles of 660 lung ADC and 484 lung SqCC tumor-normal pairs. Recurrent alterations in lung SqCCs were more similar to those of other squamous carcinomas than to alterations in lung ADCs. New significantly mutated genes included PPP3CA, DOT1L, and FTSJD1 in lung ADC, RASA1 in lung SqCC, and KLF5, EP300, and CREBBP in both tumor types. New amplification peaks encompassed MIR21 in lung ADC, MIR205 in lung SqCC, and MAPK1 in both. Lung ADCs lacking receptor tyrosine kinase-Ras-Raf pathway alterations had mutations in SOS1, VAV1, RASA1, and ARHGAP35. Regarding neoantigens, 47% of the lung ADC and 53% of the lung SqCC tumors had at least five predicted neoepitopes. Although targeted therapies for lung ADC and SqCC are largely distinct, immunotherapies may aid in treatment for both subtypes. PMID:27158780

  14. Induction of pulmonary neoplasia in the smoke-exposed ferret by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK): a model for human lung cancer.

    PubMed

    Kim, Yuri; Liu, Xiaolong S; Liu, Chun; Smith, Donald E; Russell, Robert M; Wang, Xiang-Dong

    2006-03-28

    Research into dietary chemoprevention against lung carcinogenesis has been limited by the lack of appropriate animal models that closely mimic smoking-related human lung cancer. Ferrets (Mustela putorius furo) have been used to study the biologic activities of carotenoids against smoke-induced lung lesions, but this model has yet to be thoroughly established and validated. To determine the appropriateness of the ferret as a model for human lung cancer, we have performed a 6-month in vivo study in ferrets exposed to both tobacco smoke and a carcinogen (4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, NNK) found in cigarette smoke. Results showed that six out 12 ferrets exposed to both NNK injection and cigarette smoke developed grossly identifiable lung tumors whereas none of nine ferrets from the sham treatment group developed any lung lesions. The histopathological types of these tumors (squamous cell carcinoma, adenosquamous carcinoma and adenocarcinoma) in ferret lungs are very similar to those in humans. In addition, 10 out of 12 ferrets exposed to both NNK and cigarette smoke developed preneoplastic lesions (squamous metaplasia, dysplasia, and atypical adenomatous hyperplasia) with complex growth patterns whereas the sham group did not show any of these lesions. Furthermore, the expression of proliferating cellular nuclear antigen increased markedly in both gross tumors and preneoplastic lesions in the lungs. In summary, the development of both preneoplastic lesions and gross lung tumors in ferrets provides an excellent and unique model for studying lung cancer chemoprevention with agents such as carotenoids, and for studying the molecular mechanism of carcinogenesis in the earlier stages of smoke-related lung cancer. PMID:15894421

  15. 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

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

    PubMed

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

    2013-11-15

    Acrolein, an α,β unsaturated electrophile, is an environmental pollutant released in ambient air from diesel exhausts and cooking oils. This study examines the role of acrolein in altering mitochondrial function and metabolism in lung-specific cells. RLE-6TN, H441, and primary alveolar type II (pAT2) cells were exposed to acrolein for 4 h, and its effect on mitochondrial oxygen consumption rates was studied by XF Extracellular Flux analysis. Low-dose acrolein exposure decreased mitochondrial respiration in a dose-dependent manner because of alteration in the metabolism of glucose in all the three cell types. Acrolein inhibited glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity, leading to decreased substrate availability for mitochondrial respiration in RLE-6TN, H441, and pAT2 cells; the reduced GAPDH activity was compensated in pAT2 cells by an increase in the activity of glucose-6-phosphate dehydrogenase, the regulatory control of the pentose phosphate pathway. The decrease in pyruvate from glucose metabolism resulted in utilization of alternative sources to support mitochondrial energy production: palmitate-BSA complex increased mitochondrial respiration in RLE-6TN and pAT2 cells. The presence of palmitate in alveolar cells for surfactant biosynthesis may prove to be the alternative fuel source for mitochondrial respiration. Accordingly, a decrease in phosphatidylcholine levels and an increase in phospholipase A2 activity were found in the alveolar cells after acrolein exposure. These findings have implications for understanding the decrease in surfactant levels frequently observed in pathophysiological situations with altered lung function following exposure to environmental toxicants. PMID:24056970

  17. Cell surface structures influence lung clearance rate of systemically infused mesenchymal stromal cells.

    PubMed

    Nystedt, Johanna; Anderson, Heidi; Tikkanen, Jonne; Pietilä, Mika; Hirvonen, Tia; Takalo, Reijo; Heiskanen, Annamari; Satomaa, Tero; Natunen, Suvi; Lehtonen, Siri; Hakkarainen, Tanja; Korhonen, Matti; Laitinen, Saara; Valmu, Leena; Lehenkari, Petri

    2013-02-01

    The promising clinical effects of mesenchymal stromal/stem cells (MSCs) rely especially on paracrine and nonimmunogenic mechanisms. Delivery routes are essential for the efficacy of cell therapy and systemic delivery by infusion is the obvious goal for many forms of MSC therapy. Lung adhesion of MSCs might, however, be a major obstacle yet to overcome. Current knowledge does not allow us to make sound conclusions whether MSC lung entrapment is harmful or beneficial, and thus we wanted to explore MSC lung adhesion in greater detail. We found a striking difference in the lung clearance rate of systemically infused MSCs derived from two different clinical sources, namely bone marrow (BM-MSCs) and umbilical cord blood (UCB-MSCs). The BM-MSCs and UCB-MSCs used in this study differed in cell size, but our results also indicated other mechanisms behind the lung adherence. A detailed analysis of the cell surface profiles revealed differences in the expression of relevant adhesion molecules. The UCB-MSCs had higher expression levels of α4 integrin (CD49d, VLA-4), α6 integrin (CD49f, VLA-6), and the hepatocyte growth factor receptor (c-Met) and a higher general fucosylation level. Strikingly, the level of CD49d and CD49f expression could be functionally linked with the lung clearance rate. Additionally, we saw a possible link between MSC lung adherence and higher fibronectin expression and we show that the expression of fibronectin increases with MSC culture confluence. Future studies should aim at developing methods of transiently modifying the cell surface structures in order to improve the delivery of therapeutic cells. PMID:23132820

  18. Lung Injury Combined with Loss of Regulatory T Cells Leads to De Novo Lung-Restricted Autoimmunity.

    PubMed

    Chiu, Stephen; Fernandez, Ramiro; Subramanian, Vijay; Sun, Haiying; DeCamp, Malcolm M; Kreisel, Daniel; Perlman, Harris; Budinger, G R Scott; Mohanakumar, Thalachallour; Bharat, Ankit

    2016-07-01

    More than one third of patients with chronic lung disease undergoing lung transplantation have pre-existing Abs against lung-restricted self-Ags, collagen type V (ColV), and k-α1 tubulin (KAT). These Abs can also develop de novo after lung transplantation and mediate allograft rejection. However, the mechanisms leading to lung-restricted autoimmunity remain unknown. Because these self-Ags are normally sequestered, tissue injury is required to expose them to the immune system. We previously showed that respiratory viruses can induce apoptosis in CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), the key mediators of self-tolerance. Therefore, we hypothesized that lung-tissue injury can lead to lung-restricted immunity if it occurs in a setting when Tregs are impaired. We found that human lung recipients who suffer respiratory viral infections experienced a decrease in peripheral Tregs. Pre-existing lung allograft injury from donor-directed Abs or gastroesophageal reflux led to new ColV and KAT Abs post respiratory viral infection. Similarly, murine parainfluenza (Sendai) respiratory viral infection caused a decrease in Tregs. Intratracheal instillation of anti-MHC class I Abs, but not isotype control, followed by murine Sendai virus infection led to development of Abs against ColV and KAT, but not collagen type II (ColII), a cartilaginous protein. This was associated with expansion of IFN-γ-producing CD4(+) T cells specific to ColV and KAT, but not ColII. Intratracheal anti-MHC class I Abs or hydrochloric acid in Foxp3-DTR mice induced ColV and KAT, but not ColII, immunity, only if Tregs were depleted using diphtheria toxin. We conclude that tissue injury combined with loss of Tregs can lead to lung-tissue-restricted immunity. PMID:27194786

  19. Contributions of TRPV1, endovanilloids, and endoplasmic reticulum stress in lung cell death in vitro and lung injury.

    PubMed

    Thomas, Karen C; Roberts, Jessica K; Deering-Rice, Cassandra E; Romero, Erin G; Dull, Randal O; Lee, Jeewoo; Yost, Garold S; Reilly, Christopher A

    2012-01-01

    Endogenous agonists of transient receptor potential vanilloid-1 (TRPV1) (endovanilloids) are implicated as mediators of lung injury during inflammation. This study tested the hypothesis that endovanilloids produced following lipopolysaccharide (LPS) treatment activate TRPV1 and cause endoplasmic reticulum stress/GADD153 expression in lung cells, representing a mechanistic component of lung injury. The TRPV1 agonist nonivamide induced GADD153 expression and caused cytotoxicity in immortalized and primary human bronchial, bronchiolar/alveolar, and microvascular endothelial cells, proportional to TRPV1 mRNA expression. In CF-1 mice, Trpv1 mRNA was most abundant in the alveoli, and intratracheal nonivamide treatment promoted Gadd153 expression in the alveolar region. Treatment of CF-1 mice with LPS increased Gadd153 in the lung, lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, and lung wet-to-dry weight ratio. Cotreating mice with LPS and the TRPV1 antagonist LJO-328 reduced Gadd153 induction and LDH in BAL but did not inhibit increases in lung wet-to-dry ratio. In Trpv1(-/-) mice treated with LPS, Gadd153 induction and LDH in BAL were reduced relative to wild-type mice, and the wet-to-dry weight ratios of lungs from both wild-type and Trpv1(-/-) mice decreased. Organic extracts of blood collected from LPS-treated mice were more cytotoxic to TRPV1-overexpressing cells compared with BEAS-2B cells and extracts from control mice, however, most pure endovanilloids did not produce cytotoxicity in a characteristic TRPV1-dependent manner. Collectively, these data indicate a role for TRPV1, and endogenous TRPV1 agonists, in ER stress and cytotoxicity in lung cells but demonstrate that ER stress and cytotoxicity are not essential for pulmonary edema. PMID:21949157

  20. 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

  1. 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

  2. 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.

  3. Magnetite induces oxidative stress and apoptosis in lung epithelial cells.

    PubMed

    Ramesh, Vani; Ravichandran, Prabakaran; Copeland, Clinton L; Gopikrishnan, Ramya; Biradar, Santhoshkumar; Goornavar, Virupaxi; Ramesh, Govindarajan T; Hall, Joseph C

    2012-04-01

    There is an ongoing concern regarding the biocompatibility of nanoparticles with sizes less than 100 nm as compared to larger particles of the same nominal substance. In this study, we investigated the toxic properties of magnetite stabilized with polyacrylate sodium. The magnetite was characterized by X-ray powder diffraction analysis, and the mean particle diameter was calculated using the Scherrer formula and was found to be 9.3 nm. In this study, we treated lung epithelial cells with different concentrations of magnetite and investigated their effects on oxidative stress and cell proliferation. Our data showed an inhibition of cell proliferation in magnetite-treated cells with a significant dose-dependent activation and induction of reactive oxygen species. Also, we observed a depletion of antioxidants, glutathione, and superoxide dismutase, respectively, as compared with control cells. In addition, apoptotic-related protease/enzyme such as caspase-3 and -8 activities, were increased in a dose-dependent manner with corresponding increased levels of DNA fragmentation in magnetite-treated cells compared to than control cells. Together, the present study reveals that magnetite exposure induces oxidative stress and depletes antioxidant levels in the cells to stimulate apoptotic pathway for cell death. PMID:22147200

  4. 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

  5. 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.

  6. [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

  7. Generation of ESC-derived Mouse Airway Epithelial Cells Using Decellularized Lung Scaffolds.

    PubMed

    Shojaie, Sharareh; Lee, Joyce; Wang, Jinxia; Ackerley, Cameron; Post, Martin

    2016-01-01

    Lung lineage differentiation requires integration of complex environmental cues that include growth factor signaling, cell-cell interactions and cell-matrix interactions. Due to this complexity, recapitulation of lung development in vitro to promote differentiation of stem cells to lung epithelial cells has been challenging. In this protocol, decellularized lung scaffolds are used to mimic the 3-dimensional environment of the lung and generate stem cell-derived airway epithelial cells. Mouse embryonic stem cell are first differentiated to the endoderm lineage using an embryoid body (EB) culture method with activin A. Endoderm cells are then seeded onto decellularized scaffolds and cultured at air-liquid interface for up to 21 days. This technique promotes differentiation of seeded cells to functional airway epithelial cells (ciliated cells, club cells, and basal cells) without additional growth factor supplementation. This culture setup is defined, serum-free, inexpensive, and reproducible. Although there is limited contamination from non-lung endoderm lineages in culture, this protocol only generates airway epithelial populations and does not give rise to alveolar epithelial cells. Airway epithelia generated with this protocol can be used to study cell-matrix interactions during lung organogenesis and for disease modeling or drug-discovery platforms of airway-related pathologies such as cystic fibrosis. PMID:27214388

  8. Amplification of FGFR1 gene and expression of FGFR1 protein is found in different histological types of lung carcinoma.

    PubMed

    Sousa, Vitor; Reis, Diana; Silva, Maria; Alarcão, Ana Maria; Ladeirinha, Ana Filipa; d'Aguiar, Maria João; Ferreira, Teresa; Caramujo-Balseiro, Sandra; Carvalho, Lina

    2016-08-01

    Although lung cancer continues to be the leading cause of cancer-related death, accurate diagnosis followed by personalized treatment is expected to raise the 5-year survival rate. Targeted therapies are now in routine clinical use, in particular for lung adenocarcinoma (ADC). Fibroblast growth factor receptor 1 (FGFR1) has recently emerged as a molecular target, especially in squamous cell/epidermoid carcinoma (SQC) of the lung. This paper evaluates FGFR1 expression and gene copy number in adenocarcinomas, squamous cell carcinomas, pleomorphic carcinomas (PLEOMC) and adenosquamous carcinomas (ADSQC) of the lung and also explores the epithelial-mesenchymal transition (EMT) pathway. We studied 76 lung carcinomas: 34 ADC, 24 SQC, 10 PLEOMC and 8 ADSQC. FGFR1 expression was evaluated by immunohistochemistry and gene amplification by fluorescence in situ hybridization (FISH). Higher FGFR1 protein expression was observed in all tumour types compared to non-tumour tissue. FGFR1 expression was higher in ADC and PLEOMC than in SQC. We found a tendency to higher expression in ADC than in SQC and significantly higher expression in PLEOMC than in other histological subtypes. FISH-based amplification of FGFR1 was identified in 15 (20 %) lung carcinomas: 5 (15 %) ADC, 5 (21 %) SQC, 3 (30 %) PLEOMC and 2 (25 %) ADSQC. Amplification was more frequent in SQC without significant differences. FGFR1 protein is expressed in the majority of lung carcinomas, though it is higher in ADC and PLEOMC (the latter may reflect the importance of FGFR1 control of the EMT pathway). FGFR1 amplification was identified in all types of lung carcinoma. Although FGFR1 is most frequently amplified in SQC, other histological types merit assessment of FGFR1 amplification, in order to select patients that might benefit from targeted therapy. PMID:27194548

  9. 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

  10. 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.

  11. 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

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

    PubMed Central

    Calero-Acuña, Carmen; Moreno-Mata, Nicolás; Gómez-Izquierdo, Lourdes; Sánchez-López, Verónica; López-Ramírez, Cecilia; Tobar, Daniela; López-Villalobos, José Luis; Gutiérrez, Cesar; Blanco-Orozco, Ana; López-Campos, José Luis

    2016-01-01

    Background Conflicting data exist on the role of pulmonary dendritic cells (DCs) and their maturation in patients with chronic obstructive pulmonary disease (COPD). Herein, we investigated whether disease severity and smoking status could affect the distribution and maturation of DCs in lung tissues of patients undergoing elective pneumectomy or lobectomy for suspected primary lung cancer. Materials and Methods A total of 75 consecutive patients were included. Spirometry testing was used to identify COPD. Lung parenchyma sections anatomically distant from the primary lesion were examined. We used flow cytometry to identify different DCs subtypes—including BDCA1-positive myeloid DCs (mDCs), BDCA3-positive mDCs, and plasmacytoid DCs (pDCs)—and determine their maturation markers (CD40, CD80, CD83, and CD86) in all participants. We also identified follicular DCs (fDCs), Langerhans DCs (LDCs), and pDCs in 42 patients by immunohistochemistry. Results COPD was diagnosed in 43 patients (16 current smokers and 27 former smokers), whereas the remaining 32 subjects were classified as non-COPD (11 current smokers, 13 former smokers, and 8 never smokers). The number and maturation of DCs did not differ significantly between COPD and non-COPD patients. However, the results of flow cytometry indicated that maturation markers CD40 and CD83 of BDCA1-positive mDCs were significantly decreased in smokers than in non-smokers (P = 0.023 and 0.013, respectively). Immunohistochemistry also revealed a lower number of LDCs in COPD patients than in non-COPD subjects. Conclusions Cigarette smoke, rather than airflow limitation, is the main determinant of impaired DCs maturation in the lung. PMID:27058955

  13. 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

  14. Extraosseous Benign Notochordal Cell Tumor Originating in the Lung

    PubMed Central

    Takahashi, Yusuke; Motoi, Toru; Harada, Masahiko; Fukuda, Yumiko; Hishima, Tsunekazu; Horio, Hirotoshi

    2015-01-01

    Abstract Benign notochordal cell tumors (BNCTs) are tumors originating in the axial skeleton, where chordomas occur. Although very rare, some cases of extraosseous chordoma, such as in the soft tissue and lungs, have been reported. We report a case of a primary tumor showing the notochordal characteristics of BNCTs within the axial skeleton. An asymptomatic 57-year-old woman presented with an abnormal shadow on her chest radiograph; chest computed tomography revealed a well-defined round nodule. The resected sample tissue contained a jelly-like small nodule. Histologically, it was identified as a BNCT, based on minimal nuclear atypia, extremely low mitotic activity within the tumor cells lying in a sheet-like arrangement, and focal immunopositivity for brachyury. This is the third case report of BNCT originating in the lungs; BNCTs are considered asymptomatic tumors that are identified by using highly developed chest imaging technology; however, our findings also suggest that these notochordal tumors may potentially originate from extraosseous sites that lack ideal precursor cells. Our case suggests that notochordal tumors can arise from organs that are unrelated to known notochordal development. PMID:25569657

  15. 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

  16. 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

  17. 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

  18. FTIR characterization of animal lung cells: normal and precancerous modified e10 cell line

    NASA Astrophysics Data System (ADS)

    Zezell, D. M.; Pereira, T. M.; Mennecier, G.; Bachmann, L.; Govone, A. B.; Dagli, M. L. Z.

    2012-06-01

    The chemical carcinogens from tobacco are related to over 90% of lung cancers around the world. The risk of death of this kind of cancer is high because the diagnosis usually is made only in advanced stages. Therefore, it is necessary to develop new diagnostic methods for detecting the lung cancer in earlier stages. The Fourier Transform Infrared Spectroscopy (FTIR) can offer high sensibility and accuracy to detect the minimal chemical changes into the biological sample. The aim of this study is to evaluate the differences on infrared spectra between normal lung cells and precancerous lung cells transformed by NNK. Non-cancerous lung cell line e10 (ATCC) and NNK-transformed e10 cell lines were maintained in complete culture medium (1:1 mixture of Dulbecco's modified Eagle's medium and Ham's F12 [DMEM/Ham's F12], supplemented with 100 ng/ml cholera enterotoxin, 10 lg/ml insulin, 0.5 lg/ml. hydrocortisol, 20 ng/ml epidermal growth factor, and 5% horse serum. The cultures were maintained in alcohol 70%. The infrared spectra were acquired on ATR-FTIR Nicolet 6700 spectrophotometer at 4 cm-1 resolution, 30 scans, in the 1800-900 cm-1 spectral range. Each sample had 3 spectra recorded, 30 infrared spectra were obtained from each cell line. The second derivate of spectra indicates that there are displacement in 1646 cm-1 (amine I) and 1255 cm-1(DNA), allowing the possibility to differentiate the two king of cells, with accuracy of 89,9%. These preliminary results indicate that ATR-FTIR is useful to differentiate normal e10 lung cells from precancerous e10 transformed by NNK.

  19. Mesenchymal Stromal Cells from Neonatal Tracheal Aspirates Demonstrate a Pattern of Lung-Specific Gene Expression

    PubMed Central

    Bozyk, Paul D.; Popova, Antonia P.; Bentley, John Kelley; Goldsmith, Adam M.; Linn, Marisa J.; Weiss, Daniel J.

    2011-01-01

    We have previously isolated mesenchymal stromal cells (MSCs) from the tracheal aspirates of premature neonates with respiratory distress. Although isolation of MSCs correlates with the development of bronchopulmonary dysplasia, the physiologic role of these cells remains unclear. To address this, we further characterized the cells, focusing on the issues of gene expression, origin, and cytokine expression. Microarray comparison of early passage neonatal lung MSC gene expression to cord blood MSCs and human fetal and neonatal lung fibroblast lines demonstrated that the neonatal lung MSCs differentially expressed 971 gene probes compared with cord blood MSCs, including the transcription factors Tbx2, Tbx3, Wnt5a, FoxF1, and Gli2, each of which has been associated with lung development. Compared with lung fibroblasts, 710 gene probe transcripts were differentially expressed by the lung MSCs, including IL-6 and IL-8/CXCL8. Differential chemokine expression was confirmed by protein analysis. Further, neonatal lung MSCs exhibited a pattern of Hox gene expression distinct from cord blood MSCs but similar to human fetal lung fibroblasts, consistent with a lung origin. On the other hand, limiting dilution analysis showed that fetal lung fibroblasts form colonies at a significantly lower rate than MSCs, and fibroblasts failed to undergo differentiation along adipogenic, osteogenic, and chondrogenic lineages. In conclusion, MSCs isolated from neonatal tracheal aspirates demonstrate a pattern of lung-specific gene expression, are distinct from lung fibroblasts, and secrete pro-inflammatory cytokines. PMID:21341990

  20. Current Status of Stem Cells and Regenerative Medicine in Lung Biology and Diseases

    PubMed Central

    Weiss, Daniel J.

    2014-01-01

    Lung diseases remain a significant and devastating cause of morbidity and mortality worldwide. In contrast to many other major diseases, lung diseases notably chronic obstructive pulmonary diseases (COPD), including both asthma and emphysema, are increasing in prevalence and COPD is expected to become the 3rd leading cause of disease mortality worldwide by 2020. New therapeutic options are desperately needed. A rapidly growing number of investigations of stem cells and cell therapies in lung biology and diseases as well as in ex vivo lung bioengineering have offered exciting new avenues for advancing knowledge of lung biology as well as providing novel potential therapeutic approaches for lung diseases. These initial observations have led to a growing exploration of endothelial progenitor cells and mesenchymal stem (stromal) cells in clinical trials of pulmonary hypertension and chronic obstructive pulmonary disease (COPD) with other clinical investigations planned. Ex vivo bioengineering of the trachea, larynx, diaphragm, and the lung itself with both biosynthetic constructs as well as decellularized tissues have been utilized to explore engineering both airway and vascular systems of the lung. Lung is thus a ripe organ for a variety of cell therapy and regenerative medicine approaches. Current state-of-the-art progress for each of the above areas will be presented as will discussion of current considerations for cell therapy based clinical trials in lung diseases. PMID:23959715

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

    PubMed

    Weiss, Daniel J

    2014-01-01

    Lung diseases remain a significant and devastating cause of morbidity and mortality worldwide. In contrast to many other major diseases, lung diseases notably chronic obstructive pulmonary diseases (COPDs), including both asthma and emphysema, are increasing in prevalence and COPD is expected to become the third leading cause of disease mortality worldwide by 2020. New therapeutic options are desperately needed. A rapidly growing number of investigations of stem cells and cell therapies in lung biology and diseases as well as in ex vivo lung bioengineering have offered exciting new avenues for advancing knowledge of lung biology as well as providing novel potential therapeutic approaches for lung diseases. These initial observations have led to a growing exploration of endothelial progenitor cells and mesenchymal stem (stromal) cells in clinical trials of pulmonary hypertension and COPD with other clinical investigations planned. Ex vivo bioengineering of the trachea, larynx, diaphragm, and the lung itself with both biosynthetic constructs as well as decellularized tissues have been used to explore engineering both airway and vascular systems of the lung. Lung is thus a ripe organ for a variety of cell therapy and regenerative medicine approaches. Current state-of-the-art progress for each of the above areas will be presented as will discussion of current considerations for cell therapy-based clinical trials in lung diseases. PMID:23959715

  2. Is cervical screening preventing adenocarcinoma and adenosquamous carcinoma of the cervix?

    PubMed Central

    Landy, Rebecca; Sasieni, Peter D.

    2016-01-01

    While the incidence of squamous carcinoma of the cervix has declined in countries with organised screening, adenocarcinoma has become more common. Cervical screening by cytology often fails to prevent adenocarcinoma. Using prospectively recorded cervical screening data in England and Wales, we conducted a population‐based case–control study to examine whether cervical screening leads to early diagnosis and down‐staging of adenocarcinoma. Conditional logistic regression modelling was carried out to provide odds ratios (ORs) and 95% confidence intervals (CIs) on 12,418 women with cervical cancer diagnosed between ages 30 and 69 and 24,453 age‐matched controls. Of women with adenocarcinoma of the cervix, 44.3% were up to date with screening and 14.6% were non‐attenders. The overall OR comparing women up to date with screening with non‐attenders was 0.46 (95% CI: 0.39–0.55) for adenocarcinoma. The odds were significantly decreased (OR: 0.22, 95% CI: 0.15–0.33) in up to date women with Stage 2 or worse adenocarcinoma, but not for women with Stage1A adenocarcinoma 0.71 (95% CI: 0.46–1.09). The odds of Stage 1A adenocarcinoma was double among lapsed attenders (OR: 2.35, 95% CI: 1.52–3.62) compared to non‐attenders. Relative to women with no negative cytology within 7 years of diagnosis, women with Stage1A adenocarcinoma were very unlikely to be detected within 3 years of a negative cytology test (OR: 0.08, 95% CI: 0.05–0.13); however, the odds doubled 3–5 years after a negative test (OR: 2.30, 95% CI: 1.67–3.18). ORs associated with up to date screening were smaller for squamous and adenosquamous cervical carcinoma. Although cytology screening is inefficient at preventing adenocarcinomas, invasive adenocarcinomas are detected earlier than they would be in the absence of screening, substantially preventing Stage 2 and worse adenocarcinomas. PMID:27096255

  3. Is cervical screening preventing adenocarcinoma and adenosquamous carcinoma of the cervix?

    PubMed

    Castanon, Alejandra; Landy, Rebecca; Sasieni, Peter D

    2016-09-01

    While the incidence of squamous carcinoma of the cervix has declined in countries with organised screening, adenocarcinoma has become more common. Cervical screening by cytology often fails to prevent adenocarcinoma. Using prospectively recorded cervical screening data in England and Wales, we conducted a population-based case-control study to examine whether cervical screening leads to early diagnosis and down-staging of adenocarcinoma. Conditional logistic regression modelling was carried out to provide odds ratios (ORs) and 95% confidence intervals (CIs) on 12,418 women with cervical cancer diagnosed between ages 30 and 69 and 24,453 age-matched controls. Of women with adenocarcinoma of the cervix, 44.3% were up to date with screening and 14.6% were non-attenders. The overall OR comparing women up to date with screening with non-attenders was 0.46 (95% CI: 0.39-0.55) for adenocarcinoma. The odds were significantly decreased (OR: 0.22, 95% CI: 0.15-0.33) in up to date women with Stage 2 or worse adenocarcinoma, but not for women with Stage1A adenocarcinoma 0.71 (95% CI: 0.46-1.09). The odds of Stage 1A adenocarcinoma was double among lapsed attenders (OR: 2.35, 95% CI: 1.52-3.62) compared to non-attenders. Relative to women with no negative cytology within 7 years of diagnosis, women with Stage1A adenocarcinoma were very unlikely to be detected within 3 years of a negative cytology test (OR: 0.08, 95% CI: 0.05-0.13); however, the odds doubled 3-5 years after a negative test (OR: 2.30, 95% CI: 1.67-3.18). ORs associated with up to date screening were smaller for squamous and adenosquamous cervical carcinoma. Although cytology screening is inefficient at preventing adenocarcinomas, invasive adenocarcinomas are detected earlier than they would be in the absence of screening, substantially preventing Stage 2 and worse adenocarcinomas. PMID:27096255

  4. 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

  5. Necrosis of lung epithelial cells during infection with Mycobacterium tuberculosis is preceded by cell permeation.

    PubMed

    Dobos, K M; Spotts, E A; Quinn, F D; King, C H

    2000-11-01

    Mycobacterium tuberculosis establishes infection, progresses towards disease, and is transmitted from the alveolus of the lung. However, the role of the alveolar epithelium in any of these pathogenic processes of tuberculosis is unclear. In this study, lung epithelial cells (A549) were used as a model in which to examine cytotoxicity during infection with either virulent or avirulent mycobacteria in order to further establish the role of the lung epithelium during tuberculosis. Infection of A549 cells with M. tuberculosis strains Erdman and CDC1551 demonstrated significant cell monolayer clearing, whereas infection with either Mycobacterium bovis BCG or Mycobacterium smegmatis LR222 did not. Clearing of M. tuberculosis-infected A549 cells correlated to necrosis, not apoptosis. Treatment of M. tuberculosis-infected A549 cells with streptomycin, but not cycloheximide, demonstrated a significant reduction in the necrosis of A549 cell monolayers. This mycobacterium-induced A549 necrosis did not correlate to higher levels of intracellular or extracellular growth by the mycobacteria during infection. Staining of infected cells with propidium iodide demonstrated that M. tuberculosis induced increased permeation of A549 cell membranes within 24 h postinfection. Quantitation of lactate dehydrogenase (LDH) release from infected cells further demonstrated that cell permeation was specific to M. tuberculosis infection and correlated to A549 cellular necrosis. Inactivated M. tuberculosis or its subcellular fractions did not result in A549 necrosis or LDH release. These studies demonstrate that lung epithelial cell cytotoxicity is specific to infection by virulent mycobacteria and is caused by cellular necrosis. This necrosis is not a direct correlate of mycobacterial growth or of the expression of host cell factors, but is preceded by permeation of the A549 cell membrane and requires infection with live bacilli. PMID:11035739

  6. 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

  7. Pleural mesothelial cells in pleural and lung diseases

    PubMed Central

    Antony, Veena B.

    2015-01-01

    During development, the mesoderm maintains a complex relationship with the developing endoderm giving rise to the mature lung. Pleural mesothelial cells (PMCs) derived from the mesoderm play a key role during the development of the lung. The pleural mesothelium differentiates to give rise to the endothelium and smooth muscle cells via epithelial-to-mesenchymal transition (EMT). An aberrant recapitulation of such developmental pathways can play an important role in the pathogenesis of disease processes such as idiopathic pulmonary fibrosis (IPF). The PMC is the central component of the immune responses of the pleura. When exposed to noxious stimuli, it demonstrates innate immune responses such as Toll-like receptor (TLR) recognition of pathogen associated molecular patterns as well as causes the release of several cytokines to activate adaptive immune responses. Development of pleural effusions occurs due to an imbalance in the dynamic interaction between junctional proteins, n-cadherin and β-catenin, and phosphorylation of adherens junctions between PMCs, which is caused in part by vascular endothelial growth factor (VEGF) released by PMCs. PMCs play an important role in defense mechanisms against bacterial and mycobacterial pleural infections, and in pathogenesis of malignant pleural effusion, asbestos related pleural disease and malignant pleural mesothelioma. PMCs also play a key role in the resolution of inflammation, which can occur with or without fibrosis. Fibrosis occurs as a result of disordered fibrin turnover and due to the effects of cytokines such as transforming growth factor-β, platelet-derived growth factor (PDGF), and basic fibroblast growth factor; which are released by PMCs. Recent studies have demonstrated a role for PMCs in the pathogenesis of IPF suggesting their potential as a cellular biomarker of disease activity and as a possible therapeutic target. Pleural-based therapies targeting PMCs for treatment of IPF and other lung diseases need

  8. 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

  9. 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

  10. EMX2 Is a Predictive Marker for Adjuvant Chemotherapy in Lung Squamous Cell Carcinomas

    PubMed Central

    Zhang, Yi; Tolani, Bhairavi; Mo, Minli; Zhang, Hua; Zheng, Qingfeng; Yang, Yue; Cheng, Runfen; Jin, Joy Q.; Luh, Thomas W.; Yang, Cathryn; Tseng, Hsin-Hui K.; Giroux-Leprieur, Etienne; Woodard, Gavitt A.; Hao, Xishan; Wang, Changli; Jablons, David M.; He, Biao

    2015-01-01

    Background Squamous cell carcinomas (SCC) account for approximately 30% of non-small cell lung cancer (NSCLC). Current staging methods do not adequately predict outcome for this disease. EMX2 is a homeo-domain containing transcription factor known to regulate a key developmental pathway. This study assessed the significance of EMX2 as a prognostic and predictive marker for resectable lung SCC. Methods Two independent cohorts of patients with lung SCC undergoing surgical resection were studied. EMX2 protein expression was examined by immunohistochemistry, Western blot, or immunofluorescence. EMX2 expression levels in tissue specimens were scored and correlated with patient outcomes. Chemo-sensitivity of lung SCC cell lines stably transfected with EMX2 shRNAs to cisplatin, carboplatin, and docetaxel was examined in vitro. Results EMX2 expression was down-regulated in lung SCC tissue samples compared to their matched adjacent normal tissues. Positive EMX2 expression was significantly associated with improved overall survival in stage I lung SCC patients, and in stage II/IIIA lung SCC patients receiving adjuvant chemotherapy. EMX2 expression was also associated with expression of EMT markers in both lung SCC cell lines and tissue samples. Knock-down of EMX2 expression in lung SCC cells promoted chemo-resistance and cell migration. Conclusions EMX2 expression is down-regulated in lung SCC and its down-regulation is associated with chemo-resistance in lung SCC cells, possibly through regulation of Epithelial-to-Mesenchymal Transition (EMT). EMX2 may serve as a novel prognostic marker for stage I lung SCC patients and a prediction marker for stage II/IIIA lung SCC patients receiving adjuvant chemotherapy. PMID:26132438

  11. 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

  12. 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

  13. Primary lung neoplasia in a beagle colony.

    PubMed

    Hahn, F F; Muggenburg, B A; Griffith, W C

    1996-11-01

    As part of long-term pulmonary carcinogenesis studies in dogs, it is important to analyze the incidence of spontaneous lung neoplasia. Primary lung carcinoma incidence was determined in two control populations of Beagle dogs observed for their life spans. One population comprised 216 dogs (112 males and 104 females) that were controls for life span studies, and another comprised 182 dogs (50 males and 132 females) that were retirees from a breeding colony. Forty lung neoplasms were noted in the 398 dogs; 35 neoplasms were carcinomas classified as papillary adenocarcinoma (20), bronchioloalveolar carcinoma (9), adenosquamous carcinoma (5), or bronchial gland carcinoma (1). The other five neoplasms were a malignant fibrous histiocytoma, three adenomas, and a fibroma. The crude incidence of lung carcinomas averaged for both populations was 8.8% (35/398) and was dominated by a relatively high incidence of lung neoplasia in aged dogs, those dying after the median life span of 13.6 years. PMID:8952021

  14. 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

  15. Cell-Type Specific Expression of Apc in Lung Development, Injury and Repair

    PubMed Central

    Li, Aimin; Xing, Yiming; Chan, Belinda; Heisterkamp, Nora; Groffen, John; Borok, Zea; Minoo, Parviz; Li, Changgong

    2010-01-01

    Adenomatous polyposis coli (Apc) is critical for Wnt signaling and cell migration. The current study examined Apc expression during lung development, injury and repair. Apc was first detectable in smooth muscle layers in early lung morphogenesis, and was highly expressed in ciliated and neuroendocrine cells in the advanced stages. No Apc immunoreactivity was detected in Clara or basal cells, which function as stem/progenitor cell in adult lung. In ciliated cells, Apc is associated mainly with apical cytoplasmic domain. In response to naphthalene induced injury, Apcpositive cells underwent squamous metaplasia, accompanied by changes in Apc subcellular distribution. In conclusion, both spatial and temporal expression of Apc is dynamically regulated during lung development and injury repair. Differential expression of Apc in progenitor vs. non-progenitor cells suggests a functional role in cell type specification. Subcellular localization changes of Apc in response to naphthalene injury suggest a role in cell shape and cell migration. PMID:20658693

  16. 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

  17. 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

  18. MicroRNA-126 inhibits invasion in non-small cell lung carcinoma cell lines

    SciTech Connect

    Crawford, M.; Brawner, E.; Batte, K.; Yu, L.; Hunter, M.G.; Otterson, G.A.; Nuovo, G.; Marsh, C.B.; Nana-Sinkam, S.P.

    2008-09-05

    Crk is a member of a family of adaptor proteins that are involved in intracellular signal pathways altering cell adhesion, proliferation, and migration. Increased expression of Crk has been described in lung cancer and associated with increased tumor invasiveness. MicroRNAs (miRNAs) are a family of small non-coding RNAs (approximately 21-25 nt long) that are capable of targeting genes for either degradation of mRNA or inhibition of translation. Crk is a predicted putative target gene for miR-126. Over-expression of miR126 in a lung cancer cell line resulted in a decrease in Crk protein without any alteration in the associated mRNA. These lung cancer cells exhibit a decrease in adhesion, migration, and invasion. Decreased cancer cell invasion was also evident following targeted knockdown of Crk. MiR-126 alters lung cancer cell phenotype by inhibiting adhesion, migration, and invasion and the effects on invasion may be partially mediated through Crk regulation.

  19. 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

  20. 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

  1. A pure population of lung alveolar epithelial type II cells derived from human embryonic stem cells.

    PubMed

    Wang, Dachun; Haviland, David L; Burns, Alan R; Zsigmond, Eva; Wetsel, Rick A

    2007-03-13

    Alveolar epithelial type II (ATII) cells are small, cuboidal cells that constitute approximately 60% of the pulmonary alveolar epithelium. These cells are crucial for repair of the injured alveolus by differentiating into alveolar epithelial type I cells. ATII cells derived from human ES (hES) cells are a promising source of cells that could be used therapeutically to treat distal lung diseases. We have developed a reliable transfection and culture procedure, which facilitates, via genetic selection, the differentiation of hES cells into an essentially pure (>99%) population of ATII cells (hES-ATII). Purity, as well as biological features and morphological characteristics of normal ATII cells, was demonstrated for the hES-ATII cells, including lamellar body formation, expression of surfactant proteins A, B, and C, alpha-1-antitrypsin, and the cystic fibrosis transmembrane conductance receptor, as well as the synthesis and secretion of complement proteins C3 and C5. Collectively, these data document the successful generation of a pure population of ATII cells derived from hES cells, providing a practical source of ATII cells to explore in disease models their potential in the regeneration and repair of the injured alveolus and in the therapeutic treatment of genetic diseases affecting the lung. PMID:17360544

  2. Scribble is required for normal epithelial cell-cell contacts and lumen morphogenesis in the mammalian lung.

    PubMed

    Yates, Laura L; Schnatwinkel, Carsten; Hazelwood, Lee; Chessum, Lauren; Paudyal, Anju; Hilton, Helen; Romero, M Rosario; Wilde, Jonathan; Bogani, Debora; Sanderson, Jeremy; Formstone, Caroline; Murdoch, Jennifer N; Niswander, Lee A; Greenfield, Andy; Dean, Charlotte H

    2013-01-15

    During lung development, proper epithelial cell arrangements are critical for the formation of an arborized network of tubes. Each tube requires a lumen, the diameter of which must be tightly regulated to enable optimal lung function. Lung branching and lumen morphogenesis require close epithelial cell-cell contacts that are maintained as a result of adherens junctions, tight junctions and by intact apical-basal (A/B) polarity. However, the molecular mechanisms that maintain epithelial cohesion and lumen diameter in the mammalian lung are unknown. Here we show that Scribble, a protein implicated in planar cell polarity (PCP) signalling, is necessary for normal lung morphogenesis. Lungs of the Scrib mouse mutant Circletail (Crc) are abnormally shaped with fewer airways, and these airways often lack a visible, 'open' lumen. Mechanistically we show that Scrib genetically interacts with the core PCP gene Vangl2 in the developing lung and that the distribution of PCP pathway proteins and Rho mediated cytoskeletal modification is perturbed in Scrib(Crc/Crc) lungs. However A/B polarity, which is disrupted in Drosophila Scrib mutants, is largely unaffected. Notably, we find that Scrib mediates functions not attributed to other PCP proteins in the lung. Specifically, Scrib localises to both adherens and tight junctions of lung epithelia and knockdown of Scrib in lung explants and organotypic cultures leads to reduced cohesion of lung epithelial cells. Live imaging of Scrib knockdown lungs shows that Scrib does not affect bud bifurcation, as previously shown for the PCP protein Celsr1, but is required to maintain epithelial cohesion. To understand the mechanism leading to reduced cell-cell association, we show that Scrib associates with β-catenin in embryonic lung and the sub-cellular distribution of adherens and tight junction proteins is perturbed in mutant lung epithelia. Our data reveal that Scrib is required for normal lung epithelial organisation and lumen

  3. Treatment of acute lung injury by targeting MG53-mediated cell membrane repair.

    PubMed

    Jia, Yanlin; Chen, Ken; Lin, Peihui; Lieber, Gissela; Nishi, Miyuki; Yan, Rosalie; Wang, Zhen; Yao, Yonggang; Li, Yu; Whitson, Bryan A; Duann, Pu; Li, Haichang; Zhou, Xinyu; Zhu, Hua; Takeshima, Hiroshi; Hunter, John C; McLeod, Robbie L; Weisleder, Noah; Zeng, Chunyu; Ma, Jianjie

    2014-01-01

    Injury to lung epithelial cells has a role in multiple lung diseases. We previously identified mitsugumin 53 (MG53) as a component of the cell membrane repair machinery in striated muscle cells. Here we show that MG53 also has a physiological role in the lung and may be used as a treatment in animal models of acute lung injury. Mice lacking MG53 show increased susceptibility to ischaemia-reperfusion and overventilation-induced injury to the lung when compared with wild-type mice. Extracellular application of recombinant human MG53 (rhMG53) protein protects cultured lung epithelial cells against anoxia/reoxygenation-induced injuries. Intravenous delivery or inhalation of rhMG53 reduces symptoms in rodent models of acute lung injury and emphysema. Repetitive administration of rhMG53 improves pulmonary structure associated with chronic lung injury in mice. Our data indicate a physiological function for MG53 in the lung and suggest that targeting membrane repair may be an effective means for treatment or prevention of lung diseases. PMID:25034454

  4. 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

  5. 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.

  6. 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

  7. 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.

  8. Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pulmonary neuroendocrine cells (PNECs) are proposed to be the first specialized cell type to appear in the lung, but their ontogeny remains obscure. Although studies of PNECs have suggested their involvement in a number of lung functions, neither their in vivo significance nor the molecular mechanis...

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. Inferring RBP-Mediated Regulation in Lung Squamous Cell Carcinoma

    PubMed Central

    Lafzi, Atefeh; Kazan, Hilal

    2016-01-01

    RNA-binding proteins (RBPs) play key roles in post-transcriptional regulation of mRNAs. Dysregulations in RBP-mediated mechanisms have been found to be associated with many steps of cancer initiation and progression. Despite this, previous studies of gene expression in cancer have ignored the effect of RBPs. To this end, we developed a lasso regression model that predicts gene expression in cancer by incorporating RBP-mediated regulation as well as the effects of other well-studied factors such as copy-number variation, DNA methylation, TFs and miRNAs. As a case study, we applied our model to Lung squamous cell carcinoma (LUSC) data as we found that there are several RBPs differentially expressed in LUSC. Including RBP-mediated regulatory effects in addition to the other features significantly increased the Spearman rank correlation between predicted and measured expression of held-out genes. Using a feature selection procedure that accounts for the adaptive search employed by lasso regularization, we identified the candidate regulators in LUSC. Remarkably, several of these candidate regulators are RBPs. Furthermore, majority of the candidate regulators have been previously found to be associated with lung cancer. To investigate the mechanisms that are controlled by these regulators, we predicted their target gene sets based on our model. We validated the target gene sets by comparing against experimentally verified targets. Our results suggest that the future studies of gene expression in cancer must consider the effect of RBP-mediated regulation. PMID:27186987

  18. 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

  19. Personalized therapy on the horizon for squamous cell carcinoma of the lung.

    PubMed

    Kim, Han Sang; Mitsudomi, Tetsuya; Soo, Ross A; Cho, Byoung Chul

    2013-06-01

    Squamous cell carcinoma (SQCC) of the lung is the second-largest subtype of non-small cell lung cancer (NSCLC), causing an estimated 400,000 deaths per year worldwide. Recent developments in cancer genome sequencing technology expanded our knowledge of driver mutations, which were identified as novel candidates for targeted therapy in various cancers. Successful targeted treatments for lung adenocarcinoma, NSCLC's primary subtype, with EGFR mutation or ALK fusion are clinically available, and a clinical trial of personalized targeted therapy in patients with lung adenocarcinoma is underway by the Lung Cancer Mutation Consortium. Although there are targeted treatments for lung adenocarcinoma, no personalized therapies currently exist for SQCC. Recently, comprehensive genomic characterization of lung SQCC using massively parallel sequencing has enabled us to identify several potential driver mutations/signaling pathways. These are FGFR1 amplifications, PI3KCA mutations, PTEN mutations/deletions, PDGFRA amplifications/mutations, and DDR2 mutations. The march toward personalized therapy may have taken a step forward with the discovery of these potential biomarkers for the treatment of SQCC of the lung. This article reviewed the current knowledge of genomic landscape of lung SQCC and summarized ongoing clinical trials of targeted agents for lung SQCC. Also, we will suggest several other actionable mutations with matching drugs that should be investigated in future clinical trials for the personalized treatment of lung SQCC. PMID:23489560

  20. 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

  1. 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

  2. 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

  3. CD11b(+) Mononuclear Cells Mitigate Hyperoxia-Induced Lung Injury in Neonatal Mice.

    PubMed

    Eldredge, Laurie C; Treuting, Piper M; Manicone, Anne M; Ziegler, Steven F; Parks, William C; McGuire, John K

    2016-02-01

    Bronchopulmonary dysplasia (BPD) is a common consequence of life-saving interventions for infants born with immature lungs. Resident tissue myeloid cells regulate lung pathology, but their role in BPD is poorly understood. To determine the role of lung interstitial myeloid cells in neonatal responses to lung injury, we exposed newborn mice to hyperoxia, a neonatal mouse lung injury model with features of human BPD. In newborn mice raised in normoxia, we identified a CD45(+) F4/80(+) CD11b(+), Ly6G(lo-int) CD71(+) population of cells in lungs of neonatal mice present in significantly greater percentages than in adult mice. In response to hyperoxia, surface marker and gene expression in whole lung macrophages/monocytes was biased to an alternatively activated phenotype. Partial depletion of these CD11b(+) mononuclear cells using CD11b-diphtheria toxin (DT) receptor transgenic mice resulted in 60% mortality by 40 hours of hyperoxia exposure with more severe lung injury, perivascular edema, and alveolar hemorrhage compared with DT-treated CD11b-DT receptor-negative controls, which displayed no mortality. These results identify an antiinflammatory population of CD11b(+) mononuclear cells that are protective in hyperoxia-induced neonatal lung injury in mice, and suggest that enhancing their beneficial functions may be a treatment strategy in infants at risk for BPD. PMID:26192732

  4. 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

  5. Hedgehog/Gli promotes epithelial-mesenchymal transition in lung squamous cell carcinomas

    PubMed Central

    2014-01-01

    Background Squamous cell carcinomas (SCC) account for approximately 30% of non-small cell lung cancer. Investigation of the mechanism of invasion and metastasis of lung SCC will be of great help for the development of meaningful targeted therapeutics. This study is intended to understand whether the activation of Hedgehog (Hh) pathway is involved in lung SCC, and whether activated Hh signaling regulates metastasis through epithelial-mesenchymal transition (EMT) in lung SCC. Methods Two cohorts of patients with lung SCC were studied. Protein expression was examined by immunohistochemistry, Western blot, or immunofluorescence. Protein expression levels in tissue specimens were scored and correlations were analyzed. Vismodegib and a Gli inhibitor were used to inhibit Shh/Gli activity, and recombinant Shh proteins were used to stimulate the Hh pathway in lung SCC cell lines. Cell migration assay was performed in vitro. Results Shh/Gli pathway components were aberrantly expressed in lung SCC tissue samples. Gli1 expression was reversely associated with the expression of EMT markers E-Cadherin and β-Catenin in lung SCC specimens. Inhibition of the Shh/Gli pathway suppressed migration and up-regulated E-Cadherin expression in lung SCC cells. Stimulation of the pathway increased migration and down-regulated E-Cadherin expression in lung SCC cells. Conclusions Our results suggested that the Shh/Gli pathway may be critical for lung SCC recurrence, metastasis and resistance to chemotherapy. Inhibition of the Shh/Gli pathway activity/function is a potential therapeutic strategy for the treatment of lung SCC patients. PMID:24758269

  6. Intratumoral localization and activity of 17β-hydroxysteroid dehydrogenase type 1 in non-small cell lung cancer: a potent prognostic factor

    PubMed Central

    2013-01-01

    Background Estrogens were recently demonstrated to be synthesized in non-small cell lung carcinomas (NSCLCs) via aromatase activity and aromatase inhibitor (AI) did suppressed estrogen receptor (ER) positive NSCLC growth. However, other enzymes involved in intratumoral production and metabolism of estrogens, i.e. 17β-hydroxysteroid dehydrogenases (i.e. 17βHSD1 and 17βHSD2) and others have not been studied. Therefore, in this study, we examined the clinical/ biological significance of 17β-hydroxysteroid dehydrogenases in NSCLCs. Methodology Archival materials obtained from 103 NSCLC patients were immunohistochemically evaluated using anti-17βHSD1 and anti-17βHSD2 antibodies. The findings of immunohistochemistry were then correlated with intratumoral estrone (E1) and estradiol (E2) concentration, clinicopathological factors and overall survival of the patients. We further employed NSCLC cell lines, A549 and LK87 to study the functional significance of 17βHSD1, in vitro. Results A higher 17βHSD1 immunoreactivity tended to be positively associated with aromatase (p=0.057) and tumor stage (p=0.055) whereas a higher 17βHSD2 immunoreactivity was positively associated with a squamous cell and adenosquamous cell carcinomas subtypes (p=0.031), tumor stage (p=0.004), T factor of TNM classification (p=0.010), maximum tumor diameter (p=0.002) and tended to be associated with N factor of TMN classification (p=0.065). A higher 17βHSD1 immunoreactivity was also significantly associated with lower intratumoral E1 concentration (p=0.040) and a higher intratumoral E2/E1 concentration ratio (p=0.028). On the other hand a higher 17βHSD2 immunoreactivity was significantly associated with higher intratumoral E1 concentration (p=0.035). Results of multivariate regression analysis demonstrated an increased 17βHSD1 immunoreactivity in tumor cells as an independent negative prognostic factor (HR= 2.83, p=0.007). E1 treatment in 17βHSD1 positive NSCLC cells, A549 and LK87

  7. 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

  8. 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. ...

  9. 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. ...

  10. 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. ...

  11. Isolation and Culture of Alveolar Epithelial Type I and Type II Cells from Rat Lungs

    PubMed Central

    Gonzalez, Robert F.; Dobbs, Leland G.

    2014-01-01

    The pulmonary alveolar epithelium, comprised of alveolar Type I (TI) and Type II (TII) cells, covers more than 99% of the internal surface area of the lungs. The study of isolated and cultured alveolar epithelial TI and TII cells has provided a large amount of information about the functions of both cell types. This chapter provides information about methods for isolating and culturing both of these cell types from rat lungs. PMID:23097106

  12. 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

  13. 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

  14. Resected small cell lung cancer—time for more?

    PubMed Central

    Marr, Alissa S.; Zhang, Chi

    2016-01-01

    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

  15. [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

  16. Chemoprevention of lung squamous cell carcinoma in mice by a mixture of Chinese herbs.

    PubMed

    Wang, Yian; Zhang, Zhongqiu; Garbow, Joel R; Rowland, Doug J; Lubet, Ronald A; Sit, Daniel; Law, Francis; You, Ming

    2009-07-01

    Antitumor B (ATB) is a Chinese herbal mixture of six plants. Previous studies have shown significant chemopreventive efficacy of ATB against human esophageal and lung cancers. We have recently developed a new mouse model for lung squamous cell carcinomas (SCC). In this study, lung SCC mouse model was characterized using small-animal imaging techniques (magnetic resonance imaging and computed tomography). ATB decreased lung SCC significantly (3.1-fold; P < 0.05) and increased lung hyperplastic lesions by 2.4-fold (P < 0.05). This observation suggests that ATB can block hyperplasia from progression to SCC. ATB tissue distribution was determined using matrine as a marker chemical. We found that ATB is rapidly absorbed and then distributes to various tissues including the lung. These results indicate that ATB is a potent chemopreventive agent against the development of mouse lung SCCs. PMID:19584077

  17. 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

  18. Role of innate immune cells and their products in lung immunopathology.

    PubMed

    Suzuki, Tomoko; Chow, Chung-Wai; Downey, Gregory P

    2008-01-01

    The lung, with its enormous surface area, is literally 'bathed in a sea' of potential toxins that include pathogenic microorganisms, allergens, and pollutants. To preserve homeostasis and protect itself from injury, the lung has evolved intricate defense systems that guard it from these injurious agents. This chapter will focus on the innate component of the immune system that represents the first line of defense against microbial pathogens and pollutants. The innate immune system of the lung is diverse and includes structural cells such as epithelial cells and fibroblasts as well as itinerant leukocytes such as neutrophils, monocytes, and macrophages. Dendritic cells and mast cells, although of hematopoietic origin, are resident in the lung and help sense and orchestrate immune responses in the lung. Cells of the innate immune system secrete various soluble factors that are directly or indirectly microbicidal and/or modulate the inflammatory response. Among these soluble factors, proteinases and anti-proteinases factor prominently and exert both physiological and pathological effects on the function of diverse cell types in the lung. In concert with the adaptive immune system, the innate immune system of the lung is highly effective in combating invading microbial pathogens as evidenced by the rarity with which healthy humans succumb to lung infections. PMID:18272422

  19. Circadian Timing in the Lung; A Specific Role for Bronchiolar Epithelial Cells

    PubMed Central

    Gibbs, J. E.; Beesley, S.; Plumb, J.; Singh, D.; Farrow, S.; Ray, D. W.; Loudon, A. S. I.

    2015-01-01

    In addition to the core circadian oscillator, located within the suprachiasmatic nucleus, numerous peripheral tissues possess self-sustaining circadian timers. In vivo these are entrained and temporally synchronized by signals conveyed from the core oscillator. In the present study, we examine circadian timing in the lung, determine the cellular localization of core clock proteins in both mouse and human lung tissue, and establish the effects of glucocorticoids (widely used in the treatment of asthma) on the pulmonary clock. Using organotypic lung slices prepared from transgenic mPER2::Luc mice, luciferase levels, which report PER2 expression, were measured over a number of days. We demonstrate a robust circadian rhythm in the mouse lung that is responsive to glucocorticoids. Immunohistochemical techniques were used to localize specific expression of core clock proteins, and the glucocorticoid receptor, to the epithelial cells lining the bronchioles in both mouse and human lung. In the mouse, these were established to be Clara cells. Murine Clara cells retained circadian rhythmicity when grown as a pure population in culture. Furthermore, selective ablation of Clara cells resulted in the loss of circadian rhythm in lung slices, demonstrating the importance of this cell type in maintaining overall pulmonary circadian rhythmicity. In summary, we demonstrate that Clara cells are critical for maintaining coherent circadian oscillations in lung tissue. Their coexpression of the glucocorticoid receptor and core clock components establishes them as a likely interface between humoral suprachiasmatic nucleus output and circadian lung physiology. PMID:18787022

  20. Migration of CD11b+ accessory cells during murine lung regeneration.

    PubMed

    Chamoto, Kenji; Gibney, Barry C; Lee, Grace S; Ackermann, Maximilian; Konerding, Moritz A; Tsuda, Akira; Mentzer, Steven J

    2013-05-01

    In many mammalian species, the removal of one lung leads to growth of the remaining lung to near-baseline levels. In studying post-pneumonectomy mice, we used morphometric measures to demonstrate neoalveolarization within 21 days of pneumonectomy. Of note, the detailed histology during this period demonstrated no significant pulmonary inflammation. To identify occult blood-borne cells, we used a parabiotic model (wild-type/GFP) of post-pneumonectomy lung growth. Flow cytometry of post-pneumonectomy lung digests demonstrated a rapid increase in the number of cells expressing the hematopoietic membrane molecule CD11b; 64.5% of the entire GFP(+) population were CD11b(+). Fluorescence microscopy demonstrated that the CD11b(+) peripheral blood cells migrated into both the interstitial tissue and alveolar airspace compartments. Pneumonectomy in mice deficient in CD11b (CD18(-/-) mutants) demonstrated near-absent leukocyte migration into the airspace compartment (p<.001) and impaired lung growth as demonstrated by lung weight (p<.05) and lung volume (p<.05). Transcriptional activity of the partitioned CD11b(+) cells demonstrated significantly increased transcription of Angpt1, Il1b, and Mmp8, Mmp9, Ncam1, Sele, Sell, Selp in the alveolar airspace and Adamts2, Ecm1, Egf, Mmp7, Npr1, Tgfb2 in the interstitial tissue (>4-fold regulation; p<.05). These data suggest that blood-borne CD11b(+) cells represent a population of accessory cells contributing to post-pneumonectomy lung growth. PMID:23376466

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

    SciTech Connect

    Guo, Kai; Jin, Faguang

    2015-09-25

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

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

    SciTech Connect

    Hong-geller, Elizabeth

    2008-01-01

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

  3. Non-small cell lung carcinoma metastasis to the anus.

    PubMed

    Dhandapani, Ramya Gowri; Anosike, Chinedum; Ganguly, Akash

    2016-01-01

    A 70-year-old man presenting with a lung mass was investigated and treated with pneumonectomy for adenocarcinoma of the lung. He re-presented 3 months later with a large perianal abscess and mass. Subsequent investigations and biopsies showed disseminated metastases from the lung primary. Immunohistochemical staining confirmed the nature of the anal metastasis from the lung adenocarcinoma. Lung cancer is notorious for metastases, hence it is important to be aware of the uncommon modes of spread, which will help obtain early diagnosis and optimise treatment. PMID:27130556

  4. 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

  5. Acute stress reduces intraparenchymal lung natural killer cells via beta-adrenergic stimulation

    PubMed Central

    Kanemi, O; Zhang, X; Sakamoto, Y; Ebina, M; Nagatomi, R

    2005-01-01

    There are lines of evidence that natural killer (NK) cells are sensitive to physical and psychological stress. Alterations in the immune system including NK cells are known to differ among tissues and organs. The effect of stress on the lung immune system, however, has not been well documented in spite of the fact that the lungs always confront viral or bacterial attacks as well as tumour cell metastasis. In this study, we intended to investigate the effect of restraint stress on lung lymphocytes including NK cells. C57BL/6 mice were exposed to 2 h restraint stress. The concentration of plasma epinephrine significantly rose immediately after the release from restraint as compared to home-cage control mice. Flow cytometric analysis revealed that the numbers of most lymphocyte subsets including NK cells were decreased in the lungs and blood but not in the spleen, immediately after restraint stress. Immunohistochemical examination revealed that the number of NK cells was decreased in the intraparenchymal region of the lungs, while the number of alveolar macrophages did not change. The decrease in the number of NK cells in the lungs and blood was reversed by the administration of propranolol, a nonselective beta adrenergic antagonist. Taken together, our findings suggest that acute stress reduces the number of intraparenchymal lung NK cells via activation of beta adrenergic receptors. PMID:15606610

  6. 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.

  7. 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

  8. Repopulation of the Irradiation Damaged Lung with Bone Marrow-derived Cells

    PubMed Central

    Bernard, Mark E.; Kim, Hyun; Rajagopalan, Malolan S.; Stone, Brandon; Salimi, Umar; Rwigema, Jean-Claude; Epperly, Michael W.; Shen, Hongmei; Goff, Julie P.; Franicola, Darcy; Dixon, Tracy; Cao, Shaonan; Zhang, Xichen; Wang, Hong; Stolz, Donna B.; Greenberger, Joel S.

    2012-01-01

    Aim The effect of lung irradiation on reduction of lung stem cells and repopulation with bone marrow-derived cells was measured. Materials and Methods Expression of green fluorescent protein positive cells (GFP+) in the lungs of thoracic irradiated FVB/NHsd mice (Harlan Sprague Dawley, Indianapolis, IN, USA) was determined. This was compared to the repopulation of bone marrow-derived cells found in the lungs from naphthalene treated male FVB/NHsd mice and gangciclovir (GVC) treated FeVBN GFP+ male marrow chimeric HSV-TK-CCSP. The level of mRNA for lung stem cell markers clara cell (CCSP), epithelium 1 (FOXJ1) and surfactant protein C (SP-C), and sorted single cells positive for marrow origin epithelial cells (GFP+ CD45−) was measured. Results The expression of pulmonary stem cells as determined by PCR was reduced most by GCV, then naphthalene, and least by thoracic irradiation. Irradiation, like GCV, reduced mRNA expression of CCSP, CYP2F2, and FOXJ1, while naphthalene reduced that of CCSP and CYP2F2. Ultrastructural analysis showed GFP+ pulmonary cells of bone marrow origin, with the highest frequency being found in GCV-treated groups. Conclusion Bone marrow progenitor cells may not participate in the repopulation of the lung following irradiation. PMID:22210711

  9. 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

  10. 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

  11. Lung epithelial stem cells and their niches: Fgf10 takes center stage.

    PubMed

    Volckaert, Thomas; De Langhe, Stijn

    2014-01-01

    Throughout life adult animals crucially depend on stem cell populations to maintain and repair their tissues to ensure life-long organ function. Stem cells are characterized by their capacity to extensively self-renew and give rise to one or more differentiated cell types. These powerful stem cell properties are key to meet the changing demand for tissue replacement during normal lung homeostasis and regeneration after lung injury. Great strides have been made over the last few years to identify and characterize lung epithelial stem cells as well as their lineage relationships. Unfortunately, knowledge on what regulates the behavior and fate specification of lung epithelial stem cells is still limited, but involves communication with their microenvironment or niche, a local tissue environment that hosts and influences the behaviors or characteristics of stem cells and that comprises other cell types and extracellular matrix. As such, an intimate and dynamic epithelial-mesenchymal cross-talk, which is also essential during lung development, is required for normal homeostasis and to mount an appropriate regenerative response after lung injury. Fibroblast growth factor 10 (Fgf10) signaling in particular seems to be a well-conserved signaling pathway governing epithelial-mesenchymal interactions during lung development as well as between different adult lung epithelial stem cells and their niches. On the other hand, disruption of these reciprocal interactions leads to a dysfunctional epithelial stem cell-niche unit, which may culminate in chronic lung diseases such as chronic obstructive pulmonary disease (COPD), chronic asthma and idiopathic pulmonary fibrosis (IPF). PMID:24891877

  12. 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

  13. Lung CD8+ T cells in COPD have increased expression of bacterial TLRs

    PubMed Central

    2013-01-01

    Background Toll-like receptors (TLRs) on T cells can modulate their responses, however, the extent and significance of TLR expression by lung T cells, NK cells, or NKT cells in chronic obstructive pulmonary disease (COPD) is unknown. Methods Lung tissue collected from clinically-indicated resections (n = 34) was used either: (a) to compare the expression of TLR1, TLR2, TLR2/1, TLR3, TLR4, TLR5, TLR6 and TLR9 on lung CD8+ T cells, CD4+ T cells, NK cells and NKT cells from smokers with or without COPD; or (b) to isolate CD8+ T cells for culture with anti-CD3ε without or with various TLR ligands. We measured protein expression of IFN-γ, TNF-α, IL-13, perforin, granzyme A, granzyme B, soluble FasL, CCL2, CCL3, CCL4, CCL5, CCL11, and CXCL9 in supernatants. Results All the lung subsets analyzed demonstrated low levels of specific TLR expression, but the percentage of CD8+ T cells expressing TLR1, TLR2, TLR4, TLR6 and TLR2/1 was significantly increased in COPD subjects relative to those without COPD. In contrast, from the same subjects, only TLR2/1 and TLR2 on lung CD4+ T cells and CD8+ NKT cells, respectively, showed a significant increase in COPD and there was no difference in TLR expression on lung CD56+ NK cells. Production of the Tc1 cytokines IFN-γ and TNF-α by lung CD8+ T cells were significantly increased via co-stimulation by Pam3CSK4, a specific TLR2/1 ligand, but not by other agonists. Furthermore, this increase in cytokine production was specific to lung CD8+ T cells from patients with COPD as compared to lung CD8+ T cells from smokers without COPD. Conclusions These data suggest that as lung function worsens in COPD, the auto-aggressive behavior of lung CD8+ T cells could increase in response to microbial TLR ligands, specifically ligands against TLR2/1. PMID:23374856

  14. Amniotic Fluid Stem Cells from EGFP Transgenic Mice Attenuate Hyperoxia-Induced Acute Lung Injury

    PubMed Central

    Lai, Cheng-Wei; Yen, Chih-Ching; Lee, Kun-Hsiung; Wu, Shinn-Chih; Chen, Chuan-Mu

    2013-01-01

    High concentrations of oxygen aggravate the severity of lung injury in patients requiring mechanical ventilation. Although mesenchymal stem cells have been shown to effectively attenuate various injured tissues, there is limited information regarding a role for amniotic fluid stem cells (AFSCs) in treating acute lung injury. We hypothesized that intravenous delivery of AFSCs would attenuate lung injury in an experimental model of hyperoxia-induced lung injury. AFSCs were isolated from EGFP transgenic mice. The in vitro differentiation, surface markers, and migration of the AFSCs were assessed by specific staining, flow cytometry, and a co-culture system, respectively. The in vivo therapeutic potential of AFSCs was evaluated in a model of acute hyperoxia-induced lung injury in mice. The administration of AFSCs significantly reduced the hyperoxia-induced pulmonary inflammation, as reflected by significant reductions in lung wet/dry ratio, neutrophil counts, and the level of apoptosis, as well as reducing the levels of inflammatory cytokine (IL-1β, IL-6, and TNF-α) and early-stage fibrosis in lung tissues. Moreover, EGFP-expressing AFSCs were detected and engrafted into a peripheral lung epithelial cell lineage by fluorescence microscopy and DAPI stain. Intravenous administration of AFSCs may offer a new therapeutic strategy for acute lung injury (ALI), for which efficient treatments are currently unavailable. PMID:24040409

  15. Relationship of small airway chymase-positive mast cells and lung function in severe asthma.

    PubMed

    Balzar, Silvana; Chu, Hong Wei; Strand, Matthew; Wenzel, Sally

    2005-03-01

    Distal lung inflammation may be important in asthma pathophysiology. The goal of this study was to measure cellular inflammation in the large airway and four distal lung regions (small airway inner and outer wall, alveolar attachments, and peripheral alveolar tissue) and to correlate the specific inflammatory cells with several lung function parameters. Sections of concurrently obtained endobronchial and transbronchial/surgical biopsy tissue from 20 individuals with severe asthma were immunostained for T-lymphocyte, eosinophil, monocyte/macrophage, neutrophil, and two mast cell markers (tryptase and chymase). Specific cell distributions were determined and correlated with lung function measures. The number of inflammatory cells generally increased toward the periphery, but the percentage of T-lymphocytes, eosinophils, monocytes/macrophages, and neutrophils remained similar or decreased from large to small airways. In contrast, mast cell number, percentage, and the chymase-positive phenotype increased in small airway regions. After the analysis was adjusted for multiple comparisons, only chymase-positive mast cells significantly and positively correlated with lung function. Such a relationship was seen only in the small airway/alveolar attachments lung region (r(s) = 0.61-0.89; p cells, particularly in the small airway outer wall/alveolar attachments region, may be protective for lung function in severe asthma. PMID:15563633

  16. 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

  17. Lipopolysaccharide-induced lung injury in mice. I. Concomitant evaluation of inflammatory cells and haemorrhagic lung damage.

    PubMed

    Asti, C; Ruggieri, V; Porzio, S; Chiusaroli, R; Melillo, G; Caselli, G F

    2000-01-01

    Intratracheal instillation of lipopolysaccharide (LPS) induces an inflammatory response characterized by infiltration of polymorphonuclear neutrophils (PMNs) into the extracellular matrix and by the release of mediators that play a fundamental role in lung damage. In the present study, we developed a mouse model which allows correlation of the inflammatory response and haemorrhagic tissue injury in the same animal. In particular, the different steps of the inflammatory response and tissue damage were evaluated by the analysis of three parameters: myeloperoxidase (MPO) activity in the parenchyma, reflecting PMNs accumulation into the lung, inflammatory cells count in the bronchoalveolar lavage fluid (BALF), reflecting their extravasation, and total haemoglobin estimation in BALF, a marker of haemorrhagic tissue damage consequent to PMNs degranulation. In our experimental conditions, intra-tracheal administration of 10 microg/mouse of LPS evoked an increase of MPO activity in the lung at 4 h (131%) and 6 h (147%) from endotoxin challenge. A significant increase of PMNs in the BALF was noticed at these times with a plateau between the 12nd and 24th h. PMN accumulation produced a time-dependent haemorrhagic lung damage until 24 h after LPS injection (4 h: +38%; 6 h: +23%; 12 h: +44%; 24 h: +129% increase of haemoglobin concentration in the BALF vs. control). Lung injury was also assessed histopathologically. Twenty-four hours after the challenge, diffuse alveolar haemorrhage, as well as PMN recruitment in the interstitium and alveolus were observed in the LPS group. This model was pharmacologically characterized by pretreatment of LPS-treated mice with antiinflammatory drugs acting on different steps of the . We demonstrated that: a) betamethasone (1, 3, 10, 30 mg/kg p.o.) reduced in a dose-dependent manner the MPO activity, the number of inflammatory cells and, at the same time, lung injury; b) pentoxifylline, a TNFalpha production inhibitor (200

  18. Activated polymorphonuclear cells increase sickle red blood cell retention in lung: role of phospholipids.

    PubMed

    Haynes, Johnson; Obiako, Boniface

    2002-01-01

    This study investigates the role of the activated polymorphonuclear cell (APMN) products on sickle red blood cell (SRBC) retention/adherence in the pulmonary circulation. Isolated rat lungs were perfused with (51)Cr-labeled normal RBCs (NRBC) or SRBCs (10% hematocrit) suspensions +/- PMNs. Specific activities of lung and perfusate were measured and retention (the number of SRBC/g lung) was calculated. SRBC retention was 3.5 times greater than NRBC retention. PMN activation was required to increase SRBC retention. Supernatants from APMN increased SRBC retention, which suggested soluble products such as oxidants, PAF, and/or leukotriene (LTB(4)) are involved. Heat inactivation of PMN NADPH oxidase had no effect on retention. Whereas neither platelet-activating factor (PAF) nor LTB(4) (secreted by APMN) increased SRBC retention, PAF+LTB(4) did. The PAF antagonist, WEB-2170, attenuated SRBC retention mediated by PAF+LTB(4) and APMNs. Similarly, zileuton (5-lipoxygenase inhibitor) attenuated APMN-mediated SRBC retention. We conclude the concomitant release of PAF and LTB(4) from APMN is involved in the initiation of microvascular occlusion by SRBCs in the perfused rat lung. PMID:11748055

  19. Radiation-induced lung fibrosis after treatment of small cell carcinoma of the lung with very high-dose cyclophosphamide

    SciTech Connect

    Trask, C.W.; Joannides, T.; Harper, P.G.; Tobias, J.S.; Spiro, S.G.; Geddes, D.M.; Souhami, R.L.; Beverly, P.C.

    1985-01-01

    Twenty-five previously untreated patients with small cell carcinoma of the lung were treated with cyclophosphamide 160 to 200 mg/kg (with autologous bone marrow support) followed by radiotherapy (4000 cGy) to the primary site and mediastinum. No other treatment was given until relapse occurred. Nineteen patients were assessable at least 4 months after radiotherapy; of these, 15 (79%) developed radiologic evidence of fibrosis, which was symptomatic in 14 (74%). The time of onset of fibrosis was related to the volume of lung irradiated. A retrospective analysis was made of 20 consecutive patients treated with multiple-drug chemotherapy and an identical radiotherapy regimen as part of a randomized trial. Radiologic and symptomatic fibrosis was one half as frequent (35%) as in the high-dose cyclophosphamide group. Very high-dose cyclophosphamide appears to sensitize the lung to radiotherapy and promotes the production of fibrosis.

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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.

  7. Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases. Comprehensive Review of the Recent Literature 2010–2012

    PubMed Central

    2013-01-01

    A conference, “Stem Cells and Cell Therapies in Lung Biology and Lung Diseases,” was held July 25 to 28, 2011 at the University of Vermont to review the current understanding of the role of stem and progenitor cells in lung repair after injury and to review the current status of cell therapy and ex vivo bioengineering approaches for lung diseases. These are rapidly expanding areas of study that provide further insight into and challenge traditional views of mechanisms of lung repair after injury and pathogenesis of several lung diseases. The goals of the conference were to summarize the current state of the field, to discuss and debate current controversies, and to identify future research directions and opportunities for basic and translational research in cell-based therapies for lung diseases. The goal of this article, which accompanies the formal conference report, is to provide a comprehensive review of the published literature in lung regenerative medicine from the last conference report through December 2012. PMID:23869446

  8. 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

  9. 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

  10. Autophagy in non-small cell lung carcinogenesis

    PubMed Central

    Rao, Shuan; Yang, Heng; Penninger, Josef M; Kroemer, Guido

    2014-01-01

    In a mouse model of non-small cell lung carcinogenesis, we recently found that the inactivation of the essential autophagy gene Atg5 causes an acceleration of the early phases of oncogenesis. Thus, hyperplastic lesions and adenomas are more frequent at early stages after adenoviral delivery of Cre recombinase via inhalation, when Cre—in addition to activating the KRasG12D oncogene—inactivates both alleles of the Atg5 gene. The accelerated oncogenesis of autophagy-deficient tumors developing in KRas;Atg5fl/fl mice (as compared with autophagy-competent KRas;Atg5fl/+ control tumors) correlates with an increased infiltration by FOXP3+ regulatory T cells (Tregs). Depletion of such Tregs by means of specific monoclonal antibodies inhibits the accelerated oncogenesis of autophagy-deficient tumors down to the level observed in autophagy-competent controls. Subsequent analyses revealed that the combination of KRas activation and Atg5 inactivation favors the expression of ENTPD1/CD39, an ecto-ATPase that initiates the conversion of extracellular ATP, which is immunostimulatory, into adenosine, which is immunosuppressive. Pharmacological inhibition of ENTPD1 or blockade of adenosinergic receptors reduces the infiltration of KRas;Atg5fl/fl tumors by Tregs and reverses accelerated oncogenesis. Altogether these data favor a model according to which autophagy deficiency favors oncogenesis via changes in the tumor microenvironment that ultimately entail the Treg-mediated inhibition of anticancer immunosurveillance. PMID:24413089

  11. 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

  12. 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

  13. Effective avoidance of a functional spect-perfused lung using intensity modulated radiotherapy (IMRT) for non-small cell lung cancer (NSCLC): an update of a planning study.

    PubMed

    Lavrenkov, Konstantin; Singh, Shalini; Christian, Judith A; Partridge, Mike; Nioutsikou, Elena; Cook, Gary; Bedford, James L; Brada, Michael

    2009-06-01

    IMRT and 3-dimensional conformal radiotherapy (3-DCRT) plans of 25 patients with non-small cell lung (NSCLC) were compared in terms of planning target volume (PTV) coverage and sparing of functional lung (FL) defined by a SPECT perfusion scan. IMRT resulted in significant reduction of functional V(20) and mean lung dose in stage III patients with inhomogeneous hypoperfusion. If the dose to FL is shown to be the determinant of lung toxicity, IMRT would allow for effective dose escalation by specific avoidance of functional lung. PMID:18995919

  14. 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

  15. A NOVEL TECHNIQUE FOR QUANTITATIVE ESTIMATION OF UPTAKE OF DIESEL EXHAUST PARTICLES BY LUNG CELLS

    EPA Science Inventory

    While airborne particulates like diesel exhaust particulates (DEP) exert significant toxicological effects on lungs, quantitative estimation of accumulation of DEP inside lung cells has not been reported due to a lack of an accurate and quantitative technique for this purpose. I...

  16. MORPHOMETRIC CHARACTERISTICS OF CELLS IN THE ALVEOLAR REGION OF MAMMALIAN LUNGS

    EPA Science Inventory

    Morphometric procedures have been used to study the characteristics of cells in the alveolar region of the lungs of rats, dogs, baboons, and humans. Compared with the other species, human lungs were found to contain greater numbers of macrophages and to have larger alveolar type ...

  17. The First Case of Pulmonary Alveolar Proteinosis With Small Cell Lung Carcinoma.

    PubMed

    Hiraki, Tsubasa; Goto, Yuko; Kitazono, Ikumi; Tasaki, Takashi; Higashi, Michiyo; Hatanaka, Kazuhito; Tanimoto, Akihide

    2016-04-01

    Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease characterized by alveolar accumulation of surfactant lipids and proteins. It is usually autoimmune and secondary to hematologic malignancy or infection. To date, only 5 case reports of PAP associated with lung cancers, including 2 cases of squamous cell carcinoma and 3 cases of adenocarcinoma, have been published. To the best of our knowledge, no case of PAP with small cell lung carcinoma has been reported thus far. We herein report the first case of PAP associated with small cell lung carcinoma. PMID:26519525

  18. 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

  19. 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

  20. Aptamers Selected to Postoperative Lung Adenocarcinoma Detect Circulating Tumor Cells in Human Blood

    PubMed Central

    Zamay, Galina S; Kolovskaya, Olga S; Zamay, Tatiana N; Glazyrin, Yury E; Krat, Alexey V; Zubkova, Olga; Spivak, Ekaterina; Wehbe, Mohammed; Gargaun, Ana; Muharemagic, Darija; Komarova, Mariia; Grigorieva, Valentina; Savchenko, Andrey; Modestov, Andrey A; Berezovski, Maxim V; Zamay, Anna S

    2015-01-01

    Circulating tumor cells (CTCs) are rare cells and valuable clinical markers of prognosis of metastasis formation and prediction of patient survival. Most CTC analyses are based on the antibody-based detection of a few epithelial markers; therefore miss an important portion of mesenchymal cancer cells circulating in blood. In this work, we selected and identified DNA aptamers as specific affinity probes that bind to lung adenocarcinoma cells derived from postoperative tissues. The unique feature of our selection strategy is that aptamers are produced for lung cancer cell biomarkers in their native state and conformation without previous knowledge of the biomarkers. The aptamers did not bind to normal lung cells and lymphocytes, and had very low affinity to A549 lung adenocarcinoma culture. We applied these aptamers to detect CTCs, apoptotic bodies, and microemboli in clinical samples of peripheral blood of lung cancer and metastatic lung cancer patients. We identified aptamer-associated protein biomarkers for lung cancer such as vimentin, annexin A2, annexin A5, histone 2B, neutrophil defensin, and clusterin. Tumor-specific aptamers can be produced for individual patients and synthesized many times during anticancer therapy, thereby opening up the possibility of personalized diagnostics. PMID:26061649

  1. Aptamers Selected to Postoperative Lung Adenocarcinoma Detect Circulating Tumor Cells in Human Blood.

    PubMed

    Zamay, Galina S; Kolovskaya, Olga S; Zamay, Tatiana N; Glazyrin, Yury E; Krat, Alexey V; Zubkova, Olga; Spivak, Ekaterina; Wehbe, Mohammed; Gargaun, Ana; Muharemagic, Darija; Komarova, Mariia; Grigorieva, Valentina; Savchenko, Andrey; Modestov, Andrey A; Berezovski, Maxim V; Zamay, Anna S

    2015-09-01

    Circulating tumor cells (CTCs) are rare cells and valuable clinical markers of prognosis of metastasis formation and prediction of patient survival. Most CTC analyses are based on the antibody-based detection of a few epithelial markers; therefore miss an important portion of mesenchymal cancer cells circulating in blood. In this work, we selected and identified DNA aptamers as specific affinity probes that bind to lung adenocarcinoma cells derived from postoperative tissues. The unique feature of our selection strategy is that aptamers are produced for lung cancer cell biomarkers in their native state and conformation without previous knowledge of the biomarkers. The aptamers did not bind to normal lung cells and lymphocytes, and had very low affinity to A549 lung adenocarcinoma culture. We applied these aptamers to detect CTCs, apoptotic bodies, and microemboli in clinical samples of peripheral blood of lung cancer and metastatic lung cancer patients. We identified aptamer-associated protein biomarkers for lung cancer such as vimentin, annexin A2, annexin A5, histone 2B, neutrophil defensin, and clusterin. Tumor-specific aptamers can be produced for individual patients and synthesized many times during anticancer therapy, thereby opening up the possibility of personalized diagnostics. PMID:26061649

  2. Regulation of cytochrome P4501A1 expression by hyperoxia in human lung cell lines: Implications for hyperoxic lung injury

    SciTech Connect

    Bhakta, Kushal Y. Jiang, Weiwu; Couroucli, Xanthi I.; Fazili, Inayat S.; Muthiah, Kathirvel; Moorthy, Bhagavatula

    2008-12-01

    Supplemental oxygen, used to treat pulmonary insufficiency in newborns, contributes to the development of bronchopulmonary dysplasia (BPD). Cytochrome P4501A enzymes are induced by hyperoxia in animal models, but their role in human systems is unknown. Here we investigated the molecular mechanisms of induction of CYP1A1 by hyperoxia in human lung cell lines. Three human lung cell lines were exposed to hyperoxia (95% O2) for 0-72 h, and CYP1A1 activities, apoprotein contents, and mRNA levels were determined. Hyperoxia significantly induced CYP1A1 activity and protein contents (2-4 fold), and mRNA levels (30-40 fold) over control in each cell line. Transfection of a CYP1A1 promoter/luciferase reporter construct, followed by hyperoxia (4-72 h), showed marked (2-6 fold) induction of luciferase expression. EMSA and siRNA experiments strongly suggest that the Ah receptor (AHR) is involved in the hyperoxic induction of CYP1A1. MTT reduction assays showed attenuation of cell injury with the CYP1A1 inducer beta-naphthoflavone (BNF). Our results strongly suggest that hyperoxia transcriptionally activates CYP1A1 expression in human lung cell lines by AHR-dependent mechanisms, and that CYP1A1 induction is associated with decreased toxicity. This novel finding of induction of CYP1A1 in the absence of exogenous AHR ligands could lead to novel interventions in the treatment of BPD.

  3. Pneumonia carcinomatosa from small cell undifferentiated carcinoma of the lung presenting as reverse radiation pneumonitis

    SciTech Connect

    Adelstein, D.J.; Padhya, T.; Tomashefski, J.F. Jr.; Park, C.

    1988-01-01

    We describe a patient with recurrent small cell undifferentiated lung carcinoma after chemotherapy and mediastinal radiation therapy who presented with peripheral pulmonary infiltrates on chest radiograph. At autopsy the patient was found to have carcinomatous pneumonia confined to the radiographically abnormal lung. The descriptive term reverse radiation pneumonitis is applied in view of the striking nonsegmental distribution of these pulmonary infiltrates, which occurred only outside the irradiated field. In this patient, radiation therapy successfully controlled disease in the treated lung parenchyma, thus accounting for this unusual radiologic and histologic picture. Pneumonia carcinomatosa, occurring after lung irradiation, can therefore be added to the differential diagnosis of radiographic peripheral pulmonary infiltrates.

  4. The potential for resident lung mesenchymal stem cells to promote functional tissue regeneration: understanding microenvironmental cues.

    PubMed

    Foronjy, Robert F; Majka, Susan M

    2012-12-01

    Tissue resident mesenchymal stem cells (MSCs) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis and tumor formation. Bone marrow derived mesenchymal stem cells (BM-MSCs) and endothelial progenitor cells (EPC) are currently being considered and tested in clinical trials as a potential therapy in patients with such inflammatory lung diseases including, but not limited to, chronic lung disease, pulmonary arterial hypertension (PAH), pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD)/emphysema and asthma. However, our current understanding of tissue resident lung MSCs remains limited. This review addresses how environmental cues impact on the phenotype and function of this endogenous stem cell pool. In addition, it examines how these local factors influence the efficacy of cell-based treatments for lung diseases. PMID:23626909

  5. [A case of gastric adenosquamous carcinoma with peritoneal dissemination in which treatment with S-1 plus paclitaxel therapy resulted in improved long-term survival].

    PubMed

    Hirano, Masamitsu; Ozamoto, Yuki; Ichinose, Masumi; Togawa, Takeshi; Takao, Nobuyuki; Mizumoto, Akiyoshi; Tatsuno, Manami; Yamamoto, Yoshihiro; Yonemura, Yutaka

    2014-07-01

    Gastric adenosquamous carcinoma is a rare malignancy with a poor prognosis. We recently performed palliative gastrectomy for a gastric adenosquamous carcinoma with peritoneal dissemination and provided a course of systemic chemotherapy with S-1 plus paclitaxel(PTX)after the surgery. No serious adverse events were observed, and treatment with S-1 plus PTX was continued for 1 year before being switched to adjuvant chemotherapy with S-1 alone for another year. The tumor maker levels normalized within 2 months of the initial treatment, and the peritoneal dissemination could no longer be detected by abdominal computed tomography(CT). The patient remained in clinical remission and maintained long-term survival of over 8 years. PMID:25131877

  6. 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

  7. Metastatic large cell neuroendocrine carcinoma of the lung arising from the uterus: A pitfall in lung cancer diagnosis.

    PubMed

    Ono, Kyoko; Yokota, Naho Ruiz; Yoshioka, Emi; Noguchi, Akira; Washimi, Kota; Kawachi, Kae; Miyagi, Yohei; Kato, Hisamori; Yokose, Tomoyuki

    2016-07-01

    A 41-year-old female smoker presented with a vaginal mass. Gynecological examination showed a mass filling the uterine corpus, cervix, and vagina. A total abdominal hysterectomy was performed. Macroscopic findings included a large fragile mass involving the uterine cavity, cervix, and vagina. Histology revealed atypical ducts admixed with solid components consisting of large atypical cells. The initial pathological diagnosis was grade 3 endometrioid adenocarcinoma. The patient was designated as stage II according to the 2008 International Federation of Gynecology and Obstetrics (FIGO) staging. Two years later, two nodules were found in the upper lobe of the left lung, and the patient underwent an upper lobectomy. The masses, which exhibited solid and organoid growth patterns of large atypical cells, had histological characteristics of large cell neuroendocrine carcinoma (LCNEC) of the lung. However, the tumor was immunohistochemically positive for neuroendocrine markers, such as synaptophysin in addition to estrogen receptor and progesterone receptor, and the tumor was negative for thyroid transcription factor-1. These immunohistochemical results were almost identical to those of the solid portions of the uterine carcinoma. The final diagnosis was LCNEC combined with endometrioid adenocarcinoma of the uterine corpus and lung metastasis of the LCNEC component of the endometrial carcinoma. LCNEC often arises in the lung, but it rarely arises in other organs. Some patients with metastatic components exhibited only a LCNEC pattern although the primary tumor was a mixed carcinoma consisting of LCNEC and other histology, like the present case. LCNEC is often poorly differentiated, especially in extrapulmonary primary organ LCNEC. Therefore, pathologists should consider metastatic carcinoma when they encounter lung LCNEC in a patient with a preceding extrapulmonary carcinoma composed of a poorly differentiated component or LCNEC component, and they should clarify tumor

  8. [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

  9. 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.

  10. 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.

  11. 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

  12. 76 FR 35450 - Draft Guidance for Industry on Clinical Trial Endpoints for the Approval of Non-Small Cell Lung...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-17

    .... This guidance does not address endpoints for drugs to prevent or decrease the incidence of lung cancer... the Approval of Non-Small Cell Lung Cancer Drugs and Biologics; Availability AGENCY: Food and Drug... Cell Lung Cancer Drugs and Biologics.'' This draft guidance provides recommendations to applicants...

  13. Effect of recombinant Newcastle disease virus transfection on lung adenocarcinoma A549 cells in vivo

    PubMed Central

    YAN, YULAN; JIA, LIJUAN; ZHANG, JIN; LIU, YANG; BU, XUEFENG

    2014-01-01

    Newcastle disease virus (NDV) has been reported to selectively duplicate in and then destroy tumor cells, whilst sparing normal cells. However, the effect of NDV on lung cancer has yet to be elucidated. In the present study, recombinant NDV (rl-RVG) was applied to lung adenocarcinoma A549 cell tumor-bearing mice to explore its effect on the proliferation of the cells and the immune response of the mice. Following rl-RVG transfection, RVG and NDV gene expression, decreased tumor growth, subcutaneous tumor necrosis, tumor apoptosis and an increased number of cluster of differentiation (CD)3−/CD49+ natural killer cells were more evident in the rl-RVG group. The present study demonstrated that rl-RVG transfection effectively restrained lung adenocarcinoma A549 cell growth in vivo, which may have been accomplish by inducing tumor cell apoptosis and regulating the cell immune response. PMID:25364430

  14. Role of Th17 cells and IL-17 in lung transplant rejection

    PubMed Central

    Wilkes, David S.

    2013-01-01

    In the past decade, advances in immunology have led to the recognition that T cell differentiation is not simply Th1 or Th2 but involves differentiation to other subsets, such as T regulatory cells, T follicular helper cells, and Th17 cells. Th17 cells, characterized by production of IL-17, IL-22, and IL-21, have been implicated in the pathogenesis of autoimmune diseases, like rheumatoid arthritis and multiple sclerosis, but also play an important role in host defense and mucosal immunity. IL-17, with its pleiotropic effects on stromal cells, as well as hematopoietic cells, has long been recognized as a possible mediator of rejection after lung transplantation. Recent data have implicated IL-17 and Th17 cells in the development of autoimmunity and chronic rejection after lung transplantation in both animal models and humans. In this review, we will discuss the current data on Th17 and the prospects for the future for lung transplantation. PMID:21279808

  15. Dengue viruses can infect human primary lung epithelia as well as lung carcinoma cells, and can also induce the secretion of IL-6 and RANTES.

    PubMed

    Lee, Ying-Ray; Su, Ching-Yao; Chow, Nan-Haw; Lai, Wu-Wei; Lei, Huan-Yao; Chang, Chia-Lun; Chang, Tsuey-Yu; Chen, Shun-Hua; Lin, Yee-Shin; Yeh, Trai-Ming; Liu, Hsiao-Sheng

    2007-06-01

    Dengue viruses (DENV) are herein demonstrated for the first time as being able to infect and replicate in human primary lung epithelium and various lung cancer cell lines. The detection of dengue virus particles and viral negative strand RNA synthesis in the cell, in conjunction with the release of viral progenies in culture supernatants, support the notion that lung cells are susceptible to dengue virus infection. The replication efficiency of DENV in lung cancer cells from high to low is: DEN-2 (dengue virus type-2), DEN-3, DEN-4 and DEN-1. Moreover, the susceptibility of the six lung cancer cell lines to DEN-2 infection is: SW1573>A549>H1435; H23; H520; Bes2B. DEN-2 infection significantly increased the expression levels of IL-6 and RANTES in four of the six lung cancer cell lines, which is consistent with the high expression levels of these molecules in DHF/DSS patients. IL-6 expression induced by DEN-2 infection was NF-kappaB dependent. In summary, our results indicate that lung epithelial cell is a possible target of dengue viruses and IL-6 and RANTES may play pivotal roles in lung related immuno-pathogenesis. PMID:17416433

  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. Spatiotemporal quantification of cell dynamics in the lung following influenza virus infection

    NASA Astrophysics Data System (ADS)

    Yin, Lu; Xu, Shuoyu; Cheng, Jierong; Zheng, Dahai; Limmon, Gino V.; Leung, Nicola H. N.; Rajapakse, Jagath C.; Chow, Vincent T. K.; Chen, Jianzhu; Yu, Hanry

    2013-04-01

    Lung injury caused by influenza virus infection is widespread. Understanding lung damage and repair progression post infection requires quantitative spatiotemporal information on various cell types mapping into the tissue structure. Based on high content images acquired from an automatic slide scanner, we have developed algorithms to quantify cell infiltration in the lung, loss and recovery of Clara cells in the damaged bronchioles and alveolar type II cells (AT2s) in the damaged alveolar areas, and induction of pro-surfactant protein C (pro-SPC)-expressing bronchiolar epithelial cells (SBECs). These quantitative analyses reveal: prolonged immune cell infiltration into the lung that persisted long after the influenza virus was cleared and paralleled with Clara cell recovery; more rapid loss and recovery of Clara cells as compared to AT2s; and two stages of SBECs from Scgb1a1+ to Scgb1a1-. These results provide evidence supporting a new mechanism of alveolar repair where Clara cells give rise to AT2s through the SBEC intermediates and shed light on the understanding of the lung damage and repair process. The approach and algorithms in quantifying cell-level changes in the tissue context (cell-based tissue informatics) to gain mechanistic insights into the damage and repair process can be expanded and adapted in studying other disease models.

  18. Pluripotent Allospecific CD8+ Effector T Cells Traffic to Lung in Murine Obliterative Airway Disease

    PubMed Central

    West, Erin E.; Lavoie, Tera L.; Orens, Jonathan B.; Chen, Edward S.; Ye, Shui Q.; Finkelman, Fred D.; Garcia, Joe G. N.; McDyer, John F.

    2006-01-01

    Long-term success in lung transplantation is limited by obliterative bronchiolitis, whereas T cell effector mechanisms in this process remain incompletely understood. Using the mouse heterotopic allogeneic airway transplant model, we studied T cell effector responses during obliterative airways disease (OAD). Allospecific CD8+IFN-γ+ T cells were detected in airway allografts, with significant coexpression of TNF-α and granzyme B. Therefore, using IFN-γ as a surrogate marker, we assessed the distribution and kinetics of extragraft allo-specific T cells during OAD. Robust allospecific IFN-γ was produced by draining the lymph nodes, spleen, and lung mononuclear cells from allograft, but not isograft recipients by Day 14, and significantly decreased by Day 28. Although the majority of allospecific T cells were CD8+, allospecific CD4+ T cells were also detected in these compartments, with each employing distinct allorecognition pathways. An influx of pluripotent CD8+ effector cells with a memory phenotype were detected in the lung during OAD similar to those seen in the allografts and secondary lymphoid tissue. Antibody depletion of CD8+ T cells markedly reduced airway lumen obliteration and fibrosis at Day 28. Together, these data demonstrate that allospecific CD8+ effector T cells play an important role in OAD and traffic to the lung after heterotopic airway transplant, suggesting that the lung is an important immunologic site, and perhaps a reservoir, for effector cells during the rejection process. PMID:16195540

  19. Precursor B Cells Increase in the Lung during Airway Allergic Inflammation: A Role for B Cell-Activating Factor

    PubMed Central

    Malmhäll, Carina; Rådinger, Madeleine; Ramos-Ramirez, Patricia; Lu, You; Deák, Tünde; Semitekolou, Maria; Gaga, Mina; Sjöstrand, Margareta; Lötvall, Jan; Bossios, Apostolos

    2016-01-01

    Background B cells, key cells in allergic inflammation, differentiate in the bone marrow and their precursors include pro-B, pre-B and immature B cells. Eosinophil progenitor cells increase in the lung after allergen exposure. However, the existence and possible role of B cell precursors in the lung during allergic inflammation remains elusive. Methods A BALB/c mouse model of allergic airway inflammation was utilized to perform phenotypic and quantification analyses of pro-B and pre-B cells in the lung by flow cytometry. B cell maturation factors IL-7 and B cell-activating factor (BAFF) and their receptors (CD127 and BAFFR, BCMA, TACI, respectively) were also evaluated in the lung and serum. The effect of anti-BAFF treatment was investigated both in vivo (i.p. administration of BAFF-R-Ig fusion protein) and in vitro (colony forming cell assay). Finally, BAFF levels were examined in the bronchoalveolar lavage (BAL) of asthmatic patients and healthy controls. Results Precursor pro and pre-B cells increase in the lung after allergen exposure, proliferate in the lung tissue in vivo, express markers of chemotaxis (CCR10 and CXCR4) and co-stimulation (CD40, CD86) and are resistant to apoptosis (Bax). Precursor B cells express receptors for BAFF at baseline, while after allergen challenge both their ligand BAFF and the BCMA receptor expression increases in B cell precursors. Blocking BAFFR in the lung in vivo decreases eosinophils and proliferating precursor B cells. Blocking BAFFR in bone marrow cultures in vitro reduces pre-B colony formation units. BAFF is increased in the BAL of severe asthmatics. Conclusion Our data support the concept of a BAFF-mediated role for B cell precursors in allergic airway inflammation. PMID:27513955

  20. 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

  1. Genomic landscape of small cell carcinoma of the breast contrasted to small cell carcinoma of the lung.

    PubMed

    McCullar, Brennan; Pandey, Manjari; Yaghmour, George; Hare, Felicia; Patel, Kruti; Stein, Matthew; Feldman, Rebecca; Chandler, Jason C; Martin, Michael G

    2016-07-01

    Small cell carcinoma of the breast is a rare, aggressive form of breast cancer that is associated with extremely poor outcomes [1]. In an effort to identify possible targets for treatment, we utilized comprehensive genomic profiling in small cell carcinoma of the breast. Under an IRB approved protocol, we identified patients with small cell carcinoma of the breast and small cell carcinoma of the lung profiled by Caris Life Sciences between 2007 and 2015. Tumors were assessed with up to 25 immunohistochemical stains, in situ hybridization of cMET, EGFR, HER2, PIK3CA, and TOP2A, and next generation sequencing as well as Sanger sequencing of 47 genes. 19 patients with small cell carcinoma of the breast were identified, median age was 58 years (range 37-79) and 42 % had metastatic disease at presentation; for comparison, 58 patients with small cell carcinoma of the lung were identified (66 [36-86], 65 % metastatic). By immunohistochemistry, 31 % of small cell carcinoma of the breast patients expressed ER, 13 % expressed PR, and 16 % expressed AR; small cell carcinoma of the lung patients expressed ER 0 %, PR 2 %, and AR 6 %. Small cell carcinoma of the breast and small cell carcinoma of the lung patients had similar patterns of other immunohistochemical expression (0 v 0 % PDL1, 50 v 42 % PD1, and 77 v 95 % TOP2A, respectively). All small carcinoma of the breast and small cell carcinoma of the lung patients were negative for HER2 and cMET amplification by in situ hybridization. Next generation sequencing revealed TP53 mutations in 75 % of patients both with small cell carcinoma of the breast and small cell carcinoma of the lung and PIK3CA mutations in 33 % of small cell carcinoma of the breast patients but no small cell carcinoma of the lung patients (Fisher's exact test p = 0.005, OR 0.02 [0.00-0.52]). No other mutations were found in small cell carcinoma of the breast patients and no other mutation occurred in over 10 % of small cell carcinoma of the

  2. Early Lung Computed Tomography Scan after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Cornetto, Marie Alice; Chevret, Sylvie; Abbes, Sarah; de Margerie-Mellon, Constance; Hussenet, Claire; Sicre de Fontbrune, Flore; Tazi, Abdellatif; Ribaud, Patricia; Bergeron, Anne

    2016-08-01

    A lung computed tomography (CT) scan is essential for diagnosing lung diseases in hematopoietic stem cell transplantation (HSCT) recipients. As a result, lung CT scans are increasingly prescribed in the early phase after allogeneic HSCT, with no assessment of the added value for global patient management. Among 250 patients who underwent allogeneic HSCT in our center over a 2-year period, we evaluated 68 patients who had at least 1 lung CT scan within the first 30 days post-transplantation. The median interval between allogeneic HSCT and lung CT scan was 8.5 days. Patients who underwent an early lung CT scan were more immunocompromised and had a more severe course. Fever was the main indication for the CT scan (78%). The lung CT scan was abnormal in 52 patients, including 17 patients who had an abnormal pre-HSCT CT scan. A therapeutic change was noted in 37 patients (54%) within 24 hours after the lung CT scan. The main changes included the introduction of corticosteroids (n = 23; 62%), especially in patients with a normal CT scan (89%). In univariate models, we found that a normal pretransplantation CT scan (P = .002), the absence of either dyspnea (P = .029) or hypoxemia (P = .015), and a serum C-reactive protein level <10 mg/L (P = .004) were associated with a normal post-HSCT lung CT scan. We found that the association of these variables could predict the normality of early post-HSCT lung CT scans. Pretransplantation lung CT scans are useful for the interpretation of subsequent lung CT scans following allogeneic HSCT, which are frequently abnormal. Early post-HSCT lung CT scans are helpful in patient management, but prescriptions could be more targeted. PMID:27189110

  3. Nanoparticle Albumin-bound Paclitaxel+Carboplatin Therapy for Small Cell Lung Cancer Combined with Squamous Cell Carcinoma and Interstitial Lung Disease.

    PubMed

    Azuma, Yuichiro; Tamiya, Motohiro; Shiroyama, Takayuki; Osa, Akio; Takeoka, Sawa; Morishita, Naoko; Suzuki, Hidekazu; Okamoto, Norio; Hirashima, Tomonori; Kawase, Ichiro

    2015-01-01

    It has recently been shown that nanoparticle albumin-bound paclitaxel (nab-PAC)+carboplatin (CBDCA) provides a favorable overall response rate in non-small cell lung cancer. This is the first case report of nab-PAC+CBDCA therapy in small cell lung cancer (SCLC). Our patient was a 72-year-old man with stage IV SCLC combined with squamous cell carcinoma and interstitial lung disease (ILD). We administered nab-PAC+CBDCA as a second-line chemotherapy. A partial response was evident after two cycles of chemotherapy, and no serious side effects occurred. The progression-free survival was 15 weeks. Second-line chemotherapy using nab-PAC+CBDCA was effective and well tolerated in an SCLC patient with ILD. PMID:26568008

  4. Resident Tissue-Specific Mesenchymal Progenitor Cells Contribute to Fibrogenesis in Human Lung Allografts

    PubMed Central

    Walker, Natalie; Badri, Linda; Wettlaufer, Scott; Flint, Andrew; Sajjan, Uma; Krebsbach, Paul H.; Keshamouni, Venkateshwar G.; Peters-Golden, Marc; Lama, Vibha N.

    2011-01-01

    Fibrotic obliteration of the small airways leading to progressive airflow obstruction, termed bronchiolitis obliterans syndrome (BOS), is the major cause of poor outcomes after lung transplantation. We recently demonstrated that a donor-derived population of multipotent mesenchymal stem cells (MSCs) can be isolated from the bronchoalveolar lavage (BAL) fluid of human lung transplant recipients. Herein, we study the organ specificity of these cells and investigate the role of local mesenchymal progenitors in fibrogenesis after lung transplantation. We demonstrate that human lung allograft–derived MSCs uniquely express embryonic lung mesenchyme–associated transcription factors with a 35,000-fold higher expression of forkhead/winged helix transcription factor forkhead box (FOXF1) noted in lung compared with bone marrow MSCs. Fibrotic differentiation of MSCs isolated from normal lung allografts was noted in the presence of profibrotic mediators associated with BOS, including transforming growth factor-β and IL-13. MSCs isolated from patients with BOS demonstrated increased expression of α-SMA and collagen I when compared with non-BOS controls, consistent with a stable in vivo fibrotic phenotype. FOXF1 mRNA expression in the BAL cell pellet correlated with the number of MSCs in the BAL fluid, and myofibroblasts present in the fibrotic lesions expressed FOXF1 by in situ hybridization. These data suggest a key role for local tissue-specific, organ-resident, mesenchymal precursors in the fibrogenic processes in human adult lungs. PMID:21641374

  5. 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

  6. 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

  7. Lentivirus-mediated silencing of SCIN inhibits proliferation of human lung carcinoma cells.

    PubMed

    Liu, Hongxu; Shi, Daiwang; Liu, Tieqin; Yu, Zhanwu; Zhou, Chuanjiang

    2015-01-01

    SCIN (scinderin) is a calcium-dependent actin severing and capping protein. Homologue in zebrafish has been found to be related with cell death. In the present study, we found that SCIN is highly expressed in human lung cancer specimens. However, the role of SCIN in lung cancer has not yet been determined. To investigate the function of SCIN in lung carcinoma cells, we took advantage of lentivirus-mediated RNA interference (RNAi) to knockdown SCIN expression in two lung carcinoma cell lines A549 and H1299. Silencing of SCIN significantly inhibited the proliferation and colony formation ability of both cell lines in vitro. Moreover, flow cytometry analysis showed that knockdown of SCIN led to G0/G1 phase cell cycle arrest as well as an excess accumulation of cells in the sub-G1 phase. Furthermore, depletion of SCIN resulted in a significant increase in Cyclin B1, p21 and PARP expression, and a little decrease in Cyclin D1 expression. These results suggest that SCIN plays an important role in lung carcinoma cell proliferation, and lentivirus-mediated silencing of SCIN might be a potential therapeutic approach for the treatment of lung cancer. PMID:25303873

  8. Interaction of the pathogenic mold Aspergillus fumigatus with lung epithelial cells

    PubMed Central

    Osherov, Nir

    2012-01-01

    Aspergillus fumigatus is an opportunistic environmental mold that can cause severe allergic responses in atopic individuals and poses a life-threatening risk for severely immunocompromised patients. Infection is caused by inhalation of fungal spores (conidia) into the lungs. The initial point of contact between the fungus and the host is a monolayer of lung epithelial cells. Understanding how these cells react to fungal contact is crucial to elucidating the pathobiology of Aspergillus-related disease states. The experimental systems, both in vitro and in vivo, used to study these interactions, are described. Distinction is made between bronchial and alveolar epithelial cells. The experimental findings suggest that lung epithelial cells are more than just “innocent bystanders” or a purely physical barrier against infection. They can be better described as an active extension of our innate immune system, operating as a surveillance mechanism that can specifically identify fungal spores and activate an offensive response to block infection. This response includes the internalization of adherent conidia and the release of cytokines, antimicrobial peptides, and reactive oxygen species. In the case of allergy, lung epithelial cells can dampen an over-reactive immune response by releasing anti-inflammatory compounds such as kinurenine. This review summarizes our current knowledge regarding the interaction of A. fumigatus with lung epithelial cells. A better understanding of the interactions between A. fumigatus and lung epithelial cells has therapeutic implications, as stimulation or inhibition of the epithelial response may alter disease outcome. PMID:23055997

  9. 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

  10. 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

  11. 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

  12. Hypoxia induced CCL28 promotes angiogenesis in lung adenocarcinoma by targeting CCR3 on endothelial cells.

    PubMed

    Huang, Guichun; Tao, Leilei; Shen, Sunan; Chen, Longbang

    2016-01-01

    Tumor hypoxia is one of the important features of lung adenocarcinoma. Chemokines might mediate the effects caused by tumor hypoxia. As confirmed in tumor tissue and serum of patients, CC chemokine 28 (CCL28) was the only hypoxia induced chemokine in lung adenocarcinoma cells. CCL28 could promote tube formation, migration and proliferation of endothelial cells. In addition, angiogenesis was promoted by CCL28 in the chick chorioallantoic membrane and matrigel implanted in dorsal back of athymic nude mice (CByJ.Cg-Foxn1(nu)/J). Tumors formed by lung adenocarcinoma cells with high expression of CCL28 grew faster and had a higher vascular density, whereas tumor formation rate of lung adenocarcinoma cells with CCL28 expression knockdown was quite low and had a lower vascular density. CCR3, receptor of CCL28, was highly expressed in vascular endothelial cells in lung adenocarcinoma when examining by immunohistochemistry. Further signaling pathways in endothelial cells, modulated by CCL28, were analyzed by Phosphorylation Antibody Array. CCL28/CCR3 signaling pathway could bypass that of VEGF/VEGFR on the levels of PI3K-Akt, p38 MAPK and PLC gamma. The effects could be neutralized by antibody against CCR3. In conclusion, CCL28, as a chemokine induced by tumor hypoxia, could promote angiogenesis in lung adenocarcinoma through targeting CCR3 on microvascular endothelial cells. PMID:27250766

  13. Hypoxia induced CCL28 promotes angiogenesis in lung adenocarcinoma by targeting CCR3 on endothelial cells

    PubMed Central

    Huang, Guichun; Tao, Leilei; Shen, Sunan; Chen, Longbang

    2016-01-01

    Tumor hypoxia is one of the important features of lung adenocarcinoma. Chemokines might mediate the effects caused by tumor hypoxia. As confirmed in tumor tissue and serum of patients, CC chemokine 28 (CCL28) was the only hypoxia induced chemokine in lung adenocarcinoma cells. CCL28 could promote tube formation, migration and proliferation of endothelial cells. In addition, angiogenesis was promoted by CCL28 in the chick chorioallantoic membrane and matrigel implanted in dorsal back of athymic nude mice (CByJ.Cg-Foxn1nu/J). Tumors formed by lung adenocarcinoma cells with high expression of CCL28 grew faster and had a higher vascular density, whereas tumor formation rate of lung adenocarcinoma cells with CCL28 expression knockdown was quite low and had a lower vascular density. CCR3, receptor of CCL28, was highly expressed in vascular endothelial cells in lung adenocarcinoma when examining by immunohistochemistry. Further signaling pathways in endothelial cells, modulated by CCL28, were analyzed by Phosphorylation Antibody Array. CCL28/CCR3 signaling pathway could bypass that of VEGF/VEGFR on the levels of PI3K-Akt, p38 MAPK and PLC gamma. The effects could be neutralized by antibody against CCR3. In conclusion, CCL28, as a chemokine induced by tumor hypoxia, could promote angiogenesis in lung adenocarcinoma through targeting CCR3 on microvascular endothelial cells. PMID:27250766

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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.

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  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. An Official American Thoracic Society Workshop Report 2015. Stem Cells and Cell Therapies in Lung Biology and Diseases.

    PubMed

    Wagner, Darcy E; Cardoso, Wellington V; Gilpin, Sarah E; Majka, Susan; Ott, Harald; Randell, Scott H; Thébaud, Bernard; Waddell, Thomas; Weiss, Daniel J

    2016-08-01

    The University of Vermont College of Medicine, in collaboration with the NHLBI, Alpha-1 Foundation, American Thoracic Society, Cystic Fibrosis Foundation, European Respiratory Society, International Society for Cellular Therapy, and the Pulmonary Fibrosis Foundation, convened a workshop, "Stem Cells and Cell Therapies in Lung Biology and Lung Diseases," held July 27 to 30, 2015, at the University of Vermont. The conference objectives were to review the current understanding of the role of stem and progenitor cells in lung repair after injury and to review the current status of cell therapy and ex vivo bioengineering approaches for lung diseases. These are all rapidly expanding areas of study that both provide further insight into and challenge traditional views of mechanisms of lung repair after injury and pathogenesis of several lung diseases. The goals of the conference were to summarize the current state of the field, discuss and debate current controversies, and identify future research directions and opportunities for both basic and translational research in cell-based therapies for lung diseases. This 10th anniversary conference was a follow up to five previous biennial conferences held at the University of Vermont in 2005, 2007, 2009, 2011, and 2013. Each of those conferences, also sponsored by the National Institutes of Health, American Thoracic Society, and respiratory disease foundations, has been important in helping guide research and funding priorities. The major conference recommendations are summarized at the end of the report and highlight both the significant progress and major challenges in these rapidly progressing fields. PMID:27509163

  7. Effect of TRAF6 on the biological behavior of human lung adenocarcinoma cell.

    PubMed

    Zhong, Lou; Cao, Fei; You, Qingsheng

    2013-02-01

    Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a unique adaptor protein of the tumor necrosis factor receptor-associated factor family that mediates both tumor necrosis factor receptor and interleukin-1 receptor/Toll-like receptor signaling. A recent study showed that TRAF6 played an important role in tumorigenesis and invasion through activation of nuclear factor kappa B (NF-κB). However, the biological role of TRAF6 remains unknown in lung cancer up to now. To address the expression of TRAF6 in lung cancer cells, four lung cancer cell lines (A549, HCC827, NCI-H292, and 95-D) and human bronchial epithelial cells were used to detect the expression of TRAF6 protein by western blotting. Results indicated that TRAF6 displayed an upregulation in human lung cancer cell lines. To investigate the effects of TRAF6 on the biological behavior of human lung adenocarcinoma cell, we generated human lung adenocarcinoma A549 cell line in which TRAF6 was depleted. The results showed that downregulation of TRAF6 could decrease cell viability, suppress cell proliferation and invasion, and promote cell apoptosis. At the same time, we explored the effects of TRAF6 on the expression of the following proteins: phosphor-NF-κB (p-p65), cyclin D1, caspase-3, and matrix metalloproteinase 9 (MMP9). Downregulation of TRAF6 could decrease the expression of p-p65, cyclin D1, and MMP9 and increase the expression of caspase-3. All these results suggested that TRAF6 might be involved in the potentiation of growth, proliferation, and invasion of A549 cell line, as well as the inhibition of A549 cell apoptosis by the activation of NF-κB. To make a long story short, the overexpression of TRAF6 might be related to the tumorigenesis and invasion of lung cancer. PMID:23055197

  8. 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

  9. 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

  10. 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

  11. 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

  12. Regulatory T Cell DNA Methyltransferase Inhibition Accelerates Resolution of Lung Inflammation

    PubMed Central

    Singer, Benjamin D.; Mock, Jason R.; Aggarwal, Neil R.; Garibaldi, Brian T.; Sidhaye, Venkataramana K.; Florez, Marcus A.; Chau, Eric; Gibbs, Kevin W.; Mandke, Pooja; Tripathi, Ashutosh; Yegnasubramanian, Srinivasan; King, Landon S.

    2015-01-01

    Acute respiratory distress syndrome (ARDS) is a common and often fatal inflammatory lung condition without effective targeted therapies. Regulatory T cells (Tregs) resolve lung inflammation, but mechanisms that enhance Tregs to promote resolution of established damage remain unknown. DNA demethylation at the forkhead box protein 3 (Foxp3) locus and other key Treg loci typify the Treg lineage. To test how dynamic DNA demethylation affects lung injury resolution, we administered the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) to wild-type (WT) mice beginning 24 hours after intratracheal LPS-induced lung injury. Mice that received DAC exhibited accelerated resolution of their injury. Lung CD4+CD25hiFoxp3+ Tregs from DAC-treated WT mice increased in number and displayed enhanced Foxp3 expression, activation state, suppressive phenotype, and proliferative capacity. Lymphocyte-deficient recombinase activating gene-1–null mice and Treg-depleted (diphtheria toxin-treated Foxp3DTR) mice did not resolve their injury in response to DAC. Adoptive transfer of 2 × 105 DAC-treated, but not vehicle-treated, exogenous Tregs rescued Treg-deficient mice from ongoing lung inflammation. In addition, in WT mice with influenza-induced lung inflammation, DAC rescue treatment facilitated recovery of their injury and promoted an increase in lung Treg number. Thus, DNA methyltransferase inhibition, at least in part, augments Treg number and function to accelerate repair of experimental lung injury. Epigenetic pathways represent novel manipulable targets for the treatment of ARDS. PMID:25295995

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. Human CD34+ Progenitor Cells Freshly Isolated from Umbilical Cord Blood Attenuate Inflammatory Lung Injury following LPS Challenge

    PubMed Central

    Huang, Xiaojia; Sun, Kai; Zhao, Yidan D.; Vogel, Stephen M.; Song, Yuanling; Mahmud, Nadim; Zhao, You-Yang

    2014-01-01

    Adult stem cell-based therapy is a promising novel approach for treatment of acute lung injury. Here we investigated the therapeutic potential of freshly isolated human umbilical cord blood CD34+ progenitor cells (fCB-CD34+ cells) in a mouse model of acute lung injury. At 3 h post-lipopolysaccharide (LPS) challenge, fCB-CD34+ cells were transplanted i.v. to mice while CD34− cells or PBS were administered as controls in separate cohorts of mice. We observed that fCB-CD34+ cell treatment inhibited lung vascular injury evident by decreased lung vascular permeability. In contrast, CD34− cells had no effects on lung vascular injury. Lung inflammation determined by myeloperoxidase activity, neutrophil sequestration and expression of pro-inflammatory mediators was attenuated in fCB-CD34+ cell-treated mice at 26 h post-LPS challenge compared to PBS or CD34− cell-treated controls. Importantly, lung inflammation in fCB-CD34+ cell-treated mice was returned to normal levels as seen in basal mice at 52 h post-LPS challenge whereas PBS or CD34− cell-treated control mice exhibited persistent lung inflammation. Accordingly, fCB-CD34+ cell-treated mice exhibited a marked increase of survival rate. Employing in vivo 5-bromo-2′-deoxyuridine incorporation assay, we found a drastic induction of lung endothelial proliferation in fCB-CD34+ cell-treated mice at 52 h post-LPS compared to PBS or CD34− cell-treated controls, which contributed to restoration of vascular integrity and thereby inhibition of lung inflammation. Taken together, these data have demonstrated the protective effects of fCB-CD34+ cell on acute lung injury induced by LPS challenge, suggesting fCB-CD34+ cells are an important source of stem cells for the treatment of acute lung injury. PMID:24558433

  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. Malignant Perivascular Epithelioid Cell Neoplasm of the Mediastinum and the Lung

    PubMed Central

    Liang, Wenjie; Xu, Shunliang; Chen, Feng

    2015-01-01

    Abstract A perivascular epithelioid cell neoplasm (PEComa) in the chest is rare, let alone in the mediastinum and lung. A 63-year-old man was admitted to our hospital with chest pain for more than 2 months and was found to have an opacity in his mediastinum and lung for 3 weeks. Enhanced chest computed tomography (CT) revealed a mass in both the left upper lobe and central anterior mediastinum. To identify the disease, a CT-guided percutaneous transthoracic needle biopsy of the upper left lung lesions was performed. The pathology result was consistent with epithelioid angiomyolipoma/PEComa. After a standard preparation for surgery, the neoplasms in the mediastinum and left lung were resected. The operative findings revealed extensive mediastinal tumor invasion in parts adjacent to the pericardium, including the mediastinal pleura, left pulmonary artery and vein, and phrenic nerve. The left lung tumor had invaded the lung membranes. The final pathologic diagnosis was malignant epithelioid angioleiomyoma in the left upper lung and mediastinum. Later, the mediastinal tumor recurred. The radiography of this case resembles left upper lobe lung cancer with mediastinal lymph node metastasis. Because this tumor lacks fat, the enhanced CT indicated that it was malignant but failed to identify it as a perivascular epithelioid cell neoplasm. This case reminds clinicians that, although most PEComa are benign, some can be malignant. As the radiology indicated, chest PEComas lack fat, which makes their preoperative diagnosis difficult. Therefore, needle biopsy is valuable for a definitive diagnosis. PMID:26039123

  1. Dysfunctional resident lung mesenchymal stem cells contribute to pulmonary microvascular remodeling

    PubMed Central

    Chow, Kelsey; Fessel, Joshua P.; KaoriIhida-Stansbury; Schmidt, Eric P.; Gaskill, Christa; Alvarez, Diego; Graham, Brian; Harrison, David G.; Wagner, David H.; Nozik-Grayck, Eva; West, James D.; Klemm, Dwight J.; Majka, Susan M.

    2013-01-01

    Pulmonary vascular remodeling and oxidative stress are common to many adult lung diseases. However, little is known about the relevance of lung mesenchymal stem cells (MSCs) in these processes. We tested the hypothesis that dysfunctional lung MSCs directly participate in remodeling of the microcirculation. We employed a genetic model to deplete extracellular superoxide dismutase (EC-SOD) in lung MSCs coupled with lineage tracing analysis. We crossed floxpsod3 and mT/mG reporter mice to a strain expressing Cre recombinase under the control of the ABCG2 promoter. We demonstrated In vivo that depletion of EC-SOD in lung MSCs resulted in their contribution to microvascular remodeling in the smooth muscle actin positive layer. We further characterized lung MSCs to be multipotent vascular precursors, capable of myofibroblast, endothelial and pericyte differentiation in vitro. EC-SOD deficiency in cultured lung MSCs accelerated proliferation and apoptosis, restricted colony-forming ability, multilineage differentiation potential and promoted the transition to a contractile phenotype. Further studies correlated cell dysfunction to alterations in canonical Wnt/β-catenin signaling, which were more evident under conditions of oxidative stress. Our data establish that lung MSCs are a multipotent vascular precursor population, a population which has the capacity to participate in vascular remodeling and their function is likely regulated in part by the Wnt/β-catenin signaling pathway. These studies highlight an important role for microenviromental regulation of multipotent MSC function as well as their potential to contribute to tissue remodeling. PMID:23662173

  2. Combinations of differentiation markers distinguish subpopulations of alveolar epithelial cells in adult lung.

    PubMed

    Liebler, Janice M; Marconett, Crystal N; Juul, Nicholas; Wang, Hongjun; Liu, Yixin; Flodby, Per; Laird-Offringa, Ite A; Minoo, Parviz; Zhou, Beiyun

    2016-01-15

    Distal lung epithelium is maintained by proliferation of alveolar type II (AT2) cells and, for some daughter AT2 cells, transdifferentiation into alveolar type I (AT1) cells. We investigated if subpopulations of alveolar epithelial cells (AEC) exist that represent various stages in transdifferentiation from AT2 to AT1 cell phenotypes in normal adult lung and if they can be identified using combinations of cell-specific markers. Immunofluorescence microscopy showed that, in distal rat and mouse lungs, ∼ 20-30% of NKX2.1(+) (or thyroid transcription factor 1(+)) cells did not colocalize with pro-surfactant protein C (pro-SP-C), a highly specific AT2 cell marker. In distal rat lung, NKX2.1(+) cells coexpressed either pro-SP-C or the AT1 cell marker homeodomain only protein x (HOPX). Not all HOPX(+) cells colocalize with the AT1 cell marker aquaporin 5 (AQP5), and some AQP5(+) cells were NKX2.1(+). HOPX was expressed earlier than AQP5 during transdifferentiation in rat AEC primary culture, with robust expression of both by day 7. We speculate that NKX2.1 and pro-SP-C colocalize in AT2 cells, NKX2.1 and HOPX or AQP5 colocalize in intermediate or transitional cells, and HOPX and AQP5 are expressed without NKX2.1 in AT1 cells. These findings suggest marked heterogeneity among cells previously identified as exclusively AT1 or AT2 cells, implying the presence of subpopulations of intermediate or transitional AEC in normal adult lung. PMID:26545903

  3. Autologous endothelial progenitor cells improve allograft survival in porcine lung transplantation with prolonged ischemia

    PubMed Central

    Yen, Yi-Ting; Roan, Jun-Neng; Fang, Shih-Yuan; Chang, Shi-Wei; Tseng, Yau-Lin

    2016-01-01

    Background As endothelial progenitor cells (EPCs) attenuated acute lung injury (ALI) in rabbit model, we hypothesized that autologous EPCs preserved lung graft function during the acute reperfusion period of lung transplantation and tested the therapeutic potential of EPCs in a porcine model of lung transplantation with prolonged graft ischemia. Methods Day-7 EPCs isolated from the recipient subjects or plain culture media were administered into the left pulmonary artery immediately before restoration of pulmonary blood flow in a porcine lung allotransplantation model, with the transplantation surgeons blinded to the content of injection. Hemodynamics and arterial blood gas were recorded, and the right pulmonary artery was occluded 30 min after reperfusion to evaluate the lung graft function. The lung grafts were sectioned for histological examination at the end of experiments. The total ischemic time for lung graft was approximately 14 h. Results All animals receiving plain medium died within 40 min after reperfusion, but 3 out of 5 (60%) piglets receiving EPCs survived up to 4 h after diversion of the entire cardiac output into the lung graft (P<0.01). The donor body weight, recipient body weight, cold ischemic time, and time for anastomosis were comparable between the EPC and control group (P=0.989, 0.822, 0.843, and 0.452, respectively). The mean aortic pressure decreased, and the cardiac output and mean pulmonary artery pressure elevated after right pulmonary artery occlusion. All these parameters were gradually compensated in the EPC group but decompensated in the control group. Better preservation of gas exchange function, reduced thrombi formation in the terminal pulmonary arterioles, and attenuated interstitial hemorrhage of the lung graft were observed in the EPC group. Conclusions We concluded autologous EPCs significantly enhanced the function of lung allograft and improved survival in a porcine model of lung transplantation with prolonged ischemia

  4. Bone-marrow-derived mesenchymal stem cells inhibit gastric aspiration lung injury and inflammation in rats.

    PubMed

    Zhou, Jing; Jiang, Liyan; Long, Xuan; Fu, Cuiping; Wang, Xiangdong; Wu, Xiaodan; Liu, Zilong; Zhu, Fen; Shi, Jindong; Li, Shanqun

    2016-09-01

    Gastric aspiration lung injury is one of the most common clinical events. This study investigated the effects of bone-marrow-derived mesenchymal stem cells (BMSCs) on combined acid plus small non-acidified particle (CASP)-induced aspiration lung injury. Enhanced green fluorescent protein (EGFP(+) ) or EGFP(-) BMSCs or 15d-PGJ2 were injected via the tail vein into rats immediately after CASP-induced aspiration lung injury. Pathological changes in lung tissues, blood gas analysis, the wet/dry weight ratio (W/D) of the lung, levels of total proteins and number of total cells and neutrophils in bronchoalveolar lavage fluid (BALF) were determined. The cytokine levels were measured using ELISA. Protein expression was determined by Western blot. Bone-marrow-derived mesenchymal stem cells treatment significantly reduced alveolar oedema, exudation and lung inflammation; increased the arterial partial pressure of oxygen; and decreased the W/D of the lung, the levels of total proteins and the number of total cells and neutrophils in BALF in the rats with CASP-induced lung injury. Bone-marrow-derived mesenchymal stem cells treatment decreased the levels of tumour necrosis factor-α and Cytokine-induced neutrophil chemoattractant (CINC)-1 and the expression of p-p65 and increased the levels of interleukin-10 and 15d-PGJ2 and the expression of peroxisome proliferator-activated receptor (PPAR)-γ in the lung tissue in CASP-induced rats. Tumour necrosis factor-α stimulated BMSCs to secrete 15d-PGJ2 . A tracking experiment showed that EGFP(+) BMSCs were able to migrate to local lung tissues. Treatment with 15d-PGJ2 also significantly inhibited CASP-induced lung inflammation and the production of pro-inflammatory cytokines. Our results show that BMSCs can protect lung tissues from gastric aspiration injury and inhibit lung inflammation in rats. A beneficial effect might be achieved through BMSC-derived 15d-PGJ2 activation of the PPAR-γ receptor, reducing the production of

  5. Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance.

    PubMed

    Soroosh, Pejman; Doherty, Taylor A; Duan, Wei; Mehta, Amit Kumar; Choi, Heonsik; Adams, Yan Fei; Mikulski, Zbigniew; Khorram, Naseem; Rosenthal, Peter; Broide, David H; Croft, Michael

    2013-04-01

    Airway tolerance is the usual outcome of inhalation of harmless antigens. Although T cell deletion and anergy are likely components of tolerogenic mechanisms in the lung, increasing evidence indicates that antigen-specific regulatory T cells (inducible Treg cells [iTreg cells]) that express Foxp3 are also critical. Several lung antigen-presenting cells have been suggested to contribute to tolerance, including alveolar macrophages (MØs), classical dendritic cells (DCs), and plasmacytoid DCs, but whether these possess the attributes required to directly promote the development of Foxp3(+) iTreg cells is unclear. Here, we show that lung-resident tissue MØs coexpress TGF-β and retinal dehydrogenases (RALDH1 and RALDH 2) under steady-state conditions and that their sampling of harmless airborne antigen and presentation to antigen-specific CD4 T cells resulted in the generation of Foxp3(+) Treg cells. Treg cell induction in this model depended on both TGF-β and retinoic acid. Transfer of the antigen-pulsed tissue MØs into the airways correspondingly prevented the development of asthmatic lung inflammation upon subsequent challenge with antigen. Moreover, exposure of lung tissue MØs to allergens suppressed their ability to generate iTreg cells coincident with blocking airway tolerance. Suppression of Treg cell generation required proteases and TLR-mediated signals. Therefore, lung-resident tissue MØs have regulatory functions, and strategies to target these cells might hold promise for prevention or treatment of allergic asthma. PMID:23547101

  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. 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. Jejunal intussusception caused by metastasis of a giant cell carcinoma of the lung

    PubMed Central

    Fujii, Yuki; Homma, Shigenori; Yoshida, Tadashi; Taketomi, Akinobu

    2016-01-01

    A 55-year-old woman was admitted to our hospital reporting of nausea, vomiting and anorexia. One month before admission, she had been diagnosed with lung cancer with intestinal metastasis. A CT scan confirmed intussusception due to intestinal metastasis and she underwent emergency laparoscopic surgery followed by resection of the primary lung cancer. Histopathological findings of the intestinal specimen suggested the metastasis was from a giant cell carcinoma of the lung, which had extensive necrosis. She was still alive without recurrence 11 months after the first surgery. Giant cell carcinoma of the lung is a rare type of non-small cell carcinoma and intestinal metastasis is one of the unique features. This type of tumour has such aggressive characteristics that oncological prognosis is reported to be extremely poor. In our case, however, complete surgical resection of both primary and metastatic tumours might result in a better outcome than has been reported. PMID:27485876

  9. 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

  10. Jejunal intussusception caused by metastasis of a giant cell carcinoma of the lung.

    PubMed

    Fujii, Yuki; Homma, Shigenori; Yoshida, Tadashi; Taketomi, Akinobu

    2016-01-01

    A 55-year-old woman was admitted to our hospital reporting of nausea, vomiting and anorexia. One month before admission, she had been diagnosed with lung cancer with intestinal metastasis. A CT scan confirmed intussusception due to intestinal metastasis and she underwent emergency laparoscopic surgery followed by resection of the primary lung cancer. Histopathological findings of the intestinal specimen suggested the metastasis was from a giant cell carcinoma of the lung, which had extensive necrosis. She was still alive without recurrence 11 months after the first surgery. Giant cell carcinoma of the lung is a rare type of non-small cell carcinoma and intestinal metastasis is one of the unique features. This type of tumour has such aggressive characteristics that oncological prognosis is reported to be extremely poor. In our case, however, complete surgical resection of both primary and metastatic tumours might result in a better outcome than has been reported. PMID:27485876

  11. Knockdown of HNRNPA1 inhibits lung adenocarcinoma cell proliferation through cell cycle arrest at G0/G1 phase.

    PubMed

    Liu, Xianxun; Zhou, Yan; Lou, Yuqing; Zhong, Hua

    2016-02-01

    Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), a member of heterogeneous nuclear ribonucleoprotein family in actively growing mammalian cells, is involved in a variety of RNA-related processes. HNRNPA1 can enhance the degradation of inhibitory subunit of nuclear factor κ B alpha (IκBα) and lengthen the telomeres. Recently, it is reported that HNRNPA1 is aberrantly expressed in varied tumors. In this study we found HNRNPA1 protein overexpressed in lung cancer tissues. To explore the exact role of HNRNPA1 in lung cancers, we carried out a loss of function analysis of HNRNPA1 in A549 lung cancer cells by RNA interference (RNAi). The results demonstrated that knockdown of HNRNPA1 inhibited cell viability and colony formation of lung cancer cells and arrested cell cycle in G0/G1 phase. Our study suggested that HNRNPA1 might play an important role in lung adenocarcinoma cells and provided a foundation for further study into the potential of HNRNPA1 for lung cancer therapy. PMID:26581508

  12. 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.

  13. Potential Contribution of Type I Alveolar Epithelial Cells to Chronic Neonatal Lung Disease

    PubMed Central

    Rozycki, Henry J.

    2014-01-01

    The alveolar surface is covered by large flat Type I cells (alveolar epithelial cells 1, AEC1). The normal physiological function of AEC1s involves gas exchange, based on their location in approximation to the capillary endothelium and their thinness, and in ion and water flux, as shown by the presence of solute active transport proteins, water channels, and impermeable tight junctions between cells. With the recent ability to produce relatively pure cultures of AEC1 cells, new functions have been described. These may be relevant to lung injury, repair, and the abnormal development that characterizes bronchopulmonary dysplasia (BPD). To hypothesize a potential role for AEC1 in the development of lung injury and abnormal repair/development in premature lungs, evidence is presented for their presence in the developing lung, how their source may not be the Type II cell (AEC2) as has been assumed for 40 years, and how the cell can be damaged by same type of stressors as those which lead to BPD. Recent work shows that the cells are part of the innate immune response, capable of producing pro-inflammatory mediators, which could contribute to the increase in inflammation seen in early BPD. One of the receptors found exclusively on AEC1 cells in the lung, called RAGE, may also have a role in increased inflammation and alveolar simplification. While the current evidence for AEC1 involvement in BPD is circumstantial and limited at present, the accumulating data supports several hypotheses and questions regarding potential differences in the behavior of AEC1 cells from newborn and premature lung compared with the adult lung. PMID:24904906

  14. Pulmonary natural killer T cells play an essential role in mediating hyperoxic acute lung injury.

    PubMed

    Nowak-Machen, Martina; Schmelzle, Moritz; Hanidziar, Dusan; Junger, Wolfgang; Exley, Mark; Otterbein, Leo; Wu, Yan; Csizmadia, Eva; Doherty, Glen; Sitkovsky, Michail; Robson, Simon C

    2013-05-01

    Critically ill patients are routinely exposed to high concentrations of supplemental oxygen for prolonged periods of time, which can be life-saving in the short term, but such exposure also causes severe lung injury and increases mortality. To address this therapeutic dilemma, we studied the mechanisms of the tissue-damaging effects of oxygen in mice. We show that pulmonary invariant natural killer T (iNKT) cells are unexpectedly crucial in the development of acute oxygen-induced lung injury. iNKT cells express high concentrations of the ectonucleotidase CD39, which regulates their state of activation. Both iNKT cell-deficient (Jα18(-/-)) and CD39-null mice tolerate hyperoxia, compared with wild-type control mice that exhibit severe lung injury. An adoptive transfer of wild-type iNKT cells into Jα18(-/-) mice results in hyperoxic lung injury, whereas the transfer of CD39-null iNKT cells does not. Pulmonary iNKT cell activation and proliferation are modulated by ATP-dependent purinergic signaling responses. Hyperoxic lung injury can be induced by selective P2X7-receptor blockade in CD39-null mice. Our data indicate that iNKT cells are involved in the pathogenesis of hyperoxic lung injury, and that tissue protection can be mediated through ATP-induced P2X7 receptor signaling, resulting in iNKT cell death. In conclusion, our data suggest that iNKT cells and purinergic signaling should be evaluated as potential novel therapeutic targets to prevent hyperoxic lung injury. PMID:23349052

  15. Neutrophils amplify the formation of DNA adducts by benzo[a]pyrene in lung target cells.

    PubMed

    Borm, P J; Knaapen, A M; Schins, R P; Godschalk, R W; Schooten, F J

    1997-09-01

    Inflammatory cells and their reactive oxygen metabolites can cause mutagenic effects in lung cells. The purpose of this study was to investigate the ability of activated neutrophils to modulate DNA binding of benzo[a]pyrene (B[a]P), a known carcinogen, in lung target cells. Equivalent numbers of rat lung epithelial cells (RLE-6TN cell line) and freshly isolated human blood neutrophils (PMN) were coincubated in vitro for 2 hr after addition of benzo[a]pyrene (0.5 microM) or two of its trans-diol metabolites, with or without stimulation with phorbol myristate acetate (PMA). DNA adducts of B[a]P-metabolites were determined in target cells using 32P-postlabeling; oxidative DNA damage (7-hydro-8-oxo-2'-deoxyguanosine [8-oxodG]) was evaluated by high performance liquid chromatography with electrochemical detection. Increased DNA adducts were observed in lung cells coincubated with polymorphonuclear leukocytes (PMN). Activation of PMN with PMA, or addition of more activated PMN in relation to the number of lung cells, further increased the number of adducts, the latter in a dose-response manner. Incubation with B[a]P-4,5-diol did not result in any adduct formation, while B[a]P-7,8-diol led to a significant number of adducts. Moreover, PMA-activated PMN strongly enhanced adduct formation by B[a]P-7,8-diol, but not 8-oxodG, in lung cells. The addition of antioxidants to the coincubations significantly reduced the number of adducts. Results suggest that an inflammatory response in the lung may increase the biologically effective dose of polycyclic aromatic hydrocarbons (PAHs), and may be relevant to data interpretation and risk assessment of PAH-containing particulates. PMID:9400705

  16. 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

  17. Romo1 expression contributes to oxidative stress-induced death of lung epithelial cells

    SciTech Connect

    Shin, Jung Ar; Chung, Jin Sil; Cho, Sang-Ho; Kim, Hyung Jung; Yoo, Young Do

    2013-09-20

    Highlights: •Romo1 mediates oxidative stress-induced mitochondrial ROS production. •Romo1 induction by oxidative stress plays an important role in oxidative stress-induced apoptosis. •Romo1 overexpression correlates with epithelial cell death in patients with IPF. -- Abstract: Oxidant-mediated death of lung epithelial cells due to cigarette smoking plays an important role in pathogenesis in lung diseases such as idiopathic pulmonary fibrosis (IPF). However, the exact mechanism by which oxidants induce epithelial cell death is not fully understood. Reactive oxygen species (ROS) modulator 1 (Romo1) is localized in the mitochondria and mediates mitochondrial ROS production through complex III of the mitochondrial electron transport chain. Here, we show that Romo1 mediates mitochondrial ROS production and apoptosis induced by oxidative stress in lung epithelial cells. Hydrogen peroxide (H{sub 2}O{sub 2}) treatment increased Romo1 expression, and Romo1 knockdown suppressed the cellular ROS levels and cell death triggered by H{sub 2}O{sub 2} treatment. In immunohistochemical staining of lung tissues from patients with IPF, Romo1 was mainly localized in hyperplastic alveolar and bronchial epithelial cells. Romo1 overexpression was detected in 14 of 18 patients with IPF. TUNEL-positive alveolar epithelial cells were also detected in most patients with IPF but not in normal controls. These findings suggest that Romo1 mediates apoptosis induced by oxidative stress in lung epithelial cells.

  18. 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

  19. 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 migratio